Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH2:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:12]([N:20]=[C:21]=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][NH:11][C:21]([NH:20][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:22])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C=NCCc1ccccc1
Reactant: NCc1ccc2[nH]ccc2c1
Product: O=C(NCCc1ccccc1)NCc1ccc2[nH]ccc2c1
Yield: 76 %

Procedure:
(1H-indol-5-yl)methylamine (12.5 mg) was reacted with phenethylisocyanate (30 μl) according to the similar procedure as described in step 2 of Example 1, to give 1-(1H-indol-5-ylmethyl)-3-phenethylurea (1-6) (19 mg, 76%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([Cl:11])[N:3]=1.[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13].O>C(OCC)C>[Cl:11][C:4]1[C:5]([C:9]#[N:10])=[C:6]([Cl:8])[N:7]=[C:2]([N:14]([CH2:15][CH3:16])[CH2:12][CH3:13])[N:3]=1
Reactant: N#Cc1c(Cl)nc(Cl)nc1Cl
Reactant: CCNCC
Solvent: CCOCC
Solvent: O
Product: CCN(CC)c1nc(Cl)c(C#N)c(Cl)n1
Reaction time: 1 h
Yield: 51.3 %

Procedure:
A stirred solution of 6.3 grams of 2,4,6-trichloro-5-pyrimidinecarbonitrile in 150 ml of diethyl ether was cooled to -10°, and a solution of 4.4 grams of diethylamine in 75 ml of diethyl ether was added dropwise. Upon complete addition, the reaction mixture was stirred at -10° for 1 hour. Water was added to the reaction mixture. The diethyl ether layer was separated and dried over magnesium sulfate. The mixture was filtered, and the filtrate was evaporated under reduced pressure to a residue. The residue was recrystallized from methylcyclohexane to give 3.8 grams of 4,6-dichloro-2-diethylamino-5-pyrimidinecarbonitrile; mp, 125°-126°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27]C)[CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:29]([CH3:31])[CH3:30])[NH:11]1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([CH:29]([CH3:31])[CH3:30])[NH:11]1
Reactant: COc1cccc(Cc2nc3n(-c4c(Cl)cc(Cl)cc4Cl)[nH]c(C(C)C)c-3c(=O)n2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1[nH]n(-c2c(Cl)cc(Cl)cc2Cl)c2nc(Cc3cccc(O)c3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
To a stirred solution of 65 mg (0.14 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 1 mL of CH2Cl2 was added 1 mL(1 mmol ) of 1 M boron tribromide in CH2Cl2. The solution was stirred 1 h at ambient temperature and then cooled to 0° C. The reaction was quenched with 4 mL of 1 M aq. HCl. The mixture was poured into water and extracted with 1:1 THF-EtOAc. The organic extract was washed with brine, dried (MgSO4), and concentrated under reduced pressure to afford 63 mg (100%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one as an amorphous solid. 1H NMR (300 MHz, DMSO) δ 12.46(br. s, 1H); 9.33(br. s, 1H); 7.96(s, 2H); 7.03(t, 1H, J=7.7 Hz); 6.55-7.08(m, 3H); 3.75(s, 2H); 3.19-3.36(m, 1H); 1.29(d, 6H, J=7.0 Hz).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=O)[CH:15]=2)[C:10]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:20])=[C:9]1[CH:31]([CH3:33])[CH3:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([NH2:37])[CH2:35][NH2:36].C1C(=O)N(Br)C(=O)C1>C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[NH:36][CH2:35][CH2:34][N:37]=3)[CH:15]=2)[C:10]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:20])=[C:9]1[CH:31]([CH3:32])[CH3:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C=O)cc2n1Cc1ccccc1
Reactant: NCCN
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C3=NCCN3)cc2n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-benzyl-N-(3,4-difluorobenzyl)-6-formyl-2-isopropyl-1H-indole-3-carboxamide (Compound 53, 18 mg, 0.040 mmol) in CH2Cl2 (1 ml) at 0° C. under argon was added ethylene diamine (2.5 mg, 0.042 mmol). The mixture was stirred at 0° C. for 30 minutes, and then added NBS (8 mg, 0.042 mmol). The reaction was stirred at 25° C. for 12 h, quenched with NaHCO3 (aqueous), diluted with EtOAc, washed with H2O, brine, dried over Na2SO4, concentrated in vacuo. The residue was purified by chromatography on silica gel (100% EtOAc) to yield the title compound as a light yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[F:11][C:12]([F:22])([F:21])[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.COC(OC)OC.[BH4-].[Na+]>CO>[F:11][C:12]([F:21])([F:22])[C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=2)=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: NCCc1ccc(O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
A suspension of tyramine (1 g; 7.29 mmol) in MeOH (8 ml) was treated with 4-trifluoromethyl benzaldehyde (1.27 g; 7.29 mmol) and trimethylorthoformate (5 ml). The reaction mixture was stirred at rt overnight and then treated with sodium borohydride (0.69 g; 18.23 mmol) in small portions. After stirring for 30 minutes, it was concentrated and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. Crystallization from ethyl ether-hexane provided the title compound as a white crystalline solid (1.67 g; 78% yield). 1H NMR (CDCl3) δ 7.54 (d, 2H, J=8.0), 7.37 (d, 2H, J=8.0), 7.00 (d, 2H, J=8.4), 6.68 (d, 2H, J=8.4), 4.50 (bs, 2H), 3.86 (s, 2H), 2.88 (t, 2H, J=6.9), 2.77 (t, 2H, J=6.9).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+]>C1COCC1>[CH2:12]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1cccc(OCc2ccccc2)c1
Yield: 90.9 %

