Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)Cl.[C:4]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][NH:11][C:12](=[O:29])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[C:17]([O:27]C)[CH:16]=2)[CH:5]=1.B(Br)(Br)Br>C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[C:4]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][NH:11][C:12](=[O:29])/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22]3)=[C:17]([OH:27])[CH:16]=2)[CH:5]=1
Reactant: COc1cc(/C=C/C(=O)NCc2cccc(-c3ccccc3)c2)ccc1-n1cnc(C)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cn(-c2ccc(/C=C/C(=O)NCc3cccc(-c4ccccc4)c3)cc2O)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 17.1 %

Procedure:
To a methylene chloride solution (3 mL) of (E)-N-biphenyl-3-ylmethyl-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl)acrylic acid amide (100 mg) obtained in Example 121, boron tribromide (1M pentane solution, 1.18 mL) was added dropwise at −78° C. and the reaction solution was agitated at room temperature for 6 hours. The reaction solution was diluted with a saturated sodium bicarbonate solution and ethyl acetate, and the organic layer was partitioned. The organic layer was concentrated under reduced pressure after dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (elution solvent: chloroform-methanol system), and 16.5 mg of the title compound was obtained.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[N:12]=[C:11]([C:13]([O:15]C)=[O:14])[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C.O>[N:1]1([CH2:6][C:7]2[N:12]=[C:11]([C:13]([OH:15])=[O:14])[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(CN2CCCC2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc(CN2CCCC2)n1
Temperature: 75 °C
Reaction time: 16 h
Yield: 80.1 %

Procedure:
A mixture of methyl 6-(pyrrolidin-1-ylmethyl)picolinate 73 (36 g) and NaOH (40 g, 1.0 mol) in ethanol/H2O (320 mL) was stirred at 75° C. for 16 h. The pH was adjusted to 7 with 3N HCl and extracted with EtOAc. The aqueous layer was concentrated to dryness and extracted with dichloromethane/methanol (v:v=3:1), The organic layer was dried to give 74 (27 g, 55% yield).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:18])[O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])[N:7]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:28][C:29](OC(C)=O)=[O:30]>CCOC(C)=O.[Pd]>[C:29]([NH:25][C:21]1[CH:20]=[C:19]([N:7]2[C:8]([NH:10][C:11](=[O:18])[O:12][CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])=[CH:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6]2)[CH:24]=[CH:23][CH:22]=1)(=[O:30])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc([N+](=O)[O-])c2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73 %

Procedure:
2,2,2-Trichloroethyl 3-t-butyl-1-(3-nitrophenyl)-1H-pyrazol-5-ylcarbamate (0.67 g, 1.538 mmol, 1.00 eq) in EtOAc (30 ml) was shaken under H2 (3.5 arm) at 22° C. over 10% Pd/C (0.327 g, 0.154 mmol, 0.10 eq, 50% H2O) overnight. The completed hydrogenation was treated with Ac2O (3 ml) and stirred at RT. After 45 min, the mixture was filtered through Celite, rinsing forward with EtOAc. The filtrate was treated with a roughly equal volume of satd. NaHCO3 and stirred briskly at RT for 3 h. The layers were separated and the organic layer washed with satd. NaHCO3 (2×). The combined aqueous layers were extracted with EtOAc (1×). The combined organics were washed with brine (1×), dried (MgSO4), filtered and evaporated to afford 2,2,2-trichloroethyl 1-(3-acetamidophenyl)-3-t-butyl-1H-pyrazol-5-ylcarbamate (0.50 g, 73% yield) as a white solid which was used as is in the next reaction. 1H NMR (400 MHz, DMSO-d6): δ 10.10 (s, 1H), 9.95 (brs, 1H), 7.74 (brs, 1H), 7.54-7.51 (m, 1H), 7.37-7.31 (m, 1H), 7.08 (d, J=7.6 Hz, 1H), 6.26 (s, 1H), 4.84 (s, 2H), 2.03 (s, 3H), 1.26 (s, 9H); MS (ESI) m/z: 447.0 (M+H), 449.0 ((M+2+H).
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[F:24][C:25]1[CH:47]=[CH:46][C:28]([CH2:29][N:30]2[C@H:34]([CH3:35])[CH2:33][N:32]([C:36]3[S:37][C:38]([C:42]([OH:44])=O)=[C:39]([CH3:41])[N:40]=3)[C:31]2=[O:45])=[CH:27][CH:26]=1>>[F:24][C:25]1[CH:47]=[CH:46][C:28]([CH2:29][N:30]2[C@H:34]([CH3:35])[CH2:33][N:32]([C:36]3[S:37][C:38]([C:42]([NH2:7])=[O:44])=[C:39]([CH3:41])[N:40]=3)[C:31]2=[O:45])=[CH:27][CH:26]=1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Reactant: Cc1nc(N2C[C@@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2C[C@@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(N)=O

