Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([CH:19]=[C:20]([NH:22][C:23]([CH:25]5[CH2:27][CH2:26]5)=[O:24])[N:21]=4)[N:18]=3)[CH3:12])=[N:9][N:10]=2)[CH:7]=1.N([C:30]1C=CC(C)=CN=1)N>>[CH3:30][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([CH:19]=[C:20]([NH:22][C:23]([CH:25]5[CH2:26][CH2:27]5)=[O:24])[N:21]=4)[N:18]=3)[CH3:12])=[N:9][N:10]=2)[CH:7]=1
Reactant: Cc1ccc(NN)nc1
Reactant: CC(c1ccc2nc(NC(=O)C3CC3)cn2n1)c1nnc2ccc(Br)cn12
Product: Cc1ccc2nnc(C(C)c3ccc4nc(NC(=O)C5CC5)cn4n3)n2c1

Procedure:
The title compound was synthesized using an analogous procedure to that described in the preparation of Compound 48 (Method A) using 2-hydrazinyl-5-methylpyridine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.76-0.86 (m, 4 H) 1.85 (d, J=7.07 Hz, 3 H) 1.92 (m, 1 H) 3.56 (s, 3 H) 5.02 (d, J=7.07 Hz, 1 H) 7.18 (d, J=9.35 Hz, 1 H) 7.23-7.31 (m, 1 H) 7.70 (d, J=8.84 Hz, 1H) 7.93 (d, J=9.85 Hz, 1 H) 8.10 (s, 1 H) 8.20 (s, 1 H) 11.13 (s, 1 H). MS:m/z 362.2 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][NH:4]1.[H-].[Na+].[CH2:15](OS(OCC)(=O)=O)[CH3:16].O>CS(C)=O>[CH2:15]([O:1][CH2:2][C@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][NH:4]1)[CH3:16]
Reactant: CCOS(=O)(=O)OCC
Reactant: OCC1Cc2ccccc2CN1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC[C@H]1Cc2ccccc2CN1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 500 mg (3.06 mmol) of (+)-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline in 10 mL of DMSO was added 122 mg (3.06 mmol) of NaH (60% in oil) and the mixture was stirred for 45 minutes at room temperature. Then 0.403 mL (3.06 mmol) of diethylsulfate was added via syringe. Foaming occurred and subsided in approximately 15 minutes. The reaction mixture was then stirred at room temperature overnight and poured into water. The product was extracted into ethyl acetate and dried and evaporated to an oil. This was chromatographed on silica gel to give the desired product as an oil, 190 mg. 1H-NMR (CDCl3) δ 1.22 (3H, t, J=7), 2.29 (1H, broad s), 2.55-2.70 (2H, m), 3.09-3.18 (1H, m), 3.41 (1H, t, J=7), 3.50-3.59 (3H, m), 4.06 (2H, ABq, J=5, 21), 7.00-7.13 (4H, m).
Reaction SMILES: [Na].Br[CH2:3][C:4]([O-:6])=[O:5].[K+].[CH3:8][O:9][CH2:10][CH2:11][OH:12]>>[CH3:8][O:9][CH2:10][CH2:11][O:12][CH2:3][C:4]([OH:6])=[O:5]
Reactant: COCCO
Reactant: O=C([O-])CBr
Agent: [K+]
Agent: [Na]
Product: COCCOCC(=O)O
Temperature: 25 °C
Reaction time: 19 h
Yield: 70.5 %

