Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[S:8][C:9](C(O)=O)=[CH:10][C:3]=12>C1(OC2C=CC=CC=2)C=CC=CC=1.CCCCCCC.[Cu]>[F:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]2[S:8][CH:9]=[CH:10][C:3]=12
Reactant: O=C(O)c1cc2c(F)cncc2s1
Agent: [Cu]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCCC
Product: Fc1cncc2sccc12
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 74.2 %

Procedure:
A mixture of 4-fluorothieno[2,3-c]pyridine-2-carboxylic acid (765 mg, 3.88 mmol) and copper powder (629 mg, 9.91 mmol) in diphenyl ether (3.8 mL) was heated to boiling for ˜5 min. After cooling to 40° C., the reaction mixture was diluted with heptane (10 mL), filtered through a short pad of Celite, and concentrated to remove the heptane. Purification of the residue by ISCO chromatography (5 to 45% ethyl acetate:heptane) afforded 441 mg (74%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.96 (d, J=1.8 Hz, 1 H), 8.34 (d, J=2.0 Hz, 1 H), 7.61-7.88 (m, 1 H), 7.38-7.57 (m, 1 H); MS (ESI): 154.07 [M+H]+; HPLC tR=2.97 min (ZQ3, polar—4 min).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[CH:19]=2)=[CH:11][CH:10]=1)=O)(C)(C)C.CCN=C=NCCCN(C)C.Cl.[NH2:36][C:37]1[N:38]=[C:39]([C:43]([O:45][CH3:46])=[O:44])[N:40]([CH3:42])[CH:41]=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[C:17]([C:21]([NH:36][C:37]3[N:38]=[C:39]([C:43]([O:45][CH3:46])=[O:44])[N:40]([CH3:42])[CH:41]=3)=[O:23])[N:18]([CH3:20])[CH:19]=2)=[CH:13][CH:14]=1
Reactant: Cn1cc(-c2ccc(NC(=O)OC(C)(C)C)cc2)cc1C(=O)O
Reactant: COC(=O)c1nc(N)cn1C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)c1nc(NC(=O)c2cc(-c3ccc(N)cc3)cn2C)cn1C
Reaction time: 6 h

Procedure:
0.3 gm of boc protected 6 (0.94 mmol, 1.2 eq) was dissolved in DMF (5 mL) to which 2.0 eq of EDCl and 2.5 eq of DMAP were added. The mixture was allowed to stir for 30 minutes after which methyl 4-amino-1-methyl-1H-imidazole-2-carboxylate (0.121 g, 0.79 mmol, 1.0 eq) was added. The reaction mixture was allowed to stir for a further 6 hours at which point TLC showed completion of reaction. The reaction was quenched by pouring it onto a mixture of ice/water mixture and the resulting mixture was extracted with ethyl acetate (3×150 mL). The combined extracts were sequentially washed saturated aqueous NaHCO3 (50 mL), water (50 mL), brine (50 mL) and finally dried over MgSO4. Excess ethyl acetate was evaporated by rotary evaporator under reduced pressure and the crude product 11a (0.48 gm) was used for the boc deprotection step to afford 11. For boc deprotection, the crude intermediate was dissolved in a small volume of MeOH and 4M HCl in dioxane (5 mL) was added slowly to the stirring solution. The reaction mixture was stirred for 2 hours at which point TLC showed completion of reaction. Excess solvent was evaporated under vacuum to obtain a brown coloured solid (11). The solid product was subjected to flash chromatography (n-hexane/EtOAc 9:1) to give pure 11. Yield 0.35 gm, 81% over two steps.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[S:28][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:26]([CH3:34])[C:25]=2[CH:35]=1>>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]([NH:20][C:21]2[CH:22]=[CH:23][C:24]3[S:28][C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:26]([CH3:34])[C:25]=3[CH:35]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)c1sc2ccc(N)cc2c1C
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: CCCCN1C(=O)C(Nc2ccc3sc(C(=O)OCC)c(C)c3c2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and ethyl 5-amino-3-methyl-1-benzothiophene-2-carboxylate in a similar manner as described for e.g. Examples 6-9, 22-25, 28 and 32-35. 1H NMR (400 MHz, d-THF): δ 8.85 (bs, 1H), 7.61 (d, 1H), 7.19 (dd, 1H), 7.17-7.13 (m, 2H), 7.09-7.01 (m, 3H), 6.97-6.95 (m, 1H), 4.35-4.28 (m, 2H), 3.76 (t, 2H), 2.34 (s, 3H), 1.89-1.80 (m, 2H), 1.54-1.44 (m, 2H), 1.35 (t, 3H), 1.01 (t, 3H); Mass Spectrum: M−H+ 498.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([CH2:12][CH2:13][C:14]([NH2:16])=[O:15])=[CH:4][C:3]=1[C:17]([CH3:20])([CH3:19])[CH3:18].Cl[C:22]([S:24]Cl)=[O:23]>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:3]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:4][C:5]([CH2:12][CH2:13][C:14]2[O:15][C:22](=[O:23])[S:24][N:16]=2)=[CH:6][C:7]=1[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1cc(CCC(N)=O)cc(C(C)(C)C)c1O
Reactant: O=C(Cl)SCl
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(CCc2nsc(=O)o2)cc(C(C)(C)C)c1O
Temperature: 60 °C