Procedure:
Following the procedure as described in EXAMPLE 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methyl-thiazole-5-carboxylic acid with (R)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid: mp 185-186° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.40-7.32 (m, 4H), 7.21-7.15 (m, 2H), 4.59 (d, J=15.6 Hz, 1H), 4.30 (d, J=15.6 Hz, 1H), 4.18 (dd, J=10.0, 9.1 Hz 1H), 3.77-3.70 (m, 1H), 3.54 (dd, J=10.1, 6.8 Hz, 1H), 2.45 (s, 3H), 1.22 (d, J=6.2 Hz, 3H); MS (ES+) m/z 348.9 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[S:21][N:20]=3)[CH2:15][CH2:14]2)=[CH:6][CH:5]=1)([O-])=O.C1COCC1>[Ni].C(N(CC)CC)C>[S:21]1[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][CH2:10][C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=3)[CH2:18][CH2:17]2)=[N:20]1
Reactant: O=[N+]([O-])c1ccc(CCCN2CCN(c3nsc4ccccc34)CC2)cc1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(CCCN2CCN(c3nsc4ccccc34)CC2)cc1
Yield: 100 %

Procedure:
4-[3-(4-1,2-Benzisothiazol-3-yl-piperazin-1-yl)-propyl]-phenylamine was prepared according to the general method as outlined in Preparation 3 starting from 3-{4-[3-(4-nitro-phenyl)-propyl]-piperazin-1-yl}-1,2-benzoisothiazole (0.58 g, 1.52 mmol), 50 mL of THF treated with triethylamine (0.3 mL) and wet Raney nickel (0.56 g). The resultant solid was dried in vacuo (0.535 g, 1.52 mmol). Yield 100%; MS (APCI): 353 [M+H]+.
Reaction SMILES: FC1C(NC2C=C(OC(C)C)NN=2)=NC([NH:10][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:12][OH:13])=C(C=1)C#N.[CH3:31][OH:32]>[Ni]>[NH2:10][C:11]([C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)([CH2:12][OH:13])[CH2:31][OH:32]
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cc3)c(C#N)cc2F)n[nH]1
Reactant: CO
Agent: [Ni]
Product: NC(CO)(CO)c1ccc(F)cc1
Reaction time: 2 h
Yield: 61 %