Procedure:
Sodium (1.15 g.; 50.0 mmoles) was dissolved in 2-methoxyethanol (50 ml.; anhydrous) under N2 at room temperature. The temperature rose to 110° over about a 30 minute period. The pale yellow mixture was cooled to room temperature and to this was added powdered potassium bromoacetate (8.85 g.; 50.0 mmoles) under vigorous stirring. The mixture (suspension) was stirred at room temperature overnight (19 hrs.) under N2. The excess of methoxyethanol was removed in vacuo and the residue diluted with H2O (50 ml.) and neutralized with 1 N HCl (50 ml.). After evaporation of water, the residue was extracted with CH2Cl2 (75 ml.×2) and the extracts were evaporated to dryness yielding 5.26 g. of yellowish oil. This oil was distilled under reduced pressure, yielding 2-methoxyethoxyacetic acid (4.72 g.; 35.2 mmoles; yield 70.5%) as a colorless oil: b.p. 98° C./0.3 mm Hg; nmr (CDCl3): δ ppm 3.45 (3H, s, --OCH3), 3.4-3.9 (4H, m, --OCH2CH2O--), 4.22 (2H, s, HO2CCH2O--), 9.74 (1H, br. s., --CO2H); ir (neat) 1750 cm-1 (γc=o --CO2H).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH3:13][C:14]1[CH:15]=[C:16]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[CH:17]=[C:18]2[C:23]=1[NH:22][C:21](=[O:24])[CH:20]=[CH:19]2.O[CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:13][C:14]1[CH:15]=[C:16]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:33][C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)=[CH:27][CH:26]=2)[CH:17]=[C:18]2[C:23]=1[NH:22][C:21](=[O:24])[CH:20]=[CH:19]2
Reactant: Cc1cc(-c2ccc(O)cc2)cc2ccc(=O)[nH]c12
Reactant: OCc1ccncc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(OCc3ccncc3)cc2)cc2ccc(=O)[nH]c12
Yield: 70.5 %

Procedure:
A solution of diethylazodicarboxylate (0.189 cm3) in THF (5 cm3) was added at room temperature to a stirred suspension of 8-methyl-6-[4-hydroxyphenyl]-2-(1H)-quinolone (0.25 g), 4-hydroxymethylpyridine (0.109 g) and triphenylphosphine (0.315 g) in THF (10 cm3) under nitrogen. The mixture was heated under reflux for 18 hours, silica (10 g) (Merck "MK 60.9385" [Trade Mark]) was added and voltatile material was removed in vacuo. The residue was placed on top of a silica column (Merck "MK 60.9385" [Trade Mark]) and eluted with ethyl acetate:methanol, 9:1. Combination and evaporation of the appropriate fractions in vacuo gave a solid (0.24 g) which was recrystallised from ethyl acetate-methanol to afford the title compound, m.p. 270.5°-273.5°, (0.08 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7]Br.[C:13]([NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][N:25]1[CH2:26][CH2:27][CH:22]([NH:21][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:23][CH2:24]1
Reactant: COc1ccccc1OCCBr
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccccc1OCCN1CCC(NC(=O)c2ccccc2)CC1
Yield: 83.3 %

