Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.CCOCC>[OH:1][C@@H:2]([CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([O:5][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4]
Reactant: O=C(O)[C@@H](O)CC1CCCC1
Reactant: BrCc1ccccc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)[C@@H](O)CC1CCCC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 287 mg (1.81 mmol) of 2-(S)-hydroxy-3-(cyclopentyl)propanoic acid (from Step F) in 8 mL of DMF was treated with 0.38 mL (2.72 mmol) of TEA and 0.33 mL (2.77 mmol) of benzyl bromide and stirred at rt for 22 h. The reaction was diluted with 200 ml of ether and washed with 200 mL of H2O, 200 mL of 2.0 N HCl, 200 mL of 1.0 N NaHCO3, 200 mL of H2O and 200 mL of sat'd NaCl. The organic layer was dried over MgSO4 and concentrated. Flash chromatography on silica gel using 17:3 v/v hexanes/EtOAc afforded 102 mg (22%, 95.5% ee) of the title compound: RF: 0.40 (4:1 v/v hexanes/EtOAc); 1H NMR (300 MHz): δ 1.04-1.17 (m, 2H), 1.46-1.87 (m, 8H), 1.99 (m, 1H), 2.65 (m, 1H), 4.22 (dd, J=7.8, 4.8, 11H), 5.23 (ABq, J=12.3, 2H), 7.32-7.41 (m, 5H). HPLC: Chirapak AS 4.6×250 mm column, 17:3 v/v hexanes/iPrOH, 0.5 mL/min, 220 nm. Retention times: (S)-Enantiomer, 12.2 min; (R)-enantiomer, 15.3 min.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.CN(CCN(C)C)C.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.N>CO.O>[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)=[CH:29][CH:28]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Agent: CN(C)CCN(C)C
Agent: N
Solvent: O
Solvent: CO
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.3 %

Procedure:
To a mixture of 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) containing [Cu(OH).TMEDA]2Cl2 (23.2 mg, 0.05 mmol) in dry methanol (5 mL) was added 4-fluorophenylboronic acid (140 mg, 1.0 mmol) under an air atmosphere and the resulting mixture stirred at room temperature overnight. After this time, concentrated ammonia solution (2 mL) was added and then the resulting mixture was diluted with water (20 mL) and extracted with ethyl acetate. The organic extracts were then dried over sodium sulphate and evaporated. Purification by preparative HPLC on reversed phase eluting with an acetonitrile/water [0.1% aq NH3 (25%)] gradient afforded the title compound (34 mg, 21%) which was obtained as a white solid. MS (ESI): m/e=320.0 [M+H]+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:12][C:13]([F:22])([F:21])[C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH:10]([C:7]1[CH:8]=[CH:9][C:2]([O:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:13]([F:12])([F:21])[F:22])[CH:15]=2)=[C:3]([CH:6]=1)[C:4]#[N:5])=[O:11]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: N#Cc1cc(C=O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cc(C=O)ccc1Oc1cccc(C(F)(F)F)c1
Temperature: 100 °C
Yield: 41.6 %

Procedure:
A mixture of 2-fluoro-5-formylbenzonitrile (1.0 g, 6.71 mmol), 3-(trifluoromethyl) phenol (1.087 g, 6.71 mmol), K2CO3 (2.78 g, 20.12 mmol) in DMSO (20 mL) was heated at 100° C. overnight. After cooling to room temperature, the mixture was partitioned between EA (100 mL) and water (100 mL), the aqueous layer was extracted with EA (50 mL) twice. The combine the organic layers were washed with water, brine and dried over sodium sulfate, filtered, concentrated and purified via flash chromatography to afford the title compound (820 mg, 2.79 mmol, 41.6% yield). LCMS: rt=3.33 min, [M+H+]=292
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([O:21][CH3:22])=[N:6][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[CH:13][CH:12]=2)=[N:8][CH:9]=1.[OH:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH:28]=[CH:27]2.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[F:19][CH:18]([F:20])[O:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:7]2[N:6]=[C:5]([O:21][CH3:22])[C:4]([CH2:3][O:23][C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[NH:30][C:29](=[O:34])[CH:28]=[CH:27]4)=[CH:9][N:8]=2)=[CH:12][CH:13]=1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Reactant: COc1nc(Nc2ccc(OC(F)F)cc2)ncc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(Nc2ccc(OC(F)F)cc2)ncc1COc1ccc2[nH]c(=O)ccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.8 %

