Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C@H:9]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=2[F:18])[N:5]2[CH:6]=[N:7][CH:8]=[C:4]2[C:3]1=[O:19].[F:21][C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1.CCOCC>C1COCC1>[F:18][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:10]=1[C@@H:9]1[N:5]2[CH:6]=[N:7][CH:8]=[C:4]2[C@:3]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)([OH:19])[C:2]1([CH3:20])[CH3:1])[C:14]#[N:15]
Reactant: CC1(C)C(=O)c2cncn2[C@H]1c1ccc(C#N)cc1F
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(C)[C@H](c2ccc(C#N)cc2F)n2cncc2[C@@]1(O)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
To a solution of 4-((R)-6,6-dimethyl-7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-3-fluoro-benzonitrile (157 mg, 0.45 mmol) in THF cooled to −78° C. was added a 2 M solution of 4-fluoro-phenyl-magnesium bromide in ether (0.39 mL, 0.78 mmol). The crude was allowed to warm to room temperature overnight. The crude was quenched with H2O and diluted in EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The crude was purified via flash chromatography first with EtOAc/heptane system followed by MeOH/CH2Cl2 to give 160 mg of the entitled product. MS 366.2 (M+H); LCMS condition B, retention time 1.14 min. 1H NMR (400 MHz, CDCl3) δ ppm 0.88 (s, 3H), 1.00 (s, 3H), 5.45 (s, 1H), 6.92 (t, 1H), 7.04 (s, 1H), 7.05-7.13 (m, 2H), 7.32-7.44 (m, 2H), 7.49 (s, 1H), 7.50-7.58 (m, 2H).
Reaction SMILES: [C:1]1([S:7]([OH:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH:12]([C:16]([NH2:18])=[O:17])[C:13]([NH2:15])=[O:14].O.[C:20]1(S(O)(=O)=O)C=CC=CC=1.C(OC)(OC)OC>C(O)C>[C:1]1([S:7]([OH:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20]1[NH:11][C:12]([C:13]([NH2:15])=[O:14])=[C:16]([OH:17])[N:18]=1
Reactant: NC(=O)C(N)C(N)=O
Agent: O=S(=O)(O)c1ccccc1
Solvent: CCO
Solvent: COC(OC)OC
Solvent: O
Product: NC(=O)c1[nH]cnc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
Into a suspension of benzenesulfonic acid salt of 2-aminomalonamide [4] (1.20 g; 4.37 mmol) prepared above and benzenesulfonic acid monohydrate (81 mg; 0.46 mmol) in dry ethanol (100 ml) was added trimethyl orthoformate (1.9 ml; 17.4 mmol), and was refluxed for 2 hours under an argon atmosphere. The resulting white suspension was stirred overnight at room temperature and the precipitates were collected by filtration to give colorless benzenesulfonic acid salt of SM-108 (1.02 g; 3.58 mmol; yield 82%), which was identical with that obtained in Example 2.
Reaction SMILES: [CH:1]([NH:5][CH:6]1[CH:11]([N+:12]([O-])=O)[C:10]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[CH:17][C:16]=2[Cl:25])=[CH:9][CH:8]=[N:7]1)([CH2:3][CH3:4])[CH3:2].[C:26](OC)(=[O:30])[C:27]([CH3:29])=O>C1(C)C=CC=CC=1>[CH:1]([N:5]1[C:26](=[O:30])[C:27]([CH3:29])=[N:12][C:11]2[C:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[CH:17][C:16]=3[Cl:25])=[CH:9][CH:8]=[N:7][C:6]1=2)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)NC1N=CC=C(c2ccc(OC(F)F)cc2Cl)C1[N+](=O)[O-]
Reactant: COC(=O)C(C)=O
Solvent: Cc1ccccc1
Product: CCC(C)n1c(=O)c(C)nc2c(-c3ccc(OC(F)F)cc3Cl)ccnc21

