Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C(N(CC)C(C)C)(C)C.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([C:53]([F:56])([F:55])[F:54])=[C:33]([C:35]2[CH:40]=[CH:39][N:38]([CH:41]([CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)[C:42](O)=[O:43])[C:37](=[O:52])[CH:36]=2)[CH:34]=1.[NH2:57][C:58]1[CH:70]=[CH:69][C:61]([C:62]([O:64][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:63])=[CH:60][CH:59]=1>C(OCC)(=O)C.O.C(OCC)(=O)C>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([C:53]([F:56])([F:54])[F:55])=[C:33]([C:35]2[CH:40]=[CH:39][N:38]([CH:41]([CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=3)[C:42]([NH:57][C:58]3[CH:70]=[CH:69][C:61]([C:62]([O:64][C:65]([CH3:66])([CH3:67])[CH3:68])=[O:63])=[CH:60][CH:59]=3)=[O:43])[C:37](=[O:52])[CH:36]=2)[CH:34]=1
Reactant: O=C(O)C(Cc1ccccn1)n1ccc(-c2cc(Cl)ccc2C(F)(F)F)cc1=O
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)C(Cc2ccccn2)n2ccc(-c3cc(Cl)ccc3C(F)(F)F)cc2=O)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Under argon and at 0° C., 707 mg (50% strength in ethyl acetate, 1.11 mmol) of T3P and 0.29 ml (1.67 mmol) of N,N-diisopropylethylamine were added to a solution of 470 mg (purity 50%, 0.56 mmol) of 2-{4-[5-chloro-2-(trifluoromethyl)phenyl]-2-oxopyridin-1(2H)-yl}-3-(pyridin-2-yl)propanoic acid (racemate) and 129 mg (0.67 mmol) of tert-butyl 4-aminobenzoate in 45 ml of ethyl acetate. The reaction mixture was stirred at 60° C. for 1 h, another 353 mg (50% strength in ethyl acetate, 0.56 mmol) of T3P and 0.1 ml (0.56 mmol) of N,N-diisopropylethylamine were added and the mixture was stirred at 60° C. for 1 h. After addition of water/ethyl acetate and phase separation, the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried (sodium sulphate), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel 60, dichloromethane/methanol mixtures). Yield: 163 mg (purity 93%, 46% of theory)
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:25])[NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[F:24])=[CH:12][C:11]=1Br)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)([OH:30])=[O:29].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.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]([O:5][C:6]([NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:25])[NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[F:24])=[CH:12][C:11]=1[C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([C:28]([OH:30])=[O:29])[CH:36]=1)[CH3:9])=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2F)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2F)cc1-c1cccc(C(=O)O)c1
Temperature: 130 °C

Procedure:
To a solution of {1-[2-bromo-4-(3-fluoro-pyridin-4-ylcarbamoyl)-phenyl]-ethyl}-carbamicacid tert-butyl ester (2841 μmol) and 3-carboxyphenylboronic acid (1.5 eq.) in a mixture of DME/EtOH/water: 1/1/1 (10 ml) was added Na2CO3 (4 eq) and Pd tetrakis (0.05 eq). The reaction mixture was heated in the microwave at 130° C. for 1.5 hours. The reaction mixture was diluted with water and citric acid (to acidic pH) and extracted with EtOAc. The combined organic layers were dried over MgSO4 and the solvent was removed under reduced pressure. The compound was purified by column chromatography (silicagel, DCM/MeOH gradient).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[CH3:19][OH:20]>>[CH3:19][O:20][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1
Reactant: CO
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: COc1nc(Nc2cc(C)[nH]n2)cc2ccccc12

Procedure:
Similar procedure as described in example 10 was used, starting from methanol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (1-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 255 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[O:13][CH2:14][C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].N(C(C1C=CC=CC=1)C1C=C(C=CC=1)OCC1C=CC(C(O)=O)=CC=1)=[N+]=[N-].Br[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH:60]1[O:64][CH2:63][CH2:62][O:61]1.ClCCCC1OCCO1>>[C:1]([O:5][C:6]([NH:8][CH:9]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[O:13][CH2:14][C:15]([O:17][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH:60]1[O:64][CH2:63][CH2:62][O:61]1)=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCC(=O)O)c1
Reactant: BrCCCCCC1OCCO1
Agent: ClCCCC1OCCO1
Agent: [N-]=[N+]=NC(c1ccccc1)c1cccc(OCc2ccc(C(=O)O)cc2)c1
Product: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCC(=O)OCCCCCC2OCCO2)c1

