Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[C:5]([CH3:11])=[CH:4][N+:3]=1[O-].CN(C1C=CC=CN=1)C.[C:22]([O:25]C(=O)C)(=[O:24])[CH3:23]>C(Cl)Cl>[C:22]([O:25][CH2:1][C:2]1[C:7]([CH3:8])=[C:6]([O:9][CH3:10])[C:5]([CH3:11])=[CH:4][N:3]=1)(=[O:24])[CH3:23]
Reactant: COc1c(C)c[n+]([O-])c(C)c1C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: COc1c(C)cnc(COC(C)=O)c1C
Reaction time: 0.17 h

Procedure:
A solution of 30.06 g (0.18 mole) of 2,3,5-trimethyl-4-methoxypyridine N-oxide in 100 ml of methylene chloride was added slowly (over approximately one hour) over a solution of 0.38 g of dimethylaminopyridine in 53.4 ml (0.565 mole) of acetic anhydride, heated to 90°-95° C., with the temperature being held within the abovementioned range and the methylene chloride being removed by distillation. At the end of the addition, the distillation was continued for a further 10 minutes, the mixture was cooled to below 90° C. and 7.5 ml of water were added slowly, holding the temperature below 90° C. Crude 2-acetoxymethyl-3,5-dimethyl-4-methoxypyridine was obtained by distillation at reduced pressure and was used directly as starting product for the hydrolysis (Example 2).
Reaction SMILES: [H-].[Na+].[CH2:3]([C@H:10]1[CH2:14][O:13][C:12](=[O:15])[NH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=1[C:28]1[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[C:31]([F:37])=[CH:30][C:29]=1[O:38][CH3:39]>C1COCC1>[CH2:3]([C@H:10]1[CH2:14][O:13][C:12](=[O:15])[N:11]1[CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:19]=1[C:28]1[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[C:31]([F:37])=[CH:30][C:29]=1[O:38][CH3:39])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 0.33 h

Procedure:
A stirred suspension of sodium hydride (60% in oil, 37 mg, 0.926 mmol) in THF (1 mL) was treated at 0° C. with (S)-4-benzyl-2-oxazolidinone (33 mg, 0.185 mmol) dissolved in THF (1 mL), under an atmosphere of N2. The reaction was stirred for 20 min and a solution of 2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl (Intermediate 10, 50 mg, 0.124 mmol) in THF (1 mL) was added dropwise. The reaction was stirred at room temperature for 60 h. The reaction was quenched with H2O (1 mL) and partitioned between EtOAc (25 mL) and H2O (10 mL). The aqueous phase was re-extracted with EtOAc (3×15 mL) and the combined organic extracts were washed with brine (25 mL), dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash silica-gel chromatography (0-25% EtOAc/hexanes gradient) to afford (4S)-4-benzyl-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-1,3-oxazolidin-2-one as a clear glass. LCMS=502.3 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers) δ 7.69-7.64 (m, 1H), 7.58 (s, 1H), 7.39-7.36 (m, 1H), 7.29-7.24 (m, 3H), 7.06 (d, J=8.5 Hz, 1H), 6.97-6.91 (m, 2H), 6.73 (d, J=11.7, 1H), 4.79 (d, J=15.8 Hz, 1H), 4.30 (d, J=15.8 Hz, 1H), 4.08-4.05 (m, 1H), 3.99-3.97 (m, 1H), 3.76 (s, 3H), 3.65-3.58 (m, 1H), 3.27-3.17 (m, 1H), 2.81 (dd, J=13.5, 4.1 Hz, 1H), 2.45-2.40 (m, 1H), 1.30-1.4 (m, 6H).
Reaction SMILES: Br.Br[C:3]1[CH:8]=[CH:7][N:6]=[N:5][CH:4]=1.[CH3:9][C:10]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[C:13]([CH3:26])[C:11]=1[NH2:12]>>[CH3:9][C:10]1[CH:16]=[C:15]([C:3]2[CH:8]=[CH:7][N:6]=[N:5][CH:4]=2)[CH:14]=[C:13]([CH3:26])[C:11]=1[NH2:12]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1N
Reactant: Brc1ccnnc1
Agent: Br
Product: Cc1cc(-c2ccnnc2)cc(C)c1N
Temperature: 70 °C
Reaction time: 12 h