Procedure:
A suspension of 2-(4-fluorophenyl)-2-nitroproane-1,3-diol (Method 11; 4.5 g, 20.9 mmol) and Raney nickel (0.45 g, 5.23 mmol) in MeOH (50 ml) was degassed and stirred under H2 (48 psi) for 2 hours. The catalyst was removed by filtration. The filtrate was concentrated and recrystallized from hexane:EtOAc (1:1) to give the title compound (2.35 g, 61%) as a white solid. NMR (400 MHz) □ 7.55 (m, 2H), 7.07 (m, 2H), 4.65 (t, J=5.2 Hz, 2H), 3.49 (m, 4H), 1.76 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[NH:13][C:12](=[O:16])[C:11]([CH3:17])=[N:10]1.[H-].[Na+].I[CH3:21].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[N:13]([CH3:21])[C:12](=[O:16])[C:11]([CH3:17])=[N:10]1
Reactant: CI
Reactant: Cc1nn(-c2ccc(Cl)cc2Cl)c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(-c2ccc(Cl)cc2Cl)c(=O)n(C)c1=O
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
A solution of 1.1 g (0.0040 mole) of 2-(2,4-dichlorophenyl)-6-methyl-1,2,4-triazine-3,5(2H,4H)-dione in 5 mL of N,N-dimethylformamide was added to a stirred mixture of 0.11 g (0.0045 mole) of sodium hydride in 10 mL of N,N-dimethylformamide. After 0.5 hour, 0.63 g (0.0045 mole) of iodomethane in 5 mL of N,N-dimethylformamide was added, and the resultant mixture was stirred for approximately 18 hours. The mixture was poured into water and the resulting precipitate was collected and dissolved in ethyl acetate. The organic solution was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure to leave a solid. The solid was purified by recrystallization from heptane to yield 0.52 g of 2-(2,4-dichlorophenyl)-4,6-dimethyl-1,2,4-triazine-3,5(2H,4H)-dione (mp 109°-110° C.), Compound 5 in the tables.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:21]=[CH:20][N:19]=[C:18]4[CH3:22])=[CH:13][CH:12]=3)[C:5]2=[CH:4][N:3]=1.[Br:23]N1C(=O)CCC1=O>C(Cl)Cl>[Br:23][C:4]1[N:3]=[C:2]([CH3:1])[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH:21]=[CH:20][N:19]=[C:18]4[CH3:22])=[CH:15][CH:16]=3)[C:5]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nccn1-c1ccc(-c2cccn3c(C)ncc23)cc1
Solvent: ClCCl
Product: Cc1nccn1-c1ccc(-c2cccn3c(C)nc(Br)c23)cc1

Procedure:
Combine 2.2 g (7.6 mmol) of the product of Example XIV with 1.4 g (7.9 mmol) of N-bromosuccinimide in 50 ml of methylene chloride and stir at room temperature for 1 hr. Wash the reaction with 100 ml of 10% potassium carbonate solution, dry over magnesium sulfate, treat with charcoal, and remove the solvent in vacuo. Crystallize the residue from ether to provide the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>C(Cl)Cl>[F:27][C:25]1[CH:24]=[CH:23][C:19]([C:20]([NH:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:21])=[C:18]([C:17]([F:16])([F:28])[F:29])[CH:26]=1
Reactant: CCOC(=O)CN
Reactant: O=C(Cl)c1ccc(F)cc1C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)c1ccc(F)cc1C(F)(F)F
Reaction time: 48 h

Procedure:
30.7 g (0.22 mol) of ethyl glycinate hydrochloride were suspended in CH2Cl2. At 0° C., 86.3 g (0.854 mol) of triethylamin and 50 g (0.22 mol) of 2-trifluoromethyl-4-fluorobenzoylchlorid dissolved in 250 ml of CH2Cl2 were successively added dropwise. After 48 h at RT, the solution was washed and dried, and the solvent was removed. This gave 62.2 g (97% of theory) of the title compound as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19][CH3:20])[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:31])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19]([CH3:20])=[O:31])[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2o1
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2o1
Temperature: 0 °C
Reaction time: 5 h
Yield: 73.6 %