Procedure:
Sec-butyl-[4-(chloro-4-difluoromethoxy-phenyl)-3-nitro-2,3-dihydro-pyridin-2-yl]-amine (0.145 g, 0.43 mmol) was dissolved in toluene (20 mL), followed by methyl pyruvate (77 μL, 0.86 mmol) and heated to reflux overnight. The reaction was concentrated in vacuo and purified by reverse phase prep HPLC giving 4-sec-butyl-8-(2-chloro-4-difluoromethoxy-phenyl)-2-methyl-4H-pyrido[2,3-b]pyrazin-3-one (Example 113): 1H NMR (300 MHz, CDCl3) δ 8.53–8.52 (d, 1H, J=4.8 Hz), 7.35–7.32 (m, 2H), 7.19–7.13 (m, 2H), 6.85–6.36 (t, 1H, J=73.2 Hz), 2.47 (s, 3H), 2.40–2.20 (m, 1H), 2.10–2.07 (m,1H), 1.65–1.63 (d, 3H, J=6.9 Hz), 0.89–0.84 (t, 3H, J=3.7). MS(AP) m/z 394.2 [(M+H)+, 100], 435.3 [(M+H+CH3CN)+, 10].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:15]([OH:17])=O)=[C:7]2[C:11]=1[O:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8]2.[CH3:18][N:19]1[C:23]([NH2:24])=[C:22]([CH3:25])[CH:21]=[N:20]1>>[CH3:18][N:19]1[C:23]([NH:24][C:15]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:11]3[O:10][C:9]([CH2:12][O:13][CH3:14])=[CH:8][C:7]=23)=[O:17])=[C:22]([CH3:25])[CH:21]=[N:20]1
Reactant: COCc1cc2c(C(=O)O)ccc(OC)c2o1
Reactant: Cc1cnn(C)c1N
Product: COCc1cc2c(C(=O)Nc3c(C)cnn3C)ccc(OC)c2o1
Yield: 28 %

Procedure:
Starting from 7-methoxy-2-methoxymethylbenzofuran4-carboxylic acid (0.1 g) and 2,4-dimethyl-2H-pyrazol-3-ylamine (56 mg). Purification by column chromatography on silica eluting with 20% heptane in ethyl acetate and gradient preparative HPLC on a PhenomenexLUNA(2)™ C18 column eluting with 0.05% trifluoroacetic acid in20%-65% acetonitrile in water gave the title compound as a pale yellow solid (39 mg).
Reaction SMILES: [ClH:1].Cl.Cl.[Cl:4]C1C=CC(Cl)=C2C=1C=C([C:16]1[C:17]([NH2:33])=[N:18][CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:26]=3)[CH:21]=1)N=C2.[C:34]([C:36]1[CH:45]=[CH:44][C:43]([F:46])=[C:42]2[C:37]=1[CH:38]=[C:39](OS(C(F)(F)F)(=O)=O)[N:40]=[CH:41]2)#[N:35]>>[ClH:4].[ClH:1].[ClH:4].[NH2:33][C:17]1[C:16]([C:39]2[N:40]=[CH:41][C:42]3[C:43]([F:46])=[CH:44][CH:45]=[C:36]([C:34]#[N:35])[C:37]=3[CH:38]=2)=[CH:21][C:20]([C:22]2[CH:23]=[N:24][N:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:26]=2)=[CH:19][N:18]=1
Reactant: N#Cc1ccc(F)c2cnc(OS(=O)(=O)C(F)(F)F)cc12
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1cc2c(Cl)ccc(Cl)c2cn1
Agent: Cl
Product: N#Cc1ccc(F)c2cnc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)cc12

Procedure:
The procedure for the preparation of 3-(5,8-dichloroisoquinolin-3-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine trihydrochloride was followed, except using trifluoromethanesulfonic acid 5-cyano-8-fluoroisoquinolin-3-yl ester in place of trifluoromethanesulfonic acid 5,8-dichloroisoquinolin-3-yl ester. This afforded the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=2.26-2.42 (m, 4H), 3.20-3.29 (m, 2H), 3.55-3.63 (m, 2H), 4.55-4.67 (m, 1H), 7.54 (dd, J=9.7, 8.2 Hz, 1H), 7.95 (s, 1H), 8.15 (s, 1H), 8.26 (d, J=2.0 Hz, 1H), 8.30 (d, J=2.3 Hz, 1H), 8.35 (dd, J=8.1, 5.1 Hz, 1H), 8.39 (s, 1H), 9.70 (d, J=1.0 Hz, 1H). MS (ES+): m/z=414.13 [MH+]. HPLC: tR=1.70 min (ZQ2, polar—5 min).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[N:6][C:7]=1[Cl:8].[N+:10]([C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16])([O-:12])=[O:11]>N1C=CC=CC=1.O.C(=O)(O)[O-].[Na+]>[Cl:8][C:7]1[C:2]([NH:1][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[N+:10]([O-:12])=[O:11])=[CH:3][C:4]([CH3:9])=[CH:5][N:6]=1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Cc1cnc(Cl)c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: Cc1cnc(Cl)c(NC(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.7 %

