Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[F:33][C:34]([F:44])([F:43])[C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Br)=[CH:37][CH:36]=1>O>[C:16]([O:15][C:13]([N:10]1[CH2:9][CH2:8][CH:7]([CH2:6][C:5]2[CH:20]=[CH:21][C:2]([O:1][CH2:39][C:38]3[CH:37]=[CH:36][C:35]([C:34]([F:33])([F:43])[F:44])=[CH:42][CH:41]=3)=[CH:3][CH:4]=2)[CH2:12][CH2:11]1)=[O:14])([CH3:17])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(O)cc2)CC1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
tert-Butyl 4-(4-hydroxybenzyl)piperidine-1-carboxylate (1.78 g, 6.1 mmol), potassium carbonate (1.27 g, 9.2 mmol), N,N-dimethylformamide (18 ml) and 4-(trifluoromethyl)benzylbromide (1.75 g, 7.3 mmol) were mixed and stirred at room temperature overnight. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→60:40) to afford the title compound as a colorless powder (2.64 g, 96%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([OH:16])[CH2:11]1>>[CH3:9][N:10]1[CH2:15][CH2:14][CH2:13][CH:12]([O:16][C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:11]1
Reactant: CN1CCCC(O)C1
Reactant: Brc1ccc(Br)nc1
Product: CN1CCCC(Oc2ccc(Br)cn2)C1

Procedure:
Prepared from 2,5-dibromopyridine and N-methylpiperidin-3-ol by the method of Example 10 (b).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14][CH2:15][C:16]([OH:33])([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=1)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:39].[OH2:49]>ClCCl.[Cl-].[Na+].O>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([CH2:15][C:16]([OH:33])([CH3:32])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([C:28]([F:31])([F:29])[F:30])[CH:21]=1)=[O:18])(=[O:39])=[O:49])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O
Reactant: CC(O)(CSc1ccccc1Cc1ccccc1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Agent: OO
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(O)(CS(=O)(=O)c1ccccc1Cc1ccccc1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 16 h

Procedure:
3-(2-benzylphenylthio)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide (32 mg, 0.068 mmol) was dissolved in dichloromethane (0.1 mL) and cooled to −78° C. 30% hydrogen peroxide (12 μL, 0.4 mmol) was added followed by the slow addition of trifluoroacetic anhydride (48 μL, 0.34 mmol). The reaction was stirred at room temperature for 16 h. The reaction was diluted with dichloromethane. Cold water and brine were added, and the reaction was stirred for 20 minutes. The organic layer was separated, dried over magnesium sulfate, filtered and evaporated. Purification by column chromatography (hexane:EtOAc 50:50) yielded 14 mg of desired product. Production of PLM2 was confirmed by 13-C NMR and mass spectral analysis.
Reaction SMILES: [NH2:1][C@H:2]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:3][NH:4][C:5](=[O:41])[CH2:6][NH:7][C:8]([CH:10]([CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1)[CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)=[O:9].C(N(CC)CC)C.[C:54]1([S:60](Cl)(=[O:62])=[O:61])[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.O>ClCCl>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][CH:13]([CH2:12][CH2:11][CH:10]([C:8]([NH:7][CH2:6][C:5]([NH:4][CH2:3][C@H:2]([NH:1][S:60]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)(=[O:62])=[O:61])[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:41])=[O:9])[CH2:26][CH2:27][CH:28]2[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH2:32][CH2:33]2)[CH2:14][CH2:15]1)=[O:20])([CH3:23])([CH3:24])[CH3:25]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)[C@@H](N)CNC(=O)CNC(=O)C(CCC1CCN(C(=O)OC(C)(C)C)CC1)CCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)[C@H](CNC(=O)CNC(=O)C(CCC1CCN(C(=O)OC(C)(C)C)CC1)CCC1CCN(C(=O)OC(C)(C)C)CC1)NS(=O)(=O)c1ccccc1
Reaction time: 2 h
Yield: 73.5 %

