Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](OCC)=[C:9]([CH3:16])[C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:20][NH2:21].O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:21][N:20]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:9]=2[CH3:16])=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=C(C)C(=O)C(F)(F)F)c1ccc(Cl)cc1
Solvent: O
Solvent: CO
Product: Cc1c(C(F)(F)F)n[nH]c1-c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
A solution of 5.5 g of 4-(4-chlorophenyl)-4-ethoxy-1,1,1-trifluoro-3-methyl-3-buten-2-one in 20 mL of MeOH was slowly treated with 0.70 mL of NH2NH2 and allowed to stir for two hours. Water was added to the reaction mixture and a precipitate formed. The solid was collected by filtration and washed with hexanes to yield 3.87 g of 5-(4-chlorophenyl)-4-methyl-3-(trifluoromethyl)-1H-pyrazole as a white powdery product: mp 139.0° C.; 1HNMR (CDCl3) δ 2.09 (s, 3H), 7.39 (m, 2H), 7.45 (m, 2H, 8.5 Hz), 11.75 (bs, 1H). 19 FNMR (CDCl3) δ -62.34 (3F). Anal. Calcd for C11H8 N2F3Cl: C, 50.69; H, 3,09; N, 10.57. Found: C, 50.68; H, 3.05; N, 10.81.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH2:20]([NH:22][C:23](=O)[O:24]C1C=CC=CC=1)[CH3:21]>CN(C)C=O>[CH2:20]([NH:22][C:23]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)=[O:24])[CH3:21]
Reactant: Nc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Reactant: CCNC(=O)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCNC(=O)n1ccc2cc(Oc3ccnc(N)c3)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.3 %

Procedure:
Sodium hydride (573 mg, 14.32 mmol) was suspended in N,N-dimethylformamide (30 ml) under nitrogen atmosphere. 4-(1H-5-Indolyloxy)-2-pyridinamine (3.00 g, 13.32 mmol, CAS No. 417722-11-3) described in WO 02/32872 was gradually added thereto while stirred at room temperature. After 10 minutes, the reaction mixture was cooled with an ice water bath, and phenyl N-ethylcarbamate (2.31 g, 13.98 mmol) was added. The reaction mixture was heated to room temperature and was stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, then the crystals were precipitated from ethyl acetate, filtered off, and dried under aeration to yield the title compound (3.168 g, 10.69 mmol, 80.3%) as pale brown crystals.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]#[N:24])[CH2:18][CH2:17]1)[CH3:2].N.[H][H]>[Ni].CO>[CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[CH2:15][CH:16]1[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][NH2:24])[CH2:20][CH2:21]1)[CH3:2]
Reactant: CCOCCn1c(CC2CCN(CC#N)CC2)nc2cccnc21
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Product: CCOCCn1c(CC2CCN(CCN)CC2)nc2cccnc21
Yield: 100 %

Procedure:
A mixture of 23.75 parts of 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperidineacetonitrile and 400 parts of methanol, saturated with ammonia was hydrogenated at normal pressure and at room temperature with 6 parts of Raney nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 22.7 parts (100%) of 4-[[3-(2-ethoxyethyl)-3H-imidazo[4,5-b]pyridin-2-yl]methyl]-1-piperidineethanamine as a residue (compound 179).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[C:6]([CH:15]=1)[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8].[CH2:17]([CH:19]1[O:21][CH2:20]1)Br>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH:19]2[O:21][CH2:20]2)=[C:6]([CH:15]=1)[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8]
Reactant: BrCC1CO1
Reactant: COC(=O)CCC(=O)c1cc(Cl)ccc1O
Product: COC(=O)CCC(=O)c1cc(Cl)ccc1OCC1CO1
Yield: 53 %

Procedure:
Methyl 3-(5-chloro-2-hydroxybenzoyl)propionate was reacted with epibromohydrin in a similar manner to the procedure described in Example 1 (ii) to give methyl 3-[5-chloro-2-(2,3-epoxypropoxy)benzoyl]propionate as an oil (53%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[NH:19][CH:20]=[C:21]([CH2:25][CH3:26])[C:22](=[O:24])[N:23]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:27]([F:30])([F:29])[F:28].[CH3:31]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][O:17][C:18]3[N:19]([CH3:31])[CH:20]=[C:21]([CH2:25][CH3:26])[C:22](=[O:24])[N:23]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[C:27]([F:28])([F:30])[F:29]
Reactant: CCc1c[nH]c(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CI
Product: CCc1cn(C)c(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)nc1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.5 %

