Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[O:3][CH2:2]1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.N1C=[CH:21]N=N1.C[Mg]Cl.C1COCC1.[NH4+].[Cl-]>C1(C)C=CC=CC=1.CCOCC>[CH3:21][C:7]1([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:8][CH2:9][C:4]2([O:11][CH2:1][CH2:2][O:3]2)[CH2:5][CH2:6]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: C1COCCN1
Reactant: c1c[nH]nn1
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(N2CCOCC2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
A mixture of 1,4-cyclohexanedione monoethylene acetal (7.81 g, 50.00 mmol), morpholine (4.81 mL, 55 mmol) and 1H-1,2,3-triazole (3.48 mL, 60 mmol) in toluene (50 mL) was refluxed for 6 hours while collecting water using a Dean-Stark apparatus. The white suspension containing 10 was allowed to cool to RT and added dropwise over 1 hour to a cooled (ice/salt/water bath) 3.0 M MeMgCl solution in THF (66.67 mL, 200 mmol) while maintaining the internal temperature <24° C. The reaction mixture was stirred at RT for a further 2 h. The mixture was then diluted with Et2O (500 mL). An aqueous solution of NH4Cl was added in portions until a precipitate formed. The organic layer was decanted off, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by SGC on amino silica (Chromatorex NH, Fuji Silysia) using hexane:EtOAc as eluent (gradient elution from 100:0 to 50:50, v/v) to give 11 (10.94 g, 91%) as a yellowish white solid. 1H NMR (400 MHz, CDCl3) δ 0.89 (s, 3H), 1.41-1.48 (m, 4H), 1.80-1.94 (m, 4H), 2.50 (t, J=4.2 Hz, 4H), 3.70 (t, J=4.6 Hz, 4H), 3.95 (app. t, J=1.7 Hz, 4H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.Cl.[CH:32]([C:35]1[O:36][CH:37]=[C:38](/[CH:40]=[CH:41]/[C:42]2[C:43]([OH:53])=[N:44][N:45]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH:46]=2)[N:39]=1)([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:32]([C:35]1[O:36][CH:37]=[C:38](/[CH:40]=[CH:41]/[C:42]2[C:43]([O:53][CH2:2][C:3]3[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]4[N:10]=[C:11]([C:15]5[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=5)[O:12][C:13]=4[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=3)=[N:44][N:45]([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[CH:46]=2)[N:39]=1)([CH3:34])[CH3:33]
Reactant: CC(C)c1nc(/C=C/c2cn(-c3ccccc3)nc2O)co1
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4coc(C(C)C)n4)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 15.6 %

Procedure:
A mixture of ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (0.976 g), 4-[(E)-2-(2-isopropyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-ol hydrochloride (0.83 g), potassium carbonate (0.691 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 1.5 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with acetone-hexane (1:5-1:4-1:3, v/v) to give ethyl {4-[4-({4-[({4-[(E)-2-(2-isopropyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (244 mg, yield 16%) as colorless crystals. Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 106-108° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[C:47]1([CH2:53][C:54](Cl)=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][N:43]([C:54](=[O:55])[CH2:53][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:42][CH2:41]1)=[O:39]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCN(C(=O)Cc2ccccc2)CC1
Yield: 70 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and benzeneacetyl chloride as starting materials in 70% yield. 1H NMR (300 MHz, DMSO-d6): δ 9.61 (s, 1H), 9.44 (s, 1H), 9.32 (s, 1H), 8.18 (s, 1H), 7.97 (s, 1H), 7.72 (s, 1H), 7.20 (m, 7H), 7.03 (m, 2H), 6.89 (d, 1H), 6.79 (d, 1H), 4.42 (d, 1H), 4.01 (d, 1H), 3.73 (s, 2H), 3.02 (m, 1H), 2.81 (m, 4H), 2.63 (m, 2H), 1.80 (m, 2H), 1.41 (m, 2H). LCMS for C32H32ClN6O2(M+H)+: m/z=567.2.
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][C@H:22]([N:27]2[CH2:32][CH2:31][N:30]([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:29][CH2:28]2)[C:23]([O:25]C)=[O:24])(=[O:19])=[O:18])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1.O>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([NH:20][CH2:21][C@H:22]([N:27]2[CH2:32][CH2:31][N:30]([S:33]([CH3:36])(=[O:34])=[O:35])[CH2:29][CH2:28]2)[C:23]([OH:25])=[O:24])(=[O:19])=[O:18])=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2ccccc2)cc1)N1CCN(S(C)(=O)=O)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)N1CCN([C@@H](CNS(=O)(=O)c2ccc(OCc3ccccc3)cc2)C(=O)O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.7 %