Procedure:
tert-Butyl 4-{3-{[(2-{[(2S)-2-amino-3-ethoxy-3-oxopropyl]amino}-2-oxoethyl)amino]carbonyl}-5-[1-(tert-butoxycarbonyl)-4-piperidyl]pentyl}tetrahydro-1(2H)-pyridinecarboxylate (compound 37) (3.31 g, 4.8 mmol) is dissolved in 50 ml of dichloromethane containing triethylamine (1.04 g, 5 mmol) and benzenesulphonyl chloride (0.9 g, 5 mmol) is then added at about 5° C. After 2 hours at room temperature, water is added. The organic phase is washed with 1N HCl and then with water, dried over sodium sulphate and then evaporated to give the crude product, which is purified by flash chromatography (15/1 dichloromethane/methanol) to give 2.8 g of a white solid.
Reaction SMILES: [NH2:1][C@:2]([CH3:12])([CH2:5][CH2:6][C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)[CH2:3][OH:4].[C:13](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:14].C(N(CC)CC)C.O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:12][C@@:2]1([CH2:5][CH2:6][C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[CH2:3][O:4][C:13](=[O:14])[NH:1]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C[C@](N)(CO)CCc1ccco1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C[C@@]1(CCc2ccco2)COC(=O)N1
Yield: 57.6 %

Procedure:
Subsequently, to a suspension of (2R)-2-amino-2-methyl-4-(furan-2-yl)butan-1-ol 1/2 D-(−)tartrate (51.2 mg, 0.16 mmol) obtained above in dichloromethane (1.6 ml) were added successively di-t-butyl dicarbonate (0.17 g, 0.78 mmol), triethylamine (0.22 ml, 1.58 mmol) and 4-dimethylaminopyridine (3.0 mg, 0.025 mmol) with stirring, and the resulting mixture was stirred at room temperature for 20 minutes. After stirring, water was added to the reaction mixture, and the resulting mixture was evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (1:1) as the eluent to afford (4R)-4-methyl-4-[2-(furan-2-yl)ethyl]-1,3-oxazolidin-2-one (18.0 mg, yield: 58%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:13][NH:14][CH2:15][C:16]#[N:17].N1C(C)=CC=CC=1C>C(Cl)Cl>[C:16]([CH2:15][N:14]([CH3:13])[C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:2]=1[OH:1])#[N:17]
Reactant: COc1ccc(C(=O)Cl)c(O)c1
Reactant: CNCC#N
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COc1ccc(C(=O)N(C)CC#N)c(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-hydroxy-4-methoxybenzoyl chloride (22.19 g, 118.9 mmol) in 500 CH2Cl2 were added (methylamino)acetonitrile (10 g, 142.7 mmol) and 2,6-lutidine (19.1 g, 178.4 mmol). The reaction was stirred at rt overnight. The reaction mixture was then partitioned between EtOAc and 1(N) aq HCl. Organic layer washed with 1(N) aq HCl (2×), dried over Na2SO4 and concentrated to light yellow viscous material (24.63 g, 94%). This material was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]([OH:9])=[O:8])=[O:4].Cl.[CH2:17]([O:24][C:25](=[O:31])[C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25]([C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:7](=[O:9])[C@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:31])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1.[CH2:17]([O:24][C:25]([C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:7](=[O:8])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:31])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: Cl
Product: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Yield: 15 %
Yield: 31 %

