Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)[C:13]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:12]=2[N:11]=1)[CH3:9])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[F:26][C:23]1[CH:24]=[CH:25][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=3)[C:13]=2[CH:22]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccc(F)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccc(F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
A mixture of {(S)-1-[6-fluoro-1-(5-fluoropyridin-2-yl)-1H-benzoimidazol-2-yl]ethyl}carbamic acid tert-butyl ester (33 mg, 0.09 mmol) in DCM (1 mL) and TFA (0.5 mL) was stirred at RT for 2 h. The crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford (S)-1-[6-fluoro-1-(5-fluoropyridin-2-yl)-1H-benzoimidazol-2-yl]ethylamine as a yellow oil (19 mg, 79%). LCMS (Method C): RT 0.27 and 1.84 min [M+H]+ 275.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[C:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)([OH:31])=[O:30]>>[Cl:28][C:4]1[CH:3]=[C:2]([C:36]2[CH:35]=[CH:34][CH:33]=[C:32]([C:29]([OH:31])=[O:30])[CH:37]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:27])[C:9]([OH:14])([C:15]1[CH:16]=[CH:17][C:18]2[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=2[CH:26]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Product: CC(c1ccc(-c2cccc(C(=O)O)c2)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 22, step 3) was reacted with 3-carboxyphenylboronic acid to give the title compound as an off-white solid. MS (m/e, ISP neg. ion)=518.2 [M−H+].
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:29](Cl)(=[O:31])[CH3:30]>>[C:29]([N:20]1[CH2:21][CH2:22][C:16]2[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[N:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=3)=[N:18][C:17]=2[CH2:19]1)(=[O:31])[CH3:30]
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Reactant: CC(=O)Cl
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(C)=O)C3)cc1

Procedure:
Method as example 18 using 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (example 82) and acetyl chloride as starting materials.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[CH3:27]>>[Cl:20][C:21]1[CH:22]=[C:23]([C:2]2[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=2[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: Cc1ccc(B(O)O)cc1Cl
Reactant: CS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2Br)cc1
Product: Cc1ccc(-c2cc(F)c(F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1Cl
Yield: 94.1 %

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 2.49 g (7.17 mmol) of 1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene (Example 18, Step 2) was reacted with 1.59 g (9.33 mmol) of 3-chloro-4-methylphenylboronic acid (Step 1). Purification by silica gel chromatography (HPLC) with ethyl acetate/hexane (1:5) gave 2.65 g (94%) of 1-(3-chloro-4-methylphenyl)-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene as a colorless solid: mp 138.0°-139.0° C.; NMR (CDCl3) δ 2.34 (s, 3H), 3.05 (s, 3H), 6.75 (dd, J=2, 8 Hz, 1H), 7.03-7.10 (m, 2H), 7.18-7.26 (m, 2H), 7.29 (d, J=8 Hz, 2H), 7.83 (d, J=8 Hz, 2H). MS (FAB): m/e 399 (M+Li). Anal. Calc'd for C20H15 ClF2O2S: C, 61.15; H, 3.85. Found: C, 61.12; H, 3.82.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)=[C:4]([Cl:17])[CH:3]=1.[C:18]1(=O)[O:23][C:21](=[O:22])[C:20]2[CH2:24][CH2:25][CH2:26][CH2:27][C:19]1=2.C(Cl)Cl>C(O)(=O)C>[Cl:17][C:4]1[CH:3]=[C:2]([N:1]2[C:21](=[O:22])[C:20]3[CH2:24][CH2:25][CH2:26][CH2:27][C:19]=3[C:18]2=[O:23])[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C:13](=[O:14])[C:12]([CH3:15])([CH3:16])[CH2:11][O:10]1
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: CC1(C)CON(Cc2ccc(N)cc2Cl)C1=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1(C)CON(Cc2ccc(N3C(=O)C4=C(CCCC4)C3=O)cc2Cl)C1=O
Yield: 83.6 %