Procedure:
To the solution of 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-5-ethyl-4(1H)-pyrimidinone (123 mg, 0.280 mmol) and DIPEA (0.490 mL, 2.80 mmol) in DCM (3.0 mL) was added MeI (0.175 mL, 2.80 mmol) dropwise. The reaction mixture was stirred at rt for 3 h. Purification via MDAP then afforded the title compound (40 mg, 29.9% yield). LCMS: rt=3.60 min, [M+H+]=453
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C:13]([CH2:21][CH:22]3[CH2:24][CH2:23]3)([CH2:16][C:17]3([CH3:20])[CH2:19][O:18]3)[O:12][C:11]2=[O:25])[CH3:9])=[CH:4][CH:3]=1.OO>O1CCCC1.COC(C)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([CH2:21][CH:22]3[CH2:24][CH2:23]3)([CH2:16][C:17]([OH:18])([CH3:20])[CH3:19])[O:12][C:11]2=[O:25])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CCC(CC2CC2)(CC2(C)CO2)OC1=O
Agent: OO
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@@](CC2CC2)(CC(C)(C)O)OC1=O
Temperature: 2.5 °C
Reaction time: 1.5 h

Procedure:
LiBHEt3 solution (1 mol/L, 34 mL) was added dropwise to a solution of 3-[(S)-1-(4-bromophenyl)ethyl]-6-(cyclopropylmethyl)-6-[(2-methyloxiran-2-yl)methyl]-1,3-oxazinan-2-one (1.40 g) in tetrahydrofuran (200 mL) at 0° C. The resulting solution was stirred at 2-3° C. for 1.5 h and then at room temperature for another 3 h. 30% aqueous H2O2 solution (30 mL) was added dropwise at 0° C. and the mixture was diluted with tert-butyl methyl ether (200 mL). The mixture was washed with 3% aqueous Na2S2O3 solution and saturated aqueous NaHCO3 solution (4×100 mL) and dried (Na2SO4). The solvent was evaporated and the residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate 1:1→3:1) to afford the title compound; besides, the diastereomer, 3-[(S)-1-(4-bromophenyl)ethyl]-(R)-6-(cyclopropylmethyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one was also isolated (0.40 g, 29% yield). Yield: 0.55 g (40% of theory).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(C)([O-])C.[K+].[F:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24]Br>C1COCC1.CN(C=O)C>[C:4]([O:3][C:1]([NH:8][CH:9]([CH2:10][O:11][CH2:24][C:23]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:22]=1[F:21])[C:12]([OH:14])=[O:13])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Reactant: Fc1ccc(CBr)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(COCc1ccc(F)cc1F)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
To a solution of N-Boc-(D)-serine (452 g, 2.2026 mol) in a mixture of THF (7 L) and DMF (3 L) at about 0° C. was added potassium tert-butoxide solution (515.8 g, 4.5963 mol). The reaction mixture was stirred at about 0° C. for about 30 min., then 2.4-difluorobenzyl bromide (456.5 g, 2.2051 mol) was added. After warming to room temperature, the reaction mixture was concentrated in vacuo to remove the THF. The reaction mixture was partitioned between 4.5 L H2O and 4.5 L IPE. The layers were saparated and the pH of the aqueous layer was adjusted with 1 N HCl to about 3. The aqueous layer was extracted twice with 4 L each of IPE. The organic solution was dried over Na2SO4, and concentrated in vacuo to yield a yellow waxy solid (518.0 g, yield: 70.9%). 1H-NMR (CDCl3) δ 1.44 (s, 9H), 0.73 (m, 1H), 3.94 (d, 1H). 4.44 (br s, 1H), 4.54 (s, 2H), 5.34 (m, 1H), 6.78 (m, 1H), 0.84 (m, 1H), 7.30 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-].Cl>[N+](C)([O-])=O.CCOCC>[CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCOc2ccccc21
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: C[N+](=O)[O-]
Product: CC(=O)c1ccc2c(c1)C(C)(C)CCO2
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a stirred solution of 7.94 g (48.9425 mmol) of 4,4-dimethylchroman in 70 ml of nitromethane was added under argon 4.0 g (50.96 mmol) of acetyl chloride followed by 6.8 g (51 mmol) of aluminum chloride. This was stirred at room temperature for 5.5 hours and then cooled in an ice bath and treated slowly with 70 ml 6N hydrogen chloride. The resultant mixture was stirred at room temperature for 10 minutes, then treated with 100 ml ether and the organic layer separated. The organic layer was washed with water, saturated NaHCO3 and saturated NaCl solutions and dried (MgSO4). Solvent was removed in vacuo and the residue purified by flash chromatography (silica; 10% ethyl acetate in hexanes). This was followed by kugelrohr distillation (95°-100° C.; 0.15 mm) to give the title compound as a colorless oil.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:30][C:29]([CH:31]=O)=[CH:28][C:9]=3[N:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][SiH2:20][C:21]([CH3:27])([CH3:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[CH:14]=3)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([CH2:31][C:29]2[S:30][C:8]3[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[N:12][C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([O:19][SiH2:20][C:21]([CH3:26])([CH3:27])[C:22]([CH3:25])([CH3:23])[CH3:24])[CH:14]=4)=[N:10][C:9]=3[CH:28]=2)[CH2:36][CH2:35]1
Reactant: CC(C)(C)C(C)(C)[SiH2]Oc1cccc(-c2nc(N3CCOCC3)c3sc(C=O)cc3n2)c1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN1CCN(Cc2cc3nc(-c4cccc(O[SiH2]C(C)(C)C(C)(C)C)c4)nc(N4CCOCC4)c3s2)CC1
Reaction time: 72 h
Yield: 88 %

