Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)O[C@H:6]1[CH2:10][C@@H:9]([N:11]2[CH:19]=[N:18][C:17]3[C:12]2=[N:13][C:14]([Cl:21])=[N:15][C:16]=3[Cl:20])[CH:8]=[CH:7]1)C.[NH:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:31]([N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:6]1[CH2:10][C@@H:9]([N:11]2[CH:19]=[N:18][C:17]3[C:12]2=[N:13][C:14]([Cl:21])=[N:15][C:16]=3[Cl:20])[CH:8]=[CH:7]1)([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Carbonic acid (1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl ester ethyl ester (2.5 g, 7.29 mmol), di-t-butyl iminodicarboxylate (1.74 g, 8.02 mmol), tris(dibenzylideneacetone)-dipalladium(0) (0.33 g, 0.36 mmol) and triphenylphosphine (0.29 g, 1.09 mmol) are placed ira an oven-dried flask under an atmosphere of argon. Dry deoxygenated THF (30 ml) is added and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 3 hours. The solvent is removed in vacuo and the title compound is obtained after purification by flash column chromatography (silica, ethyl acetate/isohexane 4:1) 1H nmr (CDCl3, 400 MHz); 8.70(s, 1H), 6.20(m, 1H), 5.85(m, 1H), 5.80(m, 1H), 5.40(m, 1H), 3.20(m, 1H), 2.15(m, 1H), 1.55(s, 18H), MS (ES+) m/e 470 (MH+).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:25])[C@H:7]([CH3:24])[NH:8][C:9](=[O:23])[C@@H:10]([NH:16][C@@H:17]([C:19]([O:21]C)=[O:20])[CH3:18])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].C(O)(=O)C>CO>[CH2:1]([NH:5][C:6](=[O:25])[C@H:7]([CH3:24])[NH:8][C:9](=[O:23])[C@@H:10]([NH:16][C@@H:17]([C:19]([OH:21])=[O:20])[CH3:18])[CH2:11][C:12]([CH3:15])([CH3:13])[CH3:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)[C@H](C)NC(=O)[C@H](CC(C)(C)C)N[C@H](C)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCNC(=O)[C@H](C)NC(=O)[C@H](CC(C)(C)C)N[C@H](C)C(=O)O
Yield: 48 %

Procedure:
N-[2-(S)-N(1-(R)-Methoxycarbonylethyl)amino-4,4-dimethylpentanoyl]-L-alanine N-butylamide (65 mg) in methanol (30 ml) was treated with IN-sodium hydroxide (3 ml) at 20° for 6 h. Excess acetic acid was then added and the solvent evaporated in vacuo. The residue was chromatographed on reverse phase silica (RF 18) in a gradient of 20%-80% methanol in water. Elution in 70% methanol in water afforded the title compound (30 mg) as a freeze-dried powder, m.p. 137°-138°; (Found: [m+1]+ =344.2548. C17H34N3O4 requires [m+1]+ =344.2549); δ(D2O) 0.9 (3H, t, J=6 Hz, CH2CH3); 0.94 (9H, s, C(CH3)3); 1.2-1.8 (6H, m, (CH2)2 and CH2); 1.4 (3H, d, J=8 Hz, CH3 ); 1.52 (3H, d, J=7 Hz, CH3); 3.18 (2H, t, J=6 Hz, NHCH2); 3.66 (1H, q, J=5 Hz, CHCO); 3.88 (1H, d, J=10 Hz, CHCH2) and 4.38 (1H, q, J=5 Hz, CHCH3).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>CN(C=O)C>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: C1CNCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccnc(N2CCNCC2)c1
Yield: 42.9 %

Procedure:
A solution of 2-chloro-4-(trifluoromethyl)pyridine (2.0 g, 11 mmol), piperazine (3 g, 30 mmol) and triethylamine (3.1 mL, 22 mmol) in DMF (10 mL) was heated at 100° C. overnight and concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc to EtOAc/MeOH/Et3N=9/1/0.5) to give 1.09 g (43%) of pure product. MS calculated for C10H12F3N3: (M+H) 232; found 232.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14](/[CH:17]=[CH:18]/[CH2:19][CH2:20][C:21]3[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.ClC1C=CC(N2CCN(S(/C=C\CCC3N=CC(F)=CN=3)(=O)=O)CC2)=NC=1.[NH2:55][OH:56]>O1CCCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH:18]([NH:55][OH:56])[CH2:19][CH2:20][C:21]3[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: O=S(=O)(/C=C/CCc1ncc(F)cn1)N1CCN(c2ccc(Cl)cn2)CC1