Procedure:
To a solution of 5-amino-6-chloro-3-picoline (9.54 g, 66.9 mmol) in pyridine (200 mL) was added 2-nitrobenzoyl chloride (13.65 g, 73.6 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature for 18 h. The dark mixture was then diluted with water (1500 mL) and sat. sodium bicarbonate solution was added until pH=8. The precipitate was collected by filtration, rinsed with water (30 mL×3) and dried in oven to afford N-(2-chloro-5-methylpyridin-3-yl)-2-nitrobenzamide as a pale solid (17.70 g, yield: 91%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:16]1[CH2:18][CH2:17]1)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@@H:12]([CH:16]1[CH2:18][CH2:17]1)[CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H](C(=O)O)C1CC1)OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(N[C@H](CO)C1CC1)OCc1ccccc1
Reaction time: 4 h
Yield: 49.8 %

Procedure:
A solution of (S)-benzyloxycarbonylamino-cyclopropyl-acetic acid (3.2 g, 12.8 mmol) in THF (20 mL) was cooled in an ice/water bath and treated with a 1 M solution of BH3 in THF (16.7 mL, 16.7 mmol). The reaction was stirred for 4 hours and then treated with 1 M HCl until the bubbling ceased. The reaction was stirred overnight and the organic solvent was removed by rotary evaporation. The residue was treated with ethyl acetate and transferred to a separatory funnel. The aqueous phase was discarded and the organics were washed twice with 1 M NaOH, dried over MgSO4 and the solvent was removed. The residue was purified on silica gel using a gradient of 0-100% ethyl acetate in hexane to afford 1.5 g (50% yield) of (S)-(1-Cyclopropyl-2-hydroxy-ethyl)-carbamic acid benzyl ester as a white solid; 1H NMR (CDCl3, 400 MHz) δ 0.26-0.37 (m, 1H), 0.34-0.44 (m, 1H), 0.47-0.61 (m, 2H), 0.83-0.94 (m, 1H), 2.95-3.04 (m, 1H), 3.70 (dd, 1H, J1=5.8, J2=11.1), 3.79-3.88 (m, 1H), 5.00-5.12 (m, 1H), 5.10 (s, 2H), 7.29-7.31 (m, 5H); HPLC-MS calcd. for C13H17NO3 (M+H+) 236.1. found 236.3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][C:10]2=[O:15])[CH:5]=[CH:6][C:7]=1[NH2:8].[NH2:16][C:17]1[C:22]([CH:23]=O)=[CH:21][C:20]([I:25])=[CH:19][N:18]=1.S([O-])(O)=O.[Na+].O>CN(C=O)C>[NH2:16][C:17]1[C:22]([C:23]2[NH:1][C:2]3[CH:3]=[C:4]([N:9]4[CH2:14][CH2:13][O:12][CH2:11][C:10]4=[O:15])[CH:5]=[CH:6][C:7]=3[N:8]=2)=[CH:21][C:20]([I:25])=[CH:19][N:18]=1
Reactant: Nc1ccc(N2CCOCC2=O)cc1N
Reactant: Nc1ncc(I)cc1C=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc(I)cc1-c1nc2ccc(N3CCOCC3=O)cc2[nH]1
Temperature: 150 °C
Reaction time: 18 h

Procedure:
22.4 320 mg (1.544 mmol) of 4-(3,4-diaminophenyl)morpholin-3-one are dissolved in 4 ml of DMF, and 382.99 mg (1.544 mmol) of 2-amino-5-iodopyridine-3-carbaldehyde and 0.913 ml (4.633 mmol) of 38-40% sodium hydrogensulfite solution are added at room temperature. The mixture is stirred at 150° C. for 18 hours. The batch is cooled to room temperature, poured into 20 ml of water, the precipitate which deposits in the process is separated off and washed well with about 10 ml of water. The precipitate is triturated with about 25 ml of acetonitrile, and the undissolved crystals are separated off and dried, giving 4-[2-(2-amino-5-iodopyridin-3-yl)-3H-benzimidazol-5-yl]morpholin-3-one; HPLC-MS [M+H]+ 436.0.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Li+].[CH3:12]C([N-]C(C)C)C.C1COCC1.CCCCCCC.CI.Cl>C1COCC1>[Br:1][C:2]1[C:10]2[O:9][C:8]([CH3:12])=[CH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2ccoc12
Reactant: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cc2cccc(Br)c2o1
Temperature: -70 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
A stirred solution of 7-bromobenzofuran (493 mg, 2.5 mmol) in dry THF (5 mL) was cooled to −70° C. and 2M LDA in 1:1 THF/heptane (1.4 mL, 2.8 mmol) was added dropwise over 2 min. The mixture was stirred at −70° C. for 1 h and methyl iodide (0.19 mL, 3.0 mmol) was added. The mixture was stirred at −70° C. for 3 h and at 0° C. for 1 h. The mixture was poured into 5% aq HCl (60 mL) and extracted with ether (2×50 mL). The combined ether extracts were washed with sat'd aq NaHCO3 (20 mL) and dried over MgSO4. Removal of the solvent left an oil (470 mg) which was purified by chromatography on a 40-g silica cartridge eluted with hexanes to afford 7-bromo-2-methylbenzofuran (277 mg, 52%, estimated purity ˜80%).
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:23])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24].CO>O1CCOCC1.C(Cl)(Cl)Cl>[ClH:24].[Br:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:15]([N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1)=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)c2ccccc2Br)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(c1ccccc1Br)N1CCCNCC1
Yield: 95.69 %

