Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C@@H:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][CH3:25])[CH:20]=2)[C@H:15]([C:26]2[CH:31]=[CH:30][C:29]3[O:32][CH2:33][O:34][C:28]=3[CH:27]=2)[C@H:14]1[C:35]([OH:37])=[O:36].[OH-].[Li+].[CH3:40]COC(C)=O.CCCCCC>>[CH3:40][O:36][C:35]([C@H:14]1[C@H:13]([C:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2][OH:1])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][CH3:25])[CH:20]=2)[C@@H:15]1[C:26]1[CH:31]=[CH:30][C:29]2[O:32][CH2:33][O:34][C:28]=2[CH:27]=1)=[O:37]
Reactant: CCOC(C)=O
Reactant: CCCOc1ccc2c(c1)[C@@H](c1ccc(OC)cc1OCCO)[C@H](C(=O)O)[C@H]2c1ccc2c(c1)OCO2
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCCC
Product: CCCOc1ccc2c(c1)[C@@H](c1ccc(OC)cc1OCCO)[C@H](C(=O)OC)[C@H]2c1ccc2c(c1)OCO2

Procedure:
This intermediate was isolated by flash column chromatography (SiO2, EtOAc/Hexane=30/70) of a sample of the crude reaction mixture from the preparation of (1S, 2R, 3S)-3-[2-(2-Hydroxyeth-1-yloxy)-4-methoxyphenyl)-1-(3,4-methylendioxyphenyl)-5-propoxyindane-2-carboxylic acid described above prior to the saponification with lithium hydroxide.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][N:12]([CH3:48])[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]([NH:22][C:23]2[N:28]=[C:27]([C:29]3[N:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]4=[N:31][C:30]=3[C:38]3[CH:39]=[C:40]([CH:45]=[CH:46][CH:47]=3)[C:41](OC)=[O:42])[CH:26]=[CH:25][N:24]=2)[CH:19]=[CH:20][CH:21]=1.[Cl:49][C:50]1[CH:51]=[CH:52][C:53]([F:57])=[C:54]([CH:56]=1)[NH2:55]>C1COCC1>[Cl:49][C:50]1[CH:51]=[CH:52][C:53]([F:57])=[C:54]([NH:55][C:41](=[O:42])[C:40]2[CH:45]=[CH:46][CH:47]=[C:38]([C:30]3[N:31]=[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][N:33]4[C:29]=3[C:27]3[CH:26]=[CH:25][N:24]=[C:23]([NH:22][C:18]4[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH2:14][CH2:13][N:12]([CH3:11])[CH3:48])[CH:17]=4)[N:28]=3)[CH:39]=2)[CH:56]=1
Reactant: Nc1cc(Cl)ccc1F
Reactant: COC(=O)c1cccc(-c2nc3ccccn3c2-c2ccnc(Nc3cccc(OCCN(C)C)c3)n2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCOc1cccc(Nc2nccc(-c3c(-c4cccc(C(=O)Nc5cc(Cl)ccc5F)c4)nc4ccccn34)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
A 1.0M solution of NaHMDS in THF (0.59 mL, 0.59 mmol) was added dropwise to a stirring solution of methyl 3-(3-{2-[(3-{[2-(dimethylamino)ethyl]oxy}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)benzoate (0.100 g, 0.20 mmol) and 5-chloro-2-fluoroaniline (0.09 g, 0.59 mmol) in THF (2 mL) at rt. The reaction mixture was stirred for 0.5 h at room temperature then quenched with methanol and concentrated onto silica gel. Flash chromatography afforded the title compound (0.115 g, 94%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.75 (s, 1H), 9.52-9.50 (m, 1H), 8.35 (d, J=5.2 Hz, 1H), 8.31 (s, 1H), 8.01 (d, J=7.7 Hz, 1H), 7.83 (d, J=7.7 Hz, 1H), 7.77-7.72 (m, 2H), 7.61-7.57 (m, 1H), 7.51-7.47 (m, 2H), 7.36-7.24 (m, 3H), 7.17-7.06 (m, 2H), 6.60 (d, J=5.3 Hz, 1H), 6.53 (dd, J=8.2, 2.4 Hz, 1H), 3.95 (t, J=5.9 Hz, 2H), 2.55 (t, J=5.7 Hz, 2H), 2.14 (s, 6H). MS (ES+, m/z) 622 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]2[C:23]([NH2:26])=[N:24][N:25]=[C:11]2[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])=[CH:13][N:12]2[C:23]([NH2:26])=[N:24][N:25]=[C:11]2[CH:10]=1
Reactant: CC(C)(C)OC(=O)NCc1cc2nnc(N)n2cc1-c1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cc2nnc(N)n2cc1-c1ccc(Cl)cc1Cl
Yield: 26.2 %

