Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[NH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][C:19]([C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]3)=[O:24])=[CH:18][CH:17]=4)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[F:34][C:35]([F:46])([F:45])[C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>>[CH:1]1([C:4]([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[N:15]([C:40]4[CH:39]=[CH:38][CH:37]=[C:36]([C:35]([F:46])([F:45])[F:34])[CH:41]=4)[C:16]4[C:21]([CH:22]=3)=[CH:20][C:19]([C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]3)=[O:24])=[CH:18][CH:17]=4)=[O:13])[CH2:10][CH2:11]2)=[O:5])[CH2:3][CH2:2]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCN(C(=O)C5CC5)CC4)cc3c2)CC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCN(C(=O)C4CC4)CC2)n3-c2cccc(C(F)(F)F)c2)CC1
Yield: 79 %

Procedure:
The title compound was synthesized in analogy to example 5, after stirring for 6.5 days at 35° C., from (4-cyclopropanecarbonyl-piperazin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 25) and 3-(trifluoromethyl)-phenylboronic acid to afford the desired product as a colorless gum (79%). MS (ISP): 596.3 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:3].Cl[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.O>[OH:1][CH:2]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)[CH3:3]
Reactant: ClCc1ccc2ccccc2n1
Reactant: CC(O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(O)c1cccc(OCc2ccc3ccccc3n2)c1

Procedure:
A mixture of 3-(1-hydroxyethyl)phenol (7 g), 2-chloromethylquinoline (9 g), potassium carbonate (7 g) and potassium iodide (0.3 g) in acetone (75 ml) was refluxed overnight. The reaction mixture was poured into water, and then thoroughly extracted with ethyl acetate (3×30 ml). The organic extract was washed with NaOH solution (1N), water, brine, and then dried over MgSO4. All volatiles were removed to obtain a dark brown liquid, which was chromatographed on silica gel (12% ethyl acetate in hexanes) to leave the desired product as a light yellow liquid.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[N:5]=[C:4]([C:20]([OH:22])=[O:21])[CH:3]=1.[CH2:23](O)[CH3:24]>CN(C=O)C>[CH2:23]([O:21][C:20]([C:4]1[CH:3]=[C:2]([OH:1])[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[N:5]=1)=[O:22])[CH3:24]
Reactant: CCO
Reactant: O=C(O)c1cc(O)nc(SCc2ccc3ccccc3c2)n1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(O)nc(SCc2ccc3ccccc3c2)n1
Reaction time: 1.5 h
Yield: 88 %