Procedure:
2-(2-Methoxyphenoxy)ethyl bromide (2.31 g.), 4-benzamidopiperidine (2.04 g.) and anhydrous potassium carbonate (1.38 g.) were well mixed and heatedon a steam bath for 4 hr. The resulting mass was crushed and stirred in water (200 ml.) at 60° for 12 hr. Filtration afforded the crude base of the title compound (2.95 g.). Conversion to the hydrochloride by solution in ethanol/HCl and precipitation with ether provided 3.01 g. of the title compound, as the hydrochloride m.p. 193.4°. Analysis : Found C, 64.74; H, 7.08; N, 7.14. C21H26N2O3. HCl requires C, 64.52; H, 6.96; N, 7.17%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[F:21][C:22]([F:32])([F:31])[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([C:22]([F:21])([F:31])[F:32])[CH:24]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 3-(trifluoromethyl)benzylamine (47 mg, 0.39 mmol). The title compound was obtained as a solid (87 mg, 52% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.48 (1H, m), 8.99 (2H, s), 8.47 (1H, s), 7.64 (2H, m), 7.57 (1H, m), 4.56 (2H, m). MS m/z: 506.07, 508.07 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[CH:19]=[C:20](Cl)[CH:21]=C=O.[CH2:25]([NH2:28])[CH2:26][CH3:27]>C(OCC)(=O)C>[CH2:25]([NH:28][C:12](=[O:13])[C:11]1[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=1[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:19]=[C:20]([C:9](=[O:18])[NH:8][CH2:5][CH2:4][CH3:3])[CH3:21])[CH:4]=1)=[O:18])[CH2:26][CH3:27]
Reactant: CCCN
Reactant: O=C=CC(Cl)=Cc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl
Solvent: CCOC(C)=O
Product: CCCNC(=O)C(C)=Cc1cc(NC(=O)C2=C(C(=O)NCCC)CCCC2)ccc1Cl
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of 10.9 g of N-[4-chloro-3-(2-chloro-carbonylprop-1-en-1-yl)-phenyl]-3,4,5,6-tetrahydrophthalimide in 200 ml of ethyl acetate was added dropwise to a solution of 5.9 g of n-propylamine in about 150 ml of ethyl acetate while cooling with ice. The mixture was stirred for 3 hours at about 20° C., after which the solid formed was separated off, washed twice with 5% by weight aqueous hydrochloric acid and then once with petroleum ether and then dried under reduced pressure at 40° C. The crude product was recrystallized from ethyl acetate. Mp.: 130°131° C.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH3:21])[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[OH:29][C:6]1[C:5]([C:3]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:12]2[C:7]=1[CH:8]=[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10](=[O:22])[N:11]2[CH3:21]
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2C)c1O
Agent: C[O-]
Agent: [Na+]
Product: Cn1c(=O)c(-c2ccccc2)cc2c(O)c(C(=O)NCCC(=O)O)nc(-c3cccnc3)c21
Temperature: 25 °C
Yield: 66.5 %

Procedure:
A mixture of 5-hydroxy-1-methyl-2-oxo-3-phenyl-8-pyridin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (34 mg, 0.088 mmol), β-alanine (626 mg, 7.03 mmol) and NaOMe solution (10.5 mL, 5.3 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 26 mg of the title compound as an off-white solid. MS: (+) m/z 445.26 (M+1).
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]([S:29]([CH3:32])(=[O:31])=[O:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.IC.Cl>CN(C=O)C>[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([CH3:1])([S:29]([CH3:32])(=[O:30])=[O:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:17][CH:16]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(CCc1ccc(OCc2ccccc2)cc1)S(C)(=O)=O
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(CCc1ccc(OCc2ccccc2)cc1)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Cesium carbonate (9.30 g, 28.5 mmol) was added to ethyl 4-[4-(benzyloxy)phenyl]-2-(methylsulfonyl)butanoate (8.86 g, 23.5 mmol) in DMF (100 mL) and stirred for 30 minutes. Iodomethane was added to the reaction followed by stirring overnight at room temperature. The reaction mixture was poured into 1N aqueous HCl (100 mL) and extracted with EtOAc (3×100 mL). The combined organics were washed with saturated aqueous sodium thiosulfate (100 mL) then dried (MgSO4), filtered and concentrated in vacuo to afford a crude solid. The crude product was purified via silica gel chromatography using an eluant of ethyl acetate in heptane (10-100%) to afford the title compound as a white solid (8.35 g, 90.9%). LC-MS m/z 391.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:13]([O:16][C:17]([N:19]1[CH2:23][C@H:22]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:21][C@H:20]1[CH:32]=[O:33])=[O:18])[CH:14]=[CH2:15]>O1CCCC1.CCCCCC>[CH2:13]([O:16][C:17]([N:19]1[CH2:23][C@H:22]([O:24][Si:25]([C:28]([CH3:30])([CH3:29])[CH3:31])([CH3:26])[CH3:27])[CH2:21][C@H:20]1[CH:32]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[OH:33])=[O:18])[CH:14]=[CH2:15]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(O)c1ccccn1
Reaction time: 0.25 h
Yield: 34.3 %