Procedure:
A solution of 2.0 grams (0.008 mole) of 2-[(4-amino-2-chlorophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone and 1.2 grams (0.008 mole) of 3,4,5,6-tetrahydrophthalic anhydride in 20 mL of acetic acid was stirred at ambient temperature for four hours and then was heated under reflux for six hours. The cooled reaction mixture was poured into 300 mL of methylene chloride and was washed in turn with two 100 mL portions of water, two 50 mL portions of a saturated aqueous sodium bicarbonate solution, and one 50 mL portion of water. The organic layer was dried with magnesium sulfate and was filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished with 1:1 ethyl acetate:heptane. The appropriate fractions were combined and concentrated under reduced pressure to yield 2.6 grams of 2-[[2-chloro-4-(3,4,5,6-tetrahydrophthalimido)phenyl]methyl]-4,4-dimethyl-3-isoxazolidinone; m.p. 102°-104° C.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[NH:11][C:10]2[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:9]=2[N:8]=1)=[O:5])[CH3:2].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C>CC(C)=O>[CH3:2][CH2:1][NH:3][C:4](=[O:5])[NH:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][C:13]([O:16][S:22]([C:18]3[S:17][CH:21]=[CH:20][CH:19]=3)(=[O:24])=[O:23])=[CH:12][C:10]=2[N:11]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCNC(=O)Nc1nc2ccc(O)cc2[nH]1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2cc(OS(=O)(=O)c3cccs3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.8 %

Procedure:
A stirred solution of 1-ethyl-3-(6-hydroxy-1H-benzoimidazol-2-yl)-urea (35 mg, example 84-c) and thiophene-2-sulfonyl chloride (18 mg) in acetone (3 ml) was treated with triethylamine (25 μl). After stirring at ambient temperature for 4 hours, the reaction mixture was evaporated. The residue was filtered and the filtrate evaporated. The residue was directly purified by LCMS triggered purification to give thiophene-2-sulfonic acid 2-[3-(2-ethyl)-ureido]-1H-benzoimidazol-5-yl ester (14 mg) as a off-white solid Mass spectrum: 367 [M+H]+; retention time=7.88 minutes.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15](O)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([CH3:61])[CH:56]=1>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:54][C:55]3[CH:56]=[C:57]([CH3:61])[CH:58]=[CH:59][CH:60]=3)=[O:16])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Cc1cccc(N)c1
Reactant: Nc1ncc2c(n1)CCN(c1cccc(C(=O)O)c1)C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)c2cccc(N3CCc4nc(N)ncc4C3)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (27 mg, 0.10 mmol), N,N-diisopropylethylamine (0.087 mL, 0.50 mmol), and HBTU (42 mg, 0.11 mmol) in 0.9 mL DMF was stirred at room temperature for 3 hours, then meta-toluidine (0.016 mL, 0.15 mmol) added and the reaction continued for 23 hours at room temperature. The reaction mixture was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was triturated with an EtOAc/hexane mixture to give the title compound as a light tan solid (22 mg, 62%). 1H NMR (DMSO-d6) δ: 10.07 (s, 1H), 8.13 (s, 1H), 7.54-7.62 (m, 2H), 7.50 (s, 1H), 7.31-7.41 (m, 2H), 7.19-7.26 (m, 2H), 6.92 (d, J=7.6 Hz, 1H), 6.41 (s, 2H), 4.29 (s, 2H), 3.65 (t, J=6.0 Hz, 2H), 2.77 (t, J=5.9 Hz, 2H), 2.31 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[C:44]([O:50][CH3:51])[C:4]=1[CH:5]=[CH:6][CH:7]([S:17]([CH:20]([CH:30]=[CH:31][C:32]1[C:37]([O:38][CH3:39])=[CH:36][C:35]([O:40][CH3:41])=[CH:34][C:33]=1[O:42][CH3:43])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([NH2:29])[CH:22]=1)(=[O:19])=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH2:16])[CH:9]=1.[Cl:52][CH2:53][C:54](Cl)=[O:55]>C1(C)C=CC=CC=1.O1CCOCC1>[CH3:51][O:50][C:44]1[CH:45]=[C:46]([O:48][CH3:49])[CH:47]=[C:3]([O:2][CH3:1])[C:4]=1[CH:5]=[CH:6][CH:7]([S:17]([CH:20]([CH:30]=[CH:31][C:32]1[C:33]([O:42][CH3:43])=[CH:34][C:35]([O:40][CH3:41])=[CH:36][C:37]=1[O:38][CH3:39])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([NH:29][C:54](=[O:55])[CH2:53][Cl:52])[CH:22]=1)(=[O:19])=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH:16][C:54](=[O:55])[CH2:53][Cl:52])[CH:9]=1
Reactant: O=C(Cl)CCl
Reactant: COc1cc(OC)c(C=CC(c2ccc(OC)c(N)c2)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(C=CC(c2ccc(OC)c(NC(=O)CCl)c2)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)CCl)c2)c(OC)c1
Yield: 88 %