Procedure:
A mixture of 2-(3-hydroxyphenyl)acetic acid (0.6 g, 3.95 mmol), benzyl bromide (0.710 g, 4.14 mmol), potassium hydroxide (0.550 g, 9.87 mmol), KI (13 mg, 0.079 mmol) in THF (20 mL) was refluxed for 18 h. The solvent was removed and the residue was dissolved in 50 mL of water and extracted with ether. The aqueous layer was acidified with aqueous 1N HCl and the white precipitate that formed was filtered off to afford 2-(3-(benzyloxy)phenyl)acetic acid as a gray solid (0.87 g, 91%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]([NH:25][CH2:26][C:27](O)=[O:28])=[O:24])[CH:17]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=[O:5])[CH3:2].Cl.[OH:31][C:32]1([CH3:38])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH2:1]([NH:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]([NH:25][CH2:26][C:27]([N:35]4[CH2:36][CH2:37][C:32]([OH:31])([CH3:38])[CH2:33][CH2:34]4)=[O:28])=[O:24])[CH:17]=3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=[O:5])[CH3:2]
Reactant: CC1(O)CCNCC1
Reactant: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)NCC(=O)O)c3)ccc21
Agent: Cl
Product: CCNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)NCC(=O)N4CCC(C)(O)CC4)c3)ccc21
Yield: 21.9 %

Procedure:
The reaction similar to Example 5 was performed by using ((4-(1-ethylcarbamoyl-1H-indol-5-yloxy)pyridin-2-yl)aminocarbonylamino)acetic acid (149 mg, 0.37 mmol) and 4-hydroxy-4-methylpiperidine monohydrochloride (68 mg, 0.45 mmol, Production example 8-3); purification was performed by silica gel column chromatography (Fuji Silysia BW-300, eluent, ethyl acetate:methanol=9:1; Fuji Silysia NH, eluent, ethyl acetate:methanol=10:1; and again Fuji Silysia BW-300, eluent, ethyl acetate-methanol system); and the obtained crystals were suspended in diethyl ether and filtered off, washed with diethyl ether and dried under aeration to yield the title compound as colorless crystals (40 mg, 0.081 mmol, 22%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][CH2:19][CH3:20])[C:12](=[O:21])[NH:11][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28]>>[CH2:18]([N:13]1[C:14](=[O:17])[C:15]2[NH:16][C:8]([C:5]3[CH:6]=[N:7][C:2]([NH:28][CH2:27][C:26]4[CH:29]=[CH:30][CH:31]=[C:24]([C:23]([F:22])([F:32])[F:33])[CH:25]=4)=[CH:3][CH:4]=3)=[N:9][C:10]=2[NH:11][C:12]1=[O:21])[CH2:19][CH3:20]
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: CCCn1c(=O)[nH]c2nc(-c3ccc(Cl)nc3)[nH]c2c1=O
Product: CCCn1c(=O)[nH]c2nc(-c3ccc(NCc4cccc(C(F)(F)F)c4)nc3)[nH]c2c1=O
Temperature: 200 °C
Reaction time: 48 h