Procedure:
A solution of 4-(2-bromo-benzoyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (500 mg, 1.3 mmol) in 1,4-dioxane.HCl (3 mL) was stirred at 0° C. for 30 minutes. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was concentrated under reduced pressure to get a solid, which was washed with ether and dried to afford 400 mg (95.69% Yield) of (2-bromo-phenyl)-[1,4]diazepan-1-yl-methanone hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5](N)=[C:4]([Cl:9])[CH:3]=1.[ClH:10].N([O-])=O.[Na+].[S:15](=[O:17])=[O:16]>C(O)(=O)C.O.[Cu]>[Cl:9][C:4]1[CH:3]=[C:2]([Br:1])[CH:8]=[CH:7][C:5]=1[S:15]([Cl:10])(=[O:17])=[O:16]
Reactant: Cl
Reactant: O=S=O
Reactant: Nc1ccc(Br)cc1Cl
Agent: [Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=S(=O)(Cl)c1ccc(Br)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 4-bromo-2-chloroaniline (3.99 g) in acetic acid (90 ml) at 15° C. is treated with concentrated hydrochloric acid (22 ml), followed by a solution of sodium nitrite (1.29 g) in water (4.5 ml) at 10° C. After 30 min, the mixture is added to a stirred solution of sulfur dioxide (32 g) and copper II chloride (1.3 g) in acetic acid (128 ml) and water (6.4 ml), also at 10° C. After stirring for a further 16 hours, the mixture is diluted with ice-cold water (500 ml) and extracted with ethyl acetate (4×100 ml). The combined extracts are washed successively with water (4×100 ml) and then brine, dried over magnesium sulfate, filtered and evaporated to give crude 2-chloro-4-bromobenzenesulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH:5]=[O:6].[C:11]1(C)[CH:16]=[CH:15][C:14](S(O)(=O)=O)=[CH:13][CH:12]=1.C(O)C[OH:24].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([Cl:10])[C:9]=1[C:11]1[CH:16]=[CH:15][C:14]([OH:24])=[CH:13][CH:12]=1
Reactant: O=Cc1cc(Cl)cc(Cl)c1
Reactant: OCCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: OCc1cc(Cl)c(-c2ccc(O)cc2)c(Cl)c1

Procedure:
4.66 g of 3,5-dichlorobenzaldehyde is mixed with 0.23 g of paratoluenesulphonic acid, 3 ml of ethylene glycol and 40 ml of toluene. The reaction medium is heated under reflux for 2 hours, poured into a saturated solution of sodium bicarbonate and the aqueous phase is decanted. The organic phase is dried and evaporated under reduced pressure. 5.756 g of expected product is isolated in the form of an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]2[CH3:17])=[C:6]([NH:18][C:19](=O)[CH2:20][C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=1.Cl.O.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]3[CH3:17])[C:19]([CH2:20][C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)=[N:18][C:6]=2[CH:5]=1)=[O:27]
Reactant: COC(=O)c1ccc(NC2CCCCC2C)c(NC(=O)Cc2ccco2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2c(c1)nc(Cc1ccco1)n2C1CCCCC1C
Yield: 93 %