Procedure:
A suspension of 13.45 grams of 3-[4-hydroxy-3,5-di- tert-butylphenyl]propionamide in 150 ml of toluene is admixed with 20.22 grams of chlorocarbonyl sulfenyl chloride added dropwise. After heating the reaction mixture at 60° C. for 20 hours, the solvent is removed under reduced pressure. The residue is recrystallized from heptane to give the title compound as a pale yellow crystalline solid: mp 82°-86° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:13]1C=CC=CC=1C(C)C(O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:13])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1ccccc1Cl
Reactant: O=C(O)Cc1cccc(Cl)c1
Product: CC(C(=O)O)c1cccc(Cl)c1
Yield: 57 %

Procedure:
The titled compound was prepared from m-chlorophenylacetic acid in 57% yield in the same manner as the preparation of 2-(2-Chlorophenyl)propionic acid in Example 184a. MS (ESI) 185 (MH+).
Reaction SMILES: [C:1]([C:6]1[C:15](=O)[C:14]2[C:9](=[C:10]([N:17]3[C:21](=[O:22])[C:20]4=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]4[C:18]3=[O:27])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)(O[Cl:31])=O>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:31])=[CH:13][CH:12]=[CH:11][C:10]=2[N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Cl)(Cl)OCl
Reactant: CCCC(=O)c1c[nH]c2c(N3C(=O)c4ccccc4C3=O)cccc2c1=O
Product: CCCC(=O)c1cnc2c(N3C(=O)c4ccccc4C3=O)cccc2c1Cl
Reaction time: 0.17 h
Yield: 57 %

Procedure:
3-Butyryl-8-phthalimido-4(1H)quinolone (36 g, 0.1 mol) was heated under reflux in phosphoryl oxychloride (200 ml) for 1 hour. The solvent was evaporated and the residue dissolved in chloroform and poured into a rapidly stirred mixture of ice, water and ammonia then stirred for 10 minutes. The chloroform layer was washed with brine, dried (anhyd. MgSO4), filtered and evaporated to a brown oil. Chromatography (silica gel/5% methanol in chloroform) gave 3-butyryl-4-chloro-8-phthalimidoquinoline as a light brown oil (21.5g, 57%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([OH:12])[C:3]=1[N+:13]([O-:15])=[O:14].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1.C(OCC)C>[CH2:16]([NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([OH:12])[C:3]=1[N+:13]([O-:15])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1c(Cl)cc(C(F)(F)F)nc1O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=[N+]([O-])c1c(NCc2ccccc2)cc(C(F)(F)F)nc1O
Temperature: 25 °C
Yield: 115 %