Procedure:
A solution of 5-(chloromethyl)-N-(4-(difluoromethoxy)phenyl)-4-methoxypyrimidin-2-amine hydrochloride (0.14 g, 0.398 mmol) in DMF (1.5 mL) was added to a mixture of 6-hydroxyquinolin-2(1H)-one (0.08 g, 0.496 mmol) and Cs2CO3 (0.518 g, 1.590 mmol) in DMF (6.5 mL). The reaction mixture was stirred at room temperature for 18 h, then diluted with water and filtered. The filter cake was stirred in methanol/DCM (1:1) for 18 h, filtered, and dried to give 6-((2-((4-(difluoromethoxy)phenyl)amino)-4-methoxypyrimidin-5-yl)methoxy)quinolin-2(1H)-one as a beige solid (0.082 g, 45%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.67 (s, 1H), 9.76 (s, 1H), 8.35 (s, 1H), 7.96-7.70 (m, 3H), 7.36-6.93 (m, 6H), 6.51 (d, J=9.5 Hz, 1H), 4.94 (s, 2H), 3.99 (s, 3H). LCMS: R.T.=0.82; [M+H]+=441.1.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][C:10]2[S:11][C:12]([C:15]3[N:19]=[C:18]([CH:20]([OH:22])[CH3:21])[S:17][N:16]=3)=[CH:13][N:14]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:32][S:33]([O:22][CH:20]([C:18]1[S:17][N:16]=[C:15]([C:12]2[S:11][C:10]([O:9][C:8]3[CH:23]=[CH:24][C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[CH:6][CH:7]=3)=[N:14][CH:13]=2)[N:19]=1)[CH3:21])(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Oc1ccc(Oc2ncc(-c3nsc(C(C)O)n3)s2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccc(Oc2ncc(-c3nsc(C(C)OS(C)(=O)=O)n3)s2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.8 %

Procedure:
To a solution of Example 100D (136 g, 0.0037 mol), triethylamine (0.95 g, 0.0094 mol) and 4-(dimethylamino)pyridine in dichloromethane at 0° C. was added methanesulfonyl chloride (0.52 g, 0.0045 mol) drop wise and the mixture was stirred for 2 hours at room temperature. More dichloromethane was added and the organic layer was washed with water, then brine and dried over magnesium sulfate and filtered. The filtrate was concentrated to give 1.5 g of product as a clear oil. 1H NMR (300 MHz, CDCl3) δ ppm 1.36 (d, J=6.25 Hz, 6H) 1.90 (d, J=6.62 Hz, 3H) 3.15 (s, 3H) 4.45-4.61 (m, 1H) 6.10 (q, J=6.86 Hz, 1H) 6.87-6.99 (m, 2H) 7.17-7.25 (m, 2H) 7.96 (s, 1H). MS (ESI) m/z 442.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([NH:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])([C:13]([F:21])([F:20])[CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]2([N:22]([C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:24])[CH2:14][C:13]2([F:21])[F:20])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)(C(F)(F)COS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(C1)N(C(=O)OCc1ccccc1)CC2(F)F
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of an optically-active compound of 3-benzyloxycarbonylamino-3-(1,1-difluoro-2-methanesulfonyloxyethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (565 mg) in N,N-dimethylformamide (17 ml) cooled to 0° C. was added sodium hydride (71 mg, with 40% mineral oil), and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the titled compound (397 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21](F)[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[H-].[Na+].[CH2:33]([OH:35])[CH3:34].Cl>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=[C:21]([O:35][CH2:33][CH3:34])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCO
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cc(F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cc(OCC)cc(C(F)(F)F)c1
Temperature: 150 °C
Yield: 78 %

Procedure:
[4-(3-Fluoro-5-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (prepared by the method analogous to example 1-1, 200 mg, 0.44 mmol), sodium hydride (60% dispersed in mineral oil, 89 mg, 2.22 mmol) and ethanol (202 mg, 4.4 mmol) were dissolved in N,N-dimethylformamide (2 mL). The mixture was heated in a microwave oven at 150° C. for 40 minutes. The resulting mixture was acidified with 0.1N hydrochloric acid to pH 5 and extracted with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column (gradient elution, 0-5% methanol in dichloromethane) to afford [4-(3-ethoxy-5-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (180 mg, 78%). MS cald. for C20H24F3N3O5S 475, obsd. (ESI+) [(M+H)+] 476.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([CH3:7])([CH3:6])[CH3:5].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1>C(OCC)(=O)C>[C:4]([C:3]1[N:9]=[C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]2[CH:2]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: CC(C)(C)C(=O)CBr
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cn2cc([N+](=O)[O-])ccc2n1