Procedure:
1.48 g 3-(2-Furan-2-yl-acetylamino)-4-(2-methyl-cyclohexylamino)-benzoic acid methyl ester with 15 ml of 4M hydrochloric acid in dioxane were heated in a microwave reactor to 130° C. for 15 min. Water was added to the reaction mixture and the pH was adjusted to 7 by the addition of saturated sodium bicarbonate solution. The phases were separated, and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulphate, concentrated and 1.31 g (93%) of 2-Furan-2-ylmethyl-1-(2-methyl-cyclohexyl)-1H-benzoimidazole-5-carboxylic acid methyl ester were obtained.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[CH2:22])[CH:16]=[C:15]([O:23][CH2:24][CH:25]=[CH2:26])[C:14]=1[CH2:27][CH3:28].Cl.C(=O)([O-])O.[Na+].O>CO.O1CCOCC1>[CH2:24]([O:23][C:15]1[C:14]([CH2:27][CH3:28])=[C:13]([CH2:12][CH2:11][O:10][CH2:9][CH2:8][OH:7])[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[CH2:22])[CH:16]=1)[CH:25]=[CH2:26]
Reactant: C=CCOc1cc(CCOCCOC2CCCCO2)c(CC)c(OCC=C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: C=CCOc1cc(CCOCCO)c(CC)c(OCC=C)c1
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
2-(Tetrahydro-2H-pyran-2-yloxy)-1-[2-(3,5-diallyloxy-2-ethylphenyl)ethoxy]ethane (3.0 g, 7.6 mmol) obtained in Example 59, Step 1 was dissolved in methanol (30 mL), and a 4 mol/L solution of hydrogen chloride in 1,4-dioxane (20 mL) was added thereto, followed by stirring for 30 minutes. After the reaction mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate, water was added thereto, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane 1/9-1/1) to obtain 2-[2-(3,5-diallyloxy-2-ethylphenyl)ethoxy]ethanol (1.9 g, 81%) as a colorless oil.
Reaction SMILES: [NH3:1].CO.[Br:4][C:5]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:6]=1[CH2:7][C:8]1[N:13]=[C:12]([C:14](OC)=[O:15])[C:11]([OH:18])=[C:10]([OH:19])[N:9]=1>>[Br:4][C:5]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:6]=1[CH2:7][C:8]1[NH:9][C:10](=[O:19])[C:11]([OH:18])=[C:12]([C:14]([NH2:1])=[O:15])[N:13]=1
Reactant: COC(=O)c1nc(Cc2ccc(F)cc2Br)nc(O)c1O
Reactant: N
Solvent: CO
Product: NC(=O)c1nc(Cc2ccc(F)cc2Br)[nH]c(=O)c1O
Temperature: 120 °C
Yield: 67 %

Procedure:
A solution of ammonia in MeOH (1 mL, 7.00 mmol) was added to a flask containing methyl 2-(2-bromo-4-fluorobenzyl)-5,6-dihydroxypyrimidine-4-carboxylate (50 mg, 140 μmol). The mixture was heated at 120° C. for 15 minutes in a microwave oven. The resulting product was collected by filtration, suspended in MeOH with Amberlyst resin and heated. The warm mixture was filtered and evaporated to dryness. The residue was triturated with Et2O and dried under vacuum to give the title compound as a white solid (0.032 g; 67%). LCMS: m/z=343 (MH+).
Reaction SMILES: N1C=CC=CC=1.[Si:7]([N:14]1[CH:17]([CH2:18][CH2:19][OH:20])[CH:16]([N:21]=[N+:22]=[N-:23])[C:15]1=[O:24])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[Si:7]([N:14]1[CH:17]([CH2:18][CH:19]=[O:20])[CH:16]([N:21]=[N+:22]=[N-:23])[C:15]1=[O:24])([C:10]([CH3:12])([CH3:13])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C(N=[N+]=[N-])C1CCO
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)N1C(=O)C(N=[N+]=[N-])C1CC=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Chromium trioxide (0.06 mol) is added to a solution of pyridine (0.12 mol) in methylene chloride (150 ml) and the mixture is stirred at room temperature for 15 min. A solution of N-(t-butyldimethylsilyl)-3-azido-4-(2-hydroxyethyl)-azetidin-2-one (0.01 mol) in methylene chloride (10 ml) is then added all at once. After stirring at room temperature for 5 min, the mixture is decanted and the dark, gummy residue is washed with more methylene chloride. The combined methylene chloride supernatant is concentrated under vacuum to a residue which is taken up in ether and filtered through celite. The filtrate is washed with 5% hydrochloric acid, 5% sodium bicarbonate solution, and brine, dried with magnesium sulfate, filtered, and evaporated under vacuum to yield N-(t-butyldimethylsilyl)-3-azido-4-(2-oxoethyl)-azetidin-2-one.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[O:3].[Br:14]Br>C(O)(=O)C.Cl.O>[Br:14][CH2:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:8][CH:9]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Yield: 109.9 %