Procedure:
To a solution of 2,4,6-trimethoxystyryl-3-amino-4-methoxybenzylsulfone (10 mmol) in toluene, chloroacetyl chloride (10 mmol) in dioxane (10 mL) was added and the solution was refluxed for 2 h. The solution was cooled and the solvent was removed in a rotary evaporator to give 2,4,6-trimethoxystyryl-3-chloroacetamido-4-methoxybenzylsulfone in 88% yield. M.p. 163-165° C. NMR (DMSO-d6) δ 3.83 (s, 3H), 3.84 (s, 6H), 3.85 (s, 3H), 4.14 (s, 2H), 4.22 (s, 2H) 6.08 (s, 2H), 7.11-7.20 (d, 1H vinylic), 6.90-8.33 (m, aromatic), 8.89 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:29]2[CH2:30][CH2:31][N:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc2ccc(C)cc2nc1NC(=O)N1CCN(c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 90.1 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate (26 mg, 0.10 mmol) and 1-phenylpiperazine (24 mg, 0.15 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (23 mg, 0.15 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 34 mg of the titled compound (yield, 90%). 1H NMR (300 MHz, CDCl3): δ 2.42-2.48 (m, 3H), 3.22-3.30 (m, 4H), 3.77 (s, 3H), 4.12 (s, 4H), 6.90-7.12 (m, 4H), 7.25-7.32 (m, 3H), 7.48-7.65 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](O)=[O:19])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[C:21]1([NH:27][OH:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:19])[N:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[OH:28])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: ONc1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)N(O)c1ccccc1
Yield: 26.4 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (150 mg, 0.44 mmol) and N-phenylhydroxylamine (80 mg, 0.73 mmol) to give 50 mg of the title compound (26%) after silica gel column chromatography with 2% acetic acid/ethyl acetate: mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.04 (s, 1H), 10.01 (s, 1H), 7.56 (d, 2H, J=7.9 Hz), 7.30 (t, 2H, J=7.9 Hz), 7.24 (d, 1H, J=2 Hz), 7.17 (d, 1H, J=2 Hz), 7.05 (t, 1H, J=7.4 Hz), 5.17~5.26 (m, 1H), 3.06 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1 Hz), 2.58~2.62 (m, 2H), 2.09 (dm, 1H, J=13.5 Hz), 1.81~1.95 (m, 1H).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][O:16][C:17]1[C:27]([O:28][CH3:29])=[CH:26][C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:19]=2[CH:18]=1.[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].CO>C(OCC)(=O)C>[C:30]([OH:35])(=[O:34])[C:31]([OH:33])=[O:32].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:23]3[CH2:24][CH2:25][C:19]4[CH:18]=[C:17]([O:16][CH3:15])[C:27]([O:28][CH3:29])=[CH:26][C:20]=4[CH2:21][CH2:22]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: COc1cc2c(cc1OC)CCNCC2
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OC)CCN(C[C@H](O)COc1cccc3[nH]ccc13)CC2

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 48% overall yield. FDMS m/e=396 (M+ of free base). α[D]589 =-9.34 (c=0.47, methanol).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([N:13]1[CH2:66][CH2:65][CH2:64][C@H:14]1[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:40](=[O:63])[C@@H:41]3[CH2:45][CH2:44][CH2:43][N:42]3[C:46](=[O:62])[C@H:47]([NH:54]C(OC(C)(C)C)=O)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:35][CH:34]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)=[O:16])=[O:12])[C:7]([CH3:10])([CH3:9])[CH3:8])=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([N:13]1[CH2:66][CH2:65][CH2:64][C@H:14]1[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([NH:39][C:40](=[O:63])[C@@H:41]3[CH2:45][CH2:44][CH2:43][N:42]3[C:46](=[O:62])[C@H:47]([NH2:54])[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[CH:37][CH:38]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)=[O:16])=[O:12])[C:7]([CH3:10])([CH3:9])[CH3:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@H](NC(=O)OC(C)(C)C)c3ccccc3)cc2)c2ccccc2)cc1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@H](N)c3ccccc3)cc2)c2ccccc2)cc1)C(C)(C)C
Temperature: 25 °C
Yield: 95 %