Procedure:
4-Chloro-3-nitro-6-trifluoromethyl-pyridin-2-ol (65.1 gm 268 mmol) was dissolved in tetrahydrofuran (350 mL) and stirred at room temperature under N2. Benzylamine (86.3 gm 805 mmol) in tetrahydrofuran (50 mL) was added drop wise over 30 minutes to give a bright yellow solution. The reaction was heated in an oil bath at 50° C. for 18 hours, (a solid formed during the reaction). The resulting mixture was then cooled to ambient temperature, diluted with diethyl ether (200 mL) and the resulting solid (benzylamine hydrochloride) was then filtered off. The filtrate was evaporated to low bulk under reduced pressure to give a thick yellow slurry. Added diethyl ether (300 mL) and filtered off the yellow solid, dried on the filter pad to give the benzylamine salt (96.5 gm). The desired product was liberated by partition of the solid between aqueous 2N HCl and dichloromethane and crystallization from ethyl acetate/n-pentane gave the title compound as a pale yellow solid (61.7 gm 73.4% yield).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:20][NH2:21]>C(O)CCC>[CH3:18][C:14]1[N:13]=[C:12]([O:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([C:3]([NH:20][NH2:21])=[O:2])[CH2:6][CH2:7]2)[CH:17]=[CH:16][CH:15]=1
Reactant: NN
Reactant: COC(=O)[C@H]1CC[C@H](Oc2cccc(C)n2)CC1
Solvent: CCCCO
Solvent: O
Product: Cc1cccc(O[C@H]2CC[C@H](C(=O)NN)CC2)n1
Temperature: 125 °C

Procedure:
A mixture of trans-4-(6-methyl-pyridin-2-yloxy)-cyclohexanecarboxylic acid methyl ester (0.62 g, 2.5 mmol) and hydrazine hydrate (0.55 ml, 11 mmol) in n-butanol (1 ml) was heated at 125° C. for 4 h. After cooling to room temperature the reaction mixture was partitioned between dichloromethane (75 ml) and water (75 ml). The aqueous layer was washed with dichloromethane/75 ml). The combined organic layers were washed with water (75 ml) and brine (75 ml), dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.48 g, 86%) as white solid, which was used in the next step without further purification. MS m/e: 250 (M+H+)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24]([NH:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[O:25])[CH2:20][CH2:19]3)[C:9]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:10]=3[CH2:11][CH2:12][C:3]=12.C(O)(=O)C.[Br:37]Br.C(O)(=O)C>O>[Br:37][C:7]1[C:2]([OH:1])=[C:3]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[C:8](=[C:18]3[CH2:23][CH2:22][N:21]([C:24]([NH:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[O:25])[CH2:20][CH2:19]3)[C:4]2=[N:5][CH:6]=1
Reactant: BrBr
Reactant: O=C(Nc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c(O)ccnc32)CC1
Solvent: O
Solvent: CC(=O)O
Product: O=C(Nc1cccnc1)N1CCC(=C2c3ccc(Cl)cc3CCc3c2ncc(Br)c3O)CC1
Reaction time: 0.17 h
Yield: 67 %

