Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[N:10]=[C:9]1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.P(Cl)(Cl)([Cl:27])=O>>[CH2:1]([N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[N:10]=[C:9]1[Cl:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1nc2cccnc2n1Cc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Clc1nc2cccnc2n1Cc1ccccc1
Temperature: 25 °C

Procedure:
Grams 21 3-benzyl-2-hydroxy-3H-imidazo[4,5-b]pyridine in 330 ml phosphoryl chloride are refluxed until complete dissolution then gaseous hydrogen chloride is bubbled therein for 3 and a half hours. It is then cooled to room temperature and the undissolved product filtered and washed with toluene; the solution is evaporated in vacuo to a small volume and cautiously poured into ice. The solution is then filtered on charcoal and the filtrate adjusted to pH 7.5 by adding 30% ammonium hydroxyde. The undissolved product is separated by filtration, washed with water ed evaporated in vacuo to dryness, the product thus obtained suspended in 150 ml boiling toluene and the undissolved product filtered off. From the toluene solution are obtained by crystallization 5 g 3-benzyl-2-chloro-3H-imidazo[4,5-b]pyridine melting at 74°-76° C.
Reaction SMILES: [Cl:1]CCC([O-])=O.[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:13]([O:16][CH2:17]C)(=[O:15])[CH3:14]>>[Cl-:1].[CH3:17][O:16][C:13]([CH2:14][N+:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:15]
Reactant: O=C([O-])CCCl
Reactant: c1ccncc1
Reactant: CCOC(C)=O
Product: COC(=O)C[n+]1ccccc1
Product: [Cl-]
Temperature: 80 °C
Yield: 73 %

Procedure:
In a 250 mL round-bottom flask with a stir bar was charged 2-chloromethylacetate (17.5 mL, 0.2 mol), ethyl acetate (50 mL), and pyridine (16.2 mL, 0.2 mol). The overall homogeneous solution was heated with a condenser at 80° C. for 24 h and the resulting heterogeneous white suspension was cooled to room temperature and filtrated under reduced pressure. The off-white filtrate was recrystallized from small amount of ethanol to give the title compound (27.4 g, 73%) as a white solid. MS (ES+): 152 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22](Cl)=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:25][CH3:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:27]([NH2:30])[CH2:28][CH3:29].C(N(C(C)C)CC)(C)C.Cl>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH:30][CH2:27][CH2:28][CH3:29])=[O:23])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:25][CH3:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCN
Reactant: CCc1cc(Cc2ccc(CC(=O)Cl)cc2)nc(-c2cccc(Cl)c2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCNC(=O)Cc1ccc(Cc2cc(CC)nc(-c3cccc(Cl)c3)n2)cc1
Reaction time: 2.5 h
Yield: 53.9 %

Procedure:
To a stirred solution of crude 2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)acetyl chloride (˜0.20 mmol) in dichloromethane (8 mL) at 0° C. was added n-propylamine (0.082 mL, 1.00 mmol) followed by diisopropylethylamine (0.17 mL, 1.00 mmol). After stirring for 2.5 h, the reaction mixture was diluted with dichloromethane (50 mL) and water (5 mL). The mixture was acidified with 2N aqueous HCl until pH˜5. The organic layer was washed with saturated sodium chloride (5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 1:1) as eluent followed by preparative HPLC (water/acetonitrile with 0.05% TFA) to afford the title compound (0.044 g, 55%) as a white solid. MW=407.94. M.p. 123-125° C. 1H NMR (DMSO-d6, 500 MHz) δ 8.37-8.31 (m, 2H), 7.98-7.93 (m, 1H), 7.60 (dt, J=8.5, 2.0 Hz, 1H), 7.55 (t, J=7.5 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 7.24 (s, 1H), 7.20 (d, J=8.0 Hz, 2H), 4.09 (s, 2H), 3.34 (s, 2H), 2.97 (q, J=6.0 Hz, 2H), 2.77 (t, J=7.5 Hz, 2H), 1.43-1.34 (m, 2H), 1.26 (t, J=7.5 Hz, 3H), 0.81 (t, J=7.5 Hz, 3H); APCI MS m/z 408 [M+H]+.
Reaction SMILES: [I:1][CH2:2][C:3]12[CH2:10][CH2:9][C:6]([C:11]3SC(C)=N[C:12]=3[C:17]3[CH:22]=[CH:21][CH:20]=CC=3)([CH2:7][CH2:8]1)[O:5][CH2:4]2.CC1SC=C(C2C=CC=CC=2)N=1.BrC1C=C(C=CC=1)[O:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][O:41]1>>[I:1][CH2:2][C:3]12[CH2:8][CH2:7][C:6]([C:11]3[CH:20]=[CH:21][CH:22]=[C:17]([O:39][CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][O:41]4)[CH:12]=3)([CH2:9][CH2:10]1)[O:5][CH2:4]2
Reactant: Cc1nc(-c2ccccc2)c(C23CCC(CI)(CC2)CO3)s1
Reactant: Brc1cccc(OC2CCCCO2)c1
Agent: Cc1nc(-c2ccccc2)cs1
Product: ICC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2

