Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]1[C:14]2[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([C:27](=[O:35])[CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:22][CH2:21]4)=[CH:16][S:17][C:13]=2[C:12]([CH:36]2[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]2)=[CH:11][N:10]=1>ClCCl>[C:29]1([CH2:28][C:27]([N:23]2[C:24]3[C:20](=[CH:19][C:18]([C:15]4[C:14]5[C:9]([NH2:8])=[N:10][CH:11]=[C:12]([CH:36]6[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]6)[C:13]=5[S:17][CH:16]=4)=[CH:26][CH:25]=3)[CH2:21][CH2:22]2)=[O:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cnc(N)c3c(-c4ccc5c(c4)CCN5C(=O)Cc4ccccc4)csc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(C2CCNCC2)c2scc(-c3ccc4c(c3)CCN4C(=O)Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
TFA (0.5 mL, 6.49 mmol) was added to a suspension of 1,1-dimethylethyl 4-{4-amino-3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]thieno[3,2-c]pyridin-7-yl}-1-piperidinecarboxylate (90 mg, 0.158 mmol) in Dichloromethane (DCM) (3.5 mL), and the mixture was stirred at room temperature under Nitrogen for 30 min. The reaction mixture was then concentrated in vacuo, taken up in DCM, and passed through a PL-HCO3 MP-resin cartridge, rinsing with more DCM. The filtrate was concentrated in vacuo. The solid (labeled 96-A1) was not quite pure enough for submission (impurities best visible by NMR), so the residue was purified by flash chromatography (Analogix, 24 g SiO2, DCM to 80/20/2 DCM/MeOH/NH4OH gradient over 30 minutes) to give 3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]-7-(4-piperidinyl)thieno[3,2-c]pyridin-4-amine (37 mg) as a white solid. LC/MS (ES) m/z=469 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 1.64-1.77 (m, 2H), 1.77-1.86 (m, 2H), 2.57-2.77 (m, 3H), 3.07 (d, J=12.13 Hz, 2H), 3.22 (t, J=8.34 Hz, 2H), 3.89 (s, 2H), 4.24 (t, J=8.59 Hz, 2H), 5.24 (br. s., 2H), 7.19-7.39 (m, 7H), 7.41 (s, 1H), 7.70 (s, 1H), 8.15 (d, J=8.34 Hz, 1H)
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:41][CH3:42])([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[C:27]([CH3:40])[CH:26]=2)[CH2:23][CH3:24])=[CH:18][C:17]=1[CH3:43])[C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:81][O:82][C:83](=[O:93])[C@@H:84]([C:86]1[CH:91]=[CH:90][CH:89]=[C:88](Cl)[CH:87]=1)[OH:85]>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:81][O:82][C:83](=[O:93])[C@@H:84]([C:86]1[CH:87]=[C:88]([C:28]2[CH:29]=[CH:30][C:25]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH:9]([O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:17]([CH3:43])[CH:18]=3)([CH2:23][CH3:24])[CH2:41][CH3:42])=[CH:26][C:27]=2[CH3:40])[CH:89]=[CH:90][CH:91]=1)[OH:85]
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)[C@H](O)c1cccc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOCC
Product: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2cccc([C@@H](O)C(=O)OC)c2)c(C)c1
Reaction time: 0.05 h
Yield: 23.6 %

Procedure:
Degassed tetrahydrofuran (0.14 mL) was added to t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 24-(1); 14.4 mg, 0.0237 mmol), palladium (II) acetate (1.2 mg, 0.0053 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (4.5 mg, 0.011 mmol) and potassium phosphate (13.0 mg, 0.0612 mmol). The mixture was stirred in a nitrogen atmosphere for three minutes, followed by addition of (R)-(3-chloro-phenyl)-hydroxy-acetic acid methyl ester (Example 156-(1); 0.006 mL, 6.5 mg, 0.032 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 60 to 70° C. for four hours. The reaction mixture was diluted with diethyl ether and filtered through cotton plug, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=7/1) to give the title compound (3.6 mg, 24%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[N:3]=1.[CH:23]1([CH2:27][OH:28])[CH2:26][CH2:25][CH2:24]1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>CCOC(C)=O.[Cu]I>[CH:23]1([CH2:27][O:28][C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=3)[N:4]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:3]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: OCC1CCC1
Reactant: COc1ccc(Cn2nc(I)c3cc([N+](=O)[O-])cnc32)cc1
Agent: [Cu]I
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nc(OCC3CCC3)c3cc([N+](=O)[O-])cnc32)cc1
Temperature: 115 °C
Yield: 24.5 %

