Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](Cl)[S:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH:19]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([N:27]3[CH2:28][CH2:29][N:24]([CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:25][CH2:26]3)[S:8][C:4]=2[CH:3]=1
Reactant: Clc1nc2ccc(Br)cc2s1
Reactant: C1CCC(N2CCNCC2)C1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Brc1ccc2nc(N3CCN(C4CCCC4)CC3)sc2c1
Yield: 97 %

Procedure:
To a solution of 6-bromo-2-chlorobenzothiazole (3 g, 12.1 mmol) in ethanol (50 mL) was added triethylamine (5.04 mL, 36.3 mmol) and 1-cyclopentylpiperazine (1.86 g, 12.1 mmol). The reaction mixture was heated at reflux for 16 h and then concentrated under reduced pressure. The residue was extracted with ethyl acetate and the combined organic extracts were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to afford 4.3 g (99%) of 6-bromo-2-(4-cyclopentylpiperazin-1-yl)benzothiazole.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9])=[CH:2]1.[H][H]>[Pd].C(OCC)(=O)C>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH2:2]1
Reactant: [H][H]
Reactant: O=C(O)/C=C/c1ccoc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)CCC1CCOC1
Yield: 95.4 %

Procedure:
A solution of (2E)-3-(3-furanyl)-2-propenoic acid (4.75 g, 34.4 mmol) and 10% palladium on carbon (0.366 g, 3.44 mmol) in ethyl acetate (100 ml) was hydrogentated at atmospheric pressure and room temperature for 72 hours. Hydrogen uptake ˜1.4 L (expected 2.4 L). The catalyst was filtered through Celite and concentrated in vacuo to give a brown oil. Analysis by 1H-NMR showed that the some material still contained the furan ring. Hydrogenation was continued under the same conditions with fresh catalyst for a further 24 hours with additional hydrogen uptake of 400 ml. The catalyst was filtered through Celite and the filtrate concentrated in vacuo to afford the title compound as a colourless oil (4.73 g).
Reaction SMILES: [Br:1][C:2]1[C:7]2=[N:8][S:9][N:10]=[C:6]2[C:5]([CH2:11]Br)=[CH:4][CH:3]=1.C(=O)([O-])[O-:14].[K+].[K+]>O>[Br:1][C:2]1[C:7]2[C:6](=[N:10][S:9][N:8]=2)[C:5]([CH2:11][OH:14])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccc(Br)c2nsnc12
Agent: [K+]
Solvent: O
Product: OCc1ccc(Br)c2nsnc12
Temperature: 110 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
A mixture of 4-bromo-7-bromomethyl-benzo[1,2,5]thiadiazole (Example 5.1) (29.05 g), potassium carbonate (65.2 g) and water (400 ml) was stirred at 110° C. for 16 hours. The reaction mixture was cooled to ambient temperature and quenched by addition of aqueous hydrochloric acid (2M) (400 ml). Ethyl acetate (600 ml) was added to the mixture. The phases were separated and the organic layer was washed successively with aqueous hydrochloric acid (2M) (400 ml), water (250 ml) and brine (250 ml), dried over sodium sulfate and concentrated to give (7-bromo-benzo[1,2,5]thiadiazol-4-yl)-methanol (20.22 g) as a orange solid. 1H-NMR (400 MHz, CDCl3): 7.87 (d, 1H), 7.57 (d, 1H), 5.14 (s, 2H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[N:12]([C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH:31]([C:34]1[N:35]=[N:36][N:37]([CH2:39][C:40](O)=[O:41])[CH:38]=1)([CH3:33])[CH3:32]>>[Si:22]([O:21][CH2:20][C:19]([N:12]1[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:40](=[O:41])[CH2:39][N:37]3[CH:38]=[C:34]([CH:31]([CH3:32])[CH3:33])[N:35]=[N:36]3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:30])[CH3:29])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: CC(C)c1cn(CC(=O)O)nn1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cnccc21
Product: CC(C)c1cn(CC(=O)Nc2cncc(C(=O)c3cn(C(C)(C)CO[Si](C)(C)C(C)(C)C)c4ccncc34)c2)nn1