Procedure:
The title compound is prepared from 4-bromopyridazine hydrobromide and 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline following a procedure analogous to that described in Step 2 of Intermediate 62. The mixture is stirred for 12 hours at 70° C. LC (method 9): tR=0.66 min; Mass spectrum (ESI+): m/z=200 [M+H]+.
Reaction SMILES: [CH3:1][NH2:2].[C:3](=O)([O:37]C1C=CC([N+]([O-])=O)=CC=1)[O:4][CH2:5][CH2:6][C@@:7]1([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[O:12][C:11](=[O:13])[N:10]([C@H:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])=[CH:18][CH:17]=2)[CH3:15])[CH2:9][CH2:8]1>C1COCC1>[CH3:1][NH:2][C:3](=[O:37])[O:4][CH2:5][CH2:6][C@@:7]1([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[O:12][C:11](=[O:13])[N:10]([C@H:14]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])=[CH:20][CH:21]=2)[CH3:15])[CH2:9][CH2:8]1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCOC(=O)Oc2ccc([N+](=O)[O-])cc2)(c2ccc(F)cc2)OC1=O
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)OCC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.6 %

Procedure:
Methylamine (15 mg, 0.22 mmol) and TEA (2 mL) was added to a solution of 2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl 4-nitrophenyl carbonate (70 mg, crude) in 8 mL of THF. The mixture was stirred at rt overnight. The reaction was quenched with saturated NH4Cl. The mixture was extracted with EtOAc for 3 times, washed with brine, dried over anhydrous Na2SO4 and concentrated to give the residue, which was purified by preparative HPLC to give 2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl methylcarbamate (5 mg, 9%). 1H NMR (CDCl3): 1.55 (m, 3H), 2.36 (m, 5H), 2.74 (m, 3H), 2.99 (m, 1H), 4.09 (m, 2H), 5.71 (m, 1H), 6.92 (m, 2H), 7.04 (m, 4H), 7.33 (m, 5H). LC-MS Method 3 tR=1.32 min, m/z=513, 535.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[C:5](F)=[CH:4][CH:3]=1.[CH3:30][NH:31][CH3:32].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[C:5]([N:31]([CH3:32])[CH3:30])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc(Cl)ccc1F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1ccc(Cl)nc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 160 °C
Yield: 201.8 %

Procedure:
6-Chloro-3-fluoro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (188 mg, 0.46 mmol) was placed in a microwave vial and dissolved in THF (4 ml). Dimethylamine (0.463 ml, 0.93 mmol) and DIPEA (0.485 ml) were added and the mixture was heated at 160° C. for 1 h under microwave irradiation. The solvent was removed in vacuo and the yellow residue was dissolved in DCM (10 ml) and washed with water (10 ml). The DCM was removed in vacuo and the solid was dried in vacuo on a high vacuum line to afford the title compound (400 mg) as a yellow solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([CH:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)[N:6]=[N:5][CH:4]=1.C1CCN2C(=NCCC2)CC1.[CH:24]1([N:27]2[C:36]3[C:31](=[CH:32][C:33]([F:40])=[C:34](F)[C:35]=3[O:37][CH3:38])[C:30](=[O:41])[C:29]([C:42]([OH:44])=[O:43])=[CH:28]2)[CH2:26][CH2:25]1>C(#N)C>[CH:24]1([N:27]2[C:36]3[C:31](=[CH:32][C:33]([F:40])=[C:34]([N:10]4[CH2:11][CH2:12][CH:8]([N:7]5[C:3]([CH3:2])=[CH:4][N:5]=[N:6]5)[CH2:9]4)[C:35]=3[O:37][CH3:38])[C:30](=[O:41])[C:29]([C:42]([OH:44])=[O:43])=[CH:28]2)[CH2:25][CH2:26]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: Cc1cnnn1C1CCNC1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1c(N2CCC(n3nncc3C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 6.9 %