Procedure:
A mixture of 8-(6-Chloro-pyridin-3-yl)-1-propyl-3,7-dihydro-purine-2,6-dione (0.5 g, 1.6 mmol) and 3-Trifluoromethyl-benzylamine (3 ml) was stirred in sealed tube for 48 hours at 200° C. Reaction mixture was cooled and filtered, washed with ethanol to get 1-Propyl-8-[6-(3-trifluoromethyl-benzylamino)-pyridin-3-yl]-3,7-dihydro-purine-2,6-dione as off white solid (0.61 g, 84%).
Reaction SMILES: [C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26](O)=[O:27])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]1([S:35]([NH2:38])(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:19]=[CH:20][C:21]([CH:24]=[CH:25][C:26]([NH:38][S:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:37])=[O:36])=[O:27])=[CH:22][CH:23]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1
Reactant: NS(=O)(=O)c1ccccc1
Product: O=C(C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1)NS(=O)(=O)c1ccccc1

Procedure:
Prepared by coupling 2e and benzene sulfonamide in accordance with Procedure 1, Method A described hereinabove. Yield (70%); 1H NMR (d6-DMSO) δ 12.25 (s, 1H), 7.94 (d, J=7.3 Hz, 2H), 7.66 (m, 3H), 7.42 (d, J=15.7 Hz, 1H), 7.34–7.14 (m, 10H), 6.88 (d, J=8.1 Hz, 2H), 6.72 (d, J=7.3 Hz, 1H), 6.48 (d, J=15.7 Hz, 1H), 2.79 (m, 2H), 2.28 (m, 2H), 2.09 (m, 2H); ESI m/z: 504 (M−H−, 100%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[N:16]([CH3:17])[C:15]2[C:18]([Cl:22])=[CH:19][CH:20]=[CH:21][C:14]=2[N:13]=1)[CH2:9][C:10]#[CH:11]>C(N(CC)CC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:22][C:18]1[C:15]2[N:16]([CH3:17])[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)=[N:13][C:14]=2[CH:21]=[CH:20][CH:19]=1
Reactant: Ic1ccccn1
Reactant: C#CCCc1nc2cccc(Cl)c2n1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: Cn1c(CCC#Cc2ccccn2)nc2cccc(Cl)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 6 %

Procedure:
In a dry reaction tube containing copper iodide (1 mg, 0.0055 mmol) and triethylamine (0.50 mL, 0.1 mmol), were added 2-iodopyridine (22 mg, 0.11 mmol) and Pd(PPh3)2Cl2 (2.4 mg, 0.0055 mmol). A yellow suspension was obtained and after a few minutes of stirring at room temperature, 2-(but-3-ynyl)-7-chloro-1-methyl-1H-benzo[d]imidazole (compound 191(B), 24 mg, 0.11 mmol) in triethylamine (0.2 mL) was added. Immediately the color of the reaction turns to black. The mixture was stirred at room temperature for 30 min and then at 50° C. for 3 h. Triethylamine was concentrated under reduce pressure and the residue was dissolved in DCM. The organic layer was washed with saturated NH4Cl, water and brine. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography system (prepacked silicagel column 2 g, DCM/MeOH: 98/2 as eluent) to afford 2 mg g of 7-chloro-1-methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-1H-benzo[d]imidazole (Yield: 6%) as brown solid.
Reaction SMILES: O1C=CC=C1C1C=CC(N2CCN(S(CC(C(C)C)C([NH:25][OH:26])=O)(=O)=O)CC2)=CC=1.[Br:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][N:40]([S:43]([CH2:46][C:47]3([C:53](O)=[O:54])[CH2:52][CH2:51][O:50][CH2:49][CH2:48]3)(=[O:45])=[O:44])[CH2:39][CH2:38]2)=[CH:33][CH:32]=1>>[OH:26][NH:25][C:53]([C:47]1([CH2:46][S:43]([N:40]2[CH2:39][CH2:38][N:37]([C:34]3[CH:35]=[CH:36][C:31]([Br:30])=[CH:32][CH:33]=3)[CH2:42][CH2:41]2)(=[O:44])=[O:45])[CH2:48][CH2:49][O:50][CH2:51][CH2:52]1)=[O:54]
Reactant: O=C(O)C1(CS(=O)(=O)N2CCN(c3ccc(Br)cc3)CC2)CCOCC1
Reactant: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(-c3ccco3)cc2)CC1)C(=O)NO
Product: O=C(NO)C1(CS(=O)(=O)N2CCN(c3ccc(Br)cc3)CC2)CCOCC1
Yield: 87 %