Procedure:
[3-Amino-6-(2,4-dichloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridin-7-ylmethyl]-carbamic acid tert-butyl ester (17 mg, 0.042 mmol) was dissolved in DCM (2 mL) and TFA (1 mL) and the solution was stirred at RT for 30 min. The reaction mixture was concentrated to dryness and the remaining residue purified by reverse phase prep-HPLC (Waters system) to give the title compound (2TFA salt, 5.7 mg, 0.011 mmol, 26%) as a white solid. MS: 308 [M+1]+; HPLC: AtRet=0.77.
Reaction SMILES: C([NH:8][C@H:9]([C:12]([OH:14])=O)[CH2:10][OH:11])(OC(C)(C)C)=O.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[CH2:32]([NH:39][C:12](=[O:14])[C@H:9]([CH2:10][OH:11])[NH2:8])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: N[C@@H](CO)C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
To a mixture of 4.10 g (20 mmol) of N-Boc-L-serine, 2.97 g (22 mmol) of HOBT, 2.42 mL (22 mmol) of NMM, and 2.40 mL (22 mmol) of benzylamine in 50 mL of anhydrous DMF at 0° C. was added 4.21 g of WSC. The mixture was stirred at 0° C. for 1 h and at room temperature for 3 h. This was then taken up in 300 mL of EtOAc and washed with 100 mL of H2O (2×) and brine (1×). The combined organic layers were dried over MgSO4 and concentrated. After drying under vacuum overnight, the residue was dissolved in 20 mL of CH2Cl2 and treated with 20 mL of CF3CO2H at 0-10° C. for ca. 7 h. The solvent and CF3CO2H were removed under vacuum. The trace CF3CO2H was removed azeotropically with CHCl3 at the end. The residue was purified by preparative HPLC, eluting with 8% (10% conc. NH4 0H in MeOH)--CH2Cl2 to afford 3.57 g (92%) of the serinamide: mp 97-98° C.; 1H NMR (CDCl3) δ7.82 (br s, 1H), 7.26 (m, 5H), 4.42 (ddd, J=16.7, 15.0, 6.0 Hz, 2H), 3.85 (dd, J=10.8, 5.2 Hz, 1H), 3.70 (dd, J=10.8, 5.3 Hz, 1H), 3.44 (m, 1H), 2.22 (br s, 3H); FDMS 195 (M+1). Anal. (C10H14N2O2) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:10]([CH3:28])[CH2:9]2)=[O:7])=[CH:4][C:3]=1[F:31].Cl[C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34].[CH:45]1([CH2:48][NH2:49])[CH2:47][CH2:46]1.O>ClCCl>[C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:29]=[CH:30][C:2]([NH:1][C:33]([NH:49][CH2:48][CH:45]4[CH2:47][CH2:46]4)=[O:34])=[C:3]([F:31])[CH:4]=3)[CH2:9][C@H:10]2[CH3:28])[CH:16]=1)([CH3:23])([CH3:22])[CH3:24]
Reactant: NCC1CC1
Reactant: C[C@@H]1CN(C(=O)c2ccc(N)c(F)c2)CCN1Cc1cccc(C(=O)NC(C)(C)C)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1CN(C(=O)c2ccc(NC(=O)NCC3CC3)c(F)c2)CCN1Cc1cccc(C(=O)NC(C)(C)C)c1
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
(R)-3-((4-(4-Amino-3-fluorobenzoyl)-2-methylpiperazin-1-yl)methyl)-N-tert-butylbenzamide (119 mg, 0.275 mmol) and 4-nitrophenol chloroformate (56 mg, 0.275 mmol) were combined and stirred in dichloromethane for 1 hour. Cyclopropanemethylamine (56.8 mg, 0.8 mmol, 0.0694 mL) was added and the reaction was stirred for a further 30 minutes. Water was added and the reaction mixture was flushed through a hydrophobic frit. The organic phase was concentrated under reduced pressure and purified by basic reverse phase HPLC to afford the title compound (19.8 mg). MS (ES) m/z 524.7 [M+H]+
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][CH2:8][N:7]([CH3:10])[C:6]1=[CH2:11])[CH2:2][CH2:3][CH3:4].[F:12][C:13]([F:18])([F:17])[C:14]([OH:16])=[O:15]>C(OCC)C>[CH2:1]([N+:5]1[CH:9]=[CH:8][N:7]([CH3:10])[C:6]=1[CH3:11])[CH2:2][CH2:3][CH3:4].[F:12][C:13]([F:18])([F:17])[C:14]([O-:16])=[O:15]
Reactant: C=C1N(C)CCN1CCCC
Reactant: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CCCC[n+]1ccn(C)c1C
Product: O=C([O-])C(F)(F)F
Temperature: -78 °C
Reaction time: 8 h