Procedure:
The title compound was prepared as described in Example 54 Step 1 with -(3-(((tert-Butoxycarbonyl)amino)(phenyl)methyl)phenoxy)acetic acid and 2-(5-bromopentyl)-1,3-dioxolane 4-((3-(azido(phenyl)methyl)phenoxy)methyl)benzoic acid and 2-(3-chloropropyl)-1,3-dioxolane respectively.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[C@@H:4]([NH:12]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.CO.CNC.CO>C1COCC1>[NH2:12][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)[C:3]([N:2]([CH3:31])[CH3:1])=[O:30]
Reactant: CN(C)C(=O)[C@H](Cc1ccccn1)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CNC
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C(=O)[C@@H](N)Cc1ccccn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.8 %

Procedure:
To a solution of 1.47 g of the compound obtained in Step 84-1 in a mixed solution of MeOH and THF (25 ml 4:1; v/v) was added a solution of 2 mol/L dimethylamine MeOH (5.8 ml) and the reaction solution was stirred at room temperature for 24 hours. The reaction solution was concentrated under vacuum and the obtained residue was purified by column chromatography (silicagel 60; mobile phase: CHCl3/MeOH=9/1 to 5/1; v/v) to obtain 0.60 g of the title compound (brown oil).
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]2[C:8]([O:14]C(=O)C)=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:5]=2[C:4]=1[C:18](=[O:31])[C:19]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[NH:38]1[CH:42]=[CH:41][N:40]=[CH:39]1>C(#N)C>[N:38]1([CH2:2][C:3]2[O:7][C:6]3[C:8]([OH:14])=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:5]=3[C:4]=2[C:18](=[O:31])[C:19]2[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)[CH:42]=[CH:41][N:40]=[CH:39]1
Reactant: c1c[nH]cn1
Reactant: COc1cc(C(=O)c2c(CBr)oc3c(OC(C)=O)c(OC)ccc23)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(=O)c2c(Cn3ccnc3)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Reaction time: 8 h
Yield: 19.3 %

Procedure:
To a stirred suspension of 2-bromomethyl-3-(3,4,5-tri-methoxy-benzoyl)-6-methoxy-7-acetoxy-benzo[b]furan (Example 33) (35 mg, 0.071 mmol) and potassium carbonate (20 mg, 0.15 mmol) in dry acetonitrile (1.5 mL) was added imidazole (19 mg, 0.28 mmol) and the reaction mixture was stirred for overnight (tlc). The solvent was distilled under vacuum and the crude was taken in ethyl acetate, filleted and purified over silica gel plate to afford the title compound as a light yellow solid (6 mg, 19%). 1H NMR (300 MHz, CDCl3) δ—7.66 (s, 1H), 7.19 (s, 1H), 7.09 (s, 2H, benzoyl Hs), 7.07 (s, 1H), 6.85 (d, J=8.63 Hz, 1H), 6.74 (d, J=8.63 Hz, 1H), 5.37 (s, 2H), 4.00 (s, 3H, OMe), 3.95 (s, 3H, OMe), 3.79 (s, 6H, 2×OMe).
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:28])[N:11]([CH3:27])[CH:12]=[C:13]([N:15]2[CH2:19][CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:17][C:16]2=[O:26])[CH:14]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[C:10](=[O:28])[N:11]([CH3:27])[CH:12]=[C:13]([N:15]2[CH2:19][CH:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:17][C:16]2=[O:26])[CH:14]=1
Reactant: Cn1cc(N2CC(c3ccccc3)CC2=O)cc(OCc2ccccc2)c1=O
Agent: [Pd]
Solvent: CO
Product: Cn1cc(N2CC(c3ccccc3)CC2=O)cc(O)c1=O
Reaction time: 8 h
Yield: 59.3 %