Procedure:
3-Iodo-1-(4-methoxybenzyl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (0.100 g, 0.244 mmol), cyclobutylmethanol (1.05 mL, 12.19 mmol), 1,10-phenanthroline (0.044 g, 0.244 mmol), copper (I) iodide (0.046 g, 0.244 mmol), and 40% KF/Al2O3 (0.248 g, 1.71 mmol) were combined in a reaction vial and heated to 115° C. for 24 hours. After cooling to room temperature, the mixture was diluted with EtOAc (20 mL) and filtered through GF/F filter paper. The filtrate was then concentrated and passed through a 10 g SepPak cartridge, eluting with DCM. The fractions were collected and then purified by preparative TLC (2×0.5 mm plates, 15% EtOAc/hexanes) to give 3-(cyclobutylmethoxy)-1-(4-methoxybenzyl)-5-nitro-1H-pyrazolo[3,4-b]pyridine (22 mg, 24.5%) as a solid.
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]([OH:46])[C:23]2[C:24]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[C:25]3[C:30](=[CH:31][C:32]=2[CH:33]([CH3:35])[CH3:34])[O:29][C:28]([CH3:37])([CH3:36])[CH2:27][C:26]3=[O:38])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].CO>O1CCCC1>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([C@@H:22]([OH:46])[C:23]2[C:24]([C:39]3[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=3)=[C:25]3[C:30](=[CH:31][C:32]=2[CH:33]([CH3:35])[CH3:34])[O:29][C:28]([CH3:36])([CH3:37])[CH2:27][C@@H:26]3[OH:38])=[CH:20][CH:21]=1)([CH3:14])([CH3:15])[CH3:13]
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(C)(C)C)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1[C@H](O)c1ccc(C(C)(C)C)cc1)[C@@H](O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
220 μl (1.26 mmol) of borane/N,N-diethylaniline complex are added very slowly to a solution of 7.07 mg (50 μmol) of (1R,2S)-1-aminoindan-2-ol in 7 ml of tetrahydrofuran, and the mixture is stirred at room temperature for 30 min. A solution of 150 mg (320 μmol) of rac-6-[(4-tert-butylphenyl)(hydroxy)methyl]-5-(4-fluorophenyl)-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 27A) in 7 ml of tetrahydrofuran is then added very slowly dropwise over a period of 30 min. After a further 6 h of stirring, methanol is added and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (mobile phase: gradient cyclohexane→cyclohexane/ethyl acetate 10:1→5:1) gives the diastereomerically pure target products.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:3])[CH3:2].[F-].[Cs+].C(=O)([O-])[O-].[K+].[K+].[N+](C1C=C(S(O[CH2:37][C@H:38]2[O:40][CH2:39]2)(=O)=O)C=CC=1)([O-])=O>CN(C=O)C.O>[CH:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:37][C@H:38]2[O:40][CH2:39]2)=[CH:11][CH:10]=1)([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: CC(C)OCCOCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)OCCOCc1ccc(OC[C@@H]2CO2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
p-(2-Isopropoxyethoxy)methylphenol (5 g) was dissolved in DMF (30 ml) under nitrogen atmosphere and the solution was cooled to 0° C. Cesium fluoride (0.72 g) and potassium carbonate (4.27 g) were added thereto, and the mixture was stirred for 1 hour. Then (S)-glycidyl m-nitrobenzenesulfonate (6.16 g, 99.7% e.e.) was added thereto and the mixture was stirred for 24 hours at the same temperature. After the reaction, water was added to the filtrate, the solution was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, condensed and the residue was subjected to silica gel chromatography (hexane/ethyl acetate; 1:1) to give 6.08 g of (S)-1-(p-2-isopropoxyethoxymethylphenoxy)-2,3-epoxypropane (yield 96%, optical purity 99.6% e.e.) as a colorless oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:28][C:29]4[CH:34]=CC=CC=4)[CH:24]=3)[C:19]2=[O:35])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH:36]1(N=C=N)[CH2:41]CCC[CH2:37]1.CN(C=O)C>ClCCl>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:28][CH2:29][CH:34]=[C:36]([CH3:41])[CH3:37])[CH:24]=3)[C:19]2=[O:35])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: N=C=NC1CCCCC1
Reactant: COc1cc(N2C(=O)c3ccc(Oc4ccccc4)cc3C2=O)ccc1OCCN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(N2C(=O)c3ccc(OCC=C(C)C)cc3C2=O)ccc1OCCN1CCCC1

