Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:32]=[CH:31][C:9]3[N:10]([C:13]4[CH:14]=[C:15]([NH:27][C:28](=[O:30])[CH3:29])[CH:16]=[C:17]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])[CH:18]=4)[CH:11]=[N:12][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.N1C=CC=CC=1.[CH:39]1([S:42](Cl)(=[O:44])=[O:43])[CH2:41][CH2:40]1>C(Cl)Cl>[CH:39]1([S:42]([N:1]2[CH:5]=[C:4]([C:6]3[CH:32]=[CH:31][C:9]4[N:10]([C:13]5[CH:14]=[C:15]([NH:27][C:28](=[O:30])[CH3:29])[CH:16]=[C:17]([C:19]6[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=6[F:26])[CH:18]=5)[CH:11]=[N:12][C:8]=4[CH:7]=3)[CH:3]=[N:2]2)(=[O:44])=[O:43])[CH2:41][CH2:40]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn[nH]c4)ccc32)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cnn(S(=O)(=O)C5CC5)c4)ccc32)c1
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of the compound of Example 326 (50 mg, 0.116 mmol) in DCM was added pyridine (0.5 ml) followed by cyclopropanesulfonyl chloride (20 mg, 0.139 mmol, 1.2 eq.). The mixture was stirred for 1 h, and quenched and extracted as in Example 2(b). The solvent was distilled off to afford the crude residue which was purified by preparative HPLC to give the product in 90% yield (42 mg). 1H NMR (400 MHz, CD3OD): δ 8.58 (s, 1H), 8.52 (s, 1H), 8.33 (s, 1H), 8.09 (s, 1H), 8.05 (s, 1H), 7.74-7.62 (m, 4H), 7.49 (s, 1H), 7.17-7.08 (m, 2H), 3.0 (m, 1H), 2.2 (s, 3H), 1.1 (d, 4H); LC-MS (ESI): Calculated mass: 533.5; Observed mass: 534.1 [M+H]+ (rt: 1.61 min).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](O)=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[N:21]2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C.ClCCl>[CH2:6]([O:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([Cl:3])=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=[N:21]2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Temperature: 100 °C
Reaction time: 0.42 h
Yield: 94.2 %

Procedure:
N,N-Dimethylformamide (100 mL) (DMF) was cooled to 0° C., and phosphorous oxychloride (27.5 mL, 0.295 mol) was added dropwise. The resulting solution was stirred for 25 minutes and then added dropwise to a mixture of 7-benzyloxy-3-nitroquinolin-4-ol (72.87 g, 0.2459 mol) in DMF (400 mL). Following the addition, the reaction was heated at 100° C. for 5 minutes, cooled to ambient temperature, and poured into ice water with stirring. A tan precipitate formed, which was isolated by filtration and dissolved in dichloromethane. The resulting solution was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield 72.9 g of 7-benzyloxy-4-chloro-3-nitroquinoline as a light brown solid.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:35])([F:34])[C:10]1[N:14]2[N:15]=[C:16]([N:19]3[CH2:23][CH:22]4[CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][CH:21]4[CH2:20]3)[CH:17]=[CH:18][C:13]2=[N:12][N:11]=1>ClCCl>[CH2:20]1[CH:21]2[CH2:26][NH:25][CH2:24][CH:22]2[CH2:23][N:19]1[C:16]1[CH:17]=[CH:18][C:13]2[N:14]([C:10]([C:9]([F:34])([F:35])[F:8])=[N:11][N:12]=2)[N:15]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(c3ccc4nnc(C(F)(F)F)n4n3)CC2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Trifluoroacetic acid (15 mL, 194.70 mmol) was added to a mixture of tert-butyl 5-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (3 g, 7.53 mmol) and dichloromethane (60 mL). The resulting solution was stirred at ambient temperature for 1 hour and then evaporated to leave an involatile residue. The residue was purified by ion-exchange chromatography on an SCX column using aqueous ammonia (7M) in methanol as eluant to give 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (2.200 g, 98%) as a white solid that was used without further purification.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:12].[C:13]1([C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][O:15]1)=O.Cl>CN(C=O)C.O>[C:13]1(=[C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:3][C:4]2=[O:12])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][O:15]1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C1OCc2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2C1=C1OCc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.7 %