Procedure:
3-(Benzyloxy)-1-methyl-5-(2-oxo-4-phenylpyrrolidin-1-yl)pyridin-2(1H)-one (131 mg, 0.350 mmol) was hydrogenated (balloon) with 10% Pd/C (37 mg, 0.035 mmol) in MeOH (3 mL) at RT. After stirring overnight the mixture was filtered using a 0.45 μm PTFE syringe filter then purified by preparative reversed-phase HPLC (20×150 mm Waters Sunfire (0.1% TFA), 5-50% CH3CN/water over 20 min at 20 mL/min) to give the title compound (59 mg, 59%) as an off-white solid. 1H NMR (500 MHz, CDCl3): δ 7.52 (d, J=2.6 Hz, 1 H); 7.40-7.28 (m, 5 H); 6.98 (d, J=2.6 Hz, 1 H); 4.08 (t, J=8.4 Hz, 1 H); 3.77-3.66 (m, 2 H); 3.64 (s, 3 H); 2.99 (m, 1 H); 2.76 (m, 1 H). HRMS (ES) calc (M+H)+=285.1234, found 285.1228.
Reaction SMILES: [CH:1]1([N:7]([CH2:34][CH:35]2[CH2:37][CH2:36]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:33]=[CH:32][C:20]([CH2:21][S:22]([CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])(=[O:24])=[O:23])=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>C1COCC1>[CH:1]1([N:7]([CH2:34][CH:35]2[CH2:36][CH2:37]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:16][C:17]3[CH:33]=[CH:32][C:20]([CH2:21][S:22]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])(=[O:24])=[O:23])=[CH:19][CH:18]=3)=[O:15])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCS(=O)(=O)Cc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)CCS(=O)(=O)Cc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Temperature: 45 °C
Reaction time: 24 h
Yield: 59.9 %

Procedure:
A solution of ethyl 3-({4-[({6-[cyclohexyl(cyclopropylmethyl)amino]pyrimidin-4-yl}carbonyl)amino]benzyl}sulfonyl)propanoate (Example 130, 130 mg; 0.25 mmol) in THF (5 ml) was treated with concentrated HCl (4 ml). After stirring at RT for 24 hours and 45° C. for 24 hours, the solvent was reduced in vacuo to half the volume and the mixture extracted with EtOAc. The combined organic extracts were washed with water, passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with DCM containing increasing amounts of methanol to give the title compound as a white solid (75 mg, 77%).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]3[N:14]=[C:15]([NH2:17])[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][N:25]=2)[CH2:20][CH2:19]1>>[CH:1]1([NH:7][C:8]2[N:13]3[N:14]=[C:15]([NH:17][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:24]([N:21]5[CH2:20][CH2:19][O:18][CH2:23][CH2:22]5)=[N:25][CH:26]=4)[N:16]=[C:12]3[CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)c1ccc(N2CCOCC2)nc1
Reactant: Nc1nc2cccc(NC3CCCCC3)n2n1
Product: O=C(Nc1nc2cccc(NC3CCCCC3)n2n1)c1ccc(N2CCOCC2)nc1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from N5-cyclohexyl[1,2,4]triazolo[1,5-a]pyridine-2,5-diamine ((A9), 174 mg; 0.75 mmol; 1.0 eq.) and 6-morpholinonicotinoyl chloride (255 mg; 1.12 mmol; 1.5 eq.) as a white solid (15 mg, 5%). HPLC, Rt: 2.83 min. (purity 99.0%). LC/MS, M+(ESI): 422.2, M−(ESI): 420.1.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][N:9]1[CH:16]=[C:15]([F:17])[C:13](=[O:14])[NH:12][C:10]1=[O:11])(=[O:3])[CH3:2].[C:18](OC(=O)C)(=O)C>N1C=CC=CC=1>[C:1]([O:4][CH2:5][CH2:6][O:7][CH:8]([N:9]1[CH:16]=[C:15]([F:17])[C:13](=[O:14])[NH:12][C:10]1=[O:11])[CH3:18])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCOCn1cc(F)c(=O)[nH]c1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCOC(C)n1cc(F)c(=O)[nH]c1=O