Reactant: NO
Agent: O=S(=O)(/C=C\CCc1ncc(F)cn1)N1CCN(c2ccc(Cl)cn2)CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(CC(CCc1ncc(F)cn1)NO)N1CCN(c2ccc(Cl)cn2)CC1
Reaction time: 18 h

Procedure:
To a solution of 2-((E)-4-[4-(5-chloropyridin-2-yl)piperazino]sulfonylbut-3-enyl)-5-fluoropyrimidine and 2-((Z)-4-[4-(5-chloropyridin-2-yl)piperazino]sulfonylbut-3-enyl)-5-fluoropyrimidine (0.44 g), in tetrahydrofuran (5 ml), was added hydroxylamine (1.0 ml, 50% aqueous solution). The mixture was stirred for 18 hours and then diluted with EtOAc(10 ml) and washed with saturated ammonium chloride solution(10 ml. The organic layer was dried over Na2SO4 and evaporated in vacuo to give 2-[4-[4-(5-chloropyridin-2-yl)piperazino]sulfonyl-3-(hydroxyamino)butyl]-5-fluoropyrimidine(0.483 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[CH:17][C:16](=[O:19])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28](=[O:32])[CH2:29][CH2:30][CH3:31]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[CH:17][C:16](=[O:19])[C:8]4[CH:9]=[C:10]([O:15][CH2:27][C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: O=c1ccn2c3ccc(Br)cc3c3cc(O)cc1c32
Reactant: CCCC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCC(=O)COc1cc2c(=O)ccn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
10-bromo-2-hydroxy-4H-pyrido[3,2,1-jk]carbazole-4-one (250 mg) obtained in Example 59 was suspended in dimethyl sulfoxide (10 ml), and potassium carbonate (210 mg) was added to the suspension. The mixture was stirred at room temperature for 30 minutes and 1-bromo-2-pentanone (170 mg) was added to the mixture. The mixture was stirred at room temperature for 3 hours, and the reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: methylene chloride containing 2% methanol) to obtain the title compound (130 mg, 41%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C@H:10]2[O:14][C@@H:13]([N:15]3[CH:23]=[N:22][C:21]4[C:16]3=[N:17][CH:18]=[N:19][C:20]=4[NH:24][CH:25]3[CH2:29][CH2:28][O:27][CH2:26]3)[C@H:12]([OH:30])[C@@H:11]2[OH:31])=[CH:4][CH:3]=1>C(O)C.C1CCCCC=1.[OH-].[Pd+2].[OH-]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C@H:10]2[O:14][C@@H:13]([N:15]3[CH:23]=[N:22][C:21]4[C:16]3=[N:17][CH:18]=[N:19][C:20]=4[NH:24][CH:25]3[CH2:29][CH2:28][O:27][CH2:26]3)[C@H:12]([OH:30])[C@@H:11]2[OH:31])=[CH:4][CH:3]=1
Reactant: O[C@@H]1[C@H](O)[C@@H](C=Cc2ccc(F)cc2)O[C@H]1n1cnc2c(NC3CCOC3)ncnc21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCCCC1
Product: O[C@@H]1[C@H](O)[C@@H](CCc2ccc(F)cc2)O[C@H]1n1cnc2c(NC3CCOC3)ncnc21
Reaction time: 24 h

Procedure:
To a solution of 5-[2-(4-fluorophenyl)vinyl](4S,2R,3R,5R)-2-[6-(oxolan-3-ylamino)purin-9-yl]oxolane-3,4-diol (40 mg) in ethanol (5 ml) and cyclohexene (2 ml) was added palladium hydroxide (50 mg), and the mixture was stirred for 24 hours. The catalyst was filtered off, and solvent removed under reduced pressure. The residue was purified by preparative thin layer chromatography, to give pure (4S,2R,3R,5R)-5-[2-(4-fluorophenyl)ethyl]-2-[6-(oxolan-3-ylamino)purin-9-yl]oxolane-3,4-diol, a compound of Formula I.
