Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:18][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=O)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4].Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+].[NH4+].[Cl-]>C(O)C.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]([CH:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[CH2:18][C:19](=[N:36][OH:37])[C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH3:27])[CH:22]=3)=[CH:15][CH:16]=2)=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1ccc(-c2ccc(C(CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(-c2ccc(C(CC(=NO)c3ccnc(C)c3)c3ccccc3C)cc2)cc1

Procedure:
A solution of 4′-[3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-biphenyl-4-carboxylic acid methyl ester (36 mg), hydroxylamine hydrochloride (11 mg) and sodium hydrogencarbonate (14 mg) in a mixture of ethanol (0.5 mL) and water (0.1 mL) was heated under reflux for 1.5 hours. A saturated solution of NH4Cl was added, the phases were separated and the inorganic one was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (EtOAc/n-heptane 2:1) to yield the title compound as a mixture of E and Z isomers (3.3:1) as a white foam (28 mg, 75%), MS (ESI+): m/z=465.2 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([C:21]4[N:25]=[C:24]([CH:26]5[CH2:29][N:28]([C:30]([O:32][CH3:33])=[O:31])[CH2:27]5)[O:23][N:22]=4)[CH:17]=[CH:18][C:19]=3[CH3:20])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:34][N:35]1[CH:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[N:36]1.C([O-])([O-])=O.[K+].[K+]>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.CN(C=O)C>[CH3:20][C:19]1[CH:18]=[CH:17][C:16]([C:21]2[N:25]=[C:24]([CH:26]3[CH2:27][N:28]([C:30]([O:32][CH3:33])=[O:31])[CH2:29]3)[O:23][N:22]=2)=[CH:15][C:14]=1[NH:13][C:11]([C:8]1[N:5]2[CH:6]=[CH:7][C:2]([C:37]3[CH:38]=[CH:39][N:35]([CH3:34])[N:36]=3)=[CH:3][C:4]2=[N:10][CH:9]=1)=[O:12]
Reactant: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5cc(Br)ccn45)c3)no2)C1
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)n1
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: CN(C)C=O
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(NC(=O)c4cnc5cc(-c6ccn(C)n6)ccn45)c3)no2)C1
Temperature: 80 °C

Procedure:
Methyl 3-(3-(3-(7-bromoimidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (42) (40 mg, 0.078 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (19.6 mg, 0.094 mmol) and Pd(PPh3)4 (9 mg, 0.0078 mmol) were added to a flask equipped with a stir bar. The flask was evacuated and backfilled with nitrogen several times. DMF (1 mL) and 1.8 M K2CO3 (0.094 mmol) were added by syringe. The flask was sealed and heated at 80° C. for 12 hours. The reaction was filtered and directly purified by preparative reverse phase HPLC to afford methyl 3-(3-(4-methyl-3-(7-(1-methyl-1H-pyrazol-3-yl)imidazo[1,2-a]pyridine-3-carboxamido)phenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (F56). MS m/z 513.2 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C(=O)C)[CH2:6][C:5]2([CH3:15])[CH3:14]>Cl>[CH3:14][C:5]1([CH3:15])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][CH2:6]1
Reactant: CC(=O)N1CC(C)(C)c2cc(F)ccc21
Agent: Cl
Product: CC1(C)CNc2ccc(F)cc21
Temperature: 200 °C