Procedure:
1-[1-(2-Hydroxyethoxy)ethyl]-5-fluorouracil (2 g) obtained in Example 2 was treated with acetic anhydride and pyridine as in Example 2 to give 2 g of 1-[1-(2-acetoxyethoxy)-ethyl]-5-fluorouracil.
Reaction SMILES: [C:1]1([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[NH2:20])[CH:13]=3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:25]([NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=1[O:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:16][CH2:15]2)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1Oc1ccc2c(c1)CCC(c1ccccc1)O2
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccccc1Oc1ccc2c(c1)CCC(c1ccccc1)O2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(2-Penylchroman-6-yloxy)-aniline (0.093 g) was dissolved in 1 ml of dry pyridine under nitrogen. DMAP (10 mol-%) and acetic acid anhydride (0.1 ml) were added and the solution was stirred for 4 hours at room temperature followed with quenching with 0.5 ml of H2O. The solution was evaporated to dryness and toluene was added and evaporated again. Toluene evaporation was repeated. Product was purified by column chromatography (CH2Cl2:i-PrOH/98:2 as the eluant) and recrystallized from 0.5 ml of heated absolute ethanol by cooling and adding 0.5 ml of 1H-NMR (400 MHz; d6-DMSO): δ 9.43 (s, 1H), 7.96 (m, 1H), 7.48-7.30 (m, 5H), 7.08-6.99 (m, 2H), 6.89-6.74 (m, 4H), 5.10 (dd, 1H, J=9.9, J=2.0), 3.03-2.88 (m, 1H), 2.76-2.65 (m, 1H), 2.21-2.11 (m, 1H), 2.10-1.91 (m, 1H), 2.06 (s, 3H).
Reaction SMILES: [N:1]1([S:5]([C:8]2[CH:13]=[CH:12][C:11](Cl)=[CH:10][N:9]=2)(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:15][O:16][CH2:17][C@H:18]([CH3:38])[O:19][C:20]1[CH:21]=[C:22]([OH:37])[CH:23]=[C:24]([C:26]2[NH:27][C:28]([C:31]3[O:32][C@@H:33]([CH3:36])[CH2:34][N:35]=3)=[CH:29][CH:30]=2)[CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[N:1]1([S:5]([C:8]2[CH:13]=[CH:12][C:11]([O:37][C:22]3[CH:23]=[C:24]([C:26]4[NH:27][C:28]([C:31]5[O:32][C@@H:33]([CH3:36])[CH2:34][N:35]=5)=[CH:29][CH:30]=4)[CH:25]=[C:20]([O:19][C@@H:18]([CH3:38])[CH2:17][O:16][CH3:15])[CH:21]=3)=[CH:10][N:9]=2)(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccc(Cl)cn1)N1CCC1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N3CCC3)nc2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
2-(Azetidin-1-ylsulfonyl)-5-chloropyridine (170 mg, 0.73 mmol) synthesized in Example (119b) and 3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (230 mg, 0.70 mmol) synthesized in Example (116d) were dissolved in N,N-dimethylformamide (3.5 mL), and cesium carbonate (454 mg, 1.39 mmol) was added, followed by stirring at 100° C. for 2 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (20 mL) was added, and extraction was carried out twice with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=5%-50%) to afford the desired compound (273 mg, yield 75%) as a white solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[F:12][C:13]1[C:14]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)=[N:15][CH:16]=[CH:17][CH:18]=1>>[F:12][C:13]1[C:14]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([NH:7][C:6]3[CH:8]=[CH:9][C:3]([Si:2]([CH3:11])([CH3:10])[CH3:1])=[CH:4][CH:5]=3)=[O:24])=[CH:21][CH:20]=2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)c1ccc(-c2ncccc2F)cc1
Reactant: C[Si](C)(C)c1ccc(N)cc1
Product: C[Si](C)(C)c1ccc(NC(=O)c2ccc(-c3ncccc3F)cc2)cc1
Yield: 80.23 %

Procedure:
The synthesis method of compound A-08 is similar to example 9. Just R1 and R3 of Scheme 2 are, respectively, F and p-SiMe3. namely: compound 6 is 4-trimethylsilyl aniline (compound 6a 35 mg); compound 10 is 4-(3-fluoro-pyridine-2-yl)benzoic acid (compound 10c); compound 12 is compound A-08 (62 mg, yield 80.23%).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CS(C)=O.[C:11]1([CH3:27])[CH:16]=[CH:15][C:14]([S:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]O)(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl.C(Cl)(Cl)Cl>[C:11]1([CH3:27])[CH:12]=[CH:13][C:14]([S:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:2][CH:1]=[O:5])(=[O:19])=[O:18])=[CH:15][CH:16]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)OCCCCCO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)OCCCCC=CC=O)cc1
Reaction time: 0.25 h
Yield: 113.9 %