Procedure:
To a suspension of sodium hydride (6.0 g, 150 mmol, 60% in mineral oil) in 300 mL DMF was added oxindole (10.0 g, 75.1 mmol) in 50 mL DMF over 8 min. After stirring for 15 min at room temperature, a solution of phthalide (13.1 g, 97.6 mmol) in 50 mL DMF was added over 1 min. The mixture was stirred for 1.25 h, then poured into 1100 mL H2O. Addition of 4% aqueous HCl solution gave a yellow solid which was filtered and rinsed with H2O to give the title compound (8.75 g, 47%).
Reaction SMILES: [NH:1]1[CH2:6][CH:5]([OH:7])[CH2:4][NH:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15]>O.C1(C)C=CC=CC=1>[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:1]2[CH2:6][CH:5]([OH:7])[CH2:4][N:3]([S:23]([C:20]3[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:22][CH:21]=3)(=[O:24])=[O:25])[CH2:2]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CNCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CC(O)CN(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)C2)cc1
Reaction time: 8 h
Yield: 95 %

Procedure:
A solution of hexahydro-5-pyrimidinol (1.0 g, 9.8 mmol) and sodium carbonate (1.04 g, 9.8 mmol) in 10 mL of water in a 250 mL round bottom flask was stirred with a magnetic stir bar for 10 minutes. A solution of 4-nitrobenzenesulfonyl chloride (4.4 g, 19.8 mmol) in 10 mL of toluene was added dropwise over a period of 30 minutes. The reaction mixture formed a white suspended solid. A mixture of 100 mL of water and 20 mL of toluene was added to the reaction mixture and stirred overnight. The reaction mixture was filtered and the solid was washed with 100 mL of toluene, then with 100 mL of water. The solid was dried at room temperature under reduced pressure to give 4.4 g (95%) of crude product, hexahydro-1,3-bis(4-nitrobenzenesulfonyl)-5-pyrimidinol. [1H NMR (DMSO-d6): δ2.29 (s, 1H), 2.84, 3.47 {AB q of d, J=12.4(3.8) Hz, 12.4(7.9) Hz, 4H}, 3.30 (m, 1H), 4.46, 5.07 (AB q, J=12.5 Hz, 2H), 5.31 (s, 1H), 8.11, 8.41 (AB q, J=8.7 Hz, 8H); 13C NMR (DMSO-d6): δ50.0, 59.8, 60.6, 124.6, 128.9, 143.3, 150.1].
Reaction SMILES: [CH3:1][Ge:2]([CH3:13])([CH3:12])[C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)=O.Cl>C(O)(C)C.O1CCCC1.[OH-].[K+]>[CH3:13][Ge:2]([CH3:12])([CH3:1])[C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH:10]=[CH:14][C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)c1cccc([Ge](C)(C)C)c1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C[Ge](C)(C)c1cccc(C(=O)C=Cc2ccc(C(=O)O)cc2)c1
Reaction time: 8 h
Yield: 23 %

Procedure:
3'-Trimethylgermylacetophenone (49 mg,0.2 mmol) and methyl 4-formylbenzoate (37 mg,0.23 mmol) was dissolved in 5 ml of a mixture of 50% isopropanol and tetrahydrofuran, 1 ml of 1N aqueous potassium hydroxide solution was added, and the mixture was stirred overnight. The reaction mixture was adjusted to pH1 with 2N hydrochloric acid and extracted with AcOEt. The extract was evaporated and the residue was purified by column chromatography on silica gel (eluent: MeOH-methylene chloride) and recrystallized from a mixture of AcOEt and n-hexane to give 17 mg of pale yellow prisms, m.p.186°-188° C. (yield 22%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22]Cl)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[I-:24].[Na+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22][I:24])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8]
Reactant: [I-]
Reactant: Cc1nnc(CCl)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1nnc(CI)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.9 h