Procedure:
To a solution of the product from Example 74 (136.1 mg, 0.151 mmol) in CH2Cl2 (0.2 mL) was added trifluoroacetic acid (0.20 mL). The mixture was stirred at rt and concentrated in vacuo. The crude product was partitioned between CH2Cl2 and saturated aqueous NaHCO3, and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (115 mg, 94%). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.96 (s, 8 H), 1.53 (s, 1 H), 1.74 (s, 1 H), 1.82-1.91 (m, 3 H), 1.99 (s, 2 H), 2.15 (s, 1 H), 2.69 (s, 2 H), 2.84 (s, 1 H), 3.54 (s, 3 H), 3.63 (s, 1 H), 3.79 (s, 2 H), 4.21 (d, J=8.9 Hz, 1 H), 4.41-4.47 (m, 2 H), 4.60 (s, 4 H), 5.29 (s, 1 H), 6.57 (t, J=7.2 Hz, 1 H), 6.66 (d, J=8.2 Hz, 2 H), 7.05-7.11 (m, 3 H), 7.19 (t, J=8.3 Hz, 4 H), 7.42-7.49 (m, 4 H), 7.53 (dd, J=12.8, 8.5 Hz, 5 H), 10.00 (s, 1 H), 10.09 (s, 1 H); MS (ESI) m/z 802.5 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[NH:7][S:6]1(=[O:16])=[O:15].N1C=CC=CC=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[N:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:6]1(=[O:16])=[O:15]
Reactant: O=S1(=O)Nc2ccccc2CN1CCCCl
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S1(=O)N(CCCCl)Cc2ccccc2N1c1ccccc1
Temperature: 23 °C
Reaction time: 16 h
Yield: 9.3 %