Procedure:
3-(5-methyl-1,2,3-triazol-1-yl)pyrrolidine hydrochloride (64 mg, 0.34 mmol) and DBU (77 mg, 0.51 mmol) was added to a suspension of 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (50 mg, 0.17 mmol) in acetonitrile (5 ml). The reaction mixture was refluxed for 18 hrs and then concentrated to dryness. The residue was triturated with water and thus separated solid was filtered, washed with water, acetonitrile and dried to give 5 mg of title product. m.p. 226°-228° C.; 1H NMR (TFA) δ: 9.35 (s, 1H), 8.32 (s, 1H), 8.08 (d, 1H), 5.72 (m, 1H), 4.30-4.80 (m, 4H), 4.10 (m, 1H), 3.80 (s, 3H), 2.90 (m, 2H), 2.72 (s, 3H), 1.12-1.64 (m, 4H).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:9]1)[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[O:9]1
Reactant: O=[O+][O-]
Reactant: CC=CCC1CC(=O)c2ccccc2O1
Solvent: CO
Solvent: ClCCl
Product: O=CCC1CC(=O)c2ccccc2O1
Reaction time: 2 h
Yield: 99 %

Procedure:
An ozone stream (3.5 g ozone/hour) was conducted while stirring for 2 hours through a solution, cooled to -70°, of 24.6 g of (RS)-2-(2-buten-1-yl)-4-chromanone in 450 ml of anhydrous dichloromethane and 150 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 15 minutes. After the addition of 13.4 ml of dimethyl sulfide, the mixture was stirred at room temperature for 20 hours. The reaction mixture was subsequently evaporated in a vacuum. The residue was treated with 250 ml of dichloromethane and, after the addition of 40 ml of water and 40 ml of trifluoroacetic acid, stirred at room temperature for 4 hours. The mixture was subsequently poured into 100 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 70 ml of water were added, the phases were separated and the aqueous phase was extracted twice with 120 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 22.7 g (99%) of 2-(2-oxoethyl)-4-chromanone were obtained as a yellow oil which was used in the next reaction without additional purification.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([C:8]1[N:13]=[C:12]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[O:15])[C:11]([OH:25])=[C:10]([OH:26])[N:9]=1)([CH3:7])[CH3:6].C([O-])([O-])=O.[Cs+].[Cs+].CCOCC>O1CCOCC1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:14]([C:12]2[N:13]=[C:8]3[C:5]([CH3:7])([CH3:6])[NH:4][CH2:3][CH2:2][N:9]3[C:10](=[O:26])[C:11]=2[OH:25])=[O:15])=[CH:19][CH:20]=1
Reactant: CC(C)(NCCCl)c1nc(O)c(O)c(C(=O)NCc2ccc(F)cc2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC1(C)NCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(O)c2=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2-{1-[(2-Chloroethyl)amino]-1-methylethyl}-N-(4-fluorobenzyl)-5,6-dihydroxypyrimidine-4-carboxamide (1 eq.) was dissolved in 1,4-dioxane and Cs2CO3 (1 eq.) was added. The reaction mixture was stirred at 100° C. overnight, then cooled to room temperature and the solvent was removed under reduced pressure. The resulting brown oil was suspended in MeOH, filtered and the filtrate was evaporated to give a residue that was purified on Cation Exchange Resin (Varian Mega Bond Elute SCX). After washing with MeOH, the product was collected eluting with 2N NH3 solution in MeOH. The fractions containing the desired material were concentrated under reduced pressure to yield, after trituration with Et2O the title compound as a yellow solid. A small portion of this crude was purified by RP HPLC (C18, 5 μM, H2O/MeCN with 1% of TFA as eluant) affording the pure product as TFA salt. 1H NMR (400 MHz, d6-DMSO) δ 9.41 (bs, 1H), 7.37 (dd, J=8.6 Hz, J=5.7 Hz, 2H), 7.17 (t, J=8.6 Hz, 2H), 4.48 (d, J=6.4 Hz, 2H), 3.74 (t, J=5.5 Hz, 2H), 3.06 (t, J=5.5 Hz, 2H), 1.46 (s, 6H); MS (ES) C17H19FN4O3 requires: 346. Found: 347 (M+H+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[N+:23]([O-])=O.[F:26][C:27]1[CH:28]=[CH:29][C:30]([O:37][CH3:38])=[C:31]([C:33](=[N:35]O)[NH2:34])[CH:32]=1.CCN(C(C)C)C(C)C>>[F:26][C:27]1[CH:28]=[CH:29][C:30]([O:37][CH3:38])=[C:31]([C:33]2[N:34]=[C:18]([C:17]3[CH:21]=[CH:22][C:14]([N:9]4[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]4[CH3:7])=[C:15]([CH:16]=3)[NH2:23])[O:20][N:35]=2)[CH:32]=1
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: COc1ccc(F)cc1C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1-c1noc(-c2ccc(N3CCCCC3C)c(N)c2)n1

