Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:35]=[CH:34][C:13]3=[N:14][N:15]([C:17]4[CH:18]=[C:19]([CH:26]=[C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:28]=4[OH:29])[CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[N:16]=[C:12]3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:36][C:37]1([CH3:46])[CH2:42]C(O)[CH2:40][C:39]([CH3:45])([CH3:44])[NH:38]1.[NH2-].[Li+]>>[C:1]1([S:7]([C:10]2[CH:35]=[CH:34][C:13]3=[N:14][N:15]([C:17]4[CH:18]=[C:19]([CH:26]=[C:27]([C:30]([CH3:32])([CH3:31])[CH3:33])[C:28]=4[OH:29])[CH2:20][CH2:21][C:22]([O:24][CH:25]4[CH2:40][C:39]([CH3:45])([CH3:44])[NH:38][C:37]([CH3:46])([CH3:42])[CH2:36]4)=[O:23])[N:16]=[C:12]3[CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: COC(=O)CCc1cc(-n2nc3ccc(S(=O)(=O)c4ccccc4)cc3n2)c(O)c(C(C)(C)C)c1
Agent: [Li+]
Agent: [NH2-]
Product: CC1(C)CC(OC(=O)CCc2cc(-n3nc4ccc(S(=O)(=O)c5ccccc5)cc4n3)c(O)c(C(C)(C)C)c2)CC(C)(C)N1
Temperature: 50 °C
Reaction time: 3.5 h
Yield: 103.4 %

Procedure:
Methyl 3-(5-phenylsulfonylbenzotriazol-2-yl)-5-tert-butyl-4-hydroxyhydrocinnamate (10 g, 0.02 mol), xylenes (100 g, 0.93 mol) and 2,2,6,6-tetramethyl-4-hydroxypiperidine (4.0 g, 0.025 mol) are charged to a reactor. The contents are heated to reflux in order to dry the xylenes. The contents are cooled to 50° C. at which time lithium amide (0.4 g, 0.017 mol) is added. The reaction mass is then heated to reflux and held at that temperature for 3.5 hours. The reaction is monitored by thin layer chromatography. The reaction mass is cooled to 50° C. and washed thrice with 100 g of water. The xylene is removed by distillation under vacuum to give 12.8 g of an orange oil which is subjected to silica gel chromatography for purification using ethyl acetate as the eluent. The title compound is obtained in a yield of 9.6 g (77%) as a yellow semi-solid, melting at 85-125° C., whole structure is confirmed by mass spectrometry and 1Hnmr.
Reaction SMILES: OC1C(=O)NC=C(CCC2C=CC=CC=2C)C=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]#[C:26][C:27]1[CH:28]=[C:29]([O:35]C)[C:30]([O:33]C)=[N:31][CH:32]=1>>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][CH2:26][C:27]1[CH:28]=[C:29]([OH:35])[C:30](=[O:33])[NH:31][CH:32]=1
Reactant: COc1cc(C#Cc2ccccc2F)cnc1OC
Agent: Cc1ccccc1CCc1c[nH]c(=O)c(O)c1
Product: O=c1[nH]cc(CCc2ccccc2F)cc1O

Procedure:
Prepared as described for 3-hydroxy-5-(2-methylphenethyl)pyridin-2(1H)-one (Example 27) from 5-[(2-fluorophenyl)ethynyl]-2,3-dimethoxypyridine (Intermediate 38).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][C:17]([CH3:33])([CH3:32])[C:18]([NH:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27](O)[C:22]=1[C:23]([O:25][CH3:26])=[O:24])=[O:19].N1C=CC=CC=1>C(Cl)Cl>[CH3:16][C:17]([CH3:33])([CH3:32])[C:18]([NH:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[C:22]=1[C:23]([O:25][CH3:26])=[O:24])=[O:19]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1c(O)cccc1NC(=O)C(C)(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(NC(=O)C(C)(C)C)cccc1OS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
Trifluoromethanesulphonic anhydride (6.2 g) was added dropwise to an ice cooled, stirred solution of methyl 2-(2,2-dimethylpropionylamino)-6-hydroxybenzoate (Intermediate 40, 5.02 g) and pyridine (3.16 g) in DCM (70 mL) and the mixture was stirred for 1 hour. The resulting solution was washed with 2M hydrochloric acid, filtered through a phase separator and the filtrate was evaporated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-15% to give methyl 2-(2,2-dimethylpropionylamino)-6-trifluoromethanesulfonyloxybenzoate (7.09 g) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][C:13]=3F)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.C1OCCOCCOCCOCCOCC[O:21][CH2:20]1.C[O-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][C:13]=3[O:21][CH3:20])[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1
Reactant: Cn1c(=O)c2cncc(F)c2c2ccc(Cl)cc21
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cncc2c(=O)n(C)c3cc(Cl)ccc3c12
Temperature: 100 °C
Yield: 973.3 %

