Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:33])[C@H:23]([O:25]CC4C=CC=CC=4)[CH3:24])[C@@H:18]([OH:34])[C@H:17]3[OH:35])=[C:9]([NH:36][CH2:37][CH:38]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:8]=2)[CH2:3]1.C(OC(=O)N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](NC(=O)[C@H](OCC4C=CC=CC=4)C)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1)(C)(C)C>>[NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:33])[C@@H:23]([OH:25])[CH3:24])[C@@H:18]([OH:34])[C@H:17]3[OH:35])=[C:9]([NH:36][CH2:37][CH:38]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[N:8]=2)[CH2:3]1
Reactant: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Agent: C[C@@H](OCc1ccccc1)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)OC(C)(C)C)C4)nc32)[C@H](O)[C@@H]1O
Product: C[C@H](O)C(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to (R)-N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-propionamide (Example 181, step 4), by substituting acetic acid (S)-1-{(1S,2R,3S,4R)-4-[2-((R)-3-tert-butoxycarbonylamino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentylcarbamoyl}-ethyl ester (Example 182, step 3) for {(R)-1-[9-[(1R,2S,3R,4S)-4-((R)-2-benzyloxy-propionylamino)-2,3-dihydroxy-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purin-2-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (Example 181, step 3).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:26])[C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])=[CH:8][C:7]=1[O:24][CH3:25]>O1CCOCC1>[CH2:17]([O:16][C:14]([NH:13][C:9]1[C:10]([Cl:12])=[CH:11][C:6]([C:5]([OH:26])=[O:4])=[C:7]([O:24][CH3:25])[CH:8]=1)=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1cc(Cl)c(NC(=O)OCc2ccccc2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(NC(=O)OCc2ccccc2)c(Cl)cc1C(=O)O
Reaction time: 20 h

Procedure:
200 ml 2N aqueous sodium hydroxide solution is added dropwise to a stirred solution of 72.1 g of the benzoic acid methyl ester produced in step (b) in 800 ml dioxane. The mixture is stirred for 20 hours and the organic solvent removed under a vacuum. The residue is dissolved in water and adjusted to pH 5-6 with 3N hydrochloric acid. The heading compound is filtered off and washed with water. M.pt. 182°-183° (from methanol).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].[C:12](Cl)(=O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:23](=O)([O-])[O-:24].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:23]=[O:24])=[CH:5][CH:4]=1)(=[O:2])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CCCCCCCCC(=O)Cl
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCCCCCCC(=O)c1ccc(C=O)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 2.5 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (50 mg) was added to a solution of 4-formylphenylboronic acid (0.50 g, 3.33 mmol), nonanoyl chloride (1.7 mL, 8.33 mmol) and cesium carbonate (2.70 g, 8.33 mmol) in toluene (40 mL) and heated to 80° C. After stirring overnight, the reaction was diluted with ethyl acetate (50 mL) and washed with 2N hydrochloric acid (50 mL), sat'd sodium chloride (50 mL), dried over magnesium sulfate and concentrated in vacuo. Silica gel chromatography eluting with 6% ethyl acetate/hexane gave 0.022 g (0.083 mmol, 3%) of product: 1H NMR (500 MHz) δ 10.1 (s, 1H), 8.09 (d, J=8.2 Hz, 2H), 7.98 (d, J=8.2 Hz, 2H), 3.00 (t, J=7.4 Hz, 2H), 1.70-1.80 (m, 2H), 1.22-1.42 (m, 12H), 0.88 (t, J=6.9 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[C:17]([OH:19])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:53][CH2:54][C:55](=[O:57])[CH3:56].CCN(CC)CC>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH:16]([N:20]2[C:21](=[O:30])[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]2=[O:29])[C:17]([NH:53][CH2:54][C:55](=[O:57])[CH3:56])=[O:19])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(Cc1ccc(OCc2ccccc2)cc1)N1C(=O)c2ccccc2C1=O
Reactant: CC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)CNC(=O)C(Cc1ccc(OCc2ccccc2)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