Procedure:
Oxalyl chloride (190 mg; 1.5 mmol; 3 eq.), Intermediate 8 (132 mg; 0.5 mmol; 1 eq.), Intermediate 23 (92 mg; 0.5 mmol; 1 eq.) and DIEA (194 mg; 1.5 mmol; 3 eq.) were reacted according to general procedure 2. After purification by column chromatography c-hexane/ethyl acetate, 80/20), the residue was taken up in EtOH (20 mL) and stannous chloride dihydrate (564 mg; 2.5 mmol; 5 eq.) was added. The resulting mixture was stirred at reflux for 3 hours then concentrated in vacuo. The residue was partitioned between NaOH 0.05M and ethyl acetate. The phases were separated and the organic layer was washed with brine, dried over magnesium and concentrated in vacuo. Purification by column chromatography (c-hexane/ethyl acetate, 75/25) afforded the title compound as an off-white solid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].C[Si]([N:12]=[N+:13]=[N-:14])(C)C>CO>[N:12]1[NH:13][N:14]=[C:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH:3]=1
Reactant: C#CC(=O)OCC
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: CO
Product: CCOC(=O)c1cn[nH]n1
Temperature: 100 °C

Procedure:
A mixture of ethyl 2-propynoate (4.13 ml) and trimethylsilyl azide (13.5 ml) was heated to 100° C. for 24 h. The cooled mixture was cautiously decomposed with methanol (50 ml) and evaporated in vacuo to give the title compound (5.7 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[S:10][C:11]=2[C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1.CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[S:10][C:11]=2[C:12](=[O:14])/[CH:13]=[CH:25]/[N:26]([CH3:28])[CH3:27])=[CH:21][CH:22]=1
Reactant: CC(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C/C(=O)c1sc(-c2ccncc2)nc1Cc1ccc(Cl)cc1
Yield: 90.5 %

Procedure:
A solution of 1-(4-(4-chlorobenzyl)-2-(pyridin-4-yl)thiazol-5-yl)ethanone (370 mg, 1.12 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (10.0 mL, 75.3 mmol) was heated to 80 degrees for 6 hours. The reaction was cooled and concentrated in vacuo. The residue was purified by silica gel chromatography (EA/DCM=0/100→100/0) to give 389 mg (90% yield) of the title compound as a yellow solid. LC/MS (FA) ES+ 384, 386. 1H NMR (300 MHz, CDCl3) δ: 8.70-8.68 (m, 2H), 7.81-7.75 (m, 3H), 7.36-7.33 (m, 2H), 7.26-7.24 (m, 2H), 5.41 (d, 1H, J=12.3 Hz), 4.55 (s, 2H), 3.16 (s, 3H), 2.88 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5](Br)[S:4][C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[O:15]1[CH2:20][CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH2:17][CH2:16]1.O1CCOCC1.O.C(=O)([O-])[O-].[Cs+].[Cs+]>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>[Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([C:18]2[CH2:19][CH2:20][O:15][CH2:16][CH:17]=2)[S:4][C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1sc(Br)c(C#N)c1Br
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1sc(C2=CCOCC2)c(C#N)c1Br
Temperature: 100 °C
Reaction time: 24 h
Yield: 60.4 %