Procedure:
A solution of 6-hydroxy-2-(2-naphthylmethylthio)-pyrimidine-4-carboxylic acid (2.50 g, 8.0 mmol) and 1,1-carbonyldiimidazole (1.94 g, 12 mmol) in DMF (30 ml) were stirred for 30 min, then treated with abs ethanol (8.0 ml). After 1.5 hrs of stirring, the reaction was poured onto water, stirred for 20 min, then filtered and dried to give 2.371 g (88%) of 6-hydroxy-2-(2-naphthylmethylthio)-pyrimidine-4-carboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=3[F:50])[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:51]=[O:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.C=O.[C:66](OCC)(=[O:68])C>CN(C)C=O>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=3[F:50])[CH:34]=2)([O:31][CH3:32])[O:11][C@@:10]1([CH2:66][OH:68])[CH:51]=[O:52])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc(Cc2cc([C@]3(OC)O[C@H](C=O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COc1ccc(Cc2cc([C@]3(OC)O[C@](C=O)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 21l (0.52 g, 0.68 mmol) in N,N-dimethyl formamide (20 mL) were added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.05 mL, 0.34 mmol) and formaldehyde (0.83 mL, 10.28 mmol, 37 wt % solution) in turn at room temperature. The mixture was stirred at room temperature for 16 hours, and then ethyl acetate (50 mL) was added. The resulting mixture was washed with water (60 mL×5), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 21m as yellow oil (0.52 g, 100%). This material was not further purified.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11]C(=O)OC(C)(C)C)[CH2:9][CH3:10])=[C:4]([F:19])[C:3]=1[C:20]([C:22]1[CH:23]=[N:24][C:25]([NH:28]CC2C=CC(OC)=CC=2)=[CH:26][CH:27]=1)=[O:21].FC(F)(F)C(O)=O>ClCCl>[NH2:11][C@@H:8]([C:5]1[C:4]([F:19])=[C:3]([C:2]([Cl:1])=[CH:7][CH:6]=1)[C:20]([C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[N:24][CH:23]=1)=[O:21])[CH2:9][CH3:10]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(NCc3ccc(OC)cc3)nc2)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2ccc(N)nc2)c1F
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
Step 8—To a solution of the tert-butyl N-[(1R)-1-[4-chloro-2-fluoro-3-(6-{[(4-methoxyphenyl)methyl]-amino}pyridine-3-carbonyl)phenyl]propyl]carbamate (109 g) in dichloromethane (2 vol) was carefully added trifluoroacetic acid (1 vol) at room temperature. The dichloromethane was removed under vacuum, additional trifluoroacetic acid (2 vol) was added and the mixture was stirred for 10 minutes before increasing the temperature to 70° C. and stirring overnight. The mixture was allowed to cool then poured slowly into a stirred mix of TBME (15 vol) and water (15 vol). The phases were separated and the remaining emulsion was filtered through GFA paper. The TBME layer was extracted into 2M HCl (2×3 vol) and the combined acidic extracts were basified (˜pH 12) and extracted with TBME (5×5 vol). The combined organic liquors were dried (Na2SO4) and concentrated to produce an oil/foam. The material was triturated with EtOAc to give 5-{3-[(1R)-1-aminopropyl]-6-chloro-2-fluorobenzoyl}pyridin-2-amine as a fine yellow powder 53.5 g, 84%. (Data for this compound are in Example 1).
Reaction SMILES: [N+]([O-])(O)=O.OS(O)(=O)=O.F[C:11]1C=CC=C(C)C=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21](C)[C:20]=1[N+:29]([O-:31])=[O:30]>>[F:18][C:19]1[CH:24]=[C:23]([CH3:11])[C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=1[N+:29]([O-:31])=[O:30]
Reactant: Cc1cccc(F)c1
Reactant: Cc1c([N+](=O)[O-])ccc(F)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Product: Cc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of HNO3 (60 mL) and H2SO4 (80 mL), cooled in an ice bath, was added 1-fluoro-3-methyl-benzene (27.5 g, 25 mmol) at such a rate that the temperature did not rise over 35° C. The mixture was allowed to stir for 30 min at room temperature and poured into ice water (500 mL). The resulting precipitate (a mixture of the desired product and 1-fluoro-3-methyl-2,4-dinitro-benzene, approx. 7:3) was collected via filtration and purified by recrystallization from 50 mL isopropyl ether to give 1-fluoro-5-methyl-2,4-dinitro-benzene as a white solid (18 g, 36%).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH2:38][CH:39]([OH:41])[CH3:40]>>[OH:41][CH:39]([CH3:40])[CH2:38][NH:37][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:29][CH:30]=1
Reactant: O=C(O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Reactant: CC(O)CN
Product: CC(O)CNC(=O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 82.8 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and 1-amino-2-propanol (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 46 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]+.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH:17]([CH3:22])[C:18]([O:20]C)=[O:19]>CN(C)C=O>[C:18]([CH:17]([N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3])[CH3:22])([OH:20])=[O:19]
Reactant: COC(=O)C(C)Br
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cn(C(C)C(=O)O)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of thymine (0.317 mole) and potassium carbonate (0.634 mole) in dimethylformamide (900 ml) is added methyl bromopropionate (0.634mole) and the mixture is stirred vigorously overnight under an atmosphere of nitrogen. The mixture is filtered, washed with ether and evaporated to dryness in vacuo. The solid residue is treated with water (300 ml) and 4N hydrochloric acid (12 ml), stirred for 20 minutes at 0° C., filtered and washed with water (2×100 ml). The precipitate is treated with water and 2N sodium hydroxide (60 ml), and is boiled for 10 minutes. The mixture is cooled at 0° C., filtered, and the title compound is precipitated by the addition of 4N hydrochloric acid (70 ml) to afford, after filtration, the title compound.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=O)=O)=[CH:4][CH:3]=1.[NH2:17][C:18]([NH2:20])=[O:19].Cl.C(O)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]2[C:8]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[NH:20][C:18](=[O:19])[N:17]=2)=[CH:4][CH:3]=1
Reactant: NC(N)=O
Reactant: O=C1CCCCC1C(=O)c1ccc(F)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=c1nc(-c2ccc(F)cc2)c2c([nH]1)CCCC2
Yield: 61.8 %