A mixture of 3-(4-benzyloxy-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionic acid (500 mg, 1.25 mmol), HOBt (180 mg, 2.5 mmol), and EDCI (480 mg, 2.5 mmol) in DMF (3 mL) was stirred at 0° C. for 0.5 h. To this mixture was added 1-amino-2-propanone hydrochloride (4) (272 mg, 2.5 mmol) followed by Et3N (550 □L, 0.6 mmol). The mixture was stirred at 0° C. for 0.5 h and at room temperature for 1 h. Water (10 mL) was added, and the product was extracted with EtOAc (3×15 mL). The combined extracts were dried over Na2SO4 and concentrated, and the residue was triturated with water to obtain 3-(4-benzyloxy-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-N-(2-oxo-propyl)-propionamide (5) as a solid (500 mg, 88%). 1H NMR (CDCl3): □7.78 (m, 2H), 7.70 (m, 2H), 7.35 (m, 4H), 7.1 (d, 2H), 6.8 (m, 3H), 4.92 (s, 2H), 4.2 (m, 2H), 3.6 (d, 2H), 2.2 (s, 3H); ). LCMS m/z 457.1 (M+1)
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[Br:12][C:13]1[C:14]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:15]2[CH:21]=[N:20][NH:19][C:16]2=[N:17][CH:18]=1.[C:28]([O:32][C:33]([NH:35][C@H:36]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1)[C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Br:12][C:13]1[C:14]([N:22]2[CH2:23][CH2:24][N:25]([C:37](=[O:38])[C@H:36]([NH:35][C:33](=[O:34])[O:32][C:28]([CH3:29])([CH3:30])[CH3:31])[CH2:40][C:41]3[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=3)[CH2:26][CH2:27]2)=[C:15]2[CH:21]=[N:20][NH:19][C:16]2=[N:17][CH:18]=1
Reactant: Brc1cnc2[nH]ncc2c1N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2c(Br)cnc3[nH]ncc23)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
DIEA (0.0687 mL, 0.394 mmol) was added to a solution of 5-bromo-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.050 g, 0.0986 mmol, see Example 11), (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (0.0295 g, 0.099 mmol) and TBTU (0.0380 g, 0.118 mmol) in DCM (1 mL) and stirred at room temperature for 16 hours. The reaction was concentrated to dryness. The resulting residue was dissolved in THF/MeOH (2 mL, 1:1), and an aqueous LiOH solution (1 mL, 2M) was added. The solution was stirred for 30 minutes, and then ether (20 mL) was added. The organic layer was separated, washed with brine (10 mL), and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by column chromatography (hexane:ethyl acetate, 1:1) to give (R)-tert-butyl 1-(4-(5-bromo-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-(4-chlorophenyl)-1-oxopropan-2-ylcarbamate as a solid. The solid was dissolved in DCM (1 mL), and TFA (0.4 mL) was added. The mixture was stirred at room temperature for 1 hour, and the reaction was concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (R)-2-amino-1-(4-(5-bromo-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-(4-chlorophenyl)propan-1-one dihydrochloride (0.015 g, 29%). MS APCI (+) m/z 463.1 detected.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=2)[C:7]2[C:12]([C:13]=1[C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:10]([OH:18])=[CH:9][CH:8]=2)=[O:4].[F:29][C:30]([F:41])([F:40])[C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:23][CH:24]=2)[C:7]2[C:12]([C:13]=1[C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:10]([O:18][C:34]1[CH:35]=[CH:36][C:31]([C:30]([F:41])([F:40])[F:29])=[CH:32][CH:33]=1)=[CH:9][CH:8]=2)=[O:4]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1c(C(=O)OC)n(-c2ccc(OC(C)C)cc2)c2ccc(O)cc12
Product: COC(=O)c1c(C(=O)OC)n(-c2ccc(OC(C)C)cc2)c2ccc(Oc3ccc(C(F)(F)F)cc3)cc12

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 5-hydroxy-1-(4-isopropoxyphenyl)indole-2,3-dicarboxylic acid dimethyl ester (250 mg, 0.65 mmol, see step (a) Example 19) and 4-trifluoromethylphenylboronic acid. Yield 230 mg (67%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:28][CH2:27][C:13]3([C:18]4=[CH:19][CH:20]=[CH:21][N:17]4[C:16]4[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:15]=4[O:14]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[O:29][CH3:30].C[Si](C)(C)[O:33][CH:34]=[CH2:35]>CN(C=O)C.F[Zn]F>[Cl:26][C:24]1[CH:23]=[CH:22][C:16]2[N:17]3[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]3([CH2:27][CH2:28][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([CH2:35][CH:34]=[O:33])=[C:3]([O:29][CH3:30])[CH:4]=4)=[O:9])[CH2:11][CH2:12]3)[O:14][C:15]=2[CH:25]=1