Procedure:
5-Chloro-2-[3-(chloromethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone (346 mg. 0.001 mole) is added to a stirred solution of sodium iodide (300 mg., 0.002 mole) in acetone, and the resulting mixture is stirred at ambient temperature for 6 hours 54 minutes and poured into ice water. This mixture is extracted with chloroform. The extract is washed with brine, dried and concentrated. The residue is crystallized from methylene chloride-ethyl acetate to give: 0.227 g. of melting point 185.5°-192° (decomposition) of 5-chloro-2-[3-(iodomethyl)-5-methyl-4H-1,2,4-triazol-4-triazol-4-yl]benzophenone. The analytical sample has a melting point of 185°-200° C. (decomposition).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:8]2[CH:9]=[CH:10][NH:11][C:12]=2[CH:13]=[CH:14][CH:15]=1.[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26]3[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=3)=[CH:22][NH:23]2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21]([C:26]3[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]4[CH:15]=[CH:14][CH:13]=[C:12]5[C:8]=4[CH:9]=[CH:10][NH:11]5)[CH2:30][CH:31]=3)=[CH:22][NH:23]2)=[CH:19][CH:18]=1
Reactant: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reactant: ClCCCCOc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1ccc2c(C3=CCN(CCCCOc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 99 using 1-chloro-4-(1H-indole-4-oxy)butane (0.479 g, 2.15 mmol) and 6-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.500 g, 2.13 mmol) in the presence of 2.5 equivalents of potassium carbonate (0.742 g, 5.38 mmol) in dimethylformamide at 90° C. Yield 0.220 g (24%) of a tan foam. FDMS m/e=420 (M+ of free base).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH2:2]1.O=[O+][O-].[NH2:9][CH2:10][C:11]([F:38])([F:37])[CH2:12][NH:13][C:14](=[O:36])[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([NH:22][CH2:23][C:24]2[S:28][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[N:26][CH:25]=2)[CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)Cl>[F:38][C:11]([F:37])([CH2:10][N:9]1[CH2:4][CH2:5][O:1][CH2:2][CH2:3]1)[CH2:12][NH:13][C:14](=[O:36])[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([NH:22][CH2:23][C:24]2[S:28][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[N:26][CH:25]=2)[CH:16]=1
Reactant: C1=COCC1
Reactant: NCC(F)(F)CNC(=O)c1ccc(F)c(NCc2cnc(Nc3ccccn3)s2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=[O+][O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(NCC(F)(F)CN1CCOCC1)c1ccc(F)c(NCc2cnc(Nc3ccccn3)s2)c1
Temperature: 0 °C
Yield: 51.2 %

Procedure:
A solution of dihydrofuran (35 mg, 0.5 mmol) in MeOH (1.5 mL) was treated with ozone at −78° C. until the solution turned blue. Argon was streamed through the solution to remove excess ozone. The solution was warmed to 0° C., and N-(3-Amino-2,2-difluoro-propyl)-4-fluoro-3-{[2-(pyridin-2-ylamino)-thiazol-5-ylmethyl]-amino}-benzamide (Example 107) (12 mg, 0.027 mmol)) followed by NaBH(OAc)3 (84 mg) were added over a period of 3 h. The mixture was diluted with CH2Cl2, washed with sat. NaHCO3, dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography [silica gel, 1% (NH3/MeOH(2M) in EtOAc] to afford the title compound (7 mg, 51%) as a white solid. LC/MS; (M+H)+=507. 1HNMR (CD3OD): δ 2.47 (m, 4H); 2.66 (t, 2H, J=13.7 Hz); 3.53 (m, 4H); 3.80 (t, 2H, J=14.3 Hz); 4.48 (s, 2H); 6.78 (m, 1H); 6.86 (d, 1H, J=8.25 Hz); 7.0 (m, 2H); 7.15 (s, 1H); 7.23 (m, 1H); 7.54 (m, 1H), 8.15 (d, 1H, J=4.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[C:15]=1[S:22]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:24])=[O:23]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=S(=O)(Cl)c1c(F)cc(F)cc1F
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2c(F)cc(F)cc2F)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2,4,6-trifluorobenzenesulfonyl chloride as described in the synthetic METHOD B to give a yellow solid (1.0 mg) with purity >90%. MS (pos) m/z 381.4.
Reaction SMILES: O.[C:2]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)(=[O:5])[CH:3]=[O:4].[C:17]([S:20][CH:21]1[NH:24][C:23](=[O:25])[CH2:22]1)(=[O:19])[CH3:18]>C1C=CC=CC=1>[C:17]([S:20][CH:21]1[N:24]([CH:3]([OH:4])[C:2]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[O:5])[C:23](=[O:25])[CH2:22]1)(=[O:19])[CH3:18]
Reactant: CC(=O)SC1CC(=O)N1
Reactant: O=CC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)SC1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 115.1 %