Procedure:
4-(Iodomethyl)-1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octane was prepared using a procedure analogous to 5-(4-(iodomethyl)-2-oxabicyclo[2.2.2]octan-1-yl)-2-methyl-4-phenylthiazole except that 2-methyl-4-phenylthiazole was replaced with 2-(3-bromophenoxy)tetrahydro-2H-pyran. The title compound was obtained (1.2 g, 2.80 mmol, 100% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.24 (t, J=8.0 Hz, 1H), 7.14-7.11 (m, 1H), 7.02 (ddd, J=7.8, 1.6, 1.0 Hz, 1H), 6.96 (ddd, J=8.2, 2.5, 0.9 Hz, 1H), 5.45 (t, J=3.2 Hz, 1H), 4.00-3.87 (m, 3H), 3.62 (dtd, J=11.3, 4.1, 1.2 Hz, 1H), 3.08 (s, 2H), 2.16-1.98 (m, 5H), 1.93-1.58 (m, 9H).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[CH2:5]1[C:12]2[N:8]([CH:9]=[CH:10][CH:11]=2)[CH2:7][CH2:6]1>C1(C)C=CC=CC=1.CCOCC>[CH2:11]1[C:12]2[N:8]([C:7]([C:1]([Cl:4])=[O:2])=[CH:6][CH:5]=2)[CH2:9][CH2:10]1
Reactant: c1cc2n(c1)CCC2
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C(Cl)c1ccc2n1CCC2
Temperature: 25 °C

Procedure:
To a stirred, ice-bath cooled portion (30 ml) of 12.5% phosgene in toluene was added a solution of 2,3-dihydro-1H-pyrrolizine (0.80 g, 0.0074 m) in ether (30 ml) dropwise over ca two minutes. After stirring cold for ca 2.5 hr, the reaction mixture is allowed to warm to room temperature, the volatiles are removed in vacuo, and the resultant crystalline 2,3-dihydro-1H-pyrrolizine-5-carbonyl chloride used as is in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH2:6]O)[CH2:5][O:4][CH2:3]1.[OH-].[Na+].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.O>C(Cl)Cl>[CH3:1][C:2]1([CH2:6][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH2:5][O:4][CH2:3]1
Reactant: CC1(CO)COC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)CC2(C)COC2)cc1
Temperature: 0 °C