Procedure:
2.6 ml (2.6 mmol) of an aqueous solution of lithium hydroxide having a concentration of 1M are added to a solution of 900 mg (1.8 mmol) of methyl (S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoate in 20 ml of tetrahydrofuran and 0.5 ml of water. The reaction medium is stirred at ambient temperature for 18 h and then the THF is evaporated off under vacuum. 2.8 ml of an aqueous solution of acetic acid having of concentration of 1M and then 30 ml of water are added and the product precipitates. The suspension is stirred for 30 min at 100° C. and 20 then brought back to ambient temperature, filtered and dried under vacuum. 750 mg (86%) of (S)-3-(4-benzyloxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoic acid are obtained in the form of a white solid.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([Cl:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:12][N:13]([CH2:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)[S:14]([CH3:17])(=[O:16])=[O:15]>>[Cl:11][C:9]1[N:10]=[C:3]2[C:2]([C:23]3[CH:24]=[C:19]([CH:20]=[CH:21][CH:22]=3)[CH2:18][N:13]([CH3:12])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: CN(Cc1cccc(B(O)O)c1)S(C)(=O)=O
Reactant: Clc1nc2c(Br)cccn2n1
Product: CN(Cc1cccc(-c2cccn3nc(Cl)nc23)c1)S(C)(=O)=O

Procedure:
175 b) N-[3-(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-benzyl]-N-methyl-methanesulfonamide was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (500.0 mg, 2.151 mmol) and (3-{[methyl(methylsulfonyl)amino]methyl}phenyl)boronic acid (650.0 mg, 2.674 mmol) in a manner analogous to Example 2c. Product isolated as a pale yellow foam (0.331 g, 44%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.51 (d, J=6.8 Hz, 1H), 7.99-7.95 (m, 2H), 7.74 (d, J=7.4 Hz, 1H), 7.54 (t, J=7.6 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.18 (t, J=7.1 Hz, 1H), 4.42 (s, 2H), 2.92 (s, 3H), 2.84 (s, 3H). MS=351 (MH)+.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C:2]1=[O:7].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[O:18]1[C:22]2([CH2:27][CH2:26][C:25](C3C(O)=CC=CN=3)=[CH:24][CH2:23]2)[O:21][CH2:20][CH2:19]1>CN(C=O)C>[O:18]1[C:22]2([CH2:27][CH2:26][CH:25]([N:1]3[C:5](=[O:6])[CH2:4][CH2:3][C:2]3=[O:7])[CH2:24][CH2:23]2)[O:21][CH2:20][CH2:19]1
Reactant: O=C1CCC(=O)N1
Reactant: Oc1cccnc1C1=CCC2(CC1)OCCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCC(=O)N1C1CCC2(CC1)OCCO2
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A solution of pyrrolidine-2,5-dione (210 mg, 2 mmol) in DMF was treated with sodiumhexamethyldisilazid (1.5 eq), stirred for 30 min and treated with 4-dioxaspiro[4.5]decan-8-yl methanesulfonate (250 mg, 1 mmol) from example 1, step A, and heated at 80° C. for 18 h. DMF was removed under vacuum and the residue was purified by silica column chromatography to give the title compound.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=[C:8]([C:25]#[N:26])[C:7]1=[O:27].CSC>ClCCl.FC(F)(F)C(O)=O>[F:24][C:20]1[CH:19]=[C:18]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=3)[NH:6][C:7](=[O:27])[C:8]=2[C:25]#[N:26])[CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc(Cn2c(=O)c(C#N)c(-c3cccc(F)c3)c3cc(OC)ccc32)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CSC
Product: COc1ccc2[nH]c(=O)c(C#N)c(-c3cccc(F)c3)c2c1
Reaction time: 48 h