Procedure:
A mixture of this acid (67 mg, 0.27 mmol), 3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine [Example A4] (67 mg, 0.28 mmol) and N-cyclohexylcarbodiimide resin (1.69 mol. eq./g, 0.46 g, 0.78 mmol) was stirred in a 50:50 mixture of DMF and dichloromethane (1.5 ml) at room temperature under argon for 16 h. The mixture was filtered through filter-aid and the resin washed several times with dichloromethane. The filtrate was evaporated and the crude residue purified by flash chromatography on silica gel eluting with methanol in dichloromethane to yield the title compound as a brown oil;
Reaction SMILES: [N+](C1C=CC(S(O[CH2:14][C@@H:15]2[CH2:19][C@@H:18]([CH2:20][CH2:21][CH2:22][Cl:23])[C:17](=[O:24])[NH:16]2)(=O)=O)=CC=1)([O-])=O.[N-:25]=[N+:26]=[N-:27].[Na+].[N-]=[N+]=[N-]>CN(C=O)C>[N:25]([CH2:14][C@H:15]1[NH:16][C:17](=[O:24])[C@H:18]([CH2:20][CH2:21][CH2:22][Cl:23])[CH2:19]1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1N[C@H](COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C[C@H]1CCCCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@@H]1C[C@@H](CCCCl)C(=O)N1

Procedure:
The ((2S,4R)-4-(3-chloropropyl)-5-oxopyrrolidin-2-yl)methyl 4-nitrobenzenesulfonate (18.05 g, 45.2 mmol) and NaN3 (3.23 g, 49.7 mmol, 1.1 equiv) were stirred in 100 mL of DMF for 19 h. After this time a white solid had formed and LC/MS analysis showed formation of the desired azide. The DMF was removed in vacuo and the residue partitioned between EtOAc/H2O (100+100 mL). The mixture was transferred to a separatory funnel and the layers separated. The aqueous layer was extracted with 100 mL additional EtOAc and the combined organic extracts washed with brine, dried over Na2SO4, filtered and evaporated. The (3R,5S)-5-(azidomethyl)-3-(3-chloropropyl)pyrrolidin-2-one was isolated as a pale yellow syrup (9.08 g, 94% yield).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1>C(O)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([OH:17])(=[O:15])=[O:16])=[CH:12][CH:13]=1.[CH2:8]([O:5][C:4](=[O:6])[C@H:2]([CH3:3])[NH2:1])[CH3:9]
Reactant: C[C@H](N)C(=O)O
Agent: O=S(=O)(O)c1ccc(Cl)cc1
Solvent: CCO
Product: CCOC(=O)[C@H](C)N
Temperature: 25 °C

Procedure:
L-alanine (1.50 g, 16.84 mmol) and 4-chlorobenzenesulfonic acid (4-CBS) (3.89 g, 20.20 mmol) were added to ethanol (15 ml), and the mixture was heated overnight at 70 EC to perform esterification. To complete the esterification reaction, the mixture was heated to 90 EC, and ethanol (200 ml) was added over 3.5 hours, while distilling away almost the same amount of ethanol. Thereafter, the solvent was evaporated under reduced pressure, and the residue was dried under reduced pressure. Ethanol (1 ml) and diethyl ether (60 ml) were added to partially crystallize an oily residue and the mixture was stirred at room temperature to give a slurry. This slurry was cooled overnight in a refrigerator and the crystals were separated and dried to give 3.52 g of L-alanine ethyl ester 4-chlorobenzenesulfonate (L-Ala-OEt 4-CBS salt) dry crystals (L-Ala-OEt 4-CBS salt content 93.6%, 10.64 mmol, yield 63.2%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12]([NH:15][CH2:16][CH2:17][CH3:18])=[N:13][CH:14]=1.[OH-].[K+].I[CH2:24][CH2:25][CH3:26]>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12]([N:15]([CH2:24][CH2:25][CH3:26])[CH2:16][CH2:17][CH3:18])=[N:13][CH:14]=1
Reactant: CCCNc1ncc(-c2ccc(C)cc2C)c(=O)n1C
Reactant: CCCI
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCN(CCC)c1ncc(-c2ccc(C)cc2C)c(=O)n1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.7 %