Procedure:
To a stirred solution of the acetophenone prepared in Step 2 (11.91 g, 60.5 mmol) in glacial acetic acid (133 ml) and hydrochloric acid (0.11 ml) at ambient temperature, was added a solution of bromine (8.22 g, 51.4 mmol) in glacial acetic acid (9.3 ml) over a period of three hours. The reaction mixture was diluted with water (500 ml) and extracted with chloroform. The combined chloroform extracts were dried (MgSO4) and concentrated in vacuo to give 15.66 g of crude 2-bromo-4′-(methylsulfonyl)acetophenone: 1H NMR (CDCl3) δ3.10 (s, 3H), 4.45 (s, 2H), 8.08 (d, J=9 Hz, 2H), 8.17 (d, J=9 Hz, 2H). The sample was used without further purification.
Reaction SMILES: C1C=CC(CNS(C2C=CC3N=NN(O)C=3C=2)(=O)=O)=CC=1.Cl.N1C=CC=CC=1.[O:29]1[C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=[N:30]1.[N:37]1([C:43]2[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=2[NH2:45])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>O1CCCC1.ClCCl>[N:37]1([C:43]2[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=2[NH:45][C:34]([C:33]2[O:29][N:30]=[CH:31][CH:32]=2)=[O:35])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: Nc1ccccc1N1CCCCC1
Reactant: O=C(Cl)c1ccno1
Agent: Cl
Agent: O=S(=O)(NCc1ccccc1)c1ccc2nnn(O)c2c1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccccc1N1CCCCC1)c1ccno1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To PS-HOBt resin (0.1 mmol) was added anhydrous dichloromethane (“DCM”) (1 mL) followed by pyridine (0.5 mmol) and isoxazole-5-carbonyl chloride (Lancaster) (0.3 mmol). The mixture was shaken at room temperature for 3 h and was then filtered. The resin was washed successively with tetrahydrofuran (“THF”) (3×) and DCM (3×) and dried in vacuo. To this acylated resin was added a solution of 2-piperidinoaniline (Lancaster) (0.05 mmol, 0.5 eq) in anhydrous THF (1 mL) and the mixture was shaken at room temperature for 16 h. The mixtue was then filtered and the resin washed with THF and DCM as described above. The combined filtrate and washings were concentrated under reduced pressure to yield the product. Yield: 100%. MS: 272 (M+1). LC/MS purity: 100%. 1HNMR (CDCl3, 300 MHz): δ 8.2 (d, 1H), 7.85 (t, 2H), 7.55 (m, 1H), 7.4 (m, 2H), 3.8-3.2 (bm, 4H), 2.7-1.9 (bm, 4H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][CH:5]([OH:28])[CH2:4]1)[CH3:2].[H-].[Na+].Cl[C:32]1[CH:37]=[N:36][C:35]([C:38]#[N:39])=[CH:34][N:33]=1>CN(C=O)C>[CH2:1]([CH:3]1[CH:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:26])([CH3:25])[CH3:27])[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][CH:5]([O:28][C:32]2[N:33]=[CH:34][C:35]([C:38]#[N:39])=[N:36][CH:37]=2)[CH2:4]1)[CH3:2]
Reactant: N#Cc1cnc(Cl)cn1
Reactant: CCC1CC(O)CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1CC(Oc2cnc(C#N)cn2)CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 70.2 %

Procedure:
To 3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanol (0.098 g, 0.24 mmol, prepared using FF from Preparation #KK.1) in DMF (1 mL) was added NaH (0.012 g, 0.29 mmol, 60% dispersion in mineral oil) portionwise. After about 5 min, 2-chloro-5-cyanopyrazine (0.039 g, 0.28 mmol, ArkPharm) was added. The reaction mixture was heated at about 70° C. for about 2 h. After cooling to ambient temperature, ice water (2 mL) was added and the mixture was extracted with DCM (3×5 mL). The organic layers were combined and the solvents were removed under reduced pressure. The residue was purified using silica gel chromatography (12 g) eluting with a gradient of 20-80% EtOAc in DCM to give 5-(3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyloxy)pyrazine-2-carbonitrile (0.085 g, 69%): LC/MS (Table 1, Method b) Rt=2.84 min; MS m/z: 505 (M+H)+.