Procedure:
1.84 ml (12.09 mmol) 1-n-butyl-3-methyl-2-methylene imidazoline is added to a solution of 1.38 g (12.09 mmol) trifluoroacetic acid in diethylether cooled to −78° C. by means of a syringe. The reaction mixture is slowly warmed to room temperature, wherein a white solid is formed and is stirred overnight at room temperature. Subsequently, all volatile components are removed in vacuum; the residue is washed with 20 ml hexane and, subsequently dried in vacuum. The desired product is obtained as a white solid, which can be recrystallized from dichloromethane.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([OH:10])=[CH:8][N:7]=[C:6]2[N:11]([CH2:14][C:15]3[S:19][C:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[N:17][C:16]=3[CH2:30][CH2:31][CH2:32][CH3:33])[CH:12]=[CH:13][C:5]=12)[CH:2]=[CH2:3].C(=O)([O-])[O-].[Cs+].[Cs+].C([O:44][C:45](=[O:48])[CH2:46]Br)(C)(C)C.C(OCC)(=O)C>CN(C)C=O>[CH2:30]([C:16]1[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:27])[F:29])=[CH:22][CH:21]=2)[S:19][C:15]=1[CH2:14][N:11]1[C:6]2=[N:7][CH:8]=[C:9]([O:10][CH2:46][C:45]([OH:48])=[O:44])[C:4]([CH2:1][CH2:2][CH3:3])=[C:5]2[CH:13]=[CH:12]1)[CH2:31][CH2:32][CH3:33]
Reactant: C=CCc1c(O)cnc2c1ccn2Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCCC
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1Cn1ccc2c(CCC)c(OCC(=O)O)cnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.4 %