Procedure:
To a solution of 2-bromopyridine (21.9 g) in tetrahydrofuran (310 ml) was added dropwise n-butyl lithium (1.65N) in hexane (78 ml) under -60° C. After stirring for 15 minutes, (2S,4R)-1-allyloxycarbonyl-4-(t-butyldimethylsilyloxy)-2-formylpyrrolidine (31 g) was added dropwise under -60° C. After stirring for 30 minutes, the reaction mixture was quenched with water and extracted three times with ethyl acetate. The combined organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was column chromatographed on silica gel to give 1-{(2S,4R)-1-allyloxycarbonyl-4-(t-butyldimethyl-silyloxy) pyrrolidin-2-yl}-1-(pyridin-2-yl)methanol (13.3 g).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.N[CH2:8][C@@H:9]1CC[CH2:11][N:10]1CC.C(=O)C>>[CH3:11][NH:10][CH2:9][CH2:8][N:4]1[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]1
Reactant: CCN1CCC[C@H]1CN
Reactant: O[C@H]1CCNC1
Agent: CC=O
Product: CNCCN1CC[C@H](O)C1

Procedure:
By using (S)-3-hydroxypyrrolidine (1.0 g) as a starting material, the title compound (195 mg) was obtained in the same manners as those of Reference Example 1, (1) and Reference Example 19, (3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](O)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].[C:16]1([S-:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Na+]>>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([S:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: [S-]c1ccccc1
Agent: [Na+]
Product: CCOC(=O)c1ccc(Sc2ccccc2)c([N+](=O)[O-])c1
Yield: 64.4 %

Procedure:
The product from Example 53a (22.6 g, 67.6 mmol) was reacted with sodium thiophenolate (7.54 g, 67.6 mmol) for 24 h following the procedure from Example 1e giving the title compound as a solid (13.2 g, 67%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20])[CH2:6][CH2:5]2.OS(O)(=O)=O.[N+:28]([O-])([O-:30])=[O:29].[K+]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:28]([O-:30])=[O:29])[C:8](=[O:12])[N:7]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:18]=1[C:19]([F:20])([F:21])[F:22])[CH2:6][CH2:5]2
Reactant: O=[N+]([O-])[O-]
Reactant: O=C1c2ccc(F)cc2CCN1c1cnccc1C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C1c2cc([N+](=O)[O-])c(F)cc2CCN1c1cnccc1C(F)(F)F
Yield: 80.2 %

Procedure:
6-Fluoro-2-(4-(trifluoromethyl)pyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (78A: 600 mg, 1.93 mmol) was reacted with concentrated H2SO4 (5 mL) and KNO3 (215.2 mg, 2.12 mmol) for 4 hours to afford 550 mg of the product (79.9% yield).
Reaction SMILES: [NH2:1][CH:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(O)(=O)C>[C:10]([NH:1][CH:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6])(=[O:12])[CH3:11]
Reactant: CSCCC(N)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CSCCC(NC(C)=O)C(=O)O

Procedure:
Different quantities of D,L-methionine were dissolved in 100 ml acetic acid the solution warmed in an oil bath and 1.1 equivalence of acetic anhydride were added. After 5 minutes the components were concentrated under vacuum at 100° C. bath temperature. The content of N-Acetyl-D,L-methionyl-D,L-methionine (Ac-Met-Met) was determined by HPLC. the results of these experiments are set forth in the following table.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[C:10](Cl)(Cl)=[S:11]>O.C(OCC)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:10]([SH:11])[O:9][C:3]=2[CH:4]=1
Reactant: Nc1ccc(F)cc1O
Reactant: S=C(Cl)Cl
Solvent: CCOCC
Solvent: O
Product: Fc1ccc2nc(S)oc2c1