Reaction SMILES: C(N(CC)CC)C.[OH:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].[NH2:20][C:21]1[C:30]2[N:31]=[C:32]([CH2:43]Cl)[N:33]([CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[C:29]=2[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:22]=1>CN(C=O)C>[NH2:20][C:21]1[C:30]2[N:31]=[C:32]([CH2:43][O:8][N:9]3[C:10](=[O:19])[C:11]4[C:12](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:14])[N:33]([CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[C:29]=2[C:28]2[N:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:22]=1
Reactant: CC(C)C(=O)NCCCn1c(CCl)nc2c(N)nc3cccnc3c21
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C(=O)NCCCn1c(CON2C(=O)c3ccccc3C2=O)nc2c(N)nc3cccnc3c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
Triethylamine (0.340 mL, 2.41 mmol) and N-hydroxyphthalimide (0.333 g, 2.04 mmol) were added to a suspension of N-{3-[4-amino-2-(chloromethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]propyl}-2-methylpropanamide (0.670 g, 1.86 mmol) in DMF (10 mL). The reaction was allowed to stir at room temperature for 4 hours, then was concentrated under reduced pressure. The residue was triturated with methanol to afford 0.848 g of N-[3-(4-amino-2-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)propyl]-2-methylpropanamide as a tan solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=1)=[O:31])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J11) (160 mg. 0.5 mmol) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example K3) (123 mg, 0.5 mmol) according to the general procedure M. Obtained as a yellow solid (159 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[O:5][C:6]([CH3:19])=[CH:7][C:8](=[O:18])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O[CH:21](C1OC(C)=CC(=O)C=1OCC1C=CC=CC=1)C>>[CH3:1][O:2][CH:3]([C:4]1[O:5][C:6]([CH3:19])=[CH:7][C:8](=[O:18])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:21]
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C(C)O)o1
Reactant: COCc1oc(C)cc(=O)c1OCc1ccccc1
Product: COC(C)c1oc(C)cc(=O)c1OCc1ccccc1
Yield: 97 %

Procedure:
In an analogous procedure in the preparation of 2methoxymethyl-3-benzyloxy-6-methyl-pyran-4(1H)-one using 2-(1-hydroxyethyl)-3-benzyloxy-6-methyl-pyran-4(1H)-one (2.6 g, 10 mmol, 1 eq.) yielded the title compound as an orange oil (2.65 g, 97%). Further purification by column chromatography on silica gel (eluant: EtOAc) furnished the pure product as a bright yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:14]1[CH2:18]OC[CH2:15]1>C1([Mg]Br)CC1>[CH:15]1([C:7]([OH:13])([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:14][CH2:18]1
Reactant: C1CCOC1
Reactant: CCOC(=O)C(=O)c1ccccn1
Agent: Br[Mg]C1CC1
Product: CCOC(=O)C(O)(c1ccccn1)C1CC1
Reaction time: 1 h

Procedure:
To a stirred solution of ethyl 2-(2-pyridyl)-2-oxoacetate (1.0 g, 5.6 mmol) in 10 mL of THF at −78° C. under nitrogen atmosphere was added in 0.92M cyclopropyl magnesium bromide in THF solution (6.7 mL, 7.3 mmol). The reaction was then allowed to equilibrate to 0° C. and stir for 1 h. The reaction was quenched with saturated NH4Cl solution and partitioned between EtOAc and water. The EtOAc layer was separated, dried over anhydrous Na2SO4, and filtered. The filtrate solvent was removed under reduced pressure and the residue was purified by flash silica gel chromatography using 1% methanol in dichloromethane as an eluent. After concentration of desired fractions in vacuo ethyl 2-cyclopropyl-2-(2-pyridyl)hydroxyacetate was obtained