Procedure:
A mixture of 6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole (522 mg, 1.39 mmol) and m-CPBA (282 mg, 1.39 mmol) in DCM (20 mL) was stirred at 0° C. for 5 h. The reaction mixture was washed with aq Na2S2O3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:1 to 1:5 petroleum ether/ethyl acetate to give 6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]oxaz-ole as a light yellow solid (400 mg, 73.7%). 1H NMR (300 MHz, DMSO-d6) δ 8.69 (s, 1H), 8.48 (s, 1H), 8.40 (s, 1H), 7.68 (s, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.34 (d, J=9.3 Hz, 1H), 5.60 (s, 2H), 2.73 (s, 3H). LCMS (ESI) m/z 390 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:23][C:24]1[C:32]([OH:33])=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([CH3:34])[NH:28]2.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[F:23][C:24]1[C:32]([O:33][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([CH3:34])[NH:28]2
Reactant: CCOC(=O)CCCOc1cc2ncnc(Cl)c2cc1OC
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CCCOc1cc2ncnc(Oc3ccc4[nH]c(C)cc4c3F)c2cc1OC
Temperature: 50 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
To a solution of Compound 6 (5.0 g, 15.39 mmol) and 4-fluoro-2-methyl-1H-indol-5-ol (3.56 g, 21.55 mmol) in acetonitrile (50 mL) was added cesium carbonate (15.05 g, 46.18 mmol). The reaction mixture was stirred at 50° C. for 2 h. TLC showed that no starting material remained. The inorganic material was removed by filtration and the filtrate was concentrated to give a brown solid. The solid was dissolved in ethyl acetate (100 mL) and washed with water (100 mL×2). The organic phase was concentrated and the residue was purified by silica column (gradient of hexane:ethyl acetate 5:1 to 1:2) to give Compound 7 (5.90 g) as a purple solid.
Reaction SMILES: [C:1]([NH2:4])(=[NH:3])[CH3:2].[N+:5]([C:8]1[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=1[CH:10]=[CH:11][S:12](Cl)(=[O:14])=[O:13])([O-:7])=[O:6]>>[N+:5]([C:8]1[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=1[CH:10]=[CH:11][S:12]([NH:3][C:1](=[NH:4])[CH3:2])(=[O:14])=[O:13])([O-:7])=[O:6]
Reactant: O=[N+]([O-])c1ccccc1C=CS(=O)(=O)Cl
Reactant: CC(=N)N
Product: CC(=N)NS(=O)(=O)C=Cc1ccccc1[N+](=O)[O-]

Procedure:
Reaction of acetamidine with 2-nitrostyrylsulfonyl chloride according to the above procedure affords N-(2-NITROSTYRYL-SULFONYL)ACETAMIDINE, m.p. 175°-178° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:12]1([NH2:16])[CH2:15][CH2:14][CH2:13]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][CH:12]2[CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: NC1CCC1
Solvent: ClCCl
Product: O=S(=O)(NC1CCC1)c1ccc(Br)cc1
Yield: 28.7 %

Procedure:
According to general procedure C, 4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and cyclobutylamine (0.33 mL, 3.90 mmol) were stirred together in dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-cyclobutylbenzenesulfonamide (0.13 g) was provided after purification. MS (ESI) m/z 290. HPLC purity 95.6% at 210-370 nm, 9.1 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]#[C:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.[Cu](C#N)[C:15]#[N:16]>CN1CCCC1>[CH3:11][C:10]([CH3:13])([CH3:12])[C:9]#[C:8][C:5]1[N:4]=[CH:3][C:2]([C:15]#[N:16])=[CH:7][N:6]=1
Reactant: N#C[Cu]C#N
Reactant: CC(C)(C)C#Cc1ncc(Br)cn1
Agent: CN1CCCC1
Product: CC(C)(C)C#Cc1ncc(C#N)cn1
Temperature: 200 °C
Yield: 67.5 %