Reactant: COc1cc(C(=O)N2CCC3(CC2)Oc2cc(Cl)ccc2-n2cccc23)ccc1Br
Reactant: C=CO[Si](C)(C)C
Agent: F[Zn]F
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2cc(Cl)ccc2-n2cccc23)ccc1CC=O
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a microwave vial was added Pd(tBu3P)2 (128 mg, 0.250 mmol) and difluorozinc (259 mg, 2.50 mmol). The vial was capped and purged with nitrogen for 10 minutes. DMF (1 mL) was added and the mixture was stirred for 10 minutes. A solution of (4-bromo-3-methoxy-phenyl)-(7′-chlorospiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl)methanone (244 mg, 0.500 mmol) in DMF (1.5 mL) was added followed by trimethyl(vinyloxy)silane (581 mg, 5.00 mmol). The reaction mixture was heated at 80° C. for 1 h before it was quenched with brine and extracted with EtOAc (3×). The combined organic layers were dried over sodium sulfate and the solvent was removed. The crude reaction was purified by silica gel chromatography (5%-80% ethyl acetate/hexanes) to give 2-(4-(7-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-ylcarbon-yl)-2-methoxyphenyl)acetaldehyde.
Reaction SMILES: [CH3:1][N:2]([C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)[C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(OC(N([C@@H]1CCN(C(OC(C)(C)C)=O)C1)C)=O)C1C=CC=CC=1>>[CH3:1][N:2]([C@@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)[C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CN(C(=O)OCc1ccccc1)[C@H]1CCNC1
Agent: CN(C(=O)OCc1ccccc1)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Product: CN(C(=O)OCc1ccccc1)[C@@H]1CCNC1

Procedure:
Prepared by proceeding in a similar manner to Intermediate 129, starting from tert-butyl (R)-3-(N-benzyloxycarbonyl-N-methylamino)-pyrrolidine-1-carboxylate (Intermediate 135) as a pale coloured oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH3:9])=[CH:4][CH:3]=1.P(Br)(Br)[Br:12]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([Br:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(O)c1ccc(Br)cc1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CC(Br)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
A solution of 1-(4-bromophenyl)ethanol (1.492 mmol) in dichloromethane (8 mL) at 0° C. was treated dropwise with a solution of phosphorous tribromide (0.597 mmol) in dichloromethane (2 mL). The reaction was allowed to warm to room temperature and was stirred overnight. The reaction was then quenched with saturated aq sodium bicarbonate (10 mL) and was stirred for 2 h. The biphasic mixture was further diluted with dichloromethane (50 mL) and the organic layer was separated from the aqueous layer. The organic layer was dried over sodium sulfate, filtered and concentrated to dryness in vacuo. Purification of the residue by flash chromatography (0-25% ethyl acetate/hexanes) gave the title product (91 mg, 23% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.97 (d, J=6.82 Hz, 3 H) 5.50 (q, J=6.82 Hz, 1 H) 7.48 (d, J=8.59 Hz, 2 H) 7.57 (m, J=8.59 Hz, 2 H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].I[CH3:13]>CN(C)C=O.O.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:13])=[O:6]
Reactant: O=C(O)c1cccc(Br)c1F
Reactant: CI
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Br)c1F
Temperature: 50 °C

Procedure:
To a solution of 3-bromo-2-fluorobenzoic acid (10 g, 0.045 mol) in N,N-dimethylformamide (50 mL) was added iodomethane (5 mL) dropwise. The reaction was heated to 50° C. for 24 hours. After the reaction was cooled and diluted with water (500 mL), ethyl acetate (200 mL) was added. The organic phase was separated, dried over MgSO4, filtered, and concentrated to provide the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6](=[O:41])[NH:7][C:8]1[N:40]=[C:11]2[C:12]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=3)=[C:13]([CH3:29])[C:14]([C:16]3[N:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=4)[N:18]=[CH:19][CH:20]=3)=[CH:15][N:10]2[N:9]=1.[CH3:42][N:43]([CH3:45])[CH3:44]>CC#N.CCO>[Cl-:1].[C:27]([C:24]1[CH:25]=[CH:26][C:21]([N:17]2[C:16]([C:14]3[C:13]([CH3:29])=[C:12]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=4)[C:11]4[N:10]([N:9]=[C:8]([NH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][N+:43]([CH3:45])([CH3:44])[CH3:42])=[O:41])[N:40]=4)[CH:15]=3)=[CH:20][CH:19]=[N:18]2)=[CH:22][CH:23]=1)#[N:28]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)OCCCCl)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CN(C)C
Solvent: CC#N
Solvent: CCO
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)OCCC[N+](C)(C)C)nc2c1-c1cccc(C(F)(F)F)c1
Product: [Cl-]
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
A solution of [6-[2-(4-cyano-phenyl)-2H-pyrazol-3-yl]-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-carbamic acid 3-chloro-propyl ester (Int. 20, 125 mg, 0.218 mmol) in MeCN (3.5 mL) was treated with trimethylamine solution in EtOH (4.2M, 1.5 mL) and heated for 1 hr at 100° C. using microwave irradiation. A further amount of trimethylamine in EtOH was added (1 mL) and the heating continued at 100° C. for 20 mins. The reaction mixture was concentrated in vacuo then azeotroped with toluene in vacuo. The resultant residue was subjected to preparative C18 HPLC chromatography, eluting with a gradient of 10-70% MeCN in water+0.1% formic acid) to give the title compound as a white solid (20 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[C:19](/[CH:20]=[CH:21]/[C:22]([O:24]CC)=[O:23])=[CH:18][N:17]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)[N:16]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[C:19](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:18][N:17]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:32][CH:33]=2)[N:16]=1
Reactant: CCOC(=O)/C=C/c1cn(Cc2ccc(Oc3ccccc3)cc2)nc1OCc1nc(-c2ccccc2)oc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1nn(Cc2ccc(Oc3ccccc3)cc2)cc1/C=C/C(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
After a mixture of ethyl(E)-3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-1-(4-phenoxybenzyl)-1H-pyrazol-4-yl]propenoate (450 mg), 1N sodium hydroxide solution (1.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at 50° C. for 2 hours, 1N hydrochloric acid (1.5 ml) was added to the mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain (E)-3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-1-(4-phenoxybenzyl)-1H-pyrazol-4-yl]propenoic acid (410 mg, yield: 96%). This was recrystallized from acetone-hexane. Melting point: 210–211° C.
Reaction SMILES: [NH2:1][CH:2]([CH3:20])[C:3]([NH:5][C:6]1[N:7]=[CH:8][N:9]([C:11]([CH3:19])([CH3:18])[CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:10]=1)=[O:4].[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30](O)=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1>>[F:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30]([NH:1][CH:2]([CH3:20])[C:3]([NH:5][C:6]2[N:7]=[CH:8][N:9]([C:11]([CH3:19])([CH3:18])[CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[CH:10]=2)=[O:4])=[O:31])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Product: CC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-N-[1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-propionamide was coupled with (3,5-Difluoro-phenyl)-acetic acid to provide the title compound: 1H NMR (400 MHz) 1.41 (d, 3H), 1.51 (s, 6H), 1.48 (s, 4H), 2.32 (s, 4H), 2.7 (s, 2H), 3.5 (s, 2H), 4.88-4.83 (m, 1H), 7.44 (d, 1H, J=1.4 Hz), 6.63-6.68 (m, 1H), 6.71-6.90 (M, 2h), 7.58 (d, 1H, J=1.7 Hz), 11.8 (brs, 1H) MS m/z 434.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:17]3[CH:18]=[CH:19][C:20]([C:22](O)=[O:23])=[CH:21][C:16]=3[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9]2=[O:25])=[CH:5][CH:4]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:51][CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:17]3[CH:18]=[CH:19][C:20]([C:22]([NH:51][CH2:52][CH2:53][N:54]4[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]4)=[O:23])=[CH:21][C:16]=3[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9]2=[O:25])=[CH:5][CH:4]=1