Procedure:
According to the procedure described in S. Coulton et al. WO9925709 with the following modifications. N-(4-Fluoro-phenyl)-N-(2-methyl-allyl)-acetamide (5 grams, 24.12 mmol) was added to a microwave tube with aluminum trichloride (7 grams, 52.4 mmol). The tube was capped and heated to 150° C. for 20 minutes under microwave. The slurry was worked up with water and ethyl acetate, the organic layer was extracted with 3 washes of saturated sodium bicarbonate solution and the organic layer was dried over magnesium sulfate. The solution was then filtered and rotary evaporated to yield pure 1-(5-Fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone in quantitative yield. This was converted to the free indoline by suspending the entire 5 grams of product in 20 mL of 6 M HCl and heating in a microwave to 200° C. for 10 minutes. The resulting 5-Fluoro-3,3-dimethyl-2,3-dihydro-1H-indole crystallized on cooling as the hydrochloride salt in quantitative yield. This material was identical to the previously reported compound.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[N+:8]([C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9].C(N(CC)CC)C.O>O1CCOCC1>[OH:4][CH2:3][C:2]([NH:1][S:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=1)(=[O:18])=[O:19])([CH2:5][OH:6])[CH3:7]
Reactant: CC(N)(CO)CO
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CC(CO)(CO)NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 24.8 %

Procedure:
To a stirred solution of 2-amino-2-methyl-1,3-propanediol (1.04 ml, 9.93 mmol) in dioxane (25 ml) was added at room temperature 3-nitrobenzenesulfonyl chloride (2.0 g, 9.02 mmol) and triethylamine (1.38 ml, 9.93 mmol). The light yellow suspension was stirred at room temperature for 6 h, poured into water (100 ml) and extracted with dichloromethane (3×75 ml). The combined organic layers were washed with water (100 ml) and brine (70 ml), dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (heptane/ethyl acetate 1:1) to yield N-(2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-3-nitro-benzenesulfonamide (0.65 g, 25%) as a white solid. MS (ISP) 289.1 [(M−H)−]; mp 116° C.
Reaction SMILES: [Na].[CH2:2]([OH:4])[CH3:3].[NH2:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]=[N:12]2)=[C:8](Cl)[N:7]=1>C(O)(=O)C>[CH3:3][CH2:2][O:4][C:8]1[C:9]2[NH:10][CH:11]=[N:12][C:13]=2[N:14]=[C:6]([NH2:5])[N:7]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CCO
Agent: [Na]
Solvent: CC(=O)O
Product: CCOc1nc(N)nc2nc[nH]c12
Yield: 69 %

Procedure:
Sodium (0.5 g, 22 mmol) was added to anhydrous ethanol (50 ml) under nitrogen. When all of the sodium had reacted, 2-amino-6-chloropurine (750 mg, 4.42 mmol) was added. The reaction was refluxed for 3 h. After cooling, the reaction mixture was neutralised with glacial acetic acid and the solvent was removed. Recrystallisation from water gave the product as a white solid (548 mg, 69%), m.p.>230° C.; (Found: C, 46.76; H, 4.97; N, 39.09. Calc. for C7H9N5O: C, 46.92; H, 5.06; N, 39.09%); νmax (cm−1) 3505, 3484, 3432, 3324, 3191, 3110, 2984, 2901, 2705, 2544 (NH, C—H, NH2); δH (200 MHz, d6-DMSO) 7.808 (1H, s, C(8)H), 6.224 (2H, s, NH2), 4.437 (2H, q, J=7.1 Hz, OCH2), 1.353 (3H, t, J=7.1 Hz. CH2CH3); m/z 179 (M+, 100%), 169 (19), 164 (35), 151 ([MH—Et]+, 36%), 135 ([MH—OEt]+, 43%), 131 (38), 119 (34), 109 (54), 81 (41), 69 (39), 60 (21), 55 (31), 41 (48),
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1.FC(F)(F)[C:14]([O-])=[O:15].FC(F)(F)C(O)=O.[O-2].[Mg+2]>[Pd](Cl)Cl.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:14](=[O:15])[O:9][CH2:8][C:4]=2[C:3]=1[O:10][CH3:11]
Reactant: COc1c(Br)cccc1CO
Reactant: O=C([O-])C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Mg+2]
Agent: [O-2]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1c(Br)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a flask charged with (3-bromo-2-methoxyphenyl)methanol (3.0 g, 14 mmol, 1.0 eq) was added thallic trifluoroacetate (10.0 g, 18.4 mmol, 1.3 eq). To above mixture was added trifluoroacetic acid (25 mL). The reaction was stirred at r.t. for 16 hr, then concentrated. The excess TFA was removed using high vacuum pump. To the residue was added palladium chloride (245 mg, 1.38 mmol, 0.1 eq), magnesium oxide (1.10 g, 27.6 mmol, 2.0 eq) and methanol (35 mL). The reaction was flushed with carbon monoxide three times and stirred under CO at r.t. for 2 hr. To this solution was added ethyl acetate. The mixture was filtered through a pad of celite and washed with EtOAc. The filtrate was concentrated and loaded on silica gel column. The fractions containing 5-bromo-4-methoxy-2-benzofuran-1(3H)-one were concentrated. 1H NMR (500 MHz, CDCl3, δ in ppm): 7.72 (1H, aromatic, d, J=8.0 Hz), 7.49 (1H, aromatic, d, J=8.0 Hz), 5.44 (2H, s, CH2 lactone), 4.00 (3H, s, Me). LC-MS (IE, m/z): 244.88 [M+1]+; tR=2.67 min.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C@@H:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1>ClCCl>[Br:1][CH2:2][C:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([C@@H:18]([NH:20][C:21](=[O:23])[CH3:22])[CH3:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:4]
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCNCC2)cc1
Reactant: O=C(Br)CBr
Solvent: ClCCl
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(C(=O)CBr)CC2)cc1
Temperature: 25 °C