Procedure:
Prepared according to Method Z (Preparation 8) using (5-Amino-pyridin-3-yl)-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation 28) and (4-isopropyl-[1,2,3]triazol-1-yl)acetic acid. LCMS (5 minute run) Rt=3.32 minutes MS m/z 576 [M+H]+
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([S:32][CH2:33][CH3:34])/[CH:13]=[C:14](/[CH2:16][CH2:17][CH2:18][C@@H:19]([CH2:21][CH2:22][CH2:23][C@@H:24]([CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH3:25])[CH3:20])\[CH3:15]>C(Cl)Cl>[CH2:12]([S:32]([CH2:33][CH3:34])=[O:9])/[CH:13]=[C:14](/[CH2:16][CH2:17][CH2:18][C@@H:19]([CH2:21][CH2:22][CH2:23][C@@H:24]([CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH3:25])[CH3:20])\[CH3:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSC/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Solvent: ClCCl
Product: CCS(=O)C/C=C(\C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
5.1 g of m-chloroperbenzoic acid was added to a solution of 10.0 g of ethyl phytyl thioether dissolved in 30 ml of methylene chloride. The resulting mixture was stirred for 2 hours at room temperature. After the completion of the reaction, the reaction mixture was washed with 2% aqueous sodium hdyrogensulfite solution, 3% aqueous sodium hydrogencarbonate solution and water in this order and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluant: n-hexane:ethyl acetate =9:1) to obtain 9.4 g (yield: 90%) of oily ethyl phytyl sulfoxide.
Reaction SMILES: [CH3:1][Si:2]([CH3:10])([CH3:9])[O:3][C:4]([CH3:8])([C:6]#[CH:7])[CH3:5].[CH3:11][C:12]1([CH3:19])[C:16]([CH3:18])([CH3:17])[O:15][BH:14][O:13]1.C12BC(CCC1)CCC2>O1CCCC1>[CH3:1][Si:2]([CH3:10])([CH3:9])[O:3][C:4]([CH3:8])(/[CH:6]=[CH:7]/[B:14]1[O:15][C:16]([CH3:18])([CH3:17])[C:12]([CH3:19])([CH3:11])[O:13]1)[CH3:5]
Reactant: CC1(C)OBOC1(C)C
Reactant: C#CC(C)(C)O[Si](C)(C)C
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Product: CC(C)(/C=C/B1OC(C)(C)C(C)(C)O1)O[Si](C)(C)C
Temperature: 60 °C
Yield: 22 %

Procedure:
To a solution of trimethyl(2-methylbut-3-yn-2-yloxy)silane (1.5 g, 9.60 mmol) in tetrahydrofuran (15 mL) was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.79 mL, 19.19 mmol), followed by addition of 9-BBN (9-borabicyclo[3.3.1]nonane) dimer (0.117 g, 0.480 mmol). This mixture was heated at 60° C. for 24 hours. The reaction was cooled and quenched carefully with saturated ammonium chloride solution. The reaction mixture was extracted with ethyl acetate (2×15 mL). The organics were combined, dried, concentrated and the residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-60% ethyl acetate in hexanes) to afford the title compound (600 mg, 22% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.06-0.08 (m, 9H) 1.19 (s, 12H) 1.25 (s, 6H) 5.41 (d, J=17.85 Hz, 1H) 6.53 (d, J=17.85 Hz, 1H); MS (DCI/NH3) m/z 285 (M+H)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Br:8][C:9]1[C:10]([CH3:20])=[CH:11][C:12]([OH:19])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15]>N1C=CC=CC=1>[C:1]([O:19][C:12]1[CH:11]=[C:10]([CH3:20])[C:9]([Br:8])=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(Br)c(C)cc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COC(=O)c1cc(Br)c(C)cc1OC(C)=O
Reaction time: 4 h
Yield: 97.4 %