Procedure:
3-methyl-3-oxetanemethanol (100 g, 0.98 mol) was dissolved in 250 mL methylene chloride, and a 35% solution of sodium hydroxide (143.60 g, 1.08 mol)was added, and the reaction was cooled to 0° C. A solution of p-toluenesulfonyl chloride was added (186.67 g, 0.98 mol) in 375 mL methylene chloride was added over 1 hour. A white precipitate formed immediately. The reaction was stirred for 10 additional hours. 1000 mL of water was added. The dichloromethane solution layer was then removed, and dried with sodium sulfate, and the solvent was removed. Yield: 217.77 grams of 3-methyl-3-tosylmethyloxetane as white crystals, 87%.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].CCN(CC)CC.[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH:25]([C:29]([OH:31])=O)[CH2:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C.Cl>ClCCl.CCOC(C)=O>[CH3:2][O:3][N:4]([CH3:5])[C:29]([CH:25]1[CH2:26][CH2:27][CH2:28][N:23]([C:21]([O:20][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:22])[CH2:24]1)=[O:31]
Reactant: O=C(O)C1CCCN(C(=O)OCc2ccccc2)C1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
A 1000-mL 3-necked round-bottom flask was charged with a solution of N-methoxymethan amine hydrochloride (21.45 g, 217.7 mmol, 1.10 equiv, 99%) in dichloromethane (DCM) (250 mL). To the mixture was added Et3N (22.22 g, 217.80 mmol, 1.10 equiv, 99%) at 0-10° C., followed by addition 1-(benzyloxycarbonyl)piperidine-3-carboxylic acid (58 g, 220.3 mmol, 1.00 equiv) in dichloromethane (150 mL) drop wise at 2° C. over 2 hr period. To this mixture was added EDC.HCl (42.02 g, 217.80 mmol, 1.10 equiv, 99%) in several batches while maintaining the temperature below 5° C. The resulting solution was allowed to stir at room temperature overnight. The progress was monitored by TLC (EtOAc: PE=1:1). Upon completion, the reaction was then quenched by the addition of water (500 mL). The resulting mixture was then extracted with dichloromethane (2×500 mL). Combined organic layers were dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator. The resulting residue was purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:10) affording benzyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate as a white syrup (57 g, 83%).
Reaction SMILES: [CH2:1]1[CH:13]2[N:4]([CH2:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]2=O)[C:3](=[N:15]O)[CH2:2]1.[OH-:17].[Na+]>C(OCC)(=O)C>[NH:15]1[C:3](=[O:17])[CH2:2][CH2:1][C:13]2[N:4]=[CH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:12]1=2
Reactant: O=C1c2ccccc2CN2C(=NO)CCC12
Reactant: [OH-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C1CCc2ncc3ccccc3c2N1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To 300 g of vigorously stirred polyphosphoric acid warmed to 115° C., 10 g of 1,10a-dihydropyrrolo[1,2-b]-isoquinoline-3,10[2H,5H]-dione oxime was added. The mixture was held at this bath temperature for 10 minutes. The internal temperature rose to 135°-140° C. The mixture was then poured into 1500 ml of ice water, and the mixture was basified with 50% NaOH to about pH=8 and the resultant crystalline precipitate was collected to give 7.14 g of crude product. Chromatography on a silica gel column, using ethyl acetate gave 4.8 g of pure product, m.p. 225° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33]([C:41]1[C:49]3[C:44](=[C:45]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:46]=[CH:47][CH:48]=3)[NH:43][CH:42]=1)([CH2:37][CH2:38][CH2:39]O)[CH2:32][CH2:31]2>O1CCCC1.CCOCC>[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[C:33]([C:41]1[C:49]3[C:44](=[C:45]([NH:50][S:51]([CH3:54])(=[O:53])=[O:52])[CH:46]=[CH:47][CH:48]=3)[NH:43][CH:42]=1)([CH2:37][CH2:38][CH2:39][I:25])[CH2:32][CH2:31]2
Reactant: CS(=O)(=O)Nc1cccc2c(C3(CCCO)CCc4cc(F)ccc43)c[nH]c12
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CS(=O)(=O)Nc1cccc2c(C3(CCCI)CCc4cc(F)ccc43)c[nH]c12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 40 %