Procedure:
A mixture of 5-bromo-2-(3,3-dimethylbut-1-ynyl)pyrimidine (2.5 g, 0.010 mol) and copper cyanide (1.4 g, 0.016 mol) in N-methyl pyrrolidine was heated in a sealed tube at 200° C. for 24 hours. The mixture was allowed to cool to room temperature and filtered through Celite® and the filtrate was concentrated under vaccum. The residue was purified by column chromatography on silica gel with an ethyl acetate: hexane (0-50% gradient) to give the product (1.25 g).
Reaction SMILES: C(O[C:4](=[O:21])[CH2:5][N:6]1[CH2:10][CH2:9][C@@H:8]([NH:11][S:12]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)(=[O:14])=[O:13])[CH2:7]1)C.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]2=[O:35])=[CH:25][C:24]=1[F:36]>>[Cl:20][C:17]1[S:16][C:15]([S:12]([NH:11][C@@H:8]2[CH2:9][CH2:10][N:6]([CH2:5][C:4]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]4=[O:35])=[CH:25][C:24]=3[F:36])=[O:21])[CH2:7]2)(=[O:13])=[O:14])=[CH:19][CH:18]=1
Reactant: CCOC(=O)CN1CC[C@@H](NS(=O)(=O)c2ccc(Cl)s2)C1
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Product: O=C(CN1CC[C@@H](NS(=O)(=O)c2ccc(Cl)s2)C1)Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
8.2 Using general procedure F [(R)-3-(5-chloro-thiophene-2-sulfonylamino)-pyrrolidin-1-yl]-acetic acid ethyl ester was reacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (CAS 536747-52-1, prepared according to WO 2003045912) to give 2-[(R)-3-(5-chloro-thiophene-2-sulfonylamino)-pyrrolidin-1-yl]-N-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-acetamide. White solid. MS 511.3 ([M+H]+)
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]([NH:13][C:14]1[NH:18][N:17]=[CH:16][C:15]=1[C:19]#[N:20])=[O:12].C[O-].[Na+]>O>[NH2:20][C:19]1[C:15]2[CH:16]=[N:17][NH:18][C:14]=2[NH:13][C:11](=[O:12])[C:10]=1[C:2]1[NH:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: N#Cc1cn[nH]c1NC(=O)Cc1nc2ccccc2[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: Nc1c(-c2nc3ccccc3[nH]2)c(=O)[nH]c2[nH]ncc12

Procedure:
2-(1H-Benzimidazol-2-yl)—N-(4-cyano-1H-pyrazol-5-yl)acetamide (1.0 eq) was heated in NaOMe (20 eq, 0.5 M in MeOH) at 100° C. for 2 days. H2O was added, and the mixture was extracted with EtOAc. The organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to yield a solid. The material was purified by reverse phase HPLC. LC/MS m/z 267.1 (MH+), Rt 1.57 minutes.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([Cl:19])[C:10]=1[N+:20]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(O)=O.O.[Fe]>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[N:12]=[C:11]([Cl:19])[C:10]=1[NH2:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1c(NCc2ccccc2)cc(C(F)(F)F)nc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(NCc2ccccc2)cc(C(F)(F)F)nc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 100764.1 %