Procedure:
Acetic anhydride (3.06 mL, 32.5 mmol) was added to a solution of methyl 5-bromo-2-hydroxy-4-methylbenzoate (3.98 g, 16.24 mmol), which may be prepared according to procedure described in Description 2, in Pyridine (10 mL) was added. The reaction mixture was stirred for four hours. The solvent was removed in vacuo and the residue was purified by SP4 (10-20% EtOAc/hexane) to yield the desired compound as oil (4.54 g, 97% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=2)([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:25].[Cl-].[NH4+]>O1CCCC1>[F:20][C:18]1[CH:19]=[C:14]([C:10]2([O:13][CH3:25])[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2)[CH:15]=[C:16]([F:21])[CH:17]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)cc(F)c2)C1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC1(c2cc(F)cc(F)c2)CCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.25 h
Yield: 66.3 %

Procedure:
To a solution of tert-butyl-3-(3,5-difluorophenyl)-3-hydroxypyrrolidin-1-carboxylate (3.8 g, 12.7 mmol) in dry tetrahydrofuran (50 mL), was added sodium hydride (60% dispersion in mineral oil, 0.76 g, 19 mmol). The mixture was stirred for 10 min after which iodomethane (1.58 mL, 25.4 mmol) was added. The mixture was stirred for 15 min, aqueous saturated ammonium chloride solution (50 ml) was added and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic phase was dried (Na2SO4), filtered and evaporated. Purification by flash column chromatography on silica gel (ethyl acetate/isooctane, 1:9 to 1:1) gave the title compound (2.64 g, 66%). MS m/z (rel. intensity, 70 eV) 257 (31), 240 (17), 212 (13), 127 (18), 57 (bp).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:25][NH2:26])=[N:8][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[C:10]=1[CH:11]1[CH2:13][CH2:12]1)=[O:5])[CH3:2].CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:38])[CH3:37]>C1COCC1.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:25][NH:26][C:36](=[O:38])[CH3:37])=[N:8][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:23])([F:22])[F:24])[CH:15]=2)[C:10]=1[CH:11]1[CH2:12][CH2:13]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CN)nn(-c2cccc(OC(F)(F)F)c2)c1C1CC1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(CNC(C)=O)nn(-c2cccc(OC(F)(F)F)c2)c1C1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of 3-aminomethyl-5-cyclopropyl-1-(3-trifluoromethoxy-phenyl)-1H-pyrazole-4-carboxylic acid ethyl ester (46 mg, 0.12 mmol) and iPr2NEt (0.06 ml, 0.37 mmol) in 0.5 ml THF under ice cooling was treated with acetylchloride (0.011 ml, 0.15 mmol). The yellow suspension was stirred 2 h at 0° C., then diluted with EtOAc and washed with water and brine. The aqueous phases were extracted with EtOAc. The organic layers were dried over magnesium sulfate, evaporated and chromatographed (amino-phase silica gel, EtOAc) to give the title compound as a yellow oil (37 mg, 72%). MS: 412.3 (MH+).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:15]([O:31][CH3:32])=[C:16]([C:22]2[CH:23]=[N:24][C:25]([N:28]([CH3:30])[CH3:29])=[N:26][CH:27]=2)[C:17]([CH3:21])=[C:18]([Cl:20])[CH:19]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:20][C:18]1[C:17]([CH3:21])=[C:16]([C:22]2[CH:27]=[N:26][C:25]([N:28]([CH3:30])[CH3:29])=[N:24][CH:23]=2)[C:15]([O:31][CH3:32])=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:19]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: COc1c(C(C)N)cc(Cl)c(C)c1-c1cnc(N(C)C)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1-c1cnc(N(C)C)nc1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (41 mg, 0.20 mmol), 5-[3-(1-aminoethyl)-5-chloro-2-methoxy-6-methylphenyl]-N,N-dimethylpyrimidin-2-amine (60 mg, 0.2 mmol), and N,N-diisopropylethylamine (0.065 mL, 0.37 mmol) in isopropyl alcohol (0.7 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C21H24ClN8O (M+H)+: m/z=439.2. found: 439.1. 1H NMR (DMSO-d6, 400 MHz) δ 12.91 (1H, br s), 8.29 (2H, s), 8.20 (1H, m), 8.13 (1H, s), 8.10 (1H, s), 7.61 (1H, s), 5.73 (1H, m), 3.46 (3H, s), 3.16 (6H, s), 2.06 (3H, s), 1.47 (3H, d, J=6.8 Hz) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7](=[O:19])[CH2:6][CH2:5]2.[O:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=[C:21]1[S:29](Cl)(=[O:31])=[O:30]>N1C=CC=CC=1>[CH2:12]([S:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C:7]2=[O:19])=[CH:3][C:2]=1[NH:1][S:29]([C:21]1[O:20][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH:22]=1)(=[O:30])=[O:31])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cc2c(cc1SCc1ccccc1)C(=O)CC2
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Solvent: c1ccncc1
Product: O=C1CCc2cc(NS(=O)(=O)c3cc4ccccc4o3)c(SCc3ccccc3)cc21
Yield: 97.3 %