Procedure:
530 μl (6.09 mmol) Bromoacetylbromide are added dropwise to an ice cold mixture of 1.50 g (6.09 mmol) (S)—N-[1-(4-piperidin-4-yl-phenyl)-ethyl]-acetamide (V.1) and 1.03 mL (7.31 mmol) TEA in 20 mL dichloromethane. Then the cooling is removed and the mixture is allowed to warm to rt and then quenched by the addition of water. The mixture is extracted with DCM, the org. layers are combined, washed with water and dried with MgSO4. The solvent is removed in vacuo and the crude product is used without further purification.
Reaction SMILES: O=[C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[CH:4][N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Li+]>>[CH3:2][C:7]1[N:3]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:4]2[C:5]([C:6]=1[C:8]([OH:10])=[O:9])=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: COC(=O)c1ccn(-c2ccccc2)c(=O)c1
Agent: [Li+]
Agent: [OH-]
Product: Cc1c(C(=O)O)c2ccccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
To a solution of methyl 2-oxo-1-phenyl-1,2-dihydropyridine-4-carboxylate (272 mg, 1.03 mmol) in alcohol/water (v/v=1/1, 5 mL) was added lithium hydroxide (62 mg, 1.55 mmol), and the mixture was stirred at room temperature for 8 hours. The reaction mixture was concentrated, acidified by diluted aqueous hydrochloric acid (1 N, 5 mL) and extracted with ethyl acetate (2×10 ml). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 2-methyl-1-phenyl-1H-indole-3-carboxylic acid as white solid (115 mg, 44%). LRMS (M−H+) m/z: calcd for 251.09. found 251.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:17](O)[CH:18]=[CH2:19]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH2:19][CH:18]=[CH2:17])=[O:6]
Reactant: C=CCO
Reactant: O=C(O)c1ccc(O)c(F)c1
Agent: O=S(=O)(O)O
Product: C=CCOC(=O)c1ccc(O)c(F)c1
Temperature: 100 °C
Yield: 55 %