Procedure:
Benzyl-(2-chloro-3-nitro-6-trifluoromethyl-pyridine-4-yl)-amine (345 mg, 1.0 mmol) was dissolved in a mixture of AcOH (18 ml) and water (2 ml). Fe powder (349 mg, 6.2 mmol) was added and the mixture was vigorously stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo and the residue was diluted with EtOAc (10 ml) and water (10 ml). The mixture was filtered through celite, washing through with EtOAc (20 ml). The layers were separated and the organic layer was washed with sat. NaHCO3 (aq) (2×10 ml) and brine (10 ml), dried over MgSO4 and concentrated in vacuo to give the title compound (304 g) as a pale yellow solid.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH2:18][CH3:19])[O:13][C:12]([CH3:21])([CH3:20])[CH2:11][C:10]2=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH2:18][CH3:19])[O:13][C:12]([CH3:21])([CH3:20])[CH:11]=[C:10]2[CH:1]([CH3:3])[CH3:2]
Reactant: CC(C)[Mg]Cl
Reactant: CCOc1cc2c(cc1Br)C(=O)CC(C)(C)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1Br)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure C, isopropylmagnesium chloride (2.0 M in THF, 3.3 mL, 6.6 mmol) was added to a solution of 6-bromo-7-ethoxy-2,2-dimethyl-chroman-4-one (Compound 5, 1.0 g, 3.3 mmol) in THF. The crude alcohol was treated with p-toluenesulfonic acid to afford the title compound as a colorless oil.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([CH2:24][CH2:25][C:26]([OH:28])=O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:29]1([N:35]2[C:43]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C@@H:37]3[CH2:44][NH:45][CH2:46][CH2:47][C@@H:36]23)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>ClCCl>[C:16]([CH2:24][CH2:25][C:26]([N:45]1[CH2:46][CH2:47][C@H:36]2[N:35]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:43]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C@@H:37]2[CH2:44]1)=[O:28])(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)CCC(=O)c1ccccc1
Reactant: c1ccc(N2c3ccccc3[C@@H]3CNCC[C@H]32)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CCC(=O)N1CC[C@@H]2[C@@H](C1)c1ccccc1N2c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To the suspension arising from the admixture of 865 mg. (4.20 mmole) of dicyclohexylcarbodiimide and 748 mg. (4.20 mmole) of 3-benzoylpropionic acid in 30 ml. of dichloromethane at 0° C. was added 1.0 g. (4.0 mmole) of dl-trans-5-phenyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole in 10 ml. of the same solvent. The resulting mixture was stirred and allowed to warm to room temperature over 2 hours. After cooling again to 0° C. the reaction mixture was filtered, washed with dichloromethane and the filtrates evaporated to obtain a residue of dl-trans-2-[(3-benzoyl)propionyl]-5-phenyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole which was used without purification in the next step.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17]([N:19]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][O:26][CH3:27])[C:20]3=[O:28])=[O:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:29][N:30]1[CH:34]=[C:33]([Sn](CCCC)(CCCC)CCCC)[N:32]=[CH:31]1.[F-].[K+].CCOC(C)=O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:27][O:26][CH2:25][CH2:24][N:21]1[CH2:22][CH2:23][N:19]([C:17]([NH:16][C:12]2[CH:11]=[CH:10][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:33]4[N:32]=[CH:31][N:30]([CH3:29])[CH:34]=4)[CH:7]=3)=[C:14]([CH3:15])[N:13]=2)=[O:18])[C:20]1=[O:28]
Reactant: COCCN1CCN(C(=O)Nc2ccc(Oc3ccnc(Cl)c3)c(C)n2)C1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COCCN1CCN(C(=O)Nc2ccc(Oc3ccnc(-c4cn(C)cn4)c3)c(C)n2)C1=O
Temperature: 105 °C
Reaction time: 2 h
Yield: 36.5 %

Procedure:
A mixture of Example C5 (0.150 g, 0.370 mmol), N-methyl-4-(tributylstannyl)imidazole (0.178 g, 0.480 mmol) and Pd(PPh3)4 (0.021 g, 0.018 mmol) in toluene (4 mL) was sparged with Ar and heated at 105° C. overnight. The mixture was cooled to RT, treated with 10% KF and EtOAc, stirred for 2 h and the solids removed via filtration through diatomaceous earth. The filtrate was extracted with EtOAc (3×) and the combined organics were washed with 10% KF, then brine, dried over Na2SO4 and concentrated to dryness. The material was treated with MeCN, sonicated, the solid removed via filtration and the filtrate concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was suspended in MeCN, sonicated and the solid collected via filtration. The filtrate was concentrated to dryness and further purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). The organics were removed under reduced pressure, the aqueous residue treated with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and combined with the above-isolated solid to afford 3-(2-methoxyethyl)-N-(6-methyl-5-((2-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide (61 mg, 36%). 1H NMR (400 MHz, DMSO-d6): δ 10.89 (s, 1 H), 8.35 (d, J=5.7 Hz, 1 H), 7.91 (d, J=8.8 Hz, 1H), 7.67 (d, J=1.3 Hz, 1 H), 7.64 (d, J=8.8 Hz, 1 H), 7.59 (d, J=1.3 Hz, 1 H), 7.16 (d, J=2.6 Hz, 1 H), 6.74 (dd, J=5.7, 2.6 Hz, 1 H), 3.84-3.78 (m, 2 H), 3.67 (s, 3 H), 3.54-3.47 (m, 4 H), 3.41-3.37 (m, 2 H), 3.26 (s, 3 H), 2.23 (s, 3H); MS (ESI) m/z: 452.2 (M+H+).