as a yellow oil (0.9 g; 1H NMR, 400 MHz, CDCl3, 8.52 ppm (d, 1H), 7.76 ppm (m, 2H), 7.25 ppm (m, 1H), 5.18 ppm (s, 1H), 4.23 ppm (q, 2H), 1.8 ppm (m, 1H), 1.24 ppm (t, 3H), 0.72 ppm (m, 1H), 0.47 ppm (m, 2H), 0.37 ppm (m, 1H)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH3:14])[C@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[C:20]([F:27])=[C:21]([CH2:25][NH2:26])[CH:22]=[CH:23][CH:24]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH3:14])[C@H:9]1[C:15](=[O:17])[NH:26][CH2:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[C:20]=1[F:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CO[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1C(=O)O
Reactant: NCc1cccc(Cl)c1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1C(=O)NCc1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The mixture of (2S,3R)-3-methoxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (60.0 mg, 0.245 mmol), (3-chloro-2-fluorophenyl)methanamine (0.034 mL, 0.269 mmol), HBTU (139 mg, 0.367 mmol) and DIPEA (0.085 mL, 0.489 mmol) in CH2Cl2 (5 mL) was stirred for 20 h at RT. The reaction mixture was then diluted with CH2Cl2, and the organics were washed subsequently with 0.1N aqueous HCl (3×), aqueous NaHCO3 solution (2×) and brine. The organic layers were dried (Phase separator), concentrated in vacuo and the residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm; flow: 40 mL/min; eluent: 5-100% CH3CN/H2O for 20 min, 100% CH3CN for 2 min, CH3CN and H2O containing 0.1% TFA) to afford the title compound as a white solid. MS (LC/MS): 387 [M+H]+, 331 [MH−tBu]+, 287 [MH−Boc]+; tR (HPLC conditions b): 4.26 min.
Reaction SMILES: CN(C=O)C.[CH:6]1([C:9]([NH:11][C:12]2[N:29]=[C:15]3[CH:16]=[CH:17][CH:18]=[C:19]([C:20]4[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=4)[N:14]3[N:13]=2)=[O:10])[CH2:8][CH2:7]1.C(Cl)(=O)C([Cl:33])=O>C(Cl)Cl>[CH:6]1([C:9]([NH:11][C:12]2[N:29]=[C:15]3[CH:16]=[CH:17][CH:18]=[C:19]([C:20]4[CH:28]=[CH:27][C:23]([C:24]([Cl:33])=[O:25])=[CH:22][CH:21]=4)[N:14]3[N:13]=2)=[O:10])[CH2:8][CH2:7]1
Reactant: O=C(O)c1ccc(-c2cccc3nc(NC(=O)C4CC4)nn23)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(-c2cccc3nc(NC(=O)C4CC4)nn23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 Drops of DMF are added to a solution of 4-[2-(cyclopropanecarbonyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl]-benzoic acid (1 eq) obtained by Method A using 4-carboxyphenylboronic acid in DCM under N2 atmosphere. Then oxalyl chloride (2 eq) is added dropwise to this resulting solution (gas release). The mixture is stirred at room temperature for 2 hours. After completion of the reaction by LCMS, the solvent is removed. The crude acid chloride is used without further purification in next step.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:13])=O>CCOC(C)=O.CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([Cl:13])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(Cl)s1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cl)c1ccc(Cl)s1
Reaction time: 2 h

Procedure:
To a chilled solution of 5-chlorothiophene-2-carboxylic acid (0.16 g, 1.0 mmol) in EtOAc (3 mL) and DMF (1 drop) was added neat oxalyl chloride (92 μL, 1.05 mmol). The reaction mixture was stirred cold for 2 hr and concentrated in vacuo to give crude 5-chlorothiophene-2-carbonyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:21])[C:19]=2[OH:20])[CH2:16][CH2:15][O:14][C:13]23[CH2:26][CH2:25][N:24]([C:27](=[O:32])[C:28]([O:30]C)=O)[CH2:23][CH2:22]2)=[O:9])=[C:4]([N:35]2[C:39]([CH3:40])=[N:38][CH:37]=[N:36]2)[CH:3]=1.[NH:41]([CH3:43])[CH3:42]>>[CH3:42][N:41]([CH3:43])[C:28](=[O:30])[C:27]([N:24]1[CH2:25][CH2:26][C:13]2([C:12]3=[N:11][C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:33]=[CH:34][C:2]([F:1])=[CH:3][C:4]=4[N:35]4[C:39]([CH3:40])=[N:38][CH:37]=[N:36]4)=[O:9])=[C:19]([OH:20])[C:18](=[O:21])[N:17]3[CH2:16][CH2:15][O:14]2)[CH2:22][CH2:23]1)=[O:32]