Procedure:
To a solution of 1-(2,4-dimethoxybenzyl)-4-(3-fluorophenyl)-6-methoxy-2-oxo-1,2-dihydroquinoline-3-carbonitrile (42 mg, 0.094 mmol) in 0.5 mL of dichloromethane and 1 mL of trifluoroacetic acid was added dimethyl sulfide (0.10 mL). After stirring for 2 days, the reaction was heated to reflux for 10 hours, then concentrated in vacuo. The crude product was triturated with EtOAc to provide the titled product as a pale yellow solid. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C17H11FN2O2 (M+H+): 295.0878. Found 295.0879.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:22][OH:23])[C:8]([O:20][CH3:21])=[C:9]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:24][CH:25]1[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26]1.C(N(CC)C(C)C)(C)C>C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]([CH2:22][OH:23])[C:8]([O:20][CH3:21])=[C:9]([NH:11][C:12]([NH:24][CH:25]2[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:19])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1c(CO)cc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Reactant: NC1Cc2ccccc2C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1c(CO)cc(C(C)(C)C)cc1NC(=O)NC1Cc2ccccc2C1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
To a solution of 2,2,2-trichloroethyl 5-tert-butyl-3-(hydroxymethyl)-2-methoxyphenylcarbamate (0.096 g, 0.250 mmol) and 2-aminoindane (0.033 g, 0.248 mmol) in acetonitrile (1.0 mL), N,N-diisopropylethylamine (0.065 mL, 0.38 mmol) was added, and the mixture was stirred at 70° C. for 12 hours. The reaction mixture was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=0/100-60/40) to obtain 0.092 g (quantitative) of the captioned compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]1=[O:23].[Cl:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[ClH:24].[CH2:29]([O:28][CH2:27][CH2:26][CH2:25][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]1=[O:23])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COc1cc2c(cc1OC)C(=O)N(CCC1CCCCN1)CC2
Reactant: ClCCCOCc1ccccc1
Product: COc1cc2c(cc1OC)C(=O)N(CCC1CCCCN1CCCOCc1ccccc1)CC2
Product: Cl

Procedure:
Prepared from 2-[2-(piperid-2-yl)-ethyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline and 1-chloro-3-benzyloxy-propane analogously to Example 1.
Reaction SMILES: O=S(Cl)Cl.[I:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1.[CH3:15]O>>[I:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:15])=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(I)cc1

Procedure:
2.95 ml of SOCl2 were added to a suspension of 10 g of 4-iodobenzoic acid in 100 ml of methanol and the refluxed for 24 hours and then evaporated under reduced pressure until 10.49 g of a dry extract were obtained corresponding to the expected product with a Rf=0.55 (cyclohexane/ethyl acetate 80/20).
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]3)[CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:22]=C(CCO)C=C[CH:26]=1.C(OC(C1NC2C(C=1)=C(O)C=CC=2)=O)C>>[CH3:19][O:20][C:21]1[CH:26]=[C:4]([CH2:1][CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]3)[CH:3]=[CH:2][CH:22]=1
Reactant: O=C(O)c1cc2c(OCC3CCC3)cccc2[nH]1
Reactant: COc1cccc(CCO)c1
Agent: CCOC(=O)c1cc2c(O)cccc2[nH]1
Product: COc1cccc(CCOc2cccc3[nH]c(C(=O)O)cc23)c1