Procedure:
Into a round bottom flask, there are introduced 5.35 g (35 mmoles) of 3-fluoro-4-hydroxybenzoic acid and 50 ml of allyl alcohol. 1.5 ml of concentrated sulfuric acid are added and the mixture is heated to 100° C. for 12 hours. The reaction medium is evaporated to dryness and 200 ml of water are added. The reaction medium is neutralized with sodium bicarbonate and extracted with dichloromethane. The organic phase is decanted, washed with water, dried on magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a silica column by eluting with an 80:20 mixture of dichloromethane and hexane. 3.7 g (55% yield) of the expected ester having a melting point of 42°-43° C. are recovered.
Reaction SMILES: C[O:2][C:3](=[O:30])[C@@H:4]([NH:14][C:15](=[O:29])[CH:16]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:17][S:18]C(=O)C)[CH2:5][S:6]SC[C@H](N)C(O)=O.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].SC[C@H]([C@@H](CS)O)O.O>CO>[CH2:22]([CH:16]([CH2:17][SH:18])[C:15]([NH:14][C@H:4]([C:3]([OH:30])=[O:2])[CH2:5][SH:6])=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)[C@H](CSSC[C@H](N)C(=O)O)NC(=O)C(CSC(C)=O)Cc1ccccc1
Agent: O[C@H](CS)[C@H](O)CS
Agent: [Na+]
Agent: [S-2]
Solvent: CO
Solvent: O
Product: O=C(N[C@@H](CS)C(=O)O)C(CS)Cc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 86 %

Procedure:
N-(S-Acetyl-2'-benzyl-3'-mercaptopropionyl)cystine methyl ester (50 mg) was dissolved in degassed methanol (5 ml) and treated with sodium sulfide nonahydrate (300 mg) and dithiothreitol (122 mg). The mixture was stirred at RT for 14 hours then poured into water (30 ml) and extracted with chloroform (2×20 ml), the aqueous phase acidified to pH 1-2 and re-extraced with ethyl acetate (3×10 ml), dried, (MgSO4) filtered and evaporated to a clear oil, the title compound as an approximately equimolar mixture of diastereoisomers, in 86% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]2[CH:12]=[C:13](N)[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH2:19][F:20])([CH2:17][F:18])[CH:7]=1)=[O:5])[CH3:2].S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:30].[K+]>O.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:11]2[CH:12]=[C:13]([I:30])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH2:19][F:20])([CH2:17][F:18])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(N)cc21
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(I)cc21
Yield: 65.9 %

Procedure:
To a mixture of 4.0 g of 6-amino-2,2-bisfluoromethyl-2H-1-benzopyran-4-carboxylic acid ethyl ester, 1.66 g of sulfuric acid and 40 ml of water was added a mixture of 1.09 g of sodium nitrite, 10 ml of methylene chloride and 10 ml of water with ice-cooling, and the reaction mixture was stirred with ice-cooling for 10 minutes. The reaction mixture was further combined with a mixture of 2.85 g of potassium iodide and 5 ml of water and stirred at room temperature for 1.5 hours. The reaction mixture was combined with water and extracted with methylene chloride. The organic layer was washed with an aqueous 20% sodium sulfite solution and saturated saline, then dried over sodium sulfate and concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (eluent; ethyl acetate:hexane=1:1) to give 3.67 g of 2,2-bisfluoromethyl-6-iodo-2H-1-benzopyran-4-carboxylic acid ethyl ester; m.p. 89-90° C.;
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].O.[SH-:11].[Na+].O>C(O)C>[CH2:6]([O:5][C:3](=[O:4])[C:2]([SH:11])([CH3:9])[CH3:8])[CH3:7]
Reactant: [SH-]
Reactant: CCOC(=O)C(C)(C)Br
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)(C)S
Temperature: 25 °C
Yield: 36 %