Procedure:
To a solution of the title compound from Example 263 (0.34 grams) and glacial acetic acid (10 mL) was added a 0.7 M bromine-acetic acid solution (4 mL) at 25° C. under N2. After 10 minutes, water was added and the resulting solid was filtered and washed with water several times and dried to give the title compound (Yield 0.31 grams, 67%, MH+ 527).
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13].O.[OH-].[Li+]>CO.O>[Cl:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]([NH:5][CH2:4][C:3]([OH:15])=[O:2])=[O:14]
Reactant: COC(=O)CNC(=O)c1ccccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CNC(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of above (2-chloro-benzoylamino)-acetic acid methyl ester (6 g, 26 mmol) in 30 mL of methanol, was added three equivalents of lithium hydroxide hydrate in 10 mL of water. The solution was stirred at room temperature for 1 hour, concentrated and mixed with water. Citric acid was added until pH of the solution was adjusted to pH 2 to 3. The mixture was extracted with ethyl acetate and the organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated to dryness to give (2-chloro-benzoylamino)-acetic acid as a solid. To a solution of (2-chloro-benzoylamino)-acetic acid in 40 mL of acetone at −20° C. was added excess of trifluoroacetic anhydride. The mixture was warmed up to room temperature and stirred overnight. The solvent was removed under vacuum. The residue was poured into 400 mL of water and stirred for 20 min. The solid was filtered out and washed with 2×100 mL of water, and dried under vacuum to give 2-(2-chloro-benzoylamino)-4,4,4-trifluoro-3,3-dihydroxy-butyric acid as a red solid. This red solid was suspended in 80 mL of methanol, and heated to reflux for 30 min. The solvent was removed and the mixture was purified by flash chromatography using ethyl acetate/hexane to give 2-(2-chloro-benzoylamino)-4,4,4-trifluoro-3,3-dihydroxy-butyric acid methyl ester as a light yellow solid. The methyl ester was suspended in 100 g of phosphorus oxychloride, and stirred at 80° C. overnight. The reaction mixture was concentrated to remove excess POCl3. The remaining oil was diluted with toluene, and poured into a mixture of ice-water. The layers were separated and the organic layer was washed with water and diluted sodium bicarbonate and then concentrated to dryness. The solid was dissolved in 30 mL of methanol and treated with 2.5 equivalent of lithium hydroxide in 30 mL of water, and stirred for 30 min. Methanol was removed under vacuum, and the mixture was diluted with water. pH of the solution was adjusted to about 3 with 12 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was concentrated and purified by flash chromatography to give 1.67 g of 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid as a light yellow solid. LCMS calcd for C11H5ClF3NO3 (m/e) 291, obsd 292 (M+H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][N:12]=1)#[N:10].[I:18]I>C1COCC1>[F:17][C:16]1[C:11]([C:9]#[N:10])=[N:12][CH:13]=[CH:14][C:15]=1[I:18]
Reactant: II
Reactant: N#Cc1ncccc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1nccc(I)c1F

Procedure:
A solution of LDA (40.9 mmol, prepared from 11.4 mL of diisopropyl amine and 16.4 mL of 2.5 M n-butyl lithium in hexanes) in 200 mL THF at −78° C. was treated with 2-cyano-3-fluoropyridine (5.0 g, 40.9 mmol) in 50 mL of THF drop-wise. After 10 minutes a solution of iodine (10.4 g, 40.9 mmol) in 10 mL of TBF was added. After 30 minutes the reaction was quenched with 40 mL of water followed by workup with aqueous sodium thiosulfate. The mixture was diluted with ether, washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was subjected to silica gel chromatography eluted with 0–20% ethyl acetate in hexanes to provide 3-fluoro-4-iodopyridine-2-carbonitrile that gave proton NMR spectra consistent with theory.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[CH2:17]([O:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([Cl:1])[CH:9]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(O)cc1Cl
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=Cc1ccc(OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
2-Chloro-4-hydroxy-benzaldehyde obtained in Step A was dissolved in CH3CN (20 mL). After Cs2CO3(8.7 g, 0.027 mol) was added thereto, benzyl bromide (1.5 mL, 0.013 mol) was added thereto, and the mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was filtered by using celite, concentrated under reduced pressure, and purified by column chromatography (eluent, EtOAc/Hex=1/5) to obtain the title compound (1.89 g, 59%).
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:17][CH2:16][CH2:15][C:14]3[CH:18]=[CH:19][C:20]([C:22](=[O:31])[CH2:23][CH2:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:21][C:13]=3[CH2:12]2)=[CH:6][CH:5]=1.[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1>>[ClH:32].[ClH:1].[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][N:28]2[CH2:27][CH2:26][CH:25]([CH2:24][CH2:23][C:22]([C:20]3[CH:19]=[CH:18][C:14]4[CH2:15][CH2:16][CH2:17][N:11]([CH2:10][C:7]5[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=5)[CH2:12][C:13]=4[CH:21]=3)=[O:31])[CH2:30][CH2:29]2)=[CH:35][CH:34]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: O=C(CCC1CCNCC1)c1ccc2c(c1)CN(Cc1ccc(F)cc1)CCC2
Agent: Cl
Product: O=C(CCC1CCN(Cc2ccc(Cl)cc2)CC1)c1ccc2c(c1)CN(Cc1ccc(F)cc1)CCC2