Procedure:
140 mg 4-Allyl-1-[4-butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-1H-pyrrolo[2,3- b]pyridin-5-ol were dissolved in 10 ml dimethylformamide and 195 mg cesium carbonate and 116 mg tert.-butylbromoacetate were added. The reaction mixture was stirred at room temperature for two hours when 100 ml ethyl acetate were added and the mixture was washed five times with portions of 20 ml of water The organic layer was dried over MgSO4 and the solvent removed under reduced pressure. The residue was dissolved in 10 ml dichloromethane and 4 ml trifluoroacetic acid were added. The reaction mixture was stirred at room temperature for three hours then 100 ml toluene were added and the solvents removed under reduced pressure. The residue was dissolved in 20 ml methanol and 50 mg palladium (10% on charcoal) were added. The reaction mixture was stirred at room temperature in a hydrogen atmosphere (5 bar) for one hour. The catalyst was filtered off and the solvent removed under reduced pressure. The residue was purified by RP-HPLC to provide 70 mg {1-[4-Butyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-4-propyl-1H-pyrrolo[2,3-b]pyridin-5-yloxy}-acetic acid as colorless lyophilisate.
Reaction SMILES: N1C(C)=CC=CC=1C.Cl[CH2:10][N:11]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[S:12]([Cl:15])(=[O:14])=[O:13].C1CCCCC1.[CH3:28][OH:29]>>[CH3:28][O:29][CH2:10][N:11]([CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[S:12]([Cl:15])(=[O:14])=[O:13]
Reactant: O=S(=O)(Cl)N(CCl)C1CCCCC1
Reactant: CO
Solvent: Cc1cccc(C)n1
Solvent: C1CCCCC1
Product: COCN(C1CCCCC1)S(=O)(=O)Cl
Temperature: 45 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
22 parts of 2,6-lutidine are added in the course of 15 minutes, at from -5 to +5° C., to a mixture of 50 parts of N-chloromethyl-N-cyclohexylsulfamic acid chloride in 110 parts of cyclohexane and 55 parts of methanol. The reaction mixture is stirred for 20 minutes at 25° C. and one hour at 45° C. After concentrating the solvent under reduced pressure and removing the hydrochloride which has precipitated, distillation gives 30 parts (60% of theory) of N-methoxymethyl-N-cyclohexylsulfamic acid chloride of boiling point 102-106° C./0.01 mbar and nD25 = 1.4857.
Reaction SMILES: [BH4-].[Na+].[I:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1.O>O1CCOCC1>[I:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: OCc1ccc(I)cc1
Temperature: 100 °C
Yield: 96.3 %

Procedure:
(Acheson, R. M.; Lee, G. C. M. J. Chem. Soc. Perkin Trans. I 1987, 2321–2332.) To a stirred suspension of sodium borohydride (5.68 g, 150 mmol, 2.0 equiv) in 50 mL dioxane at 0° C. was added dropwise a solution of 4-iodobenzoyl chloride (19.99 g, 75 mmol, 1.0 equiv) in 50 mL dioxane over 25 min. The resulting mixture was heated to 100° C. for 90 min under a reflux condenser then cooled to 0° C. 50 mL H2O was added cautiously under a flowing stream of nitrogen. [CAUTION: Evolves gas!] The mixture was extracted 3×125 mL CH2Cl2 and the combined organic extracts were washed with 2× H2O, 2×0.1N HCl, 2×1N NaOH, H2O, and brine, dried (MgSO4), filtered, and evaporated to yield 16.9 g of crude 4-iodobenzyl alcohol as a white solid, determined by NMR to contain 78% desired product with the remainder residual starting material and 4-iodobenzoic acid. The crude product was used without further purification. mp: 61.0–66.5° C. TLC Rf=0.27 (3:1 hexanes/EtOAc). IR (film): 3306, 1005, 791. 1H-NMR (400 MHz, CDCl3): δ 7.69 (d, 2H, J=8.3, C4-H, C6-H), 7.12 (d, 2H, J=8.5, C3-H, C7-H), 4.66 (br d, 2H, J=4.1, C1—H2), 1.67 (br t, 1H, C1-OH). 13C-NMR (125 MHz, CDCl3): δ 140.4, 137.6, 128.8, 93.0, 64.6. EI-MS m/z (rel int): 234 (M+, 100).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:12]([F:23])[CH:11]=1.C(OCC)(=O)C>CN(C)C=O.[Cl-].[Na+].O>[NH2:9][C:10]1[C:22]([Cl:1])=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])=[C:12]([F:23])[CH:11]=1.[NH2:9][C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])=[C:12]([F:23])[C:11]=1[Cl:1]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1F
Reactant: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(N)cc1F
Product: CC(C)(C)OC(=O)c1ccc(N)c(Cl)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 28 %
Yield: 23 %