Procedure:
To a microwave vial containing a suspension of ethyl 3,5-dibromo-4-cyanothiophene-2-carboxylate (300.0 mg, 0.8849 mmol, prepared as in MPI10-008P1M) and 3,6-dihydro-2h-pyran-4-boronic acid pinacol ester (204 mg, 0.973 mmol) in 1,4-dioxane (8.98 mL, 115 mmol) and water (0.925 mL, 51.3 mmol) were added tetrakis(triphenylphosphine)palladium(0) (102 mg, 0.0885 mmol) and cesium carbonate (865 mg, 2.65 mmol). The vial was sealed, degassed by bubbling argon through for 10 minutes, and then heated at 100° C. with stirring for 24 h. The reaction was then cooled to room temperature and partitioned between EtOAc and water. Layers were separated, and, the aqueous layer was extracted 2× with EtOAc. Combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Residue was subjected to column chromatography as a solution in DCM (40 g column, gradient elution 0 to 25% EtOAc/hexanes) to afford ethyl 3-bromo-4-cyano-5-(3,6-dihydro-2H-pyran-4-yl)thiophene-2-carboxylate as a white solid (183 mg, yield 63%). LCMS: (FA) ES+ 342, 344; 1H NMR (400 MHz, DMSO) δ 6.86-6.79 (m, 1H), 4.36-4.27 (m, 4H), 3.82 (dd, J=5.4, 5.4, 2H), 2.53 (ddd, J=2.1, 4.9, 10.0, 2H), 1.30 (dd, J=7.1, 7.1, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[NH:5][C:4](=[O:18])[C:3]=1[C:19]([O:21]C)=O.[NH3:23]>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[NH:5][C:4](=[O:18])[C:3]=1[C:19]([NH2:23])=[O:21]
Reactant: CCCOc1ccccc1-c1cc(C)c(C(=O)OC)c(=O)[nH]1
Reactant: N
Product: CCCOc1ccccc1-c1cc(C)c(C(N)=O)c(=O)[nH]1

Procedure:
Methyl 1,2-dihydro-4-methyl-2-oxo-6-(2-propoxyphenyl)-pyridine-3-carboxylate (0.53 g) and saturated methanolic ammonia (25 ml) was heated in a sealed vessel at 70°-85° C. for 34 hours. The residue after evaporation was triturated with methanol (10 ml) to give a solid, 0.28 g, m.p. 239°-242° C. Recrystallisation from ethanol afforded the title compound, 0.18 g , m.p. 244°-246° C.
Reaction SMILES: CC([Si](C)(C)[O:6][CH2:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:15]=2)[CH:11]=[CH:12][CH:13]=1)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:6][CH2:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH:15]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: COc1cc(CNC(=O)OC(C)(C)C)cc(-c2cccc(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc(CNC(=O)OC(C)(C)C)cc(-c2cccc(CO)c2)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of 1,1-dimethylethyl {[3′-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-5-(methyloxy)-3-biphenylyl]methyl}carbamate (1.5 g, 3.28 mmol) in THF (20 mL) was added a solution of nBu4NF (0.94 g, 3.61 mmol) in THF (10 mL). This mixture was stirred at room temperature over night. After the solvent was removed under reduced pressure, the residue was diluted with EtOAc (30 mL). The organic layer was washed with water (10 mL×2), brine (10 mL×2), and dried over Na2SO4. The product, 1,1-dimethylethyl {[3′-(hydroxymethyl)-5-(methyloxy)-3-biphenylyl]-methyl}carbamate, (0.9 g) was purified by flash column chomatography (PE:EA=3:1). (Yield: 80%). 1H NMR (400 MHz, CDCl3) δ 1.47 (s, 9H), 3.86 (s, 3H), 4.35 (d, J=7.6 Hz, 2H), 4.76 (s, 2H), 4.89 (s, 1H), 6.83 (s, 1H), 7.02 (s, 1H), 7.09 (s, 1H), 7.34-7.58 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 28.4, 44.7, 55.4, 65.2, 79.6, 111.9, 118.7, 125.8, 126.1, 126.4, 129.0, 140.9, 141.2, 141.5, 142.8, 156.0, 160.3. HPLC: retention time: 11.558 min; purity: 98.7%; MS: m/z 343 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[OH-].[Na+].C([O-])(=O)C.[Na+].[C:17](=[C:20]([CH2:23][CH2:24]Cl)[CH2:21]Cl)([CH3:19])[CH3:18]>O>[C:17](=[C:20]1[CH2:23][CH2:24][C:6]2([CH:7]=[C:2]([CH3:1])[C:3](=[O:9])[CH:4]=[C:5]2[CH3:8])[CH2:21]1)([CH3:19])[CH3:18]
Reactant: Cc1ccc(C)c(O)c1
Reactant: CC(C)=C(CCl)CCCl
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1=CC2(CCC(=C(C)C)C2)C(C)=CC1=O
Temperature: 15 °C
Reaction time: 6 h
Yield: 106.9 %