Reactant: COC(=O)C(=O)N1CCC2(CC1)OCCn1c2nc(C(=O)NCc2ccc(F)cc2-n2ncnc2C)c(O)c1=O
Reactant: CNC
Product: Cc1ncnn1-c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1O)CCOC21CCN(C(=O)C(=O)N(C)C)CC1
Yield: 36 %

Procedure:
A solution of Example 26 and 2M Me2NH/MeoH (2 mL, 4 mmol) was stirred for 18 h. at room temperature. Concentration gave an oil that was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to give the title compound as white solid (0.227 g, 36%). 1H NMR (300 MHz, CDCl3) δ: 8.61 (1H, s), 8.34 (1H, t, J=5.3 Hz), 7.69 (1H, dd, J=8.6, 5.7 Hz), 7.27 (1H, td, J=8.1, 2.3 Hz), 7.01 (1H, dd, J=8.0, 2.2 Hz), 4.48-4.41 (2H, m), (4.18 (1H, dd, J=14.4, 5.3 Hz), 4.02 (4H, s), 3.64-3.59 (1H, m), 3.48-3.40 (1H, m), 3.09-3.04 (1H, m), 3.03 (3H, s), 3.00 (3H, s), 2.54 (3H, s), 2.39-2.29 (1H, m), 2.21-2.10 (1H, m), 1.99-1.88 (1H, m). HRMS (M+H) calcd for C26H30FN8O6: 569.2272; found: 569.2272.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:30][CH3:31])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[O:27][CH2:28][CH3:29])=[N:13][C:14]=1[CH2:15][CH3:16].[CH:32]1(C2C(N[C@@H]3C4C(=CC=CC=4)C[C@@H]3O)=NC(CC)=C(C3C=CC(Cl)=CC=3Cl)N=2)CC1>>[CH:30]1([C:11]2[C:12]([NH:17][C@@H:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][C@@H:19]3[O:27][CH2:28][CH3:29])=[N:13][C:14]([CH2:15][CH3:16])=[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[N:10]=2)[CH2:32][CH2:31]1
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(C2CC2)nc1-c1ccc(Cl)cc1Cl
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1C1CC1

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[3-cyclopropyl-5-(2,4-dichlorophenyl)-6-ethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 0.87-1.21, 1.58, 1.80-1.85, 2.51, 3.15-3.17, 3.46-3.56, 3.66-3.76, 4.40-4.45, 5.88, 6.04, 7.21-7.34, 7.47-7.50; MS (ESI+) for C26H27Cl2N3O m/z 469 (M+H)+.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[CH2:17][C:16]2([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=3)[N:12]([C:13](=[O:35])[N:14]([C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=3)[C:15]2=[O:26])[CH2:11][CH2:10]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:6]([CH2:8][N:9]1[CH2:17][C:16]2([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=3)[N:12]([C:13](=[O:35])[N:14]([C:27]3[CH:28]=[C:29]([Cl:34])[CH:30]=[C:31]([Cl:33])[CH:32]=3)[C:15]2=[O:26])[CH2:11][CH2:10]1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)CN1CCN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)C2(Cc2ccc(Br)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CCN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)C2(Cc2ccc(Br)cc2)C1
Reaction time: 48 h

Procedure:
To a solution of 4-(tert-butoxycarbonylmethyl)-6-(4-bromobenzyl)-8-(3,5-dichlorophenyl)-1,4,8-triazabicyclo[4.3.0]nonane-7,9-dione (0.080 g) in CH2Cl2 (10 mL) was added TFA (0.10 mL). Additional TFA (0.5 mL) was added after 3 and 22 hours. After stirring for 48 hours, the mixture was concentrated and purified by chromatography (Silica gel: 8% MeOH/CH2Cl2, Chromatotron) afforded the titled compound. (0.083 g). MS (m/z) 526 (MH+). mp 236.5° C.