Procedure:
A mixture of 2-(4-fluorobenzoyl)cyclohexanone (14 g), urea (7.6 g), conc. hydrochloric acid (8 ml) and ethanol (40 ml) is refluxed for 8 hours. After cooling, the reaction mixture is diluted with water and washed with methylene chloride. The aqueous layer is made alkaline with potassium carbonate, and the precipitated crystal is separated by filtration and recrystallized from N,N-dimethylformamide-ethanol to give the desired compound (9.6 g), m.p. 248°-253° C.
Reaction SMILES: CC(S([NH:7][C:8]1([C:18]2[S:19][C:20]([C:23]3[CH:28]=[C:27]([NH:29][C:30]4[N:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][N:31]=4)[CH:26]=[C:25]([CH3:40])[CH:24]=3)=[CH:21][N:22]=2)[CH2:17][CH2:16][C:11]2(OCC[O:12]2)[CH2:10][CH2:9]1)=O)(C)C.C(Cl)(Cl)Cl.[N-:45]=[N+]=[N-].[Na+].CS(O)(=O)=O>O>[NH2:7][C:8]1([C:18]2[S:19][C:20]([C:23]3[CH:28]=[C:27]([NH:29][C:30]4[N:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][N:31]=4)[CH:26]=[C:25]([CH3:40])[CH:24]=3)=[CH:21][N:22]=2)[CH2:17][CH2:16][NH:45][C:11](=[O:12])[CH2:10][CH2:9]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(NS(=O)C(C)(C)C)CCC4(CC3)OCCO4)s2)c1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(N)CCNC(=O)CC3)s2)c1
Temperature: 65 °C
Yield: 63.8 %

Procedure:
To the product of Step 2 (100 mg, 0.13 mmol) was added chloroform (630 μL), sodium azide (24.5 mg, 0.38 mmol), and methanesulfonic acid (98 μL, 1.51 mmol). The mixture was heated to 65° C. for 1.5 h., cooled to room temperature, diluted with water, and extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by reverse phase HPLC (35:65 to 70:30 acetonitrile:water with a 0.1% trifluoroacetic acid modifier). The fractions containing the desired product were diluted with ethyl acetate and free based with saturated aqueous sodium bicarbonate. The separated organic layer was dried over magnesium sulfate, filtered and concentrated to afford the title compound (38 mg, 0.083 mmol, 66% yield) as an orange oil. MS ESI: [M+H]+ m/z 463. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.83 (s, 1H), 8.75 (s, 1H), 8.02 (s, 1H), 7.93 (s, 1H), 7.49 (s, 1H), 7.28 (d, J=4.7, 1H), 7.16 (s, 1H), 2.39-2.08 (m, 9H), 1.30-0.99 (m, 4H). rhSYK activity=+++
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[C:8]([C:14]([O:16]C(C)(C)C)=[O:15])[NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].C1(C)C=CC=CC=1>C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[C:8]([C:14]([OH:16])=[O:15])[NH:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: COC(=O)c1cccc2[nH]c(C(=O)OC(C)(C)C)cc12
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc2[nH]c(C(=O)O)cc12

Procedure:
To a solution of 3.8 g 1H-Indole-2,4-dicarboxylic acid 2-tert-butyl ester 4-methyl ester were dissolved in 100 ml TFA. After 1 h at RT 150 ml toluene were added and the solvents were removed under reduced pressure. The residue was lyophilised after addition of water and acetonitrile. Yield: 2 g.
Reaction SMILES: [C:1]1([C@H:11]([N:13]([CH2:21][C@@H:22]2[C@@H:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][NH:24][CH2:23]2)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=1>CC(C)=O>[OH:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([N:24]2[CH2:25][C@H:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@@H:22]([CH2:21][N:13]([C@@H:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH3:12])[C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:19])[CH3:17])[CH2:23]2)=[O:39])=[CH:36][CH:35]=1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(O)cc1
Solvent: CC(C)=O
Product: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)c2ccc(O)cc2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C