Procedure:
Ethyl 2-bromoisobutyrate (48.8 g, 0.250 mole), sodium hydrosulfide hydrate (84 g, 1.5 mole), water (100 mL), ethyl alcohol (200 mL). Let reaction mix stir at room temperature. Next day, no starting material observed. Crude yield: 74.3%; distillation yield: 36.0%.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[CH3:7][N:8]1[CH2:29][C:14]23[CH2:15][CH2:16][CH:17]4[CH:26]([CH:13]2[CH2:12][CH2:11][CH:10]3[CH:9]1[CH3:30])[CH2:25][CH:24]=[C:23]1[C:18]4([CH3:28])[CH2:19][CH2:20][C:21](=O)[CH2:22]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1(C)C=CC=CC=1.C1COCC1>[CH:1](=[C:21]1[CH2:22][C:23]2[C:18]([CH3:28])([CH:17]3[CH:26]([CH2:25][CH:24]=2)[CH:13]2[CH2:12][CH2:11][CH:10]4[CH:9]([CH3:30])[N:8]([CH3:7])[CH2:29][C:14]24[CH2:15][CH2:16]3)[CH2:19][CH2:20]1)[CH3:2]
Reactant: CC1C2CCC3C4CC=C5CC(=O)CCC5(C)C4CCC32CN1C
Reactant: CC(C)(C)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC=C1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 46.5 %

Procedure:
Potassium t-butoxide (1.0 M in THF, 0.3 mL, 0.30 mmol) was added dropwise to a stirred solution of ethyl triphenylphosphonium bromide (156 mg, 0.42 mmol) in 2 mL anhydrous toluene. A bright orange suspension resulted and was stirred at room temperature for 5 hours. Compound 130B (25 mg, 0.076 mmol) in 1 mL THF was added to the above suspension and stirred overnight. The reaction was quenched with saturated ammonium chloride and extracted with dichloromethane to give the crude product, which was purified on silica gel column eluted with 0.3% ammonium hydroxide and 3% methanol in dichloromethane to give the desired product (12 mg, 46% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][NH:14][C:15]=3[CH3:16])[S:10][C:5]=2[C:4](=[O:17])[NH:3]1.Cl.C([O-])(O)=O.[Na+].[F:25][C:26]([F:32])([F:31])CC(=O)C.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[O-]S([O-])(=O)=O.[Mg+2]>CCCCCCC.CCOC(C)=O.CC(N(C)C)=O.CO>[CH3:1][C:2]1([CH2:18][C:26]([F:32])([F:31])[F:25])[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][NH:14][C:15]=3[CH3:16])[S:10][C:5]=2[C:4](=[O:17])[NH:3]1
Reactant: CC(=O)CC(F)(F)F
Reactant: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC(C)(C)N2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC(C)(CC(F)(F)F)N2
Temperature: 50 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
A mixture of 2,2-dimethyl-6-(5-methyl-1H-pyrazol-4-yl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one, 1 M HCl (1.2 mL, 1.2 mmol) and MeOH (4 mL) was stirred at 50° C. for 2 h. Then, the reaction mixture was poured into excess saturated aqueous NaHCO3 and extracted with EtOAc, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was mixed with 4,4,4-trifluorobutan-2-one (0.433 g, 3.43 mmol), CSA (7.97 mg, 0.034 mmol), MgSO4 (0.041 g, 0.343 mmol) and DMA (1 mL). The mixture was microwave-irradiated at 140° C. for 1 h. The mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc then to 90:10 EtOAc/MeOH). The obtained oil was purified again by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc) to give yellow oil. This oil was dissolved with small amount of EtOAc and poured into heptane (100 mL) with stirring. After 5 min, the precipitate was collected by filtration to afford the title compound (33.5 mg, 30%) as a yellow solid:
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.[OH-].[Na+]>CO.O1CCOCC1>[NH2:24][C:8]1[N:7]=[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH:16]1[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: CCCCNc1nc(N)c2nc(OC)n(CC3CCOCC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CCCCNc1nc(N)c2[nH]c(=O)n(CC3CCOCC3)c2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.2 %