Procedure:
Operations similar to Production Example 1-(2) were conducted using 1-bromopinacolone and 2-amino-5-nitropyridine. The solid whereupon obtained was suspended in ethyl acetate, and washed with saturated aqueous sodium hydrogencarbonate solution to provide the title compound as yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][CH3:21])=[O:19])=[CH:16][CH:15]=1>[Zn+2].[Br-].[Br-].CC(O)(C)C.ClCCCl>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)[N:7]=1
Reactant: CNC(=O)c1ccc(N)cc1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCCl
Solvent: CC(C)(C)O
Product: CNC(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,4-dichloro-5-trifluoromethyl-pyrimidine (8.63 mmol) in 1:1 t-BuOH/DCE (10 mL) was cooled to 5° C., treated with solid ZnBr2 (22.5 mmol), and stirred at 5° C. for 30 minutes. The resultant solution was maintained at 5° C. and treated first with solid 4-amino-N-methyl-benzamide (7.5 mmol) followed by TEA (16.5 mmol). The resultant white mixture was allowed to warm 25° C., and it was mixed at 25° C. for 20 hours. The mixture was adsorbed onto silica gel, and the fraction eluting 0-10% methanol/DCM was collected and concentrated. The resultant residue was triturated with water and filtered to provide B20. Yield: 3.0 mmol, 40%. LCMS 2.3 min, MZ+=331.1 1H NMR (500 MHz, d6-DMSO) δ ppm 10.89 (s, 1H), 8.87 (s, 1H), 8.34 (d, J=4.67 Hz, 1H), 7.73-7.89 (m, 3H), 2.78 (d, J=4.67 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[S:30]
Reactant: COc1cc(C(=O)N2CCNCC2)cc(OC)c1OC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: COc1cc(C(=S)N2CCNCC2)cc(OC)c1OC
Yield: 61.5 %

Procedure:
A mixture of 1-(3,4,5-trimethoxybenzoyl)piperazine (2.0 g), a Lawesson reagent ([2,4-bis(4-methoxypehnyl)-1,3-dithia-2,4-diphosphethane-2,4-disulfide]) (2.9 g) and benzene (20 ml) is heated under reflux for 30 minutes. After cooling, insolubles are filtered off, and the filtrate is concentrated under reduced pressure. To the residue is added 1N hydrochloric acid (100 ml) and following ethyl acetate (50 ml), and the mixture is shaken. The aqueous layer is separated, and to the aqueous layer is added a 1N aqueous solution of sodium hydroxide to make the system alkaline, followed by extraction with methylene chloride. The organic layer is washed with water and dried, then the solvent is distilled off. The residue is recrystallized from ethyl acetate - hexane to afford 1-(3,4,5-trimethoxythiobenzoyl)piperazine as pale yellow prisms (1.3 g), m.p. 116°-118° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[CH2:15][S:14][N:13]=[C:12]([N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]3=[N:32][N:33]([CH2:35][C:36]4[C:41]([CH3:42])=[C:40]([O:43][CH3:44])[C:39]([CH3:45])=[CH:38][N:37]=4)[N:34]=[C:9]([C:10]=23)[CH:8]=1)(=O)=O.[N:48]1[CH:53]=[C:52](B(O)O)[CH:51]=[N:50][CH:49]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:44][O:43][C:40]1[C:39]([CH3:45])=[CH:38][N:37]=[C:36]([CH2:35][N:33]2[N:34]=[C:9]3[CH:8]=[C:7]([C:52]4[CH:53]=[N:48][CH:49]=[N:50][CH:51]=4)[C:16]4[CH2:15][S:14][N:13]=[C:12]([N:17]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[C:11]([C:10]=43)=[N:32]2)[C:41]=1[CH3:42]
Reactant: COc1c(C)cnc(Cn2nc3cc(OS(=O)(=O)C(F)(F)F)c4c-3c(n2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Reactant: OB(O)c1cncnc1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(C)cnc(Cn2nc3cc(-c4cncnc4)c4c-3c(n2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Temperature: 40 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
4-[Bis(tert-butoxycarbonyl)amino]-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-yl trifluoromethanesulfonate (50 mg) was dissolved in 1,4-dioxane (4 ml). Pyrimidine-5-boronic acid (13 mg), a 2 N sodium carbonate solution (2 ml) and bis(triphenylphosphine)palladium (II) dichloride (5 mg) were added and the mixture was stirred at 40° C. for two hours. Water was placed into the reaction solution, followed by extraction with ethyl acetate. The resulting organic layer was sequentially washed with water and brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound as an oil (45 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=3)[S:17][C:10]=12.[CH2:25]([O:27][CH:28](O)[C:29]([F:32])([F:31])[F:30])[CH3:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:25]([O:27][CH:28]([NH:24][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[CH:15]=[C:16]([C:18]4[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=4)[S:17][C:10]=23)=[C:2]([F:1])[CH:3]=1)[C:29]([F:32])([F:31])[F:30])[CH3:26]
Reactant: Cn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: CCOC(O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(Nc1ccc(Oc2ccnc3cc(-c4cn(C)cn4)sc23)c(F)c1)C(F)(F)F
Yield: 68.7 %