Procedure:
Using 1-[2-[(4-fluorophenyl)methyl]-2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl]-3-(4-piperidinyl)-1-propanone(free base) obtained in Example 211, and 4-chlorobenzyl bromide, the procedure of Example 51-3 was otherewise repeated to provide the title compound as colorless amorphous powders.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[O:10])[C:5]([N+:18]([O-])=O)=[C:4]([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)[N:3]=1>CCO.CCOC(C)=O.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[O:10])[C:5]([NH2:18])=[C:4]([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)[N:3]=1
Reactant: Nc1nc(NC(=O)c2ccc(Cl)nc2)c([N+](=O)[O-])c(-c2ccco2)n1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1nc(NC(=O)c2ccc(Cl)nc2)c(N)c(-c2ccco2)n1

Procedure:
A solution of N-(2-amino-6-(2-furyl)-5-nitropyrimidine-4-yl)-6-chloropyridine-3-carboxamide (153 mg, 0.423 mmol) and 10% Pd/C (82 mg, 42.3 μmol) in EtOH (20 mL) and EtOAc (5 mL) was stirred under an hydrogen atmosphere for 3 h, filtered through Celite and concentrated in vacuo to give N-(2,5-diamino-6-(2-furyl)pyrimidin-4-yl)-6-chloropyridine-3-carboxamide as a yellow oil. A solution of this product in EtOH (5 mL) and 2-M HCl (5 mL) at 0° C. was treated dropwise with an ice-cold solution of sodium nitrite (87 mg, 1.27 mmol) in water (2 mL). The mixture was stirred at 0° C. for 1 h, stirred at room temperature for 1 h, neutralised with 5-M NaOH, stirred for 16 h and the resulting solid was filtered to give title compound (40 mg, 28%) as a brown solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1.C([Li])CCC.[Br:18]CCBr.[Cl-].[NH4+]>O1CCCC1.O>[CH3:1][O:2][CH2:3][C:4]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([Br:18])[N:6]2[N:5]=1
Reactant: BrCCBr
Reactant: COCc1cc2ccccn2n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COCc1cc2cccc(Br)n2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(methoxymethyl)pyrazolo[1,5-a]pyridine (3.5 g) dissolved in tetrahydrofuran (350 mL) was added n-butyllithium (2.66M hexane solution; 10.5 mL) dropwise at −78° C. under a nitrogen stream, and the reaction mixture was stirred for 30 minutes. 1,2-Dibromoethane (2.05 mL) was added dropwise to the obtained reaction mixture and stirring was continued for 30 minutes. After adding saturated aqueous ammonium chloride to the reaction mixture, the temperature was raised to room temperature, water was added and extraction was performed with ethyl acetate. The organic extract was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography and the title compound (2.75 g) was obtained as a light yellow oil from the n-hexane:ethyl acetate (10:1) fraction.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:17][C:15]=3[N:16]=2)[CH:7]=1.CO.[OH-].[Na+]>C1COCC1>[C:21]1([C:18]2[CH:19]=[CH:20][C:14]3[O:13][C:12]([C:8]4[CH:7]=[C:6]([CH:5]=[CH:4][C:3]([OH:27])=[O:2])[CH:11]=[CH:10][CH:9]=4)=[N:16][C:15]=3[CH:17]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)C=Cc1cccc(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C=Cc1cccc(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Reaction time: 2 h