Procedure:
To a solution of N2-butyl-8-methoxy-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purine-2,6-diamine (310 mg) in dry methanol (30 ml) at room temperature and under nitrogen was added 4.0M hydrogen chloride in 1,4-dioxane (5.5 ml) in one go. The reaction was left to stir at room temperature for 16 hours. The reaction was neutralised by the addition of 2.0M sodium hydroxide solution and concentrated in vacuo. The residue was taken up in water (10 ml) and the solid filtered and dried on the rotary evaporator (60° C.) for 30 minutes. This afforded the title compound as a solid (170 mg).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]2[NH:11][C:10](=O)[NH:9][C:6]2=[N:7][CH:8]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:10]1[NH:11][C:5]2[C:6]([N:9]=1)=[N:7][CH:8]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2cc(C(F)(F)F)cnc2[nH]1
Product: FC(F)(F)c1cnc2nc(Cl)[nH]c2c1
Temperature: 25 °C

Procedure:
A solution of 6-trifluoromethyl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one from step (c) above (161 mg, 0.789 mmol) in POCl3 (5 mL) was heated at 95° C. for 16 h. The reaction mixture was cooled to room temperature, the solvent was removed in vacuo and the resulting oily residue was purified by silica gel column chromatography, eluting with EtOAc/hexane (1:3) to give the title compound as a light-yellow solid. MS (ESI positive ion) m/z: 222 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[C:4]#[N:5].CO.O.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH2:4][NH2:5]
Reactant: N#Cc1c(Cl)cc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: NCc1c(Cl)cc(Cl)cc1Cl
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,4,6-trichlorobenzonitrile (0.69 mmol) in 2 mL THF was added a solution of BH3 (2.77 mmol, 1M in THF). The reaction mixture was heated to 40° C. for 2 h and then cooled to RT. 1 mL MeOH was added and the mixture was stirred at RT for 30 min. Water was added, the mixture was basified with 1M NaOH solution and extracted twice with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product as slightly yellow oil.
Reaction SMILES: Cl.O1CCOC[CH2:3]1.[C:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([F:19])[CH:11]=1)#[N:9]>CO>[CH3:3][O:15][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][C:10]([C:8]#[N:9])=[CH:11][C:12]=1[F:19]
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(C#N)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
Add 4N hydrochloride in 1,4-dioxane (100 mL, 400 mmol) to 4-cyano-2-fluoro-benzoic acid (10.0 g, 60.5 mmol) in methanol (100 mL). Stir the reaction mixture at room temperature overnight. Concentrate the reaction mixture. Purify the residue by column chromatography (silica gel) eluting with 20% ethyl acetate/hexane to give the title compound (6.8 g, 38.0 mmol).
Reaction SMILES: [O:1]([CH2:19][C:20]1([CH2:28][CH2:29]O)[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22][CH2:21]1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[N+:64]([C:67]1[NH:68][CH:69]=[CH:70][N:71]=1)([O-:66])=[O:65]>O1CCCC1>[O:1]([CH2:19][C:20]1([CH2:28][CH2:29][N:68]2[CH:69]=[CH:70][N:71]=[C:67]2[N+:64]([O-:66])=[O:65])[CH2:21][O:22][C:23]([CH3:27])([CH3:26])[O:24][CH2:25]1)[Si:2]([C:15]([CH3:17])([CH3:18])[CH3:16])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: CC1(C)OCC(CCO)(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CO1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OCC(CCn2ccnc2[N+](=O)[O-])(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.6 %

Procedure:
48 mg (0.112 mmol equivalents) of 5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-5-hydroxyethyl-1,3-dioxane was dissolved in 1 mL of tetrahydrofuran, 32 mg (0.123 mmol equivalents) of triphenylphosphine, 24 μL (0.123 mmol equivalents) of diisopropyl azodicarboxylate, and 38 mg (0.336 mmol equivalents) of 2-nitroimidazole were added thereto, and the mixture was stirred at room temperature (25° C.) for 4 hours. After completion of the reaction, the mixture was concentrated under vacuum, and the obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=4/1) to give 46 mg (0.088 mmol equivalents) of 5-(t-butyldiphenylsiloxymethyl)-2,2-dimethyl-5-[2-(2-nitro-1H-imidazol-1-yl)ethyl]-1,3-dioxane.