Procedure:
Reaction of 1.0 g of (R)-methoxycarbonylamino-phenyl-acetic acid and 1.16 g of (L)-proline benzyl ester hydrochloride according to the procedure described in example 91b gave 0.59 g (31%) of the title compound as a white solid and 0.28 g (15%) of 1-[(S)-methoxycarbonylamino-phenyl-acetyl]-pyrrolidine-2-(S)-carboxylic acid benzyl ester (+)-APCI-MS: 397 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C@H:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]3)=[C:5]([O:29][CH3:30])[CH:4]=1)#[N:2].[SH2:31].C(NCC)C>CN(C=O)C>[NH2:2][C:1]([C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C@H:17]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]3)=[C:5]([O:29][CH3:30])[CH:4]=1)=[S:31]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C#N)cc3OC)ccc21
Reactant: S
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(C(N)=S)cc3OC)ccc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
Into a solution of ethyl {(1S)-5-[3-(4-cyano-2-methoxyphenoxy)propoxy]-2,3-dihydro-1H-inden-1-yl}acetate (2.2 g, 5.4 mmol) (Example 145) in DMF (anhydrous, 20 mL) under argon at rt was passed H2S gas at a moderate rate for 30 min. A solution of diethylamine (0.8 g, 8.1 mmol) in DMF (5 mL) was added in one portion, and the reaction was stirred at 60° C. for 3 h. Then the reaction was cooled to rt and argon was passed through the reaction mixture for 1 h to remove residual H2S. The reaction mixture was then concentrated under reduced pressure and the residue purified by silica gel flash chromatography (EtOAc/Hexane (v/v)=1:1) to afford 1.9 g (81%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 1.21 (t, 3H), 1.60-1.68 (m, 1H), 2.15-2.22 (m, 2H), 2.23-2.34 (m, 1H), 2.38 (q, 1H), 2.70-2.86 (m, 3H), 3.38-3.44 (m, 1H), 3.80 (s, 3H), 4.05-4.16 (m, 4H), 4.19 (t, 2H), 6.70 (d, 1H), 6.80 (s, 1H), 6.97 (d, 1H), 7.06 (d, 1H), 7.56-7.64 (m, 2H), 9.33-9.40 (s, 1H), 9.65 (s, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([N:21]1[CH2:42][CH2:41][C:24]2([C:28](=[O:29])[N:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)[CH2:26][CH2:25]2)[CH:23]([OH:43])[CH2:22]1)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([N:21]1[CH2:42][CH2:41][C:24]2([C:28](=[O:29])[N:27]([C:30]3[CH:31]=[CH:32][C:33]([O:36][C:37]([F:39])([F:40])[F:38])=[CH:34][CH:35]=3)[CH2:26][CH2:25]2)[C:23](=[O:43])[CH2:22]1)(=[O:19])=[O:20]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccccc1Cl)CC2O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C1CN(S(=O)(=O)c2ccccc2Cl)CCC12CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
In a 10 mL round-bottomed flask, oxalyl chloride (46.1 mg, 31.8 μl, 356 μmol) was combined with DCM (5 mL) to give a colorless solution. DMSO (27.8 mg, 25.3 μl, 356 μmol) was added drop wise at −78° C. The reaction was stirred for 15 min. A solution of 8-(2-chlorophenylsulfonyl)-6-hydroxy-2-(4-(trifluoromethoxy)phenyl)-2,8-diazaspiro[4.5]decan-1-one (124 mg, 246 μmol) in DCM (1 mL) was added. The reaction mixture was stirred for 30 min at −40° C. Triethylamine (74.6 mg, 103 μl, 737 μmol) was added drop wise and the reaction mixture was heated to r.t. and stirred for 3 h. The reaction mixture was poured into 15 mL DCM and washed with H2O (2×10 mL).The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by flash chromatography (0 to 100% AcOEt in heptane) to afford the title compound as an off-white solid (73 mg, 59%). MS (ESI): 503.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[N:4][CH:3]=1.CC#N.N1C=CC=CC=1.[C:17]1([O:23][C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:24](=[O:25])[O:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:3][N:4]=1
Reactant: Nc1ccnnc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(Nc1ccnnc1)Oc1ccccc1
Reaction time: 18 h
Yield: 35.3 %

Procedure:
A solution of 4-aminopyridazine (2.5 g, 26.3 mmol) in a mix of 1:1 THF:MeCN (20 mL), and pyridine (2.18, 27.6 mmol) was treated dropwise with phenylchloroformate (1.3 g, 27.6 mmol) in THF (10 mL). After stirring for 18 h, the resulting solid was collected and dried to provide the title compound (2 g, 37%).
Reaction SMILES: O[C@:2]1([C:9]2[O:10][C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=C(C3C=CC=CC=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[OH:8].COC(OC)(OC)C.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37](S(O)(=O)=O)=[CH:36][CH:35]=1>C(Cl)Cl>[C:34]1([C:44]2[N:13]=[C:9]([C@:2]34[O:8][C@H:3]3[CH2:4][CH2:5][CH2:6][CH2:7]4)[O:10][C:11]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O[C@H]1CCCC[C@]1(O)c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: COC(C)(OC)OC
Solvent: ClCCl
Product: c1ccc(-c2nc([C@@]34CCCC[C@@H]3O4)oc2-c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 38251.2 %