Procedure:
4-[2-(3-Methoxy-phenyl)-ethoxy]-1H-indole-2-carboxylic acid (16k) is synthesized analogous to 16a from 2-(3-methoxy-phenyl)-ethanol and 4-hydroxy-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=[CH:12][C:4]=2[CH2:3]1.C(N(CC)CC)C.[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[C:27]([C:34]([F:37])([F:36])[F:35])[CH:26]=1>C1COCC1.[Pd].Cl>[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:13][C:10]2[CH:11]=[CH:12][C:4]3[CH2:3][C:2]([CH3:16])([CH3:1])[O:7][B:6]([OH:8])[C:5]=3[CH:9]=2)=[O:30])=[C:27]([C:34]([F:35])([F:36])[F:37])[CH:26]=1
Reactant: CC1(C)Cc2ccc([N+](=O)[O-])cc2B(O)O1
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)Cc2ccc(NC(=O)c3ccc(F)cc3C(F)(F)F)cc2B(O)O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3,3-dimethyl-7-nitro-3,4-dihydro-benzo[c][1,2]oxaborinin-1-ol (80 mg, 0.36 mmol) in dry THF (8 mL) was passed through a Thales Nano H-Cube hydrogenator (10% Pd/C catalyst, 1 mL/min flow rate, 1 atm, 30° C.), flushing with an additional 2 mL of THF. To the reaction solution was then added an excess of triethylamine (0.3 mL) and 4-fluoro-2-trifluoromethylbenzoyl chloride (100 mg, 0.44 mmol). The reaction was stirred at room temperature for 16 hours, and then diluted with aqueous hydrochloric acid (10 mL, 1 M). After vigorous mixing, the mixture was extracted with EtOAc (3×5 mL). The combined organic portions were dried over magnesium sulfate and concentrated to dryness. The crude product was purified by silica gel chromatography to produce the title compound as a white solid. LCMS (M/Z): 382 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (s, 6H) 2.83 (s, 2H) 7.14 (d, J=8.4 Hz, 1H) 7.55-7.73 (m, 2H) 7.71-7.86 (m, 2H) 7.90 (d, J=2.3 Hz, 1H) 8.35 (s, 1H) 10.47 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([NH2:13])=[O:12])=[C:7]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[Br:23]Br>C(O)(=O)C>[NH2:1][C:2]1[C:3]([Br:23])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([NH2:13])=[O:12])=[C:7]2[S:14]([N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)(=[O:16])=[O:15]
Reactant: NC(=O)c1[nH]c2c(N)cccc2c1S(=O)(=O)N1CCOCC1
Reactant: BrBr
Solvent: CC(=O)O
Product: NC(=O)c1[nH]c2c(N)c(Br)ccc2c1S(=O)(=O)N1CCOCC1
Reaction time: 0.5 h

Procedure:
To a solution of 7-amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 7 (109 mg, 0.336 mmol) in 5 mL of acetic acid was added a 3.3 M stock solution of bromine in acetic acid (0.12 mL, 0.40 mmol). After 30 minutes, the mixture was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by preparative reversed phase HPLC provided the titled compound. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C13H16BrN4O4S (M+H+): 403.0070. Found 403.0069.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(N(CC)CC)C.Cl[C:20](=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>O1CCCC1>[C:8]([O:7][C:5](=[O:6])[CH2:4][CH2:3][NH:2][C:20](=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])([CH3:11])([CH3:10])[CH3:9]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)NCCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
10 g (55.05 mmol) tert.-butyl β-alaninate hydrochloride are dissolved in 50 ml tetrahydrofuran, and 11.14 g (110.1 mmol) triethylamine and 5.53 g (36.7 mmol) ethyl 3-chloro-3-oxopropanoate are added at 0° C. The reaction mixture is stirred at room temperature for 18 hours. The solvent is removed in vacuo and the product is isolated by column chromatography (silica, eluent dichloromethane/methanol 100:1→50:1).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[N:11]1[CH:16]=[CH:15][C:14]([C:17](O)=O)=[CH:13][N:12]=1.N>>[N:11]1[CH:16]=[CH:15][C:14]([C:17]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)=[CH:13][N:12]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccnnc1
Agent: N
Product: c1cncc(-c2noc(-c3ccnnc3)n2)c1

Procedure:
The titled compound was prepared according to the procedure of Method C using N′-hydroxynicotinimidamide (Aldrich) and pyridazine-4-carboxylic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.67 (ddd, J=8.1, 5.0, 0.8 Hz, 1 H), 8.45 (dd, J=5.4, 2.4 Hz, 1 H), 8.60 (dt, J=8.1, 1.9 Hz, 1 H), 8.78 (dd, J=5.1, 1.7 Hz, 1 H), 9.34 (dd, J=2.2, 0.8 Hz, 1 H), 9.55 (dd, J=5.4, 1.4 Hz, 1 H), 9.94 (dd, J=2.2, 1.2 Hz, 1 H) ppm; MS (DCI/NH3) m/z=226 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:24])[CH:3]=1.[I-:25].[Na+].C1(C)C=CC=CC=1.CNCCNC>[Cu]I.O>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([I:25])=[CH:3][C:4]=3[CH3:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: [I-]
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3C)CC2)c(C)c1
Yield: 59.5 %