Procedure:
A 5 ml acetone solution of 260 mg of tert-butyl {[(3R,4S)-1-(4-hydroxybenzoyl)-4-phenylpyrrolidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate obtained from tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate and 4-hydroxybenzoic acid, by amidation in the same manner as in Reference Example 19, was mixed with 130 mg of potassium carbonate, and then the reaction solution was mixed with 0.1 ml of ethyl bromoacetate and heated under reflux for 3 hours. After cooling down to room temperature, the insoluble matter was removed by filtration, and the filtrate was concentrated under a reduced pressure. The residue was purified by a silica gel column chromatography (hexane-ethyl acetate) to obtain 264 mg of ethyl (4-{[(3R,4S)-3-({(tert-butylcarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}phenoxy)acetate a colorless amorphous substance. FP: 637.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Br[CH2:17][CH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][OH:19])[CH2:12][CH2:11]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCO)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A mixture of 2.29 g (10 mmol) 1-(2-methoxy-phenyl)-piperazine hydrochloride, 7.1 mL (100 mmol) 2-bromo-ethanol, 5.52 g (40 mmol) potassium carbonate and 100 mL acetonitrile is stirred at 60° C. overnight. Filtration and concentration in vacuum yields the crude product which is purified via column chromatography over silica gel eluting with dichloromethane/ammonia-saturated methanol 98:2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@@H:19]2[CH2:25][C:24]([F:27])([F:26])[CH2:23][CH2:22][NH:21][C:20]2=[O:28])[CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[C:36]([N:16]1[CH2:15][CH2:14][CH:13]([CH2:12][N:11]([C@@H:19]2[CH2:25][C:24]([F:27])([F:26])[CH2:23][CH2:22][NH:21][C:20]2=[O:28])[S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])[CH2:18][CH2:17]1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1NCCC(F)(F)C[C@H]1N(CC1CCNCC1)S(=O)(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1NCCC(F)(F)C[C@H]1N(CC1CCN(C(=O)c2ccccc2)CC1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
4-Chloro-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-N-piperidin-4-ylmethyl-benzenesulfonamide (0.04 g, 0.09 mmol) and triethylamine (19 mg, 0.18 mmol) were dissolved in dichloromethane (1.5 ml). Then benzoyl chloride (0.018 g, 0.13 mmol) was added and the mixture was stirred overnight at room temperature. The reaction mixture was partitioned between aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified over silica gel (heptane/ethyl acetate 1:1) to yield 29 mg (58%) of the title compound;
Reaction SMILES: [CH:1]([C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([O:14][CH3:15])=[CH:8][C:4]=1[C:5](O)=[O:6])=O.O.[NH2:17][NH2:18]>C(O)C>[CH3:13][O:12][C:11]1[CH:10]=[C:9]([O:14][CH3:15])[CH:8]=[C:4]2[C:3]=1[CH:1]=[N:17][NH:18][C:5]2=[O:6]
Reactant: COc1cc(OC)c(C=O)c(C(=O)O)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1cc(OC)c2cn[nH]c(=O)c2c1
Yield: 86 %

Procedure:
The 2-formyl-3,5-dimethoxybenzoic acid (2.7 g, 13 mmol) is partially dissolved in 300 mL of ethanol, and 6.2 mL of hydrazine hydrate are then added. The mixture is refluxed for 6 hours. After cooling, the precipitate formed is filtered off and then dried. 2.3 g of a white solid are obtained (86% yield).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:39][N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:7](=[O:21])[N:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([O:19]C)=[O:18])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C1COCC1.CO>[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]3[NH:39][N:38]=[N:37][N:36]=3)=[CH:25][CH:24]=2)[C:7](=[O:21])[N:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([OH:19])=[O:18])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(Cc2ccccc2C(=O)OC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1nn(Cc2ccccc2C(=O)O)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.3 %