Procedure:
To the solution of 8-chloro-1-fluoro-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (40 mg, 0.152 mmol), prepared as described in Example 85, Part E, in MeOH (0.2 mL) in a microwave vial, 18-crown-6 (4.03 mg, 0.015 mmol) and sodium methoxide (32.9 mg, 0.152 mmol) in methanol were added and heated in a microwave oven at 100° C. for 30 min. Upon completion, the reaction mixture was diluted with water and extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 8-chloro-1-methoxy-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (40 mg, 0.146 mmol, 96% crude yield) as a white solid. The material was carried forward without further purification. LC/MS (ESI) m/e 275.0 [(M+H)+, calcd for C14H12ClN2O2 275.05]; LC/MS retention time (method D): tR=0.72 min.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:19])[C:7]=2[CH:6]=1)=[N+]=[N-].[H][H]>CN(C)C=O>[NH2:1][CH2:4][C:5]1[CH:18]=[CH:17][C:16]2[S:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](=[O:19])[C:7]=2[CH:6]=1
Reactant: [H][H]
Reactant: [N-]=[N+]=NCc1ccc2sc3ccccc3c(=O)c2c1
Solvent: CN(C)C=O
Product: NCc1ccc2sc3ccccc3c(=O)c2c1
Temperature: 60 °C
Yield: 95.3 %

Procedure:
5 g of 2-azidomethylthioxanthone are dissolved in 50 ml of N,N-dimethylformamide, and 0.5 g of Pd-on-charcoal is added, in an autoclave. Hydrogen is then passed in. The reaction is monitored by means of IR spectroscopy. It has ended when the band at 2,100 cm-1 has disappeared. The reaction mixture is diluted with N,N-dimethylformamide, heated to 60° C. and filtered, the filtrate is cooled and water is added. The crystals which have precipitated are separated off by filtration and dried. 4.3 g (95.3% of theory) of 2-aminomethylthioxanthone are obtained. Melting point: 134°-136° C.
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:7][C:6]([CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]#[N:15])=[CH:16][CH:17]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)CCc1ccc(C#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 100 %

Procedure:
A 2.31 g portion of 4-(2-t-butoxycarbonylethyl)-benzonitrile was admixed with 3 ml of trifluoroacetic acid and 30 ml of methylene chloride. The mixture was stirred at room temperature for 13 hours and concentrated. The resulting concentrate was subjected to azeotropic distillation with use of toluene, giving 1.75 g (yield 100%) of crude 4-(2-hydroxycarbonylethyl)benzonitrile. This compound was used for the subsequent reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[CH3:15])[NH2:5].[CH3:16][S:17](Cl)(=[O:19])=[O:18].[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][S:17]([CH3:16])(=[O:19])=[O:18])[CH:6]=[CH:7][C:8]=1[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[CH3:15]
Reactant: Cc1ccncc1-c1ccc(N)cc1Cl
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccncc1-c1ccc(NS(C)(=O)=O)cc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 3.4 %