Procedure:
Following General Procedure B, the title compound (752 mg, 47%) was prepared from 5-Amino-6-(benzylthio)-2,3-dihydro-1H-inden-1-one (463 mg, 1.72 mmol) and benzofuran-2-sulfonyl chloride (371 mg, 1.72 mmol) in pyridine (3 ml).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](O)([CH3:11])[CH3:10].FC(F)(F)C(O)=O.[NH:20]=[N+:21]=[N-:22]>CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]([N:20]=[N+:21]=[N-:22])([CH3:11])[CH3:10]
Reactant: CC(C)(O)c1c(F)cccc1F
Reactant: [N-]=[N+]=N
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Product: CC(C)(N=[N+]=[N-])c1c(F)cccc1F
Reaction time: 24 h

Procedure:
20.6 g (120 millimoles) of 2-(2,6-difluorophenyl)propan-2-ol are dissolved in 300 ml of hydrazoic acid solution (1N, in benzene) and 22.8 g (200 millimoles) of trifluoroacetic acid are added to this solution. After 24 hours at room temperature, the reaction solution is diluted with 500 ml of hexane, washed with water and then with sodium bicarbonate until free of acid and dried over sodium sulfate. The solvent is removed by evaporation and the residue is distilled, affording 2-(2,6-difluorophenyl)-2-azidopropane of bp15 =85°-87° C.
Reaction SMILES: [C:1]12([N:11]=[C:12]=[S:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>CCOCC>[C:1]12([NH:11][C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[S:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: S=C=NC12CC3CC(CC(C3)C1)C2
Reactant: C1COCCN1
Solvent: CCOCC
Product: S=C(NC12CC3CC(CC(C3)C1)C2)N1CCOCC1

Procedure:
The thiourea is prepared by reacting 5.0 g. (0.026 mole) of 1-adamantyl isothiocyanate with 2.5 g. (0.029 mole) of morpholine in 250 ml. of ether for ca. 1 hr. at room temperature. The solid which separates is collected and combined with additional compound from concentration of ether filtrate to a small volume: 6.65 g. (91 percent), m.p. 145-147. The analytical sample is recrystallized from ether, m.p. 148.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH:11]1[CH2:14][CH2:13][CH2:12]1.[OH-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH:11]2[CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: BrCC1CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Brc1ccc(OCC2CCC2)cc1
Yield: 37.2 %