Procedure:
A mixture of 12 (Scheme 3) (500 mg, 1.47 mmol), trifluoroacetaldehyde ethyl hemiacetal (0.35 mL, 2.94 mmol) and 4-toluenesulfonic acid monohydrate (280 mg, 1.47 mmol) in ethanol (25 mL) was heated to reflux for 48 h. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (eluent methanol-dichloromethane 5:95 to 8:92) to afford title compound 318 (470 mg, 1.01 mmol, 68% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.42 (d, J=5.5 Hz, 1H), 7.85 (d, J=1.2 Hz, 1H), 7.72 (d, J=0.8 Hz, 1H), 7.67 (s, 1H), 7.29 (t, J=9.2 Hz, 1H), 7.08-7.02 (m, 2H), 3.86 (dd, J=9.2, 2.0 Hz, 1H), 6.52 (d, J=5.5 Hz, 1H), 5.68 (qd, J=10.4, 5.2 Hz, 1H), 3.72 (s, 3H), 3.76-3.59 (m, 2H), 1.15 (t, J=7.0 Hz, 3H). LRMS (M+1) 467.0 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([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]3[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@H:19]3[C@@H:18]([C:26]([NH:28][NH2:29])=[O:27])[O:17]2)=[C:4]([F:32])[CH:3]=1.C(N(C(C)C)CC)(C)C.[C:42](Cl)(=[O:44])[CH3:43]>CN(C=O)C>[C:42]([NH:29][NH:28][C:26]([C@@H:18]1[C@H:19]2[C@@H:20]([O:21][C:22]([CH3:24])([CH3:25])[O:23]2)[C@H:16]([N:11]2[CH:10]=[N:9][C:8]3[C:12]2=[N:13][CH:14]=[N:15][C:7]=3[NH:6][C:5]2[CH:30]=[CH:31][C:2]([Cl:1])=[CH:3][C:4]=2[F:32])[O:17]1)=[O:27])(=[O:44])[CH3:43]
Reactant: CC1(C)O[C@@H]2[C@@H](O1)[C@H](n1cnc3c(Nc4ccc(Cl)cc4F)ncnc31)O[C@@H]2C(=O)NN
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NNC(=O)[C@H]1O[C@@H](n2cnc3c(Nc4ccc(Cl)cc4F)ncnc32)[C@@H]2OC(C)(C)O[C@H]21
Temperature: 0 °C
Reaction time: 5 h
Yield: 45.8 %

Procedure:
To a stirred solution of (3aR,4S,6R,6aR)-6-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole4-carbohydrazide (50 mg) in N,N′-dimethylformamide (2 ml) at 0° C. was added diisopropylethylamine (28 μl) and acetyl chloride (9 mg). The reaction mixture was stirred at 0 ° C. for 5 h. The mixture was partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was washed with brine (20 ml), dried (MgSO4) and the solvent removed in vacuo. The residue was purified by automated preparative HPLC (gradient profile 5-95% (ii) over 18.5 min) to give the title compound (25 mg).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:31])[N:10]([C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][C:19]=2[OH:30])[CH:15]=[CH:16][CH:17]=1)[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cl:32][CH2:33][CH2:34][CH2:35]I.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:32][CH2:33][CH2:34][CH2:35][O:30][C:19]1[CH:20]=[C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:22]=[CH:23][C:18]=1[C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([N:10]([CH3:11])[C:9]([NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:31])[CH:13]=1
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCCCl)c1
Yield: 111.4 %