Procedure:
2-Amino-5-fluorophenol [CAS:53981-24-1] (18.4 g) in 100 ml of water was stirred at room temperature while thiophosgene (16.8 g) was added dropwise as a solution in 100 ml of diethyl ether at such a rate that the resultant exotherm was controlled.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:66]([O:70][C:71]([NH:73][C:74]1[S:78][C:77]([C:79]2[C:84]([F:85])=[CH:83][CH:82]=[CH:81][C:80]=2[F:86])=[N:76][C:75]=1[C:87](O)=[O:88])=[O:72])([CH3:69])([CH3:68])[CH3:67]>C(Cl)Cl>[C:66]([O:70][C:71]([NH:73][C:74]1[S:78][C:77]([C:79]2[C:84]([F:85])=[CH:83][CH:82]=[CH:81][C:80]=2[F:86])=[N:76][C:75]=1[C:87]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:9][CH2:8]1)=[O:88])=[O:72])([CH3:69])([CH3:67])[CH3:68]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CN(CC1CCN(c2c(N)cnn2C)CC1)C(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC1CCN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)cnn2C)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of Intermediate 1, tert-butyl methyl((1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidin-4-yl)methyl)carbamate (145 mg, 0.41 mmol) in MeOH (40 mL) was passed through the H-Cube® (full H2, 50° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to afford crude tert-butyl (1-(4-amino-1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)methyl(methyl)carbamate as a red-brown oil (117 mg). To a solution of this amine (115 mg, 0.36 mmol) in DCM (20 mL) was added DIPEA (1.0 mL), PyBOP (0.46 g, 0.89 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 (127 mg, 0.36 mmol) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM (80 mL) and washed with water (20 mL). The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (75% EtOAc/isohexane) gave tert-butyl (1-(4-(5-tert-butoxycarbonylamino-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)piperidin-4-yl)methyl(methyl)carbamate as a lilac foam (200 mg). This foam (200 mg, 0.30 mmol) was stirred with HCl in 1,4-dioxane (4 M, 3.8 mL, 15.1 mmol) in MeOH (5 mL) at room temperature for 3 days. The solvents were removed under reduced pressure and the crude residue was re-dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and eluted with 7 N ammonia in MeOH to yield 101 as a beige solid (99 mg, 53% over three steps). 1H NMR (400 MHz, d6-DMSO) δ 8.75 (s, 1H), 7.59-7.49 (m, 3H), 7.44 (s, 1H), 7.32-7.22 (m, 2H), 6.90 (br s, 1H), 3.63 (s, 3H), 3.14-2.96 (m, 4H), 2.66 (d, J=6.8 Hz, 2H), 2.45 (s, 3H), 1.77 (d, J=12.6 Hz, 2H), 1.78-1.55 (m, 1H), 1.36-1.22 (m, 2H). LCMS (ES+) m/z 462 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:6](=[O:7])[O:5][CH2:4][C:3]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[C:9]1=[O:25].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:6](=[O:7])[O:5][CH2:4][C:3]=1[N:8]1[CH2:12][CH2:11][C:10]2([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[C:9]1=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=C(Cl)C(=O)OC1)C2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1OCC(N2CCC3(CCNCC3)C2=O)=C1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-(4-chloro-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (2.26 g, 6.09 mmol) in methylene chloride (10 mL) was added trifluoroacetic acid (9.39 mL, 122 mmol) and the resulting solution was stirred at rt for 1 h. After removing the volatiles, the residue was partitioned between methylene chloride (100 mL) and 1N sodium hydroxide (100 mL). The alkaline phase was extracted with methylene chloride (2×100 mL). The combined organic phase was dried over sodium sulfate and concentrated to give 2-(4-chloro-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one. LCMS: (M+1)+: 271.07, 272.96.
Reaction SMILES: F[C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[NH3:10]>CS(C)=O.C(Cl)(Cl)Cl>[NH2:10][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: N#Cc1ncccc1F
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: N#Cc1ncccc1N
Temperature: 70 °C