Procedure:
4-Bromophenol (2.5 g, 14.5 mmol), (bromomethyl)cyclobutane (1.6 mL, 15 mmol), sodium hydroxide (0.8 g, 20 mmol) and DMF (3 mL) were allowed to react to yield the sub-title compound (1.3 g, 36%).
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([N:11]=[C:12]([NH:14][C:15]([CH:17]3[CH2:19][CH2:18]3)=[O:16])[N:13]=2)[CH:10]=1.[Cl-].[NH4+]>C(O)C.O>[NH2:24][C:22]1[CH:21]=[CH:20][C:3]([O:4][C:5]2[CH:6]=[CH:7][C:8]3[N:9]([N:11]=[C:12]([NH:14][C:15]([CH:17]4[CH2:19][CH2:18]4)=[O:16])[N:13]=3)[CH:10]=2)=[C:2]([F:1])[CH:23]=1
Reactant: O=C(Nc1nc2ccc(Oc3ccc([N+](=O)[O-])cc3F)cn2n1)C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c(F)c1
Yield: 34.1 %

Procedure:
A solution of N-[6-(2-fluoro-4-nitrophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (400 mg, 1.12 mmol), reduced iron (312 mg, 5.59 mmol) and ammonium chloride (600 mg, 11.2 mmol) in ethanol (8 mL) and water (2 mL) was heated under reflux for 1.5 hr. The reaction mixture was filtered through celite, and the filtrate was diluted with water and ethyl acetate and extracted 3 times with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2→ethyl acetate/methanol=9/1) to give the title compound (125 mg, 34%) as a white solid.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[CH3:7][S:8][C:9]1[N:10]=[C:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:15]2=[O:31])[S:12][CH:13]=1>O.C(O)(C)C.C(Cl)(Cl)Cl>[CH3:7][S:8]([C:9]1[N:10]=[C:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH2:23][C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[C:15]2=[O:31])[S:12][CH:13]=1)=[O:1]
Reactant: CSc1csc(-n2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)n1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CS(=O)c1csc(-n2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)n1
Reaction time: 2 h

Procedure:
A solution of OXONE® in H2O (0.5 mL) was added to a solution of tert-butyl {3-[4-(methylthio)-1,3-thiazol-2-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}acetate from Step C (110 mg, 0.291 mmol) in isopropanol (1 mL) and CHCl3 (1 mL) at 0° C. After 2 h, the mixture was quenched with saturated aqueous NaCl and extracted with CHCl3 (2×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—90:10 to 50:50, to give the title compound. MS: m/z=394 (M+1).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:27]([OH:29])=[O:28])[CH2:3][C:4](=[O:26])[NH:5][C:6]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]1[CH:13]=[CH:12][C:10]([CH3:11])=[CH:9][CH:8]=1.O>CO.Cl.[Pd]>[NH2:1][C@H:2]([C:27]([OH:29])=[O:28])[CH2:3][C:4](=[O:26])[NH:5][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:7]1[CH:8]=[CH:9][C:10]([CH3:11])=[CH:12][CH:13]=1
Reactant: Cc1ccc(C(NC(=O)C[C@H](NC(=O)OCc2ccccc2)C(=O)O)(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1ccc(C(NC(=O)C[C@H](N)C(=O)O)(c2ccccc2)c2ccccc2)cc1
Yield: 80 %

Procedure:
A suspension of 52.3 g Z-Asn(Mtt)OH (100 mM) in 400 ml methanol and 100 ml IN hydrochloric acid is hydrogenated at room temperature and normal pressure in the presence of 2 g of a palladium on carbon (10%) catalyst. On completion of hydrogen uptake the catalyst is filtered off, washed with methanol and the filtrate, after addition of 13.9 ml triethylamine (100 mM) and 100 ml water, condensed in vacuo to a volume of about 300 ml. The crystalline precipitate is collected by filtration and washed with water until the washings are chloride-free. The obtained H-Asn(Mtt)OH contains 0.5-1 mole of water and decomposes above 222° C. Yield 80%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])=[C:14]([CH3:25])[C:13]=2[CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO.O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)[OH:18])=[C:14]([CH3:25])[C:13]=2[CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)C2CCCCC2)oc2ccc(OCc3ccccc3)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(O)C2CCCCC2)oc2ccc(OCc3ccccc3)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 106.9 %