Procedure:
To a solution of Intermediate 27 (0.102 g, 0.466 mmol) and methanesulfonyl chloride (0.043 mL, 0.560 mmol) in DMF (3.26 mL) was added sodium hydride (0.037 g, 0.933 mmol) at room temperature. The reaction mixture was allowed to stir at room temperature for 3 days, then quenched with saturated aqueous NH4Cl solution and diluted with EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (5×). The organic phases were combined, dried over Na2SO4, filtered, and concentrated to afford a yellow residue, which was further dried under high vacuum. The crude material was dissolved in CH2Cl2 and purified by silica gel chromatography using an ISCO machine (12 g column, 30 mL/min, 0-10% MeOH in CH2Cl2 over 25 min, tr=14 min) to afford the title compound (5.1 mg, 0.016 mmol, 3.54% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[C:13]([CH3:18])=[N:14][O:15][C:16]=2[CH3:17])=[CH:7][C:3]=1[C:4]([OH:6])=O.CN([C:22]([O:26][N:27]1N=NC2C=CC=N[C:28]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CNOC>CN(C=O)C>[NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[C:13]([CH3:18])=[N:14][O:15][C:16]=2[CH3:17])=[CH:7][C:3]=1[C:4]([N:27]([O:26][CH3:22])[CH3:28])=[O:6]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1noc(C)c1-c1cc(N)c(N)c(C(=O)O)c1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cc(-c2c(C)noc2C)cc(N)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)benzoic acid (22 g, 0.089 mol) was dissolved in DMF (C=3.0 M) and HATU (1.3 eq), DIPEA (7 eq), and N,O-dimethylhydroxylamine hydrochloride (2.5 eq) were added in one portion and the reaction was allowed to stir under air at room temperature for 1 hr. The reaction was concentrated in vacuo and the residue was dissolved in ethyl acetate. The solution was washed once with NaHCO3 and three times with brine. The crude was concentrated in vacuo and purified via silica gel chromatography to give 2,3-diamino-5-(3,5-dimethylisoxazol-4-yl)-N-methoxy-N-methylbenzamide as a light brown powder.
Reaction SMILES: OS(O)(=O)=O.[Cl:6][C:7]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:8]=1[O:9][CH2:10][C:11]([OH:13])=[O:12].[CH2:19](O)[CH3:20]>>[Cl:6][C:7]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:8]=1[O:9][CH2:10][C:11]([O:13][CH2:19][CH3:20])=[O:12]
Reactant: CCO
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)COc1ccc(Cl)cc1Cl
Yield: 53 %

Procedure:
1.3 g (14 mmol) of H2SO4 were added to 15.0 g (68 mmol) of 2,4-dichlorophenoxyacetic acid in 20 ml of ethanol, and the mixture was refluxed for 5 hours. The mixture was subsequently concentrated in vacuo, the residue was poured into 100 ml of ice-water, the organic phase was separated off, and the aqueous phase was extracted using ether. The combined organic phases were washed using 2N Na2CO3 solution and water, dried over magnesium sulfate and concentrated. 8.9 g (53% of theory) of ethyl 2,4-dichlorophenoxyacetate were obtained as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:4]=2[N:3]=1>N>[Cl:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]2[OH:9])[C:5]2[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:4]=2[N:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)nc3ccc(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: N
Product: OC[C@H]1O[C@@H](n2c(Cl)nc3ccc(Cl)cc32)[C@H](O)[C@@H]1O
Reaction time: 5 h