Procedure:
A solution of 3-fluoro-2-cyanopyridine (Sakamoto et. al., Chem. Pharm. Bull. 1985, 33: 565-571) (10 g, 82 mmol) in DMSO (30 mL) was placed in a pressure vessel and saturated with ammonia gas. The reaction was capped and heated to 70 degrees C. overnight. The reaction was cooled, vented and re-saturated with ammonia, then sealed and re-heated for several hours. The reaction was cooled, vented, diluted with CHCl3 and the solids that had formed were filtered off. The solution was added to the top of a silica gel column (150 mm×7 inches) saturated with CHCl3 and the column was eluted with a gradient of 100% CHCl3 to 100% CHCl3 saturated with NH3. The fractions were collected and concentrated to give the product which contained some residual DMSO. This was used a in the next step.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([NH:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[C:24]2[C:19](=[C:20]([CH3:32])[C:21]3[NH:27][C:26]4[CH:28]=[CH:29][N:30]=[CH:31][C:25]=4[C:22]=3[CH:23]=2)[CH:18]=[CH:17][N:16]=1)[CH3:9]>C1(C)C=CC=CC=1>[CH2:8]([N:10]([CH2:11][CH2:12][CH2:13][NH:14][C:15]1[C:24]2[C:19](=[C:20]([CH3:32])[C:21]3[NH:27][C:26]4[CH:28]=[CH:29][N:30]=[CH:31][C:25]=4[C:22]=3[CH:23]=2)[CH:18]=[CH:17][N:16]=1)[C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])[CH3:9]
Reactant: CCNCCCNc1nccc2c(C)c3[nH]c4ccncc4c3cc12
Reactant: O=C1CCC(=O)O1
Solvent: Cc1ccccc1
Product: CCN(CCCNc1nccc2c(C)c3[nH]c4ccncc4c3cc12)C(=O)CCC(=O)O

Procedure:
A solution of 75 mg of succinic anhydride (0.75 mM) and 250 mg (0.75 mM) of N-ethyl-N′-(6-methyl-5H-pyrido[3′,4′:4,5]pyrrolo[2,3-g]isoquinolin-10-yl)propane-1,3-diamine in 80 ml of dry toluene was brought to reflux for 4 h. The precipitate obtained after cooling was dried and recrystallized with acetone. 240 mg (65.6%) was obtained in the form of solid (F˜150°). Centesimal analysis for C24H27N5O3+3H2O; Calc.: C, 59.12; H, 6.82; N, 14.37; Exp.; C, 59.14; H, 6.88; N, 14.17. NMR and MS in agreement.
Reaction SMILES: CS([O:5][S:6]([CH3:9])(=[O:8])=[O:7])(=O)=O.[Cl:10][C:11]1[N:12]=[C:13]([CH:16]([C:22]2[NH:23][C:24]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=3)=[C:25]3[C:30](=[O:31])[N:29]([CH3:32])[C:28](=[O:33])[N:27]([CH3:34])[C:26]=23)[CH:17]([CH2:20]O)[CH2:18]O)[S:14][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:9][S:6]([O:5][CH2:20][C:17]([CH:16]([C:13]1[S:14][CH:15]=[C:11]([Cl:10])[N:12]=1)[C:22]1[NH:23][C:24]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=2)=[C:25]2[C:30](=[O:31])[N:29]([CH3:32])[C:28](=[O:33])[N:27]([CH3:34])[C:26]=12)=[CH2:18])(=[O:7])=[O:8]
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]c(C(c3nc(Cl)cs3)C(CO)CO)c2n(C)c1=O
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(COS(C)(=O)=O)C(c1nc(Cl)cs1)c1[nH]c(-c2cccc(F)c2)c2c(=O)n(C)c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methanesulfonic anhydride (1699 mg, 9.75 mmol) was added to a solution of 7-(1-(4-chlorothiazol-2-yl)-3-hydroxy-2-(hydroxymethyl)propyl)-5-(3-fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (934 mg, 1.950 mmol) and triethylamine (1.631 mL, 11.70 mmol) in DCM (20 mL). The mixture was stirred at room temperature for 16 hours. Further portions of triethylamine (1.631 mL, 11.70 mmol) and methanesulfonic anhydride (1699 mg, 9.75 mmol) were added as necessary to allow the reaction to run to completion. The reaction was quenched with saturated NaHCO3(aq) and extracted with DCM (3×). The combined organic extracts were passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 20-100% EtOAc/hexane, afforded the title compound.