Procedure:
2,5-Dimethylphenol (9.7 g, 0.08 mol) was added to a solution of sodium hydroxide (3.2 g, 0.08 mol) and sodium acetate (3.3 g, 0.04 mol) in distilled water (50 mL). The mixture was cooled to 15° C. and 2-isopropylidene-1,4-dichlorobutane (15 g, 0.09 mol) was added over 1 hour under nitrogen. After stirring at room temperature for 6 hours, the reaction mixture was extracted with ether. The ether extracts were washed with 10% sodium hydroxide, water, and dried (Na2SO4). Concentration gave 18.5 g of crude material consisting of mainly the alkylated phenol having the structure: ##STR38## A sample purified by column chromatography (silica gel) had the following spectral characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[C:19]([F:23])=[CH:18][C:17]=4[O:24][C:25]([C:28]([O:30][CH3:31])=[O:29])([CH3:27])[CH3:26])[CH2:14][C:13](=O)[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:43]>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[C:19]([F:23])=[CH:18][C:17]=4[O:24][C:25]([C:28]([O:30][CH3:31])=[O:29])([CH3:27])[CH3:26])[CH2:14][C:13](=[S:43])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=3[CH3:40])[C:5]2=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)C(C)(C)Oc1cc(F)c(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)Oc1cc(F)c(Cl)cc1C1CC(=S)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 50 °C
Yield: 62.6 %

Procedure:
A mixture of racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-4-fluoro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.067 mmol) and P2S5 (45 mg, 0.20 mmol) in THF (2 mL) was heated at 50° C. for 2 h, and then diluted with toluene (10 mL). The mixture was concentrated and the residue was washed with DCM twice. The DCM solutions were combined and concentrated. The residue was purified by flash column to give the title compound as white solid (26 mg).
Reaction SMILES: C[O:2][C:3]1[CH:34]=[CH:33][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][C:28]([O:31]C)=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)=[O:17])=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>O>[OH:31][C:28]1[CH:27]=[CH:26][C:25]([O:24][C:21]2[CH:20]=[CH:19][C:18]([C:16]([C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:7][C:6]4[CH:33]=[CH:34][C:3]([OH:2])=[CH:4][CH:5]=4)=[CH:9][CH:10]=3)=[O:15])=[O:17])=[CH:23][CH:22]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc(Oc2ccc(C(=O)C(=O)c3ccc(Oc4ccc(OC)cc4)cc3)cc2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(C(=O)c1ccc(Oc2ccc(O)cc2)cc1)c1ccc(Oc2ccc(O)cc2)cc1
Temperature: 220 °C
Yield: 81 %

Procedure:
In a 250 ml round-bottom flask with a stirbar were placed 4,4'-bis(4-methoxyphenoxy)benzil (7.81 g, 20 mmol) and pyridine hydrochloride (13.87 g, 120 mmol). The mixture was heated under nitrogen in a 220° C. oil bath for 45 mins after which time deprotection was complete. The mixture was cooled to 80° C. and diluted to a volume of 250 ml by dropwise addition of water. The crude product was isolated by suction filtration, washed with water and then recrystallized from acetic acid to give the product (6.91 g, 81%). (mp=220°-221° C.).