Procedure:
A solution of 300 mg (0.703 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate (prepared in Example 15f), 319 mg (2.11 mmol, 3 eq) of 1-chloro-3-iodopropane and 583 mg (4.22 mmol, 6 eq) of potassium carbonate in 10 ml of methyl ethyl ketone is refluxed for 7 hours. The insoluble matter is filtered off, the solvent is evaporated off and the oil obtained is chromatographed on silica gel (35 g FlashSmart column) eluted with 60/40 heptane/ethyl acetate. 394 mg of methyl 3-[2-(3-chloropropoxy)-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate are obtained in the form of a yellowish oil. Quantitative yield.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[C:5]=1[C:6]([O:8][CH3:9])=[O:7])([O-])=O>CO.[Pd].C(Cl)(Cl)Cl>[NH2:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1c(N)cccc1N
Reaction time: 2 h
Yield: 96 %

Procedure:
Methyl 2,6-dinitrobenzoate (15.0 gm.) is suspended in methanol (500 ml.) and 5% palladium on charcoal (1.5 gm.) added. Reduction is carried out on a Parr apparatus for 2 hours. The solution is filtered with suction and the catalyst washed with a few ml. of methanol. Removal of the methanol gives a brown crystalline product. Extraction with chloroform (50 ml.) and treatment with Darco gives the product (10.9 gm. 96% yield, m.p. 78°-79.5°). The thin layer chromatogram (Silica gel, 3% methanol in chloroform) shows the material to be homogeneous.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:39]=[CH:38][C:20]([C:21]([N:23]([CH3:37])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Cl)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[C:40]1(=[O:50])[NH:44][C:43](=[O:45])[C:42]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:41]12.[K].[I-].[Na+]>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:39]=[CH:38][C:20]([C:21]([N:23]([CH3:37])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:44]4[C:43](=[O:45])[C:42]5=[CH:46][CH:47]=[CH:48][CH:49]=[C:41]5[C:40]4=[O:50])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCCCCCl)cc2)cc1
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3OCCCCCN3C(=O)c4ccccc4C3=O)cc2)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 114.2 %

Procedure:
To a solution of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(5-chloropentyloxy)phenyl]benzamide (800 mg) in N,N-dimethylformamide (15 ml) was added Potassium phthalimide (821 mg) and sodium iodide (cat.) at ambient temperature. The reaction mixture was stirred at 80° C. for 18 hours. The reaction mixture was cooled and extracted with ethyl acetate and washed with water and brine. The organic solution was dried over magnesium sulfate. The solvent was removed by evaporation and subjected to silica gel column chromatography (SiO2; 50 g, 0.5% methanol in chloroform) to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-[2-(5-phthalimidopentyloxy)phenyl]benzamide (1.1 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[N:7][C:8]#[N:9].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(#N)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[N:7][C:8]#[N:9])[CH3:22]
Reactant: CCOC(=O)CCl
Reactant: N#CN=C1CCCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN1CCCCC1=NC#N
Temperature: 85 °C
Yield: 98.4 %

Procedure:
Piperidin-2-ylidene-cyanamide (C) (9.67 g, 78.5 mmol) was dissolved in acetonitrile (150 mL) under a low heat. Potassium carbonate (13.0 g, 94.2 mmol, 1.2 eq.) and Ethyl chloroacetate (11.7 mL, 109.9 mmol, 1.4 eq.) were then added thereto and the resulting suspension was heated for 16 hours at 85° C. A further amount of ethyl chloroacetate (1.67 mL, 15.7 mmol, 0.2 eq.) was then added. The reaction mixture was heated under reflux for 6 hours. The cooled suspension was then filtered and the solid residue was washed with DCM. The filtrate was reduced under vacuum and, after column chromatographic purification (SiO2, heptane/EtOAc 2:3), 16.16 g (98%) of the desired product (2-cyanoimino-piperidin-1-yl)-acetic acid ethyl ester (D) was obtained.