Procedure:
To a solution of triphenylphosphine (422 mg, 1.61 min ol, 1.30 equivalents) and imidazole (219 mg, 3.22 mmol, 2.60 equivalents) in anhydrous tetrahydrofuran (10 ml) add iodine (410 mg, 1.61 mmol, 1.30 equivalents). After stirring for 20 minutes at room temperature under nitrogen, add N-{3-[5-Fluoro-1-(3-hydroxy-propyl)-indan-1-yl]-1H-indol-7-yl}-methanesulfonamide (500 mg, 1.24 mmol) and stir for 48 hours. Dilute with ether, wash with water (2×), wash with 1N aqueous hydrochloric acid (2×), dry over anhydrous sodium sulfate, filter, and concentrate the solution. Purify the residue on silica eluting with 50 to 100% ethyl acetate/hexanes over 25 minutes to obtain the title compound as a white solid (254 mg, 40%). LC-MS m/z 385.0 (M+−I).
Reaction SMILES: [OH:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[N:12]1[CH2:17][CH2:16][CH:15]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])[CH2:14][CH2:13]1.N1C=CN=C1.[CH3:29][C:30]([Si:33](Cl)([CH3:35])[CH3:34])([CH3:32])[CH3:31]>C(Cl)Cl>[Si:33]([O:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1[N:12]1[CH2:13][CH2:14][CH:15]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])[CH2:16][CH2:17]1)([C:30]([CH3:32])([CH3:31])[CH3:29])([CH3:35])[CH3:34]
Reactant: CON(C)C(=O)C1CCN(C2Cc3ccccc3CC2O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(C2Cc3ccccc3CC2O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
To a solution of 22 (400 mg, 1.25 mmol) and imidazole (400 mg) in CH2Cl2 (50 mL), TBDMSCl (2.5 mmol) was added. The reaction mixture was stirred overnight at room temperature until TLC indicated that the reaction was complete. The reaction mixture was washed by brine and 1M NaH2PO4 (30 mL×3). The organic layer was dried and concentrated to a residue. The crude product was purified with column chromatography to afforded 23 (400 mg, 70%). 1H NMR (CDCl3,): δ 0.12 (s, 6H), 0.91 (s, 9H), 1.65-1.77 (m, 4H), 2.46-3.05 (m, 9H), 3.17 (s, 3H), 3.69 (s, 3H), 4.13 (br, 2H), 7.04-7.12 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=4[F:34])=[O:22])=[C:16]([F:35])[CH:15]=3)[CH:9]=[C:10]([CH2:11][CH2:12]Br)[N:6]2[N:5]=[CH:4][N:3]=1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C(N(CC)CC)C.[I-].[Na+]>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=4[F:34])=[O:22])=[C:16]([F:35])[CH:15]=3)[CH:9]=[C:10]([CH2:11][CH2:12][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(CCBr)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c12
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncnn2c(CCN3CCOCC3)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c12
Temperature: 55 °C
Yield: 34.4 %

Procedure:
A mixture of the crude 1-{4-[4-amino-7-(2-bromoethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-fluorophenyl}-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea (500 mg, crude, 0.331 mmol), morpholine (0.10 ml, 1.12 mmol), triethylamine (0.08 ml, 0.60 mmol) and sodium iodide (7 mg, 0.05 mmol) in 4 ml DMF was heated at 55° C. in a closed vial for 16 h. Cooled to rt, the crude was diluted with 20 ml EtOAc and was washed with aq saturated NaHCO3, brine and dried over Na2SO4. The crude was concentrated and purified via column chromatography (95:5 v/v CH2Cl2—CH3OH) to afford 64 mg of the title compound (yield 47%). 1H-NMR (DMSO-d6 and 1 drop TFA-d) δ 9.44 (d, J=3 Hz, 1H), 9.33(d, J=3 Hz, 1H), 8.65(dd, J=7, 2 Hz, 1H, 8.32(t, J=8 Hz, 1H), 8.15(s, 1H), 7.55-7.51(m, 1H), 7.48-7.24(m, 4H), 6.83(s, 1H), 4.03-4.01 (m, 2H), 3.69-3.49(m, 8H), 3.38-3.33(m, 2H); MS [M+H]+=562.3; LCMS RT=2.84 min.
Reaction SMILES: CO.S(=O)(=O)(O)O.[CH3:8][O:9][C:10]1[C:15]2[O:16][CH2:17][CH2:18][O:19][C:14]=2[C:13]([C:20]([OH:22])=[O:21])=[CH:12][C:11]=1[S:23](=[O:26])(=[O:25])[NH2:24].[C:27](=O)([O-])[O-].[Na+].[Na+]>O>[CH3:27][O:21][C:20]([C:13]1[C:14]2[O:19][CH2:18][CH2:17][O:16][C:15]=2[C:10]([O:9][CH3:8])=[C:11]([S:23](=[O:26])(=[O:25])[NH2:24])[CH:12]=1)=[O:22]
Reactant: COc1c(S(N)(=O)=O)cc(C(=O)O)c2c1OCCO2
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc(S(N)(=O)=O)c(OC)c2c1OCCO2
Yield: 96.5 %