Procedure:
To a solution of N-chlorosuccinimide (950 mg, 7.1 mmol) in N,N-dimethylformamide (25 mL) was added dropwise a solution of tert-butyl 4-amino-2-fluorobenzoate (1.5 g, 7.1 mmol) in N,N-dimethylformamide (22 mL). The resulting mixture was stirred at room temperature for 3 hours and then brine solution (80 mL) and ethyl acetate (100 mL) were added. The organic phase was collected and washed three times with brine (50 mL). Combined organic phases were dried on magnesium sulphate and evaporated under reduced pressure. Purification of the residue via silica gel column chromatography (4% EtOAc in iso-hexane) gave tert-butyl 4-amino-5-chloro-2-fluorobenzoate (400 mg, 23%, 1H NMR (400 MHz, DMSO-d6): δ 7.63 (d, J=7.6 Hz, 1H), 6.55 (d, J=13.2 Hz, 1H), 6.46 (brs, 2H), 1.52 (s, 9H)) and tert-butyl 4-amino-3-chloro-2-fluorobenzoate (490 mg, 28%, 1H NMR (400 MHz, DMSO-d6): δ 7.52 (t, J=8.4 Hz, 1H), 6.64 (dd, J=1.2 Hz and J=8.4 Hz, 1H), 6.50 (brs, 2H), 1.53 (s, 9H)) both as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:54])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@H:16]([CH2:47][C:48]([CH3:53])([CH3:52])[C:49]([OH:51])=O)[CH2:15]2)=[CH:10][CH:9]=1.[CH3:55][NH2:56]>>[CH3:1][O:2][CH2:3][C@H:4]([CH3:54])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:38])=[O:39])[C@H:16]([CH2:47][C:48]([CH3:53])([CH3:52])[C:49]([NH:56][CH3:55])=[O:51])[CH2:15]2)=[CH:10][CH:9]=1
Reactant: CN
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)O)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Product: CNC(=O)C(C)(C)C[C@@H]1C[C@H](c2ccc(COC[C@@H](C)COC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1S(=O)(=O)c1ccc(C)cc1

Procedure:
According to general procedure D, 1.0 mmol of 3-[(2S,4R,5R)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid are reacted with methylamine (8M in EtOH) to afford the title compound as yellow oil. Rf=0.25 (EtOAc/heptane 3:1); Rt=5.36 (gradient I).
Reaction SMILES: [CH:1]1([CH2:7][Mg]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[C:15]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]=[O:28])=[CH:21][C:20]=1[NH:29][C:30](=[O:46])[CH2:31][CH:32]1[C:45]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[O:39][C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)([CH3:18])([CH3:17])[CH3:16].[Cl-].[NH4+]>C(OCC)C>[C:15]([C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]([OH:28])[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:21][C:20]=1[NH:29][C:30](=[O:46])[CH2:31][CH:32]1[C:45]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[O:39][C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)([CH3:18])([CH3:16])[CH3:17]
Reactant: Br[Mg]CC1CCCCC1
Reactant: CC(C)(C)c1ccc(CCC=O)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CCC(O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
0.18 ml of a 1M solution of cyclohexylmethylmagnesium bromide in diethyl ether was added to 2 ml of tetrahydrofuran, and the mixture was cooled to -78° C. 2 ml of a tetrahydrofuran solution containing 50 mg (0.12 mmol) of N-[2-t-butyl-5-(3-oxopropyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Preparation 19) was then added dropwise to this solution, over a period of 5 minutes. The mixture was then stirred for 40 minutes at this temperature, after which the temperature was allowed to return gradually to 0° C. The reaction was then stopped by the addition of a saturated aqueous solution of ammonium chloride. Diethyl ether was added, which caused the title compound to be distributed between the organic solvent and water. The organic layer was separated and washed with water, after which the solvent was removed by distillation under reduced pressure. The resulting residue was subjected to column chromatography through 10 g of silica gel. Elution with a 100:15 by volume mixture of methylene chloride and ethyl acetate afforded 41 mg (yield 67%) of the title compound as crystals, melting at 145°-146° C. (after recrystallization from a mixture of methylene chloride and diethyl ether).
Reaction SMILES: CS(O)(=O)=O.[CH3:6][N:7]([CH2:9][C:10]1[O:14][C:13]([CH2:15][OH:16])=[CH:12][CH:11]=1)[CH3:8].[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21]O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O>[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:16][CH2:15][C:13]1[O:14][C:10]([CH2:9][N:7]([CH3:6])[CH3:8])=[CH:11][CH:12]=1
Reactant: NCCCCO
Reactant: CN(C)Cc1ccc(CO)o1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(COCCCCN)o1
Yield: 29.2 %