Procedure:
p-Nitrobenzyl glyoxylate hydrate (63.4 g., 0.278 mole) was added to a solution of 4-acetylthio-2-azetidinone (36.2 g., 0.250 mole) in 1200 ml. of benzene. The mixture was refluxed for 17 hours in a Dean-Stark apparatus. The solution was concentrated on a rotary evaporator to give the title product as a yellow oil (102 g., 100%). This oil was found to be identical with the product of Example 1A.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][CH3:18])=[CH:14][C:13]2=[O:19])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:25]=[CH:24][N:23]([CH2:26][C:27]([CH3:30])([OH:29])[CH3:28])[N:22]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][CH3:18])=[CH:14][C:13]2=[O:19])[C:9]([NH:20][C:21]2[CH:25]=[CH:24][N:23]([CH2:26][C:27]([OH:29])([CH3:28])[CH3:30])[N:22]=2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=CC(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50.8 %

Procedure:
A solution of (S)-3-cyclohexyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid (1.3 g, 4.87 mmol) in dichloromethane (25 mL) was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 830 mg, 5.36 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (2.60 g, 5.84 mmol) and triethylamine (1.48 g, 14.61 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 80 g; 0% to 10% methanol/dichloromethane) to afford (S)-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide (1.0 g, 51%) as a heavy yellow oil: LR-ES-MS m/z calculated for C21H32N4O4 [M]+ 404, observed [M+H]+ 405.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1.C([Li])(C)(C)C.[Cl:13][C:14]1[CH:45]=[CH:44][C:17]([C:18]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]([CH3:30])[C:25](=[O:31])[CH:24]=[C:23]3[C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Si:38]([CH3:41])([CH3:40])[CH3:39])[C:33]=2[C:42]#[CH:43])=[O:19])=[CH:16][CH:15]=1>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]([OH:19])([C:4]2[N:3]([CH3:7])[C:2]([SH:1])=[N:6][CH:5]=2)[C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]([CH3:30])[C:25](=[O:31])[CH:24]=[C:23]3[C:32]2[CH:33]=[CH:42][CH:43]=[C:36]([C:35]#[C:34][Si:38]([CH3:41])([CH3:39])[CH3:40])[CH:37]=2)=[CH:44][CH:45]=1
Reactant: C#Cc1c(-c2cc(=O)n(C)c3ccc(C(=O)c4ccc(Cl)cc4)cc23)cccc1[Si](C)(C)C
Reactant: Cn1ccnc1S
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: Cn1c(C(O)(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2cccc(C#C[Si](C)(C)C)c2)cc(=O)n3C)cnc1S
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
2-Mercapto-1-methylimidazole (2.08 g, 18.2 mMol) was dissolved in anhydrous THF (200 mL) under an atmosphere of dry N2. The solution was cooled to −78° C. and a solution of tert-butyl lithium (1.7 M in pentane, 22 mL, 37 mMol) was added. The solution was then warmed to 0° C. After a yellow precipitate formed, the solution was cooled to −78° C. and a solution of 6-(4-chloro-benzoyl)-1-methyl-4-(3-trimethylsilanyl ethynyl-phenyl)-1H-quinolin-2-one (8.55 g, 18.2 mmol) in anhydrous THF (25 mL) was added. After 30 minutes, the solution was warmed to 0° C. and stirred at this temperature for 1 hour. The reaction mixture was then warmed to ambient temperature and stirred overnight. The reaction was quenched with 20 mL of saturated aqueous ammonium chloride (NH4Cl) and then partitioned between DCM and water. The DCM layer was dried over sodium sulfate (Na2SO4), filtered and concentrated under vacuum. The residue was chromatographed on flash silica gel eluting with a gradient from DCM to MeOH/DCM (3:97) to give 5.0 g of the titled compound as a solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:19][O:20][Si](C(C)(C)C)(C)C)[O:11][S:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[K+]>CO>[CH2:1]([O:8][CH2:9][CH:10]([CH2:19][OH:20])[O:11][S:12][CH2:13][C:14]([OH:16])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CSOC(COCc1ccccc1)CO[Si](C)(C)C(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CSOC(CO)COCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
1-O-Benzyl-3-O-t-butyldimethylsilyl-2-(ethoxycarbonylmethylthio)glycerol (1 g) was added to a solvent mixture of water (8 ml) and methanol (16 ml), and potassium hydroxide (1 g) added thereto and the mixture stirred overnight at room temperature. The reaction mixture was extracted with ethyl ether twice to remove the impurities, and the pH of the extract was adjusted to 1 to 2 with 6N hydrochloric acid. Then the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the desired product (0.6 g).
Reaction SMILES: [CH:1]1([SH:4])[CH2:3][CH2:2]1.C1(Br)CC1.[H-].[Na+].Br[C:12]([F:19])([F:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CS(C)=O.CCOCC>[CH:1]1([S:4][C:12]([F:19])([F:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:3][CH2:2]1
Reactant: SC1CC1
Reactant: CCOC(=O)C(F)(F)Br
Agent: BrC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)SC1CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46 %