Procedure:
2,6-Dichloro-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)benzimidazole (66) (1.8 grams) was dissolved in methanolic ammonia (35 ml). The reaction material was.stirred in a pressure bottle for 5 hours at room temperature. Volatile materials were evaporated in vacuo to provide a white powdery precipitate. This residue was recrystallized from MeOH to yield 561 mg (2 crops, 85%) of 67 as colorless needles. MP 162°-163° C. 1H NMR (DMSO-d6): d 8.30 (d, 1, 7-H, J7-5 =2.0 Hz), 7.64 (d, 1, 4-H, J4.5 =8.5 Hz), 7.31 (dd, 1, 5-H), 5.89 (d, 1, 1'-H, J1'-2' =8.0 Hz), 5.49 (d, 1, 2'-OH, J2'-2' =6 5 Hz), 5.35 (t, 1, 5'-OH, J5'-5'OH =5.0 Hz), 5.28 (d, 1,3'-OH, J3'-3'OH =4.5 Hz), 4.46 (m, 1,2'-H, J2'-3' =5.5 Hz), 4.14 (m, 1,3'-H, J3'-4' =2.0 Hz), 4.00 (m, 1,4'-H, J4'-5' =J4'-5' =3.0 Hz), 3.70 (m, 2, 5'-H and 5"-H, J5'-5' =12.0 Hz). 13C NMR (DMSO-d6) d 140.72 (C2), 140.17 (C3a), 133.56 (C7a), 127.86 (C6), 123.23 (C5), 128.34 (C6), 120.03 (C4), 113.15 (C7), 89.00 (C1'), 86.26 (C4'), 71.37 (C2'), 69.72 (C3'), 61.12 (C5').
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1.N(C[CH2:34][N:35]([CH3:37])[CH3:36])N>>[CH3:34][N:35]([CH3:37])[CH2:36][CH2:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:4]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)=[N:3]1
Reactant: CN(C)CCNN
Reactant: Cn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Product: CN(C)CCn1cc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(1-Methyl-4-pyridin4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline but substituting (2-hydrazino-ethyl)-dimethyl-amine provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.44 (dd, J=4.6, 1.7, Hz, 2 H), 8.18 (d, J=8.3 Hz, 1 H), 8.06 (d, J=8.3 Hz, 1H), 7.82 (d, J=8.7 Hz, 1 H), 7.71 (m 2H), 7.55 (t, J=7.1 Hz, 1H), 7.38 (d, J=8.7 Hz, 2H), 7.15 (d, J=6.2 Hz, 2H) 7.00 (d, J=8.7 Hz, 2H), 5.38 (s, 2H), 4.25 (t, J=6.6 Hz, 2H), 2.82 (t, J=6.6 Hz, 2H), 2.28 (s, 6H); MS: (M+H m/z=450.4).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:29])[N:18]([C@@H:22]4[CH2:27][CH2:26][NH:25][CH2:24][C@H:23]4[F:28])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH:40](=O)[CH3:41]>>[F:39][C:2]([F:38])([F:1])[C:3]1[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:29])[N:18]([C@@H:22]4[CH2:27][CH2:26][N:25]([CH2:40][CH3:41])[CH2:24][C@H:23]4[F:28])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CCNC[C@H]1F
Reactant: CC=O
Product: CCN1CC[C@@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)C2=O)[C@H](F)C1

Procedure:
(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(trans)-1-ethyl-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(cis/trans)-3-fluoropiperidin-4-yl]-1,3-thiazolidine-2,4-dione (Example 274) and acetaldehyde (in place of formaldehyde) following General Procedure R2.
Reaction SMILES: [F:1][C:2]1[C:11](OS(C(F)(F)F)(=O)=O)=[CH:10][CH:9]=[C:8]([F:20])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C([O-])([O-])=O.[K+].[K+]>CO.O1CCOCC1.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>[F:1][C:2]1[C:11]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([F:21])[CH:27]=2)=[CH:10][CH:9]=[C:8]([F:20])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(F)ccc(OS(=O)(=O)C(F)(F)F)c1F
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1c(F)ccc(-c2cccc(F)c2)c1F
Temperature: 80 °C
Yield: 67.9 %

Procedure:
A mixture of methyl 2,6-difluoro-3-(trifluoromethylsulfonyloxy)benzoate (3.0 g, 9.4 mmol, 1.0 eq), 3-fluorophenylboronic acid (1.57 g, 11.2 mmol, 1.2 eq), K2CO3 (5.2 g, 37.6 mmol, 4.0 eq) and Pd(PPh3)4 (543 mg, 0.47 mmol, 0.05 eq) in a mixture of MeOH (10 mL) and dioxane (30 mL) was heated to 80° C. under N2 overnight. After cooling, the resulting mixture was concentrated in vacuo and purified by flash column chromatography (EtOAc:petroleum ether, 0:1 to 1:10) to give the title compound as an oil (1.7 g, 68%).
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([O:39][C:40]([CH3:42])=[O:41])[C:5]([C@@:7]1(C)[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[C@:11]2(OC(C)=O)[CH2:31][O:32][C@@H:10]2[CH2:9][C@@H:8]1[OH:37])=[O:6]>CC(C)=O.[O-2].[O-2].[Mn+4]>[CH3:1][C:2]1[C:19](=[O:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:16])([CH3:17])[C:3]=1[CH:4]([O:39][C:40]([CH3:42])=[O:41])[C:5]([C@@H:7]1[CH:8]([OH:37])[CH2:9][CH:10]3[C@@H:11]([CH2:31][O:32]3)[C@H:12]1[C@@H:13]2[O:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24])=[O:6]
Reactant: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](O)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: CC(=O)OC1C(=O)[C@@H]2C(O)CC3OC[C@H]3[C@H]2[C@H](OC(=O)c2ccccc2)[C@]2(O)CC(=O)C(C)=C1C2(C)C