Reaction SMILES: Cl[S:2]([C:5]1[C:6]([F:19])=[CH:7][C:8]([O:16][CH2:17][CH3:18])=[C:9]([CH:15]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:4])=[O:3].[CH3:20][NH:21][CH3:22]>C(Cl)Cl>[CH3:20][N:21]([CH3:22])[S:2]([C:5]1[C:6]([F:19])=[CH:7][C:8]([O:16][CH2:17][CH3:18])=[C:9]([CH:15]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:4])=[O:3]
Reactant: CCOC(=O)c1cc(S(=O)(=O)Cl)c(F)cc1OCC
Reactant: CNC
Solvent: ClCCl
Product: CCOC(=O)c1cc(S(=O)(=O)N(C)C)c(F)cc1OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
Ethyl 5-chlorosulfonyl-2-ethoxy-4-fluorobenzoate (1.5 g, 4.84 mmol; prepared as described in example 2) was taken up in 36 mL of anhydrous methylene chloride and cooled to 0° C. Dimethylamine (7.3 mL, 14.5 mmol) was added and the reaction mixture was stirred at 0° C. for 2 h and concentrated in vacuo. Purification of the crude residue by flash column chromatography (silica gel, eluting with 20-40% ethyl acetate in hexanes) gave ethyl 5-dimethylsulfamoyl-2-ethoxy-4-fluoro-benzoate as a white solid (1.02 g, 68%). LC-MS: 320.2 [(M+H)+].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br.[N+](C1C2C(=CC=CC=2)NN=1)([O-])=O>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([F:19])[CH:21]=1)[N:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: Fc1cccc(CBr)c1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1n[nH]c2ccccc12
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(cnn2Cc2cccc(F)c2)c1
Temperature: 20 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
5-nitro indazole (1 equiv.), cesium carbonate (1.1 equiv.) and DMF (5 volumes) were charged to a vessel. The mixture was heated to 70–80° C. and 3-fluoro benzyl bromide was added over 75 mins. The reaction was assayed by HPLC for completion (<2 AP of nitro indazole vs combined isomers) and then cooled to 20° C. The salts were filtered and the cake was washed with DMF (2.7 volumes). The product was crystallized by charging water (1.35 to 1.45 volumes) between 15–21° C. The crystal slurry was held for 4 h, crystals were filtered and washed with 2:1 DMF:water mix (2.1 volumes), water (2 volumes) and finally 3:1 cold ACN:water mix (1.5 volumes). The wet cake was dried <45° C. to LOD <1% and the yield was about 49%
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[CH:10]([Mg]Br)=[CH2:11]>C1COCC1>[NH:1]1[C:4]2[C:9](=[CH:8][CH:7]=[N:6][CH:5]=2)[CH:11]=[CH:10]1
Reactant: O=[N+]([O-])c1cccnc1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: c1cc2cc[nH]c2cn1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A solution of 3-nitropyridine in THF at −78° C. is treated with vinyl magnesium bromide (3 eq), stirred at −20° C. for 8 h and quenched with 20% ammonium chloride. The phases are separated and the aqueous phase is extracted with EtOAc. The organic phase and the combined extracts are mixed together, dried over MgSO4 and concentrated in vacuo. The resultant residue is chromatographed over silica gel to afford the title 6-azaindole.