Procedure:
To a solution containing 0.2 g (0.74 mmol) of 5-(2,4-dimethylphenyl)-3-methyl-2-propylaminopyrimidin-4(3H)-one in 5 ml of tetrahydrofuran under a nitrogen atmosphere was added 0.12 g (2.2 mmol) of potassium hydroxide followed by 0.38 g (2.2 mmol) of 1-iodopropane. The reaction was allowed to stir at room temperature for 12 h, diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried over magnesium sulfate. Filtration, removal of solvent and purification of the residue via Biotage chromatography eluting with 30% ethyl acetate/dichloromethane gave 0.15 g (65%) of product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[C:27]4[C:26]([NH:28][C@H:29]([C:31]5[N:36]([C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=6)[C:35](=[O:43])[C:34]6=[C:44]([CH3:47])[CH:45]=[CH:46][N:33]6[N:32]=5)[CH3:30])=[N:25][CH:24]=[N:23][C:22]=4[N:21](COCC[Si](C)(C)C)[CH:20]=3)[CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.N>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[C:27]4[C:26]([NH:28][C@H:29]([C:31]5[N:36]([C:37]6[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=6)[C:35](=[O:43])[C:34]6=[C:44]([CH3:47])[CH:45]=[CH:46][N:33]6[N:32]=5)[CH3:30])=[N:25][CH:24]=[N:23][C:22]=4[NH:21][CH:20]=3)[CH:14]=2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cccc(-c3cn(COCC[Si](C)(C)C)c4ncnc(N[C@@H](C)c5nn6ccc(C)c6c(=O)n5-c5ccccc5)c34)c2)cc1
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)Nc2cccc(-c3c[nH]c4ncnc(N[C@@H](C)c5nn6ccc(C)c6c(=O)n5-c5ccccc5)c34)c2)cc1
Yield: 100.5 %

Procedure:
(S)-4-Methoxy-N-(3-(4-((1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)benzenesulfonamide (25 mg, 0.02 mmol) was treated with trifluoroacetic acid (500 μl, 6.49 mmol) and a solution of ammonia (7N in methanol, 500 μl, 3.50 mmol) according to the method described in Example 27. The residue was purified using SP1® Purification System (0% to 100% n-hexane-ethyl acetate) to obtain 13 mg (86% yield) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][P:6](=[O:13])([O:10]CC)[O:7]CC.Br[Si](C)(C)C.O>ClCCl.CO>[F:17][C:15]1[CH:14]=[C:4]([CH:3]=[C:2]([F:1])[CH:16]=1)[CH2:5][P:6](=[O:7])([OH:13])[OH:10]
Reactant: CCOP(=O)(Cc1cc(F)cc(F)c1)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: O=P(O)(O)Cc1cc(F)cc(F)c1
Reaction time: 6 h
Yield: 83.5 %

Procedure:
Diethyl 3,5-difluorobenzylphosphonate (3.00 g, 11.4 mmol) was dissolved in dry dichloromethane (25 mL). Bromotrimethylsilane (4.9 mL, 37 mmol) was added via syringe. The reaction was capped with a greased glass stopper and allowed to stir for 6 hours. The volatiles were removed under reduced pressure to yield a yellow oil. This was dissolved in 8:1 methanol:water (25 mL) and allowed to stir overnight. After removing the solvents, recrystallization in acetonitrile yielded a white crystalline solid (1.98 g, 91% yield). 1H NMR (400.14 MHz, DMSO) δ 7.05 (dt, J=9.49, 2.09 Hz), 6.95 (d, J=8.54 Hz, 2H), 3.02 (d, J=21.57 Hz, 2H). 31P {1H} NMR (161.97 MHz, DMSO): δ 20.63. Analysis calculated (found) %: C, 40.40 (40.67), H, 3.39 (3.39).
Reaction SMILES: C(N(CC)[C:4](=[O:26])[CH:5]([CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:6](=[O:15])[C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=1[OH:14])C.CS(O)(=O)=O>C1(C)C=CC=CC=1>[Cl:13][C:11]1[CH:10]=[CH:9][C:8]2[O:14][C:4](=[O:26])[C:5]([CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:6]([OH:15])[C:7]=2[CH:12]=1
Reactant: CCN(CC)C(=O)C(CCCOc1ccccc1)C(=O)c1cc(Cl)ccc1O
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: O=c1oc2ccc(Cl)cc2c(O)c1CCCOc1ccccc1
Reaction time: 0.33 h
Yield: 7.3 %