Procedure:
Baccatin III (150 g, 0.25 mol) was dissolved in acetone (1.43 I). Commercially available manganese dioxide (450 g) was added in three portions under strong stirring. After the starting product disappeared (4 h) the suspension was filtered and the solvent evaporated off. The crude was suspended in EtOAc (100 ml) and refluxed for 1 h, then c-Hex (100 ml) was added. The title compound was obtained from mother liquors, after evaporation of the solvent, as white solid (140 g, 95%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Li])[CH:18]=1.C([Li])CCC.BrC1C=NC=CC=1>C(OCC)C.O.C(O)(C)C>[CH3:16][O:15][CH:3]([O:2][CH3:1])[C:4]([OH:14])([C:19]1[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13]
Reactant: [Li]c1cccnc1
Reactant: COC(OC)C(=O)Cc1ccc(Cl)cc1Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)O
Solvent: CCOCC
Product: COC(OC)C(O)(Cc1ccc(Cl)cc1Cl)c1cccnc1
Temperature: 0 °C

Procedure:
At -70° C., 88.9 g (0.337 mol) of 1,1-dimethoxy-3-(2,4-dichlorophenyl)propan-2-one in 100 ml of diethyl ether (Et2O) is dripped into a solution of 0.371 mol of 3-pyridyllithium in 1.1 liters of Et2O prepared from n-butyllithium and 3-bromopyridine. After half an hour at -70° C., the solution is slowly heated up to 0° C. Isopropanol and then water is added, and the reaction solution is extracted with 1N hydrochloric acid. The acidic aqueous phase is then neutralized with NaHCO3 and extracted with methylene chloride (CH2Cl2). After drying over Na2SO4, all the volatile constituents are removed in a rotary evaporator. A yellowish red oil is obtained. Yield: 56.1 g (48.7%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.CN1CCOCC1.Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:18]>C(Cl)Cl>[C:17](=[O:18])([O:19][C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1)[O:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN1CCC(O)CC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN1CCC(OC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a solution of 4-hydroxy-1-methyl piperidine (3.00 g, 26.1 mmol) and NMM (3.0 mL, 27.3 mmol) in DCM (50 mL) at 0° C. was added p-nitrophenyl chloroformate (5.51 g, 27.4 mmol). The reaction mixture was stirred at room temperature for 4 hours, and a cream precipitate gradually formed. The reaction mixture was filtered and the residue was washed with DCM (50 mL) to give 1-methylpiperidin-4-yl 4-nitrophenyl carbonate (7.24 g, 99%) as a cream solid.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=O)[C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:6]=2[CH:5]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:3][C:4]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[N:2][CH3:1])[C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:6]=2[CH:5]=1
Reactant: Cc1cc2ccncc2c(=O)c2ccccc12
Reactant: CN
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CN=c1c2cnccc2cc(C)c2ccccc12
Reaction time: 4 h