Procedure:
To a solution of (1R,2S)-1,2-dihydroxy-1-(4,5-diphenyloxazol-2-yl)cyclohexane (18 g) in methylene chloride (200 ml) were added orthoacetic acid trimethyl ester (9.7 ml) and p-toluenesulfonic acid (20 mg) at room temperature under N2. After stirring the mixture for 30 minutes, the solvent was evaporated in vacuo. The residue was diluted with methylene chloride (200 ml) and acetyl bromide (5.8 ml) was added to the solution at 0° C. under N2. After stirring the mixture for 2 hours at room temperature, the solvent was evaporated in vacuo, the residue was diluted with MeOH (200 ml), and potassium carbonate (12 g) was added to the solution at room temperature. The mixture was stirred for 2 hours at the same temperature and partitioned between EtOAc and water. The organic layer was washed with 1N-hydrochloric acid, water, saturated sodium hydrogencarbonate and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give (1R,2S)-1-(4,5-diphenyloxazol-2-yl)-1,2-epoxycyclohexane (14.1 g).
Reaction SMILES: F[S:2]([CH2:5][CH2:6][N:7]([CH2:14][CH3:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:4])=[O:3].[OH-:16].[K+:17]>O>[K:17][CH:5]([S:2]([OH:16])(=[O:4])=[O:3])[CH2:6][N:7]([CH2:14][CH3:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [K+]
Reactant: CCN(CCS(=O)(=O)F)c1ccccc1
Reactant: [OH-]
Solvent: O
Product: CCN(CC([K])S(=O)(=O)O)c1ccccc1

Procedure:
N-(2-Fluorosulfonylethyl)-N-ethylaniline (22.8 g, 0.1 n) is stirred in water (200 ml) and potassium hydroxide (10 g) for 1-3 hrs. or until thin-layer chromatography shows reaction to be complete. The product is not isolated but is used as an aqueous solution in the coupling reaction.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[I:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[I:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)=[O:13])=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: Cn1ccnc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1ccnc1C(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.82 g (10 mmol) of 1-methyl-imidazole and 2.7 g (10 mmol) of 4-iodobenzoic acid chloride are combined in 10 ml of acetonitrile while cooling with an ice bath, 1.4 ml (10 mmol) of triethylamine are added and the mixture is then stirred for 16 hours at ambient temperature. The crude product is taken up in 30 ml of ethyl acetate, washed with H2O, dried, concentrated in vacuo and purified by flash chromatography (silica gel; methylene chloride).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[C:12]([NH:17][CH2:18][CH3:19])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:9])=[CH:6][C:5]([Br:20])=[CH:4][N:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].C1COCC1>N1C=CC=CC=1>[Br:20][C:5]1[CH:4]=[N:3][C:2]2[N:17]([CH2:18][CH3:19])[C:12]3[N:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:8](=[O:9])[C:7]=2[CH:6]=1
Reactant: CCNc1ncccc1NC(=O)c1cc(Br)cnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCN1c2ncccc2NC(=O)c2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.1 %

Procedure:
To a solution of 2-chloro-N-{2-(ethylamino)-3-pyridinyl}-5-bromo-3-pyridinecarboxamide (54.9 g, 154.4 mmol) in pyridine (308 mL) at 50° C. was added drop-wise a 1 M solution of NaHMDS (sodium hexamethyldisilazide) in THF (355 mL, 355 mmol). After 10 min, the reaction was allowed to cool to room temperature, and then was poured over ice water (2 L). The resulting solid was filtered, rinsed with water and then hexane. The solid was dried under reduced pressure to give the title compound (36 g, 75% yield) as a dark green solid.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[C:25]1(=O)[CH2:28][CH2:27][CH2:26]1>CN(C)C(=O)C>[C:25]1(=[N:1][N:2]2[C:7](=[O:8])[C:6]([C:9]3[NH:14][C:13]4[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=4[S:11](=[O:20])(=[O:19])[N:10]=3)=[C:5]([OH:21])[C:4]3[S:22][CH:23]=[CH:24][C:3]2=3)[CH2:28][CH2:27][CH2:26]1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: O=C1CCC1
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1N=C1CCC1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
The product of Example 268D (0.10 g, 0.27 mmol) was reacted with cyclobutanone (1.0 g, 14.3 mmol) in N,N-dimethylacetamide (2 mL) in a sealed tube at 135° C. for 60 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with diethyl ether and filtered to give the title compound (0.086 g 77%).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH:19]1([CH2:25][C:26](O)=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([CH2:25][C:26]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)CC1CCCCC1
Product: O=C(CC1CCCCC1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-cyclohexylacetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.8, 1.4 Hz, 1H), 8.03 (dd, J=8.1, 1.3 Hz, 1H), 7.97-8.00 (m, 1H), 7.91 (td, J=7.5, 1.3 Hz, 1H), 3.75-3.83 (m, 4H), 3.08-3.10 (m, 4H), 2.16 (d, J=7.0 Hz, 2H), 1.61-1.83 (m, 6H), 0.96-1.28 (m, 5H); MS (ESI−) M/Z 369 (M−H)−.
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:9]=[C:8]([C:10]2[N:14]=[C:13]([C:15]3[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH:22][CH:23]([CH3:25])[CH3:24])[N:16]=3)[O:12][N:11]=2)[CH:7]=[C:6]([CH3:26])[C:5]=1[CH2:27][CH2:28][C:29](O)=[O:30])[CH3:3].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:63]([NH:70][CH2:71][CH2:72][NH2:73])([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64]>CN(C=O)C.CCOC(C)=O>[C:66]([O:65][C:63](=[O:64])[NH:70][CH2:71][CH2:72][NH:73][C:29](=[O:30])[CH2:28][CH2:27][C:5]1[C:6]([CH3:26])=[CH:7][C:8]([C:10]2[N:14]=[C:13]([C:15]3[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([NH:22][CH:23]([CH3:25])[CH3:24])[N:16]=3)[O:12][N:11]=2)=[CH:9][C:4]=1[CH2:2][CH3:3])([CH3:67])([CH3:68])[CH3:69]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(NC(C)C)n3)n2)cc(C)c1CCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCc1cc(-c2noc(-c3cc(C)nc(NC(C)C)n3)n2)cc(C)c1CCC(=O)NCCNC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 80.2 %