Procedure:
A mixture of 4-morpholin-4-yl-2-[3-(1,1,2,2-tetramethyl-propylsilanyloxy)-phenyl]-thieno[3,2-d]pyrimidine-6-carbaldehyde (6.67 g, 14.66 mmol), N-methylpiperazine (2.11 mL, 1.3 equivalents) and acetic acid (838 μL, 1.0 eq.) was stirred in 1,2-dichloroethane (70 mL) at room temperature. To this was added sodium triacetoxyborohydride (3.42 g, 1.1 equivalents) and the reaction mixture was stirred for 3 days. The reaction mixture was then quenched with aqueous sodium bicarbonate solution, extracted exhaustively with chloroform, dried (MgSO4), and the solvent removed in vacuo to yield a yellow oil. This was purified using flash chromatography (silica, ethyl acetate to ethyl acetate/methanol) to yield 6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-2-[3-(1,1,2,2-tetramethyl-propylsilanyloxy)-phenyl]-thieno[3,2-d]pyrimidine (6.95 g, 88%).
Reaction SMILES: N#N.[O:3]=[C:4]([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:10][CH:11]=[C:12]([C:14](O)=[O:15])[N:13]=1.CN(C=O)C.C(Cl)(=O)C([Cl:26])=O>C1(C)C=CC=CC=1>[O:3]=[C:4]([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[O:10][CH:11]=[C:12]([C:14]([Cl:26])=[O:15])[N:13]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)CCCCc1nc(C(=O)O)co1
Agent: N#N
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(=O)CCCCc1nc(C(=O)Cl)co1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of 2-(5-oxo-hexyl)-oxazole-4-carboxylic acid (403 mg, 1.91 mmol) in toluene (19 mL) was treated at 0° C. with a drop of DMF followed by oxalyl chloride (0.20 mL, 2.29 mmol) and the resulting yellow solution was stirred at rt for 1 h. The solvent was then removed under reduced pressure (coevaporation with toluene) to give 2-(5-oxo-hexyl)-oxazole-4-carbonyl chloride as a brown oil.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:9][CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=1>CN(C)C=O>[CH:3]1([CH2:9][CH2:10][O:11][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[C:15]([C:21]([F:22])([F:24])[F:23])[CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Reactant: OCCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCC2CCCCC2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75.6 %

Procedure:
Sodium hydride (343.2 mg, 8.58 mmol, 60% dispersed oil) was slowly added to cyclohexaneethanol (1 g, 7.8 mmol) dissolved in 30 ml of dried dimethylformamide under nitrogen at room temperature while stirring. The mixture was further stirred at room temperature for 30 minutes. Then, 4-fluoro-2-(trifluoromethyl)benzaldehyde (1.2 g, 7.8 mmol) dissolved in dried dimethylformamide was added thereto over 10 minutes and stirred at room temperature for 18 hours until the initial product disappeared. Subsequently, ice water was added thereto, and the resulting mixture was extracted with ethyl acetate and water. The organic layer was washed with water several times, dried with anhydrous magnesium sulfate, filtered and solvent-evaporated. The residual oil was chromatographed on the silica gel column (hexane:ethyl acetate-20:1) to afford the intermediate, 4-(2-cyclohexylethoxy)-2-(trifluoromethyl)benzaldehyde (1.77 g, yield: 75.6%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][C@H:28]1[C:33]([OH:35])=[O:34].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:27]2[CH2:32][CH2:31][O:30][CH2:29][C@H:28]2[C:33]([OH:35])=[O:34])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)[C@@H]1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C1=C(CN2CCOC[C@H]2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.7 %