Procedure:
To a mixture of (4-bromo-2-methylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (842 mg) described in Preparation Example 118, sodium iodide (650 mg) and copper(I) iodide (246 mg) were added toluene (2.2 mL) and N,N′-dimethylethylenediamine (1.62 mL), and the mixture was stirred with heating under reflux for 18 hr under a nitrogen stream. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer, and the residue was purified by column chromatography (chloroform:methanol) to give the title compound (562 mg).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:9]=2)[N:4]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[CH:3]=1.N#N.[Na].Cl.[CH3:40][OH:41]>O>[CH3:40][O:41][C:3]1[N:4]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:5]2=[N:6][C:7]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[N:9]=[C:10]2[CH:2]=1
Reactant: CO
Reactant: CCOC(=O)CCCCCCn1cc(Br)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: Cl
Agent: N#N
Agent: [Na]
Solvent: O
Product: COc1cc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc2n1CCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture comprising ethyl 7-(7-bromo-2,3-di-p-tolyl-5H-pyrrolo[2,3-b]pyrazin-5-yl)heptanoate (step 1)(50 mg, 0.094 mmol) in anhydrous MeOH (1 ml) was degassed with N2 and treated with sodium (10.75 mg, 0.468 mmol). After stirring at room temperature for 30 minutes, the mixture was heated to 120° C. using microwave radiation for 1 hour. The mixture was diluted with water (20 ml) and the pH was adjusted to pH1 using 2M HCl. The aqueous was extracted with DCM (×3) and the combined organic extracts were concentrated under reduced pressure. Purification of the crude product by chromatography on silica elutuing with 0-100% EtOAc in iso-hexane followed by 10% MeOH in EtOAc afforded the titled compound as an orange solid;
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[N:3]=1.C(N(CC)CC)C.[CH2:20]([NH:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH3:21]>C(O)C>[Cl:11][C:6]1[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][CH2:25][CH3:26])[N:3]=[C:4]([CH3:12])[N:5]=1
Reactant: CCCCNCC
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCN(CC)c1nc(C)nc(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 92 %

Procedure:
Part A. A solution of 4,6-dichloro-2-methyl-5-nitropyrimidine (prepared using the methods of Albert, et al., J. Chem. Soc. 1954, p. 3832) (2.77 g, 13.3 mmol) in absolute ethanol (25 mL) was cooled to 0° C., and treated with triethylamine (2.00 mL, 14.3 mmol). Then, a solution of ethylbutylamine (1.80 mL, 13.2 mmol) in ethanol (3 mL) was added dropwise with stirring. The mixture was allowed to stir and warm to ambient temperature overnight, then was partitioned between water and ethyl acetate (100 mL each). The organic phase was seperated, washed with satd. aq. brine (100 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was separated by column chromatography (silica gel, dichloromethane) to afford 4-chloro-6-(ethylbutylamino)-2-methyl-5-nitropyrimidine as an oil (3.34 g, 12.2 mmol, 92%). Spectral data: TLC RF 0.59 (dichloromethane). 1H NMR (300 MHz, CDCl3): δ3.45 (2H, q, J=7.0 Hz), 3.38 (2H, t, J=7.7 Hz), 2.50 (3H, s), 1.62-1.52 (2H, m), 1.38-1.26 (2H, m), 1.20 (3H, t, J=7.0 Hz), 0.94 (3H, t, J=7.3 Hz). MS (NH3—CI): m/e 276 (4), 275 (40), 274 (16), 273 (100).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]23[CH2:18][CH:16]([CH2:17]2)[C:15](=[O:19])[NH:14][C:13]3=[O:20])=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH2:21](Br)[CH2:22][CH2:23][CH3:24]>CN(C)C=O>[CH2:21]([N:14]1[C:15](=[O:19])[CH:16]2[CH2:17][C:12]([C:9]3[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:11][CH:10]=3)([CH2:18]2)[C:13]1=[O:20])[CH2:22][CH2:23][CH3:24]
Reactant: O=C1NC(=O)C2(c3ccc([N+](=O)[O-])cc3)CC1C2
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.36 g of sodium hydride is added to a solution of 2.46 g of 1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 25 ml of N,N-dimethylformamide and the whole is stirred at room temperature for 30 minutes. 1.6 ml of n-butyl bromide dissolved in 10 ml of N,N-dimethylformamide are then added dropwise thereto. When the reaction is complete, the reaction mixture is freed of N,N-dimethylformamide. The residue is partitioned between ethyl acetate and water, and the organic phase is dried over magnesium sulphate and, after concentration by evaporation and subsequent recrystallisation from ethyl acetate/petroleum ether, the product is obtained having a melting point of 120°-123°.