Procedure:
Prepared according to the method for the preparation of 2-[4-(4-furan-2-yl-phenyl)piperazine-1-sulfonylmethyl]-N-hydroxy-3-methylbutyramide, from 4-[4-(4-bromophenyl)piperazine-1-sulfonylmethyl]tetrahydropyran-4-carboxylic acid (4.54 g), to yield the title compound as a white solid (4.07 g, 87%).
Reaction SMILES: [Br:1]Br.[OH:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:21])=[N:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:9]1.[OH-].[NH4+]>C(Cl)(Cl)Cl.CC(O)=O>[Br:1][C:11]1[C:10]([NH:13][C:14]([NH2:21])=[N:15][CH2:16][C:17]([F:20])([F:18])[F:19])=[N:9][N:8]([CH2:7][CH2:6][CH2:5][CH2:4][OH:3])[CH:12]=1
Reactant: BrBr
Reactant: NC(=NCC(F)(F)F)Nc1ccn(CCCCO)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: NC(=NCC(F)(F)F)Nc1nn(CCCCO)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
A solution (2.75 ml.) of bromine (80 mg.) in chloroform was added to a solution of 1-(4-hydroxybutyl)-3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazole (140 mg.) in HOAc (2 ml.). After stirring at room temperature for 1 hour the mixture was basified with 6 N aqueous ammonium hydroxide and then extracted with EtOAc (6×10 ml.). The combined extracts were dried (MgSO4) and evaporated to dryness in vacuo to give 4-bromo-1-(4-hydroxybutyl)-3-[2-(2,2,2-trifluoroethyl)guanidino]pyrazole (145 mg., 82%) having the following n.m.r. spectrum in d6DMSO: 7.7 (s, 1H); 4.2 (br t, 2H); 3.9 (t, 2H); 3.3 (t, 2H); 1.5 (br m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:22])[C:16]([C:19](O)=[O:20])=[CH:17][N:18]=3)[S:13][C:6]=12.CN(C=O)C.C(Cl)(=O)C([Cl:38])=O>C1COCC1>[F:1][C:2]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:22])[C:16]([C:19]([Cl:38])=[O:20])=[CH:17][N:18]=3)[S:13][C:6]=12
Reactant: Cn1c(C(=O)O)cnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1c(C(=O)Cl)cnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Yield: 100 %

Procedure:
To a pre-cooled solution of acid 214 (1.25 g, 3.02 mmol, scheme 52) in THF (12.07 mL) was added DMF (0.023 mL, 0.302 mmol) and oxalyl chloride (0.660 mL, 7.54 mmol) and the resultant solution was stirred at 0° C. for 30 min. The solvent was evaporated, the residue was triturated with ether and dried under high vacuum to give title compound 219 (1.306 g, 3.02 mmol, 100% yield) as a beige solid. MS: 429.2 (MH+, COOMe), 433.1 (COCl, MH+).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:20][C@H:21]([CH3:33])[CH2:22][S:23][C:24]2[S:25][C:26]3[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=3[N:28]=2)[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH3:34][N:35](C)[CH:36]=O>>[S:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:24]1[S:23][CH2:22][C@H:21]([NH:20][C:4]1[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=[C:2]([N:35]([CH3:36])[CH3:34])[N:3]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11])[CH3:33]
Reactant: C[C@H](CSc1nc2ccccc2s1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: CN(C)C=O
Product: C[C@H](CSc1nc2ccccc2s1)Nc1nc(N(C)C)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 12 %