Procedure:
To a suspension of Intermediate 10 (25 mg, 0.061 mmol) in DMF is added DIPEA (16 μL, 0.092 mmol) followed by TBTU (23.5 mg, 0.073 mmol). The reaction mixture is stirred for 5 min before adding N-Boc-ethylenediamine (12 μL, 0.073 mmol) and stirring is continued for 2 h. The reaction mixture is diluted with EtOAc (20 mL) and is washed with sat. aq. NaHCO3 (15 mL). The org. phase is then dried over Na2SO4, filtered, and evaporated to give a yellow oil that is purified by prep. TLC (eluting with DCM/MeOH 95:5) to afford [2-(3-{2-ethyl-4-[5-(2-isopropylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-propionylamino)-ethyl]-carbamic acid tert-butyl ester (27 mg) as a white solid; LC-MS: tR=1.09 min; [M+1]+=552.30.
Reaction SMILES: O=C1CCC(=O)N1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:26]([O-:28])=O)=[C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[CH:15]=2)[N:10]([CH2:29][C:30]([F:33])([CH3:32])[CH3:31])[N:9]=1.[NH2:34][C@H:35]1[CH2:39][CH2:38][NH:37][C:36]1=[O:40]>ClCCl.C(OCC)(=O)C>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[C:26]([NH:34][C@H:35]1[CH2:39][CH2:38][NH:37][C:36]1=[O:40])=[O:28])[N:10]([CH2:29][C:30]([F:33])([CH3:32])[CH3:31])[N:9]=[CH:8]2
Reactant: CC(C)(F)Cn1nc(N2C(=O)CCC2=O)c2cc(Oc3ccc(F)cc3F)c(C(=O)[O-])cc21
Reactant: N[C@H]1CCNC1=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(F)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCNC3=O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 1032.3 %

Procedure:
To a solution of 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazole-6-carboxylate (prepared according to Example 26; 100 mg, 0.217 mmol) in dichloromethane (1 mL) was added (S)-3-aminopyrrolidin-2-one (4a) 521 mg, 4.56 mmol), and the reaction mixture was allowed to stir overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on a silica gel column, eluting with 50% acetone/hexanes to yield (S)-5-(2,4-difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-N-(2-oxopyrrolidin-3-yl)-1H-indazole-6-carboxamide (Ik) (1.00 g, 99%). Mass spec: 447 (M+1). 1H NMR (CDCl3) δ 8.42 (s, 1H), 8.21 (br, 1H), 7.15 (m, 1H), 7.03 (s, 1H), 7.01 (m, 1H), 6.91 (m, 1H), 6.59 (br, 1H), 4.58 (m, 1H), 4.55 (d, 2H), 3.43 (m, 2H), 2.84 (m, 1H), 2.06 (m, 1H), 1.40 (d, 3H), 1.39 (d, 3H).