Procedure:
A solution of titanium tetrachloride (0.7 ml., 0.006 mole) in benzene (20 ml.) is added rapidly to a stirred solution of methylamine (1.24 g., 0.04 mole) and 6-methylbenzo[5,6]cyclohepta[1,2-c]pyridin-11-one (2.21 g., 0.01 mole) in benzene (150 ml.). After 4 hours, anhydrous potassium carbonate is added and the reaction mixture is filtered. The filtrate is evaporated to a pale yellow oil, (2.95 g.).
Reaction SMILES: [NH:1]1[CH2:19][CH2:18][CH2:17][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].C(N(CC)CC)C.O.[CH3:28][C:29]([O:32][C:33](ON=C(C1C=CC=CC=1)C#N)=[O:34])([CH3:31])[CH3:30]>CC(C)=O>[N:1]1([C:33]([O:32][C:29]([CH3:31])([CH3:30])[CH3:28])=[O:34])[CH2:19][CH2:18][CH2:17][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: O=C(O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 9 h
Yield: 144.5 %

Procedure:
To a solution of L-Pro-L-Phe (1.0 g, 3.8 mmol) and triethylamine (0,794 ml, 5.7 mmol) in 1:1 water:acetone (38 ml) was added Boc-ON (1.13 g, 4.6 mmol), and the reaction mixture stirred at room temperature for 9 hours. Acetone was removed by evaporation under reduced pressure and the resulting aqueous solution diluted with a solution of saturated sodium bicarbonate and then washed with ether. The remaining aqueous phase was acidified to pH 2.0 and extensively extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated to yield 1.99 g of N-Boc-L-Pro-L-Phe as a white glassy solid.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].[CH:5](=[O:9])/[CH:6]=[CH:7]/[CH3:8]>>[C:1]([S:3][CH:7]([CH3:8])[CH2:6][CH:5]=[O:9])(=[O:4])[CH3:2]
Reactant: C/C=C/C=O
Reactant: CC(O)=S
Product: CC(=O)SC(C)CC=O

Procedure:
Thioacetic acid (385 mL, 5.4 mol, commercially available from Sigma-Aldrich, Inc., Inc.) and crotonaldehyde (440 mL, 5.4 mol, commercially available from Acros Organics) were used to provide 3-(acetylthio)butanal (640 g), which was treated with sodium borohydride (NaBH4, commercially available from Acros Organics) to provide 3-acetylthio-1-butanol, which was consequently hydrolyzed, and distilled under vacuum to provide the product of 3-mercapto-1-butanol (165 g), which had boiling points of 90° C. at a pressure of 29 mmHg, and 85° C. at 18 mmHg.
Reaction SMILES: C[N:2]1[CH2:11][CH2:10][C:9]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:4]([CH3:20])([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3]1.ClC([O-])=O>ClCCCl>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([C:9]23[CH2:8][CH2:7][CH2:6][CH2:5][C:4]2([CH3:20])[CH2:3][NH:2][CH2:11][CH2:10]3)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(C23CCCCC2(C)CN(C)CC3)c1
Agent: O=C([O-])Cl
Solvent: ClCCCl
Product: COc1cccc(C23CCCCC2(C)CNCC3)c1
Temperature: 25 °C

Procedure:
To a solution of 430 mg (1.59 mmol) of 9 in anhydrous 1,2-dichloroethane (15 mL) at reflux was added 250 mg (1.75 mmol) of 1-chloethyl chloroformate drop wise. The resulting solution was heated under reflux for 20 h and then cooled to room temperature. The mixture was washed with saturated sodium bicarbonate solution, water, the organic layer evaporated, and the resulting oil dissolved immediately in methanol and refluxed overnight. After cooling to room temperature, the methanol was removed under reduced pressure, and the residue was treated with saturated sodium bicarbonate solution. The mixture was extracted with 3:1, methylene chloride/THF, and the combined organic extracts were washed once with water. Removal of a solvent provided 0.36 g (89%) of crude 10 as yellow oil: 1H NMR (300 MHz, CDCl3) δ 1.04 [s, 3H], 2.45-1.43 [m, 13H], 3.06 [m, 2H], 3.80 [s, 3H], 6.76 [m, 1H], 6.98 [m, 3H]; 13CNMR (300 MHz, CDCl3) δ 159.0, 128.3, 122.2, 116.9, 110.0, 55.6, 55.5, 43.8, 43.5, 36.4, 35.3, 30.7, 24.4, 22.4, 21.9