Procedure:
396 g of methanol were introduced into a balloon flask provided with a condenser and then 51 g of sulfuric acid and 114.5 g of 8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid were added while cooling. The mixture was heated under reflux and then poured into 485 cm3 of water and 40 g of sodium carbonate. The precipitate was dried off, washed and dried. 110.5 g of methyl-8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylate were obtained (M.P.: 202°-203° C.; yield: 92%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[CH:22]=[CH:21][N:20]([CH2:23][CH3:24])[N:19]=1>CN(C=O)C>[CH2:23]([N:20]1[CH:21]=[CH:22][C:18]([CH2:17][S:8][C:6]2[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=2)=[N:19]1)[CH3:24]
Reactant: Cc1cc(O)nc(S)n1
Reactant: CCn1ccc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1ccc(CSc2nc(C)cc(O)n2)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 39.1 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (341 mg, 2.4 mmol) was dissolved in anhydrous DMF (20 mL), then potassium carbonate (995 mg, 7.2 mmol) and 3-(bromomethyl)-1-ethyl-1H-pyrazole (590 mg, 3.1 mmol) were added. The mixture was stirred for 2.5 hours at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 8% DCM in MeOH to afford 2-{[(1-ethyl-1H-pyrazol-3-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (235 mg, 39% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 1.34 (t, J=7.2 Hz, 3H), 2.20 (s, 3H), 4.07 (q, J=7.3 Hz, 2H), 4.32 (s, 2H), 5.99 (bs, 1H), 6.19 (d, J=2.2 Hz, 1H), 7.63 (d, J=2.2 Hz, 1H); LRMS (ES+) m/z 251 (100%, M+1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[NH:6][C:7]([CH2:13][CH2:14][CH3:15])=[N:8]2.[C:16]([O:20][C:21]([C:23]1[C:24]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35]Br)=[CH:31][CH:30]=2)=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[Cl:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[N:6]=[C:7]([CH2:13][CH2:14][CH3:15])[N:8]2[CH2:35][C:32]1[CH:33]=[CH:34][C:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CCCc1nc2ncnc(Cl)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(Cl)ncnc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 40 °C
Reaction time: 0.33 h

Procedure:
To a suspension of NaH (0.20 g) in dry DMF (3 ml), 6-chloro-8-propyl-purine (0.06 g, 0.3 mmol) was added, and the mixture was stirred at 40° C. for 20 minutes. t-Butyl-4-bromomethylbiphenyl-2'-carboxylate (0.11 g, 0.31 mmol) was then added at room temperature and stirring continued for 3 hours at 40° C. The content of the flask was poured into ice-water (100 ml and extracted with ethylacetate. The organic phase was separated and dried over MgSO4. Removal of the solvent under reduced pressure gave the crude product which was then purified by flash-chromatography on silica-gel using ethylacetate-hexane (1:1). The pure titled compound was obtained as a glass-like solid (0.073 g, 53%). NMR (CDCl3): δ 1.04 (t, J=9 Hz, 3H), 1.213 (s, 9H), 1.91 (m, 2H), 2.89 (t, 2H), 5.52 (s, 2H), 7.15-7.52 (m, 7H), 7.79 (dd, J1 =8 Hz and J2 =2 Hz, 1H), 8.72 (s, 1H); FAB-MS: m/e 463 and 465 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@:12]([F:15])([CH3:14])[CH2:11][N:10]1[C:16](=[O:38])[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([O:27]CC3C=CC=CC=3)=[CH:24][CH:25]=2)[C:20]([C:35](=[O:37])[CH3:36])=[CH:19]1)=[O:8].C(O)(C(F)(F)F)=O.C1(SC)C=CC=CC=1>>[Cl:1][C:2]1[C:3]([F:42])=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:13][C@:12]([F:15])([CH3:14])[CH2:11][N:10]1[C:16](=[O:38])[CH2:17][N:18]1[C:26]2[C:21](=[CH:22][C:23]([OH:27])=[CH:24][CH:25]=2)[C:20]([C:35](=[O:37])[CH3:36])=[CH:19]1)=[O:8]
Reactant: CC(=O)c1cn(CC(=O)N2C[C@](C)(F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccc(OCc3ccccc3)cc12
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cn(CC(=O)N2C[C@](C)(F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccc(O)cc12