Procedure:
The ester (33) (41 mg, 0.12 mmol) was hydrolysed using Method C, except that MeOH (3 mL), THF (3 mL) and 1M NaOH (5 mL) were used, and the reaction was stirred for 2 hours. Yield: 21 mg, 53%; LC-MS tr 1.74 min; HPLC Purity: 96%; MS (ES+) m/z 342 (M+H); 1H NMR (400 MHz; DMSO): δ 6.7 (d, 1H), 7.4 (t, 1H), 7.45-7.55 (t, 2H), 7.70-7.80 (m, 5H), 7.9 (d, 1H), 8.05 (d, 1H), 8.10 (s, 1H), 8.30 (d, 1H), 8.50 (s, 1H), 12.55 (br. s, 1H)
Reaction SMILES: [C:1]([S:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:7]=1[CH2:24][C:25]([CH3:31])([CH3:30])[C:26]([O:28][CH3:29])=[O:27])([CH3:4])([CH3:3])[CH3:2].[CH2:32](Br)[CH:33]=[CH:34][CH3:35]>CC1C=CC(C)=CC=1.[Cl-].[Cl-].[Zn+2]>[C:1]([S:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[C:13]=2[CH2:32][CH:33]=[CH:34][CH3:35])[N:8]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:7]=1[CH2:24][C:25]([CH3:31])([CH3:30])[C:26]([O:28][CH3:29])=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Reactant: CC=CCBr
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccc(C)cc1
Product: CC=CCc1c(O)ccc2c1c(SC(C)(C)C)c(CC(C)(C)C(=O)OC)n2Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of KH (35% dispersion in oil, 547 mg, 4.78 mmol) in p-xylene (20 mL) there was added methyl 3-[3-tert-butylthio-1-(4-chlorobenzyl)-5-hydroxyindol-2-yl]-2,2-dimethylpropanoate from Example 1, Method A, Step 3 (2.0 g, 4.35 mmol) and the mixture was refluxed for 20 minutes; after cooling, there was added freshly fused ZnCl2 (68 mg, 0.5 mmol) and the mixture was again refluxed for one hour, then cooled down to r.t. To the solution was added crotyl bromide (882 mg, 6.53 mmol) and stirring was continued at room temperature overnight. The mixture was quenched with saturated aqueous NH4Cl (20 mL) and 2 mL of 1N HCl. The organic phase was collected and the aqueous phase extracted with EtOAc. The combined organic phases were washed with H2O 3 times, dried and evaporated. The residue was chromatographed to afford the title compound as the minor component, as a yellow oil.
Reaction SMILES: N1C=CN=C1.[OH:6][CH2:7][C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1.[C:14]([Si:18](Cl)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl.O>[Si:18]([O:6][CH2:7][C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1N[C@@H](CO)CO1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](OC[C@H]1COC(=O)N1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
Imidazole (1.74 g, 25.6 mmol, 2.0 equiv) was added to a solution of (S)-4-(hydroxymethyl)oxazolidin-2-one (1.5 g, 12.8 mmol) and tert-butylchlorodiphenylsilane (3.95 mL, 15.4 mmol, 1.2 equiv) in DCM (43 mL) at room temperature. A white precipitate formed. The solution was stirred at room temperature for 16 hours and then diluted with water (50 mL). The layers were separated and the aqueous layer was extracted with DCM (50 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (50 mL), dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 20 to 65%) provided (R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)oxazolidin-2-one (3.55 g, sticky colorless oil) in 78% yield. 1H NMR (400 MHz, CDCl3) δ 7.64 (m, 4H), 7.50-7.38 (m, 6H), 5.31 (m, 1H), 4.44 (t, J=8.7 Hz, 1H), 4.15 (m, 1H), 4.00 (m, 1H), 3.65 (d, J=5.5 Hz, 2H), 1.07 (s, 9H). MS m/z 356.1 (M+H)+; Rt-1.00 min.