Procedure:
The title compound was prepared according to general method B by reaction of N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]-2-chloroadenosine (1.02 g, 2.0 mmol) (Example 5) in dimethylformamide (10 ml) to provide the desired N-[(R)-1-(2-benzothiazolyl)thio-2-propyl]-2-(dimethylamino)adenosine (0.12 g, 12%) as a foam (following column chromatography), 1H NMR (DMSO6) δ1.38 (3H, d, --CHCH3), 2.92 (6H, s, --N(CH3)2), 3.40-3.72 (4H, m, H-5'a and H-5'b and --CH2 --), 3.88 (1H, q, H-4'), 4.15 (1H, q, H-3'), 4.65 (1H, q, H-2'), 4.72-4.85 (1H, m, --CH--), 4.89 (1H, t, 5'-OH), 5.14, 5.36 (2H, 2d, 2'- and 3'-OH), 5.75 (1H, d, H-1'), 7.35, 7.46 (2H, 2 t, Ar--H), 7.50 (1H, d, N--H), 7.84, 7.99 (2H, 2d, Ar--H), 7.94 (1H, s, H-8). HPLC retention time 16.8 min [gradient elution, 20-80% acetonitrile/water (containing 0.1% TFA)].
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][C:20](=[O:24])[N:21]([CH3:23])[CH3:22])[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:22][N:21]([CH3:23])[C:20]([CH2:19][O:18][C:14]1[C:11]2[C:12]([CH3:13])=[C:8]([C:6]([OH:7])=[O:5])[O:9][C:10]=2[CH:17]=[CH:16][CH:15]=1)=[O:24]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(OCC(=O)N(C)C)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C(=O)O)oc2cccc(OCC(=O)N(C)C)c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The above 4-dimethylcarbamoylmethoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was dissolved into a 40% TFA/methylene chloride solution, and stirred at room temperature for four hours. Evaporation of solvent gave 4-dimethylcarbamoylmethoxy-3-methyl-benzofuran-2-carboxylic acid in quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7](B(O)O)[CH:8]=1.Br[C:13]1[CH:18]=[C:17]([F:19])[C:16]([C:20]([N:22]2[CH2:26][CH2:25][CH2:24][C@H:23]2[CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:21])=[C:15]([F:33])[CH:14]=1>>[F:19][C:17]1[CH:18]=[C:13]([C:7]2[CH:6]=[N:5][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=2)[CH:14]=[C:15]([F:33])[C:16]=1[C:20]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH2:27][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:21]
Reactant: O=C(c1c(F)cc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: COc1cncc(B(O)O)c1
Product: COc1cncc(-c2cc(F)c(C(=O)N3CCC[C@H]3CN3CCCC3)c(F)c2)c1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure WW starting from 3-methoxypyridine-5-boronic acid and (4-bromo-2,6-difluoro-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone to give 20 mg (19%). MS (ES+) 402 m/z
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([S:5]([C:8]2[CH:9]=[C:10]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=2)[C:11]([N:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[O:28][CH3:29])[CH3:14])=[O:12])(=[O:7])=[O:6])[CH2:2]1.[S:37](=[O:41])(=[O:40])(N)[NH2:38]>C(OC(=O)C)(C)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[N:13]([CH3:14])[C:11](=[O:12])[C:10]2[CH:30]=[C:31]([C:33]([F:34])([F:36])[F:35])[CH:32]=[C:8]([S:5]([CH:3]3[CH2:4][N:1]([S:37](=[O:41])(=[O:40])[NH2:38])[CH2:2]3)(=[O:7])=[O:6])[CH:9]=2)=[C:22]([O:28][CH3:29])[CH:23]=1
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)C2CNC2)c1
Reactant: NS(N)(=O)=O
Solvent: CC(=O)OC(C)C
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)C2CN(S(N)(=O)=O)C2)c1