Procedure:
To a solution of 20 mg (0.038 mmole) of 5-n-butyl-2-[2-(carbomethoxy)benzyl]-2,4-dihydro-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-3H-1,2,4-triazol- 3-one (from Example 6) in 200 μl of dry THF was added all at once 84 μl (0.084 mmole) of 1N sodium hydroxide in methanol. The mixture was stirred overnight at room temperature and then evaporated to dryness. The residual solid was dissolved in 1.5 ml of methanol and treated with 90 μl of 1N HCl in methanol (final pH 2). The solvent was evaporated, and the residue was leached with CHCl3. After removal of insoluble solid (NaCl) by filtration through glass wool, the filtrate was concentrated in vacuo and then re-concentrated from toluene. The residue was dried overnight in the presence of P2O5 to give 20 mg (95%) of the titled compound as a stiff, white foam, mp>106° C. (gradual), homogeneous by TLC in 90:10:0.1 CH2Cl2 --MeOH--AcOH; mass spectrum (FAB) m/e 510 (M+1)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Si:11]([O:18][C@H:19]1[CH2:24][CH2:23][NH:22][CH2:21][C@@H:20]1[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>CN(C=O)C>[Si:11]([O:18][C@H:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:21][C@@H:20]1[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@H]1CNCC[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CN(c2ccncc2[N+](=O)[O-])CC[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 98 %

Procedure:
Method 1 was followed using 1 eq each of 4-chloro-3-nitropyridine, tert-butyl (3S,4S)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate and triethylamine in DMF yielding tert-butyl(3S,4S)-4-(tert-butyldimethylsilyloxy)-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate, (98%). LCMS (m/z): 453.3 (MH+); LC Rt=4.01 min.
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:8])[C:2]1C=C[CH:5]=[CH:4][CH:3]=1.[O:20]1C=CC=C1C(Cl)=O>>[O:20]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:1]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:8]
Reactant: O=C(Cl)c1ccco1
Reactant: CCOC(=O)CCCCCCC(=O)c1ccccc1
Product: CCOC(=O)CCCCCCC(=O)c1ccco1
Yield: 71 %

Procedure:
Following a procedure analogous to that described above for 49a, but substituting 2-furanoyl chloride, the title compound was obtained in 71% yield: 1H NMR (300 MHz, CDCl3) δ 7.59 (d, J=1.8 Hz, 1H), 7.19 (d, J=3.3 Hz, 1H), 6.54 (dd, J=3.3, 1.8 Hz), 4.12 (q, J=6.9 Hz, 2H), 2.82 (t, J=7.5 Hz, 2H), 2.30 (t, J=7.5 Hz, 2H), 1.72 (m, 2H), 1.64 (m, 2H), 1.38 (m, 4H), 1.25 (t, J=6.9 Hz, 3H); 13C NMR (75.4 MHz, CDCl3) δ 14.07, 23.87, 24.58, 28.68, 28.72, 34.05, 38.14, 59.98, 111.97, 116.68, 146.05, 152.60, 173.52, 189.39.
Reaction SMILES: [CH3:1][N:2]([C:13]1[CH:26]=[CH:25][C:16]([O:17][CH:18]([CH3:24])[C:19]([O:21]CC)=[O:20])=[CH:15][CH:14]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:6]=2[N:7]=1.[OH-].[Na+]>C(O)(C)C.O>[CH3:1][N:2]([C:13]1[CH:26]=[CH:25][C:16]([O:17][CH:18]([CH3:24])[C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)C(C)Oc1ccc(N(C)c2nc3cc(Cl)ccc3o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(Oc1ccc(N(C)c2nc3cc(Cl)ccc3o2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 63 %

Procedure:
Ethyl 2-{4-[N-methyl-N-(5-chloro-2-benzoxazolyl)amino]phenoxy}propionate (10.0 g; see Example 7) was suspended in isopropyl alcohol (50 ml) and a solution of sodium hydroxide (1.12 g) in water (50 ml) was added over a period of 45 minutes. Further isopropyl alcohol (60 ml) was added and the mixture was stirred at room temperature for a period of 48 hours. The alcohol was removed by distillation under reduced pressure, the residue was dissolved in water and the aqueous solution was acidified to pH 4 by the addition of aqueous 2 M hydrochloric acid. The precipitate was collected by filtration, dried and recrystallised from ethyl acetate to give the title compound (5.83 g; 63%), mp 152°-154° C. The pmr spectrum of the compound was consistent with the assigned structure.