Procedure:
A mixture of ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (7.7 g, 15.3 mmol), (S)-morpholine-3-carboxylic acid (2 g, 15.3 mmol) and potassium carbonate (4.23 g, 30.6 mmol) in anhydrous ethanol (154 mL) was stirred at 25° C. for 16 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=25/1) to give the title compound as a yellow solid (7.26 g, 86%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[C:19]([F:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:15]=2[F:24])(=[O:13])=[O:12])=[CH:6][CH:5]=1)[CH3:3].[CH3:25][Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH3:3][N:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:25])[S:11]([C:14]2[C:15]([F:24])=[C:16]([F:23])[C:17]([F:22])=[C:18]([F:21])[C:19]=2[F:20])(=[O:13])=[O:12])=[CH:6][CH:5]=1)[CH3:1]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CN(C)c1ccc(NS(=O)(=O)c2c(F)c(F)c(F)c(F)c2F)cc1
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)c1ccc(N(C)S(=O)(=O)c2c(F)c(F)c(F)c(F)c2F)cc1
Reaction time: 0.17 h
Yield: 60 %

Procedure:
4-(N,N-Dimethylamino)-1-(pentafluorophenylsulfonamido)benzene (100 mg, 0.273 mmol) was dissolved in dry THF (2.5 mL) and to the system was added under N2 at room temperature a 1M solution of lithium bis(trimethylsilyl)amide (0.274 mL). The reaction mixture was stirred for 10 min followed by addition of Mel (65 mg, 0.028 mL). The reaction mixture was stirred overnight, the solvent was evaporated under reduced pressure and the crude product purified by HPLC using silica as the stationary phase and eluting with 20% EtOAc/Hex (v/v) to afford the product as a white solid in 60% yield (62 mg). EI m/z: 380(35, M+), 149(100). 1H NMR (CD3OD) 7.05(d, J=8 Hz, 2H), 6.68(d, J=8 Hz, 2H), 3.33(s, 3H) 2.93(s, 6H). Anal. calcd. for C15H13F5SO2N2 : C, 47.37, H, 3.45, N 7.37. Found: C, 47.37, H, 3.49, N, 7.32.
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]4[C:22]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][C:29]6[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=6)[CH:27]=5)=[CH:21][N:20]([S:36]([C:39]5[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=5)(=[O:38])=[O:37])[C:17]4=[N:18][CH:19]=3)=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:46][C@H:47]1[CH2:49][O:48]1.CCN(C(C)C)C(C)C>C(O)C>[F:35][C:31]1[CH:30]=[C:29]([CH:34]=[CH:33][CH:32]=1)[CH2:28][N:26]1[CH:27]=[C:23]([C:22]2[C:16]3[C:17](=[N:18][CH:19]=[C:14]([C:11]4[CH:12]=[CH:13][C:8]([N:1]5[CH2:7][CH2:6][CH2:5][N:4]([CH2:46][C@@H:47]([OH:48])[CH3:49])[CH2:3][CH2:2]5)=[CH:9][CH:10]=4)[CH:15]=3)[N:20]([S:36]([C:39]3[CH:40]=[CH:41][C:42]([CH3:43])=[CH:44][CH:45]=3)(=[O:38])=[O:37])[CH:21]=2)[CH:24]=[N:25]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCCNCC5)cc4)cnc32)cc1
Reactant: C[C@H]1CO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCCN(C[C@H](C)O)CC5)cc4)cnc32)cc1
Yield: 91.5 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 5-(4-(1,4-diazepan-1-yl)phenyl)-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.161 mmol) was alkylated using (S)-2-methyloxirane (14 mg, 0.241 mmol), DIPEA (62 mg, 0.48 mmol) and ethanol (3 mL) to get 100 mg (91.7% yield) of the titled compound. MS: m/z=679.6 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11](O)(=[O:15])[C:12](O)=[O:13]>Cl>[I:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[C:5]=1[NH:9][C:11](=[O:15])[C:12](=[O:13])[NH:10]2
Reactant: O=C(O)C(=O)O
Reactant: Nc1cc(Cl)cc(I)c1N
Agent: Cl
Product: O=c1[nH]c2cc(Cl)cc(I)c2[nH]c1=O
Temperature: 25 °C
Yield: 74.2 %