Procedure:
To a solution of oxalic chloride (19.9 ml, 0.229 mol) in dichloromethane (400 ml) was added dimethyl sulfoxide (32.4 ml, 0.457 mol) at -78° C. and the mixture was stirred for 15 minutes. To the reaction mixture was added dropwise over 30 minutes a solution of 5-hydroxypentyl p-toluenesulfonate (19.65 g, 76.16 mmol) in dichloromethane (50 ml) and the mixture was stirred for 15 minutes and then triethylamine (95.5 ml, 0.686 mol) was added dropwise over 10 minutes and allowed to rise to room temperature. After chloroform (200 ml) was added to the reaction mixture, it was washed successively with 5% aqueous hydrochloric acid (200 ml), saturated aqueous sodium hydrogen carbonate (200 ml) and saturated aqueous sodium chloride (200 ml), dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give 7-(p-toluenesulfonyloxy)-2-heptenal (24.5 g). This aldehyde was used for the subsequent reaction without purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16](F)=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:4].[F:31][C:32]([F:36])([F:35])[CH2:33][OH:34].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:34][CH2:33][C:32]([F:36])([F:35])[F:31])=[CH:15][C:14]=2[C:20]([F:21])([F:22])[F:23])(=[O:12])=[O:11])[CH2:7][N:6]1[C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2C(F)(F)F)CN1C(=O)OC(C)(C)C
Reactant: OCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(OCC(F)(F)F)cc2C(F)(F)F)CN1C(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described in example 306, (2S,4R)-4-(4-fluoro-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (example 208 c) was treated with 2,2,2-trifluoroethanol and cesium carbonate to give a mixture of the title compound and starting material as yellow oil. MS (ESI): m/z=436.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH:19]=O)[CH:6]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([NH2:33])([CH3:32])[CH3:31])=[CH:25][CH:24]=1.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO.C(O)(=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][NH:33][C:30]([CH3:32])([CH3:31])[CH2:29][C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Reactant: CC(C)(N)Cc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CNC(C)(C)Cc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
[3-(4-Bromo-2-formyl-phenoxy)-phenyl]-acetic acid methyl ester (0.150 g, 0.43 mmol), 1-(4-fluorophenyl)-2-methyl-2-propylamine (0.079 g, 0.47 mmol), and sodium cyanoborohydride (0.041 g, 0.65 mmol) were combined in MeOH (2 mL). Acetic acid (2 drops) was added, and the reaction was stirred for 5 hours at room temperature. The mixture was worked-up with EtOAc and saturated aqueous NaHCO3, and the organic layer was dried and concentrated to give the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:14]([CH2:15][OH:16])=[CH:13][C:12]([C:17](=[O:19])[CH3:18])=[C:11]([F:20])[C:10]=2[F:21])[CH2:3]1.C[N+]1([O-])CCOCC1>C(Cl)Cl.CC#N.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[C:17]([C:12]1[C:11]([F:20])=[C:10]([F:21])[C:9]([N:4]2[CH2:3][C@H:2]([CH3:1])[O:7][C@H:6]([CH3:8])[CH2:5]2)=[C:14]([CH:13]=1)[CH:15]=[O:16])(=[O:19])[CH3:18]
Reactant: CC(=O)c1cc(CO)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1F
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Solvent: CC#N
Product: CC(=O)c1cc(C=O)c(N2C[C@@H](C)O[C@@H](C)C2)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of 1-[4-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-2,3-difluoro-5-hydroxymethyl-phenyl]-ethanone (Intermediate 10, 3.2 g, 9.72 mmol) in CH2Cl2/CH3CN mixture (20 mL, 1:1 v/v) was added NMO (2.2 g, 19.44 mmol) followed by TPAP (340 mg, 0.97 mmol) and mixture stirred for 2 hours at room temperature. The reaction mixture filtered thorough silica gel bed and washed with EtOAc. The organic phase concentrated under reduced pressure to give the title compound as a yellow crystalline solid. Yield: 3.0 g (94%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[CH3:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=1[C:26]([OH:28])=[O:27].[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br>O1CCCC1>[Br:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=1[C:26]([OH:28])=[O:27]
Reactant: BrCCCCCCBr
Reactant: Cc1ccccc1C(=O)O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1CCCCCCCBr
Temperature: 0 °C

Procedure:
Diisopropylamine (61.8 ml, 441 mmoles) was dissolved in tetrahydrofuran (200 ml) and cooled to 0° C. in an ice-methanol bath while stirring under argon. A 2.6 M solution of n-butyllithium in hexane (170 ml, 441 mmoles) was added dropwise. Toluic acid (30.0 g, 221 mmoles) was then added and the reaction immediately turned a deep red color. This mixture was added slowly to a solution of 1,6-dibromohexane (84 ml, 551 mmoles) in tetrahydrofuran (200 ml) at 0° C. Following the addition, the ice bath was removed and the reaction mixture was stirred at room temperature under argon for 18 hours. The solvent was evaporated and the residue dissolved in ether. The ether was extracted with cold 1 N sodium hydroxide solution. The pH of the aqueous phase was adjusted to 8.0 with cold concentrated hydrochloric acid and extracted with ether. The ether extract was dried over anhydrous magnesium sulfate, filtered and evaporated to afford the desired product.