Procedure:
[5-(Benzyloxy)-3-methyl-1-benzofuran-2-yl](cyclohexyl)methanone (23.4 g) synthesized in Example A82(2) was dissolved in methanol (40 mL)-tetrahydrofuran (400 mL), and sodium tetrahydroborate (90%) (5.64 g) was added to the solution at 0° C. The reaction mixture was stirred at 0° C. for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to give the title compound (25.17 g, 100%) as a colorless oil.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][OH:23])[C:6](=[O:24])[N:5]([CH3:25])[C:4]=2[N:3]=1.B(O)(O)[C:27]1[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pt]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][OH:23])[C:6](=[O:24])[N:5]([CH3:25])[C:4]=3[N:3]=[C:2]2[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[CH:13][CH:14]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cn1c(=O)n(CCCO)c(=O)c2c1nc(Br)n2Cc1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pt]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(-c2nc3c(c(=O)n(CCCO)c(=O)n3C)n2Cc2ccc(F)cc2)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 40.9 %

Procedure:
To a solution of 8-bromo-7-(4-fluorobenzyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (50 mg, 0.121 mmol, intermediate 62) in toluene (2 mL) and ethanol (0.5 mL) was added p-tolylboronic acid (19.7 mg, 0.145 mmol) followed by aqueous sodium carbonate solution (0.5 mL), and the mixture was degassed under nitrogen atmosphere three times. Tetrakis(triphenylphosphine)platinum (7.5 mg, 0.006 mmol) was added to the reaction under nitrogen and the resulting mixture was stirred at 100° C. for 16 h. The mixture was partitioned between ethyl acetate and brine. The organic phase was dried and concentrated to give crude product, which was purified via preparative HPLC to give 7-(4-fluorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-p-tolyl-1H-purine-2,6(3H,7H)-dione (20.9 mg, 40.9% yield) as white solid. 1H-NMR (CD3OD) δ 7.51-7.53 (d, 2H), 7.34-7.36 (d, 2H), 6.97-7.07 (m, 4H), 5.66 (s, 2H), 4.09-4.12 (t, 2H), 3.59-3.62 (t, 2H), 3.59 (s, 3H), 2.44 (s, 3H), 1.85-1.89 (m, 2H). LCMS retention time 2.306; LCMS MH+ 423.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:11])[C:5]([O:9][CH3:10])=[C:6]([F:8])[CH:7]=1.[F:12][C:13]([F:19])([F:18])[C:14](OC)=[O:15].Cl>C1COCC1>[F:8][C:6]1[CH:7]=[C:2]([C:14](=[O:15])[C:13]([F:19])([F:18])[F:12])[CH:3]=[C:4]([F:11])[C:5]=1[O:9][CH3:10]
Reactant: COc1c(F)cc(Br)cc1F
Reactant: COC(=O)C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Product: COc1c(F)cc(C(=O)C(F)(F)F)cc1F
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
Isopropyl magnesium chloride lithium chloride complex (22.0 mL, 28.02 mmol) was added dropwise to a stirred solution of 5-bromo-1,3-difluoro-2-methoxybenzene (5.0 g, 22.42 mmol) at −5° C. in THF (100 mL) and the reaction mixture was stirred at same temperature for 30 min. Methyl trifluoroacetate (3.67 g, 28.69 mmol) was added dropwise and the reaction mixture was stirred at ambient temperature for 2 h. A 2 N HCl solution (200 mL) was added to quench the reaction and then it was extracted with diethylether. The combined organic layers were washed with brine, dried (Na2SO4) filtered and concentrated to afford the title compound (5.4 g, crude) as a yellow liquid. The material was taken to next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.68-7.60 (m, 2H) 4.19 (s, 3H); ESIMS m/z 240.1 ([M]+).