Procedure:
A suspension of 3-(azetidin-3-ylsulfonyl)-N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-N-methyl-5-(trifluoromethyl)benzamide (0.05 g, 95.5 μmol, example 280) and sulfuric diamide (36.7 mg, 382 μmol) in isopropylacetate (1 mL) was heated at reflux for 19 hours. The reaction mixture was evaporated and the product purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Light brown solid (0.035 g; 60%). MS (ESI): m/z=603.10 [M+H]+.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:13](=O)([O:16]C)[O:14][CH3:15].[H-].[Na+].Cl>O1CCCC1.O>[O:12]=[C:11]1[CH:10]([C:13]([O:14][CH3:15])=[O:16])[CH2:9][CH2:8][CH2:7][C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: COC(=O)OC
Reactant: O=C1CCCCc2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1CCCc2ccccc2C1=O

Procedure:
To a solution of 6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one (24.99 g, 156.0 mmol) and dimethyl carbonate (42.2 g, 468 mmol) in tetrahydrofuran (150 ml) was added a suspension (12.5 g, 312 mmol) of 60% sodium hydride in liquid paraffin at room temperature and the mixture was heated under reflux for 1 hr. The reaction solution was poured into water, acidified with 1N hydrochloric acid and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=15/1) to give methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylate as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[O:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:31].[CH3:32][C:33]([CH3:35])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:10]([CH3:11])=[N:9][C:8]2[N:4]([N:5]=[C:6]3[CH2:14][N:13]([C:15]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=4[O:24][CH:25]4[CH2:30][CH2:29][N:28]([CH:33]([CH3:35])[CH3:32])[CH2:27][CH2:26]4)=[O:16])[CH2:12][C:7]3=2)[C:3]=1[CH3:31]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1OC1CCNCC1)C3
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1OC1CCN(C(C)C)CC1)C3
Yield: 56 %

Procedure:
A mixture of Example 64 (110 mg; 0.25 mmol; 1 eq.), acetone (109 μL; 1.49 mmol; 6 eq.) and sodium triacetoxyborohydride (210 mg; 0.99 mmol; 4 eq.) in DCM (6 mL) was stirred at room temperature for 60 hours. The reaction mixture was diluted with DCM, washed with sat. aq. NaHCO3, dried over sodium sulfate and concentrated in vacuo. Purification by mass directed preparative HPLC afforded the title compound (68 mg, 56%) as a yellow powder. 1H NMR (CDCl3) δ 7.33 (td, J=8.2, 6.7 Hz, 1H), 6.80-6.63 (m, 2H), 5.05-4.91 (m, 2H), 4.67 (br s, 2H), 4.36 (br s, 1H), 2.91 (s, 2H), 2.86 (s, 1H), 2.78-0.52 (m, 6H), 2.46-2.24 (m, 2H), 2.06-1.88 (m, 2H), 1.88-1.70 (m, 2H), 0.94 (d, J=6.5 Hz, 6H). HPLC (max plot) 94.1%, Rt 3.02 min. UPLC/MS: (MS+) 486.5 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].C[Si]([C:20]#[CH:21])(C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[CH:8]=[C:9]([OH:10])[CH:21]=[CH:20]2
Reactant: C#C[Si](C)(C)C
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Oc1ccc2cc(F)ccc2c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A solution of 2-(4-fluorophenyl)acetyl chloride (5.0g; 29 mmol) in CH2Cl2 was added to AlCl3 (7.73g;58 mmol) in CH2Cl2 at −20° C. over 30 min. Trimethylsilyl acetylene (9.96g; 101.43 mmol) was added also over 30 min and stirred at −10° C. for 1h. The mixture was poured in ice and extracted with EtOAc. The organic phase was washed with water, NaHCO3 and brine. After purification by gel silica chromatography (10% EtOAc in hexane) 2.43 g (36%) of 3-(trimethylsilyl)-6-chloro-2-naphthol was collected. The desylilation was done with TFA in CH2Cl2 at rt overnight. Purification by gel silica chromatography (10% EtOAc in hexane) afforded the title compound in 69% yield.