Reactant: NCCN1CCCCC1
Reactant: COc1ccc(Cn2c(=O)c3cccnc3c3cc(C(=O)O)ccc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3cccnc3c3cc(C(=O)NCCN4CCCCC4)ccc32)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 193.6 %

Procedure:
The compound (30 mg, 0.09 mmol) prepared in Step 1, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC, 48 mg, 0.25 mmol), and 1-hydroxy-benzotriazole hydrate (HOBt, 34 mg, 0.25 mmol) were dissolved in N,N-dimethylformamide (5 ml) and added with 1-(2-aminoethyl)piperidine (0.033 ml, 0.23 mmol) at room temperature. The resulting mixture was stirred for 18 hours and poured into ice water. After extraction with chloroform, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was then purified by flash column chromatography (chloroform:methanol=7:1) to obtain the title compound (82 mg, yield: 92%, white solid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][SH:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].Br[CH2:15][C:16]([C:18]1[C:23]([O:24][CH3:25])=[CH:22][C:21]([O:26][CH3:27])=[CH:20][C:19]=1[O:28][CH3:29])=[O:17]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][CH2:15][C:16]([C:18]2[C:19]([O:28][CH3:29])=[CH:20][C:21]([O:26][CH3:27])=[CH:22][C:23]=2[O:24][CH3:25])=[O:17])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12]
Reactant: COc1cc(OC)c(C(=O)CBr)c(OC)c1
Reactant: COc1ccc(CS)cc1[N+](=O)[O-]
Product: COc1cc(OC)c(C(=O)CSCc2ccc(OC)c([N+](=O)[O-])c2)c(OC)c1

Procedure:
According to Scheme 5, (4-methoxy-3-nitrophenyl)methanethiol 10 (an aromatic mercaptan according to Formula IIb) is reacted with 2-bromo-1-(2,4,6-trimethoxyphenyl)ethanone (a compound according to Formula IIa) to form 2-(4-methoxy-3-nitrobenzylthio)-1-(2,4,6-trimethoxyphenyl)ethanone 11 (a sulfide according to Formula II). Suitable reaction conditions for this reaction are as described above for the reaction of a Formula IIa compound and a Formula IIb compound.
Reaction SMILES: [C:1]([CH:18]([OH:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].[C:26](Cl)([Cl:28])=[O:27]>O1CCCC1>[Cl:28][C:26]([O:25][CH:18]([C:1]([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:27]
Reactant: NCCCCCC(O)C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Product: NCCCCCC(OC(=O)Cl)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of FMOC-6-aminohexanol (617.2 mg, 1.5 mmol) in tetrahydrofuran (6 ml) was heated and then cooled to room temperature. To this solution was then added phosgene (2.9 ml, 1.93M in toluene). The reaction was stirred at room temperature for 15 hours and concentrated in vacuo to yield FMOC-6-aminohexanol chloroformate which was used immediately without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:30]([O:32]CC)=[O:31])=[C:8]([CH2:27][CH2:28][CH3:29])[N:9]2[C:14]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[N:10]2)=[O:5])[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:30]([OH:32])=[O:31])=[C:8]([CH2:27][CH2:28][CH3:29])[N:9]2[C:14]=1[C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[N:10]2)=[O:5])[CH3:2]
Reactant: CCCc1c(C(=O)OCC)c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCc1c(C(=O)O)c(C(=O)OCC)c2c(-c3ccccc3)cc(N3CCOCC3)nn12
Temperature: 25 °C

Procedure:
A mixture of 2-morpholin-4-yl-4-phenyl-7-propyl-pyrrolo[1,2-b]pyridazine-5,6-dicarboxylic acid diethyl ester (15) (3.9 g, 8.38 mmol) and 10 mL of a 2N solution of NaOH in 50 mL of ethanol and 30 mL of water was heated at reflux for 5 h. The reaction mixture was cooled to r.t. and concentrated to about half of the original volume. 25 mL of 1N HCl were added and the resulting precipitate was collected by vacuum filtration, washed with cold water and died in vacuo to provide the title compound as a solid. 1H NMR (DMSO-d6) δ 1.04-1.10 (m, 6H), 1.79-1.87 (m, 2H), 3.34 (t, 2H, 7.3 Hz), 3.66-3.74 (m, 6H), 3.86-3.91 (m, 4H), 6.91 (s, 1H), 7.56-7.64 (m, 5H), 12.53 (brs, 1H). Mass Spectrum (ES+) m/e=460.1 (M+23).