Procedure:
To a solution of N,N-diethyl-2-hydroxy-5-chloro-β-oxo-α-(3-phenoxypropyl)benzenepropanamide (0.25 g; 6.6 mmol) (prepared in Example I) in toluene (5 ml) was added methanesulfonic acid (0.07 g; 0.7 mmol). The resulting mixture was heated to reflux and stirred for 20 minutes. The mixture was cooled and the solvent removed under reduced pressure. The residue was dissolved in a 1:1 mixture of EtOAc/Et2O (10 ml), washed with saturated aqueous NaCl, and dried (MgSO4). The solvent was removed in vacuo to provide an oil which crystallized from Et2O to provide 0.16 g (83% yield) of the title compound, m.p. 162°-163° C. NMR (DMSO-d6) δ1.90 (m, 2H), 2.68 (t, 2H), 3.99 (t, 2H), 6.91 (m, 3H), 7.26 (m, 2H), 7.41 (d, 1H), 7.63 (dd, 1H), 7.95 (d, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[O:12][CH:13]=2)=[C:5]([O:21][CH3:22])[CH:4]=1.[OH:23][C:24]1[C:28]([CH:29]=[O:30])=[CH:27][N:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]=1.CN(C)C=O.[H-].[Na+]>O>[O:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[C:11]1[O:12][CH:13]=[C:9]([CH2:8][O:7][C:6]2[CH:19]=[CH:20][C:3]([CH2:2][O:23][C:24]3[C:28]([CH:29]=[O:30])=[CH:27][N:26]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:25]=3)=[CH:4][C:5]=2[O:21][CH3:22])[N:10]=1
Reactant: COc1cc(CCl)ccc1OCc1coc(-c2ccco2)n1
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1coc(-c2ccco2)n1
Temperature: 90 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
To a mixture of 4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-2-(2-furyl)-1,3-oxazole (0.80 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (0.45 g) and N,N-dimethylformamide (30 mL) was added sodium hydride (60% in oil, 0.10 g) at room temperature, and the mixture was stirred at 90° C. for 2 hrs. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration to give 3-[(4-{[2-(2-furyl)-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde as pale-yellow crystals (0.93 g, yield 82%). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 162-163° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[CH:4][N:3]=1.[N:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)=[O:23])=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:14][C@@H:9]1[N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:28]3[CH:27]=[CH:26][C:25]([NH:24][C:22]([NH:21][C:18]4[CH:17]=[CH:16][N:15]=[CH:20][CH:19]=4)=[O:23])=[CH:30][CH:29]=3)[N:7]=2)[CH2:13][CH2:12][O:11][CH2:10]1
Reactant: C[C@H]1COCCN1c1ccnc(Cl)n1
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3ccncc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: C[C@H]1COCCN1c1ccnc(-c2ccc(NC(=O)Nc3ccncc3)cc2)n1

Procedure:
(S)-4-(2-chloropyrimidin-4-yl)-3-methylmorpholine (intermediate 3) (100 mg, 0.47 mmol) was stirred with 1-(pyridin-4-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 30) (175 mg, 0.52 mmol), Na2CO3 (149 mg, 1.4 mmol) and Pd(dppf)Cl2:DCM (19 mg, 0.02 mmol) in DME:Water (4:1)(5 ml) for 30 mins at 130° C. in a microwave. The reaction mixture was filtered through a celite545 cake and washed with methanol. The solvent was removed in vacuo and the crude residue was purified by prep HPLC at high pH. Further purification was achieved using an SCX-2 cartridge yielding the title compound. (32 mg, 17%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:18]([C:20]([C:22]1[S:26][C:25]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:28])=[CH:24][CH:23]=1)=[O:21])[NH2:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15](=[N:19][NH:18][C:20]([C:22]3[S:26][C:25]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:28])=[CH:24][CH:23]=3)=[O:21])[CH3:17])[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc(C(=O)NN)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: CC(=NNC(=O)c1ccc(C(=O)NCCC(=O)OC(C)(C)C)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 25 °C
Yield: 84.3 %

Procedure:
2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (24 mg, 0.083 mmol) in isopropanol (2.0 mL) was heated with tert-butyl 3-{[5-(hydrazinocarbonyl)thiophene-2-carbonyl]amino}propionate (18 mg, 0.057 mmol) prepared in Reference Synthetic Example 7 and 6 mg of p-toluenesulfonic acid monohydrate at 100° C. for 8 hours and allowed to cool to room temperature. Water was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water, methanol and chloroform and dried to give 28 mg of the desired product (yield 85%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[CH:14]=[C:15]([S:20](Cl)(=[O:22])=[O:21])[CH:16]=[CH:17][C:18]=1[Cl:19]>>[Cl:12][C:13]1[CH:14]=[C:15]([S:20]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:21])=[O:22])[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: NCCCCCCCC(=O)O
Product: O=C(O)CCCCCCCNS(=O)(=O)c1ccc(Cl)c(Cl)c1

Procedure:
8-Aminooctanoic acid (1.0 g, 0.006 mol) was treated with 3,4-dichlorobenzenesulphonylchloride (1.54 g, 0.006 mol), according to the method described in Example 4, to give the title compound which was recrystallised from 2-propanol/water (1.2 g, m.p. 115°-6° C.).