Procedure:
A mixture of methanesulphonic acid (86 g), 5-[(dimethylamino)methyl]-2-furanmethanol (15.5 g) and 4-aminobutanol (17.8 g) in dry tetrahydrofuran was heated at 100° for 11/2 h. Excess sodium carbonate was added to the cooled solution, the suspension was filtered and the filtrate was evaporated to give a red oil which was dissolved in water and extracted with ether. The extract was distilled to give the title compound as an oil (6.6 g) b.p. 100°-110°, 0.08 mm. TLC silica, methanol/ammonia 0.88 80:1, Rf 0.3.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)(=[O:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+].O>C(C(C)=O)C.C(OCC)(=O)C>[C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:16][C:3]1[C:2]([Br:1])=[CH:11][C:10]2[C:9]([CH3:12])([CH3:13])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=2[CH:4]=1)(=[O:19])[CH3:18]
Reactant: CC1(C)CCC(C)(C)c2cc(Br)c(O)cc21
Reactant: CC(=O)OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)OCCCCCOc1cc2c(cc1Br)C(C)(C)CCC2(C)C

Procedure:
A solution of 3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ol (10 g, 0.35 mol), 5-bromopentyl acetate (8.15 g) and potassium carbonate (33.6 g) in methyl ethyl ketone (200 ml) is refluxed for 2 hours. The reaction medium is treated with water and ethyl acetate. After separation of the phases by settling, the organic phase is washed twice with water, dried over magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The product is purified by flash chromatography on a column of silica.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23].C[O:25][C:26](=[O:35])[CH:27](Br)[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH:29]1([CH2:28][CH:27]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:23][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[F:16])[CH:6]=[N:5]2)[C:26]([OH:25])=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Oc1ccccc1F
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: COC(=O)C(Br)CC1CCCC1
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2F)cc1=O
Yield: 70 %

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2-fluoro-phenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[4-(2-fluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (10.2 g, 70%); ESI-MS 347 [M+H+]; HPLC: >98% (purity). 1H-NMR (300 MHz, CDCl3) δ 7.91 (s, 1H), 7.18-7.33 (m, 4H), 5.98 (s, 1H), 5.51-5.56 (m, 1H), 2.30-2.40 (m, 1H), 2.07-2.16 (m, 1H), 1.50-1.80 (m, 7H), 1.11-1.21 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([OH:22])=[CH:21][C:14]=3[O:13]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:23](Cl)(=[O:25])[CH3:24].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][C:23](=[O:25])[CH3:24])=[CH:21][C:14]=3[O:13]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(=O)Cl
Reactant: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1OC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(C=C2Oc3cc(OC(C)=O)ccc3C2=O)cc1OC
Temperature: 25 °C

Procedure:
After 2-[(3,4-dimethoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, acetyl chloride 0.2 ml was added, and the mixture was refluxed for two hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml twice. After the ethyl acetate phase was dehydrated with anhydrous magnesium sulfate, it was concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 341.3 mg.