Procedure:
A solution of 3-(3-chloropropyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.46 g, 1.75 mmol) in dichloromethane (10 mL) was treated with pyridine (0.16 mL, 2.6 mmol), phenylboronic acid (0.43 g, 3.5 mmol) and copper(II) acetate (0.48 g, 2.6 mmol) and stirred at 23° C. for 16 hours. The reaction mixture was quenched by the addition of ammonium hydroxide (10 mL), diluted with methanol (2.0 mL), extracted with dichloromethane (3×10 mL), dried (Na2SO4), and evaporated. Flash chromatography (SiO2, 3-40% ethyl acetate/hexanes) provided 3-(3-chloropropyl)-1-phenyl-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.055 g, 9.4%) as a yellow film:
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]2[CH2:18][CH2:19][C:20](=[O:21])[C:5]=2[CH:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[NH:3]1.C(N(CC)C(C)C)(C)C.Cl[C:40]([O:42][CH2:43][CH3:44])=[O:41]>ClCCl.CN(C)C1C=CN=CC=1>[C:26]([C:25]1[CH:24]=[CH:23][C:22]([CH:4]2[N:3]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:2](=[O:1])[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=3)[C:6]3[CH2:18][CH2:19][C:20](=[O:21])[C:5]2=3)=[CH:29][CH:28]=1)#[N:27]
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CC3)cc1
Reactant: CCOC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 1, 40 mg, 0.10 mmol) in dichloromethane (1.0 mL) is treated with N,N-diisopropylethylamine (70 μL, 0.4 mmol) and 4-dimethylaminopyridine (13 mg, 0.11 mmol). Ethyl chloroformate (11 μL, 0.11 mmol) is added and the mixture is stirred at room temperature for 2 h. All volatiles are evaporated pi and the residue is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 46 mg; ESI mass spectrum [M+H]+=470; Retention time HPLC: 0.90 min (Z011_S03).
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2](Cl)=O.[Cl:7][C:8]1[NH:12][C:11]2[CH:13]=[C:14]([NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])=[O:22])[CH:15]=[C:16]([C:17]([OH:19])=O)[C:10]=2[N:9]=1>C1COCC1.CN(C=O)C>[Cl:7][C:8]1[NH:12][C:11]2[CH:13]=[C:14]([NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])=[O:22])[CH:15]=[C:16]([C:17]([NH:9][C:10]3[CH:11]=[CH:13][CH:2]=[C:1]([Cl:6])[C:16]=3[CH3:15])=[O:19])[C:10]=2[N:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(Nc1cc(C(=O)O)c2nc(Cl)[nH]c2c1)c1ccccc1C(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2[nH]c(Cl)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (1.42 mL) was added dropwise to a stirring solution of 2-chloro-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxylic acid (1.27 g) in THF (13 mL) under ice-cooling. To the mixture was added DMF (five drops), and it was stirred at room temperature for 2 hours. From the reaction mixture was removed the solvent and excessive oxalyl chloride under reduced pressure. To the residue was added toluene, and it was concentrated under reduced pressure, dried, and then dissolved in THF (10 mL). The solution was dropped slowly to a solution of 3-chloro-2-methylaniline (0.42 mL) and N,N-diisopropylethylamine (2.3 mL) in THF (10 mL) under ice-cooling for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified on column chromatography to obtain the titled compound (0.58 g) as white powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[C:4]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)[CH:5]=[CH:6][CH:7]=1.[F:25][C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([CH3:21])([CH3:23])[CH3:22])=[N:9][C:8]=2[C:4]2[C:3]([F:24])=[C:2]([NH:1][S:32]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=3)(=[O:34])=[O:33])[CH:7]=[CH:6][CH:5]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 4-[4-(3-amino-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinamine (65 mg, 0.189 mmol) and 3-fluorobenzenesulfonyl chloride (0.030 mL, 0.227 mmol), the title compound was obtained as an off white solid (64 mg, 67% yield). MS (ESI): 502.2 [M+H]+.
Reaction SMILES: CO[C:3](=[O:24])[CH2:4][NH:5][C:6]([C:8]1[C:9]2[CH:16]=[N:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:10]=2[CH:11]=[N:12][CH:13]=1)=[O:7].O.[NH2:26][NH2:27].O>CCO>[NH:26]([C:3]([CH2:4][NH:5][C:6]([C:8]1[C:9]2[CH:16]=[N:15][N:14]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[C:10]=2[CH:11]=[N:12][CH:13]=1)=[O:7])=[O:24])[NH2:27]
Reactant: COC(=O)CNC(=O)c1cncc2c1cnn2-c1ccc(F)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)CNC(=O)c1cncc2c1cnn2-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
To a solution of {[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-acetic acid methyl ester (0.50 g, 1.5 mmol) in EtOH (6 mL) was added hydrazine hydrate (2 mL) and the mixture was warmed at 60° C. After 18 hours, the mixture was cooled to room temperature and poured into water (100 mL). The solid was collected by filtration to afford 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid hydrazinocarbonylmethyl-amide (purity 90%).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[C:14]([CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)=[CH:13][N:12]([C:18]2[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=2)[N:11]=4)[CH2:3]1.Br[CH2:29][C:30]([NH2:32])=[O:31].CO>O>[CH:23]([N:19]1[C:18]([N:12]2[N:11]=[C:10]3[C:14]([CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([CH:4]5[CH2:5][N:2]([CH2:29][C:30]([NH2:32])=[O:31])[CH2:3]5)[CH:27]=[CH:26][C:9]=43)=[CH:13]2)=[N:22][CH:21]=[N:20]1)([CH3:25])[CH3:24]
Reactant: NC(=O)CBr
Reactant: CC(C)n1ncnc1-n1cc2c(n1)-c1ccc(C3CNC3)cc1OCC2
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)n1ncnc1-n1cc2c(n1)-c1ccc(C3CN(CC(N)=O)C3)cc1OCC2

Procedure:
Following the procedure for 143, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene hydrochloride was reacted with bromo acetamide, the crude product was subjected to reverse phase HPLC (Gemini C18 column gradient 10 to 90% MeOH in water+0.1% HCO2H) to give 181 as a white solid. 1H NMR (400 MHz, DMSO-d): δ 8.33 (s, 1H); 8.21-8.14 (m, 2H); 8.04 (s, 1H); 7.21 (dd, J=8.42, 1.92 Hz, 2H); 7.12-7.02 (m, 2H); 5.44-5.36 (m, 1H); 4.32 (t, J=5.05 Hz, 2H); 3.80-3.61 (m, 3H); 3.30 (t, J=7.44 Hz, 2H); 3.16-3.09 (m, 4H); 1.52 (d, J=6.59 Hz, 6H). LCMS: RT=6.49 min, M+H+=408