Procedure:
The title compound was prepared in a similar manner as described above for Example 577 from (2S,4R)-1-[2-(3-acetyl-5-benzyloxy-indol-1-yl)-acetyl]-4-fluoro-4-methyl-pyrrolidine-2-carboxylic acid 3-chloro-2-fluoro-benzylamide (57.0 mg, 0.096 mmol), TFA (3 mL), and thioanisole (0.114 mL, 0.960 mmol). Solid. MS (LC/MS): 504 [M+H]+; tR (HPLC, conditions k): 3.22 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:16]2[C@@H:15]3[CH2:17][C@@H:14]3[CH2:13][C:12]=2[C:11]([C:18](Cl)=[O:19])=[N:10]1.[C:21]([C:25]1[O:29][N:28]=[C:27]([NH2:30])[CH:26]=1)([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[C:21]([C:25]1[O:29][N:28]=[C:27]([NH:30][C:18]([C:11]2[C:12]3[CH2:13][C@H:14]4[CH2:17][C@H:15]4[C:16]=3[N:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[N:10]=2)=[O:19])[CH:26]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(Cl)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Reactant: CC(C)(C)c1cc(N)no1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)c2nn(-c3ccc(F)cc3F)c3c2C[C@H]2C[C@@H]32)no1
Temperature: 23 °C
Reaction time: 2.5 h
Yield: 72 %

Procedure:
(1aR,5aR)-2-(2,4-difluorophenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl chloride (40 mg, 0.136 mmol) was added to a solution of 5-tert-butylisoxazol-3-amine (19.03 mg, 0.136 mmol), triethylamine (0.038 mL, 0.271 mmol), and DMAP (1.658 mg, 0.014 mmol) in dichloromethane (1 mL). The orange solution was stirred at 23° C. for 2.5 h. The mixture was purified by silica gel flash chromatography to give the title compound (39 mg) as a white solid. LCMS m/z=399.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.52 (td, J=4.8, 3.3 Hz, 1H), 1.20 (td, J=7.8, 4.9 Hz, 1H), 1.36 (s, 9H), 2.14-2.20 (m, 1H), 2.29-2.35 (m, 1H), 2.98 (d, J=16.9 Hz, 1H), 3.08 (dd, J=16.6, 6.4 Hz, 1H), 6.79 (s, 1H), 7.01-7.08 (m, 2H), 7.63-7.69 (m, 1H), 9.17 (s, 1H).
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:26]2[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[S:29][CH:30]=2)\[C:23](O)=[O:24])[CH2:19][CH2:18]1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:39][C@@H:40]1[C:43](=[O:44])[NH:42][C@@H:41]1[CH2:45][N:46]1[N:50]=[C:49]2[CH2:51][N:52]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:53][C:48]2=[N:47]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH:1]([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:26]2[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[S:29][CH:30]=2)\[C:23]([NH:39][C@@H:40]2[C:43](=[O:44])[NH:42][C@@H:41]2[CH2:45][N:46]2[N:50]=[C:49]3[CH2:51][N:52]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:53][C:48]3=[N:47]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)O)cs1
Reactant: CC(C)(C)OC(=O)N1Cc2nn(C[C@H]3NC(=O)[C@H]3N)nc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2nc3c(n2)CN(C(=O)OC(C)(C)C)C3)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
To a cooled (0° C.) slurry of (Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)-imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (15.3 mg, 0.028 mmol), tert-butyl 2-(((2R,3S)-3-amino-4-oxoazetidin-2-yl)methyl)-4,6-dihydropyrrolo[3,4-d][1,2,3]triazole-5(2H)-carboxylate (8.3 mg, 0.027 mmol) and HATU (11.4 mg, 0.029 mmol) in DMF (500 μL) was added DIPEA (9.5 μL, 0.054 mmol). After stirring at rt for 16 h, it was diluted with EtOAc and washed with LiCl (5%, aq). The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc-Heptane) to afford the title compound (18.1 mg, 81%) as a white solid. Rt=1.08 min, m/z=828.5 (M+1) Method 2m_acidic.