Procedure:
An ether solution of cyclopropyl mercaptan synthesized from cyclopropyl bromide (50.0 g, 413 mmol) in accordance with the process described in literature (J. Am. Chem. Soc., 114, 3492 (1992)) was added dropwise to a solution of 60% sodium hydride (5.4 g, 135 mmol) in dimethyl sulfoxide (100 ml) under cooling with ice, and the mixture was stirred at room temperature for 10 minutes. A solution of ethyl bromodifluoroacetate (27.4 g, 135 mmol) in dimethyl sulfoxide (200 ml) was added dropwise to this solution under cooling with ice, and the resultant mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was poured into ice water to conduct extraction with ether. The solvent was distilled out of the resultant extract under reduced pressure. The resultant residue was distilled under reduced pressure to obtain the intended product (12.3 g; yield: 46.0%) as a colorless oil.
Reaction SMILES: [B:1]1([C:10]2[CH:15]=[CH:14][C:13]([CH2:16]Br)=[CH:12][CH:11]=2)[O:5][C:4]([CH3:7])([CH3:6])[C:3]([CH3:9])([CH3:8])[O:2]1.[CH3:18][N:19]1[C:23](=[O:24])[CH2:22][NH:21][C:20]1=[O:25].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:18][N:19]1[C:23](=[O:24])[CH2:22][N:21]([CH2:16][C:13]2[CH:14]=[CH:15][C:10]([B:1]3[O:5][C:4]([CH3:7])([CH3:6])[C:3]([CH3:9])([CH3:8])[O:2]3)=[CH:11][CH:12]=2)[C:20]1=[O:25]
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Reactant: CN1C(=O)CNC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C1=O
Temperature: 45 °C

Procedure:
2-[4-(Bromomethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaboronate (5.00 g, 16.84 mmol), 3-methylimidazolidine-2,4-dione (2.11 g, 18.52 mmol, 1.1 equiv) and potassium carbonate (4.65 g, 33.7 mmol, 2 equiv) were combined and treated with N,N-dimethylformamide (17 mL). The mixture heated for 3 hours at 45° C., cooled to ambient temperature, diluted with ethyl acetate and washed with water (3×) and brine. The organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo to afford the titled compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[CH3:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:30]=1[C:29](=O)[CH2:28][CH2:27]2.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:29]3[C:30]4[C:26](=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:21])[CH2:27][CH2:28]3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: Cc1cccc2c1C(=O)CC2
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: Cc1cccc2c1C(Nc1ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c1)CC2

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 7-methyl-indan-1-one using decaborane yielded a mixture of epimers of the title compound as a colorless waxy solid. MS (ESI): m/z=409.3 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:1][CH2:2][CH2:3][N:4]([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:14])[CH3:13]
Reactant: CN(CCO)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCN(C)c1ccccc1
Temperature: 0 °C

Procedure:
A solution of 74.0 g (0.489 mol) of N-(2-hydroxyethyl)-N-methylaniline in 100 mL of pyridine was treated dropwise with 55 g (0.54 mol) of acetic anhydride. The resulting mixture was heated at reflux for 10 hr, then cooled and poured onto 500 g of ice. The mixture was extracted three times with dichloromethane (3×100 mL), the combined extracts were dried using magnesium sulfate (MgSO4) and the solvent was evaporated. The residue was distilled at reduced pressure, producing 84.2 g of a slightly yellow oil, b.p. 107°-116° C. (0.4 mm).