Procedure:
Synthesis of 5-1-do-7-chloro-1,4-dihydro-2,3-quinoxalinedione: The procedure of Foged, C. and Journal, P. (J. of Lab. Compd. and Radiopharmac. XXXI (5):365-373 (1992)) was adapted. To a stirred mixture of 4-chloro-6-iodo-1,2-phenylenediamine (366 mg, 1.253 mMol) in 2N HCl (30 mL) was added oxalic acid (160 mg, 1.269 mMol, used as received) in one portion. The mixture was refluxed at 120°-5° C. for 3 h, then cooled to room temperature overnight. The mixture was centrifuged and the liquid layer was removed. The red solid was washed twice with cold water (2×2 mL),. collected by filtration, and dried at 60° C. with reduced pressure for 2 h, giving 300 mg of crude 5-iodo-7-chloro-1,4-dihydro-2,3-quinoxalinedione (74%), as a red powder containing some impurities (by NMR). A 300 mg sample of crude product was dissolved in 1N NaOH (10 mL). Some insoluble material was removed by filtration, and the filtrate was then acidified to pH=6, giving 260 mg of purer product. Crystallization from DMSO/H2O, gave 169 mg of pure product (42%), as red microcrystals, mp: >350° C. (dec. from 295° C.). IR (KBr, cm-1) 3443, 3212, 1750, 1706, 1606, 1587, 1393. NMR (1H DMSO-d6): δ7.133 (d, 1H, J=1.5 Hz); 7.628 (d, 1H, J=1.5 Hz); 10.386 (d, 1H, J=1.5 Hz); 12.015 (d, 1H, J=1.8 Hz). HRMS: calcd for C8H4N2O2ClI (M+) m/z: 321.9004; found: 321.8995. Potency relative to DCK: 28.4%.
Reaction SMILES: [OH-].[K+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]([O:17]CC)=[O:16])=[CH:9]2)([O-:5])=[O:4].[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:22]=1[CH2:23]Cl.Cl>CS(C)=O.O>[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:22]=1[CH2:23][N:11]1[C:12]2[C:8](=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:14][CH:13]=2)[CH:9]=[C:10]1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Reactant: Fc1cccc(F)c1CCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc([N+](=O)[O-])ccc2n1Cc1c(F)cccc1F
Reaction time: 0.5 h

Procedure:
Under an atmosphere of argon, 5.49 g (83.2 mmol, 85% pure) of potassium hydroxide (powder) are initially charged in 110 ml of dimethyl sulphoxide, 6.43 g (27.5 mmol) of ethyl 5-nitro-1H-indole-2-carboxylate (A. Guy, J.-P. Guetté, Synthesis 1980, 222–223) are added at RT and the mixture is stirred for 30 min. With ice-cooling, at an internal temperature of 5–10° C., 2,6-difluorobenzyl chloride (10.0 g, 61.5 mmol) is then added dropwise over a period of 15 min, and the mixture is stirred at RT for 16 h. For work-up, the mixture is poured into 500 ml of water and acidified with dil. hydrochloric acid and the precipitated solid is filtered off with suction and pre-purified chromatographically on silica gel 60 (mobile phase gradient dichloromethane→dichloromethane-methanol 3:1). The resulting product is recrystallized from ethanol. This gives 4.33 g (47% of theory) of a pale-yellow crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:44])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[C:40]([O:41][CH3:42])=[CH:39][C:34]([C:35]([O:37]C)=[O:36])=[C:33]([F:43])[CH:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.C1COCC1.[OH-].[Na+]>CO>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@@:12]2([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10][C@@H:9]([C:28]([NH:30][C:31]3[C:40]([O:41][CH3:42])=[CH:39][C:34]([C:35]([OH:37])=[O:36])=[C:33]([F:43])[CH:32]=3)=[O:29])[C@@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:44])=[C:16]([F:22])[CH:17]=1
Reactant: COC(=O)c1cc(OC)c(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)c(F)cc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Temperature: 40 °C
Reaction time: 2 h

Procedure:
In a 25 mL round-bottomed flask, methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-2-fluoro-5-methoxybenzoate (80 mg, 123 μmol, Eq: 1.00) was combined with THF (2 ml) and MeOH (4 ml) at 45° C. to give a colorless solution. 1 N NaOH (0.5 ml, 1.00 mmol, Eq: 8.11) was added. The reaction mixture was stirred at 40° C. for 2 hr.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[C:23](O)=[O:24].N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:23]([C:14]3[CH:15]=[CH:16][C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:13]=3)=[O:24])[CH2:3]1)[CH2:9]2
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc2ccccc2c1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 2-naphthoic acid according to methods A and C. 1H NMR (300 MHz, methanol-d4) δ ppm 2.08-2.34 (m, 5H), 2.51 (s, 2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H), 7.51-7.67 (m, 2H), 7.85-8.07 (m, 4H), 8.46 (s, 1H). MS (DCI/NH3) m/z 308. Anal. Calculated for C20H22N2O.HCl: C, 70.06; H, 6.76; N, 9.14. Found: C, 69.72; H, 6.58; N, 8.03.