Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=[CH:11][C:3]=1[C:4]([N:6]([CH2:9]C)CC)=[O:5].NC1C([C:31](NC)=[O:32])=C(OC)C(Br)=CC=1.NC1C=CC(Br)=CC=1C(N(CC)CC)=O>>[NH2:1][C:2]1[C:3]([C:4]([NH:6][CH3:9])=[O:5])=[C:11]([O:32][CH3:31])[C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=[CH:13][CH:14]=1
Reactant: CNC(=O)c1c(N)ccc(Br)c1OC
Reactant: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Agent: CCN(CC)C(=O)c1cc(Br)ccc1N
Product: CNC(=O)c1c(N)ccc(-c2cnn(CCCO)c2)c1OC

Procedure:
Prepared analogously to Compound 3C substituting 6-amino-3-bromo-2-methoxy-N-methylbenzamide (Compound 30D) for 2-amino-5-bromo-N,N-diethylbenzamide (Compound 3D). MS (ESI): m/z=305.23 [M+H]+. HPLC: tR=2.48 min (ZQ3: polar—5 min).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:5][CH:4]=1.[OH:23][C:24]1[C:25]([CH3:37])=[C:26]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:7]1[N:8]=[C:3]([CH2:2][O:23][C:24]2[C:25]([CH3:37])=[C:26]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:27]=[CH:28][CH:29]=2)[CH:4]=[CH:5][C:6]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22]
Reactant: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Reactant: CCOC(=O)CCc1cccc(O)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1C
Yield: 86.9 %

Procedure:
To a solution of 6-(chloromethyl)-2-(2,2-dimethylpropyl)-3-(2-fluoro-5-methoxyphenyl)pyridine (300 mg) in acetonitrile (20 mL) were added ethyl 3-(3-hydroxy-2-methylphenyl)propanoate (197 mg) and cesium carbonate (511 mg), and the mixture was heated under reflux for 15 hr. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (400 mg) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:18][C@H:17]3[N:13]([CH2:14][CH2:15][CH2:16]3)[C:12]3[N:19]=[C:20]([S:23][CH3:24])[N:21]=[CH:22][C:11]=3[C:10]2=[O:25])[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.[NH2:27][OH:28].[CH:29](N(CC)C(C)C)([CH3:31])[CH3:30].C(Cl)(=O)CC>C(O)C.C(OCC)(=O)C>[CH2:29]([C:31]1[O:28][N:27]=[C:1]([C:3]2[CH:4]=[C:5]([N:9]3[CH2:18][C@H:17]4[N:13]([CH2:14][CH2:15][CH2:16]4)[C:12]4[N:19]=[C:20]([S:23][CH3:24])[N:21]=[CH:22][C:11]=4[C:10]3=[O:25])[CH:6]=[CH:7][CH:8]=2)[N:2]=1)[CH3:30]
Reactant: NO
Reactant: CCN(C(C)C)C(C)C
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C#N)c1)C2=O
Agent: CCC(=O)Cl
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1nc(-c2cccc(N3C[C@@H]4CCCN4c4nc(SC)ncc4C3=O)c2)no1
Temperature: 70 °C
Reaction time: 3 h
Yield: 69.8 %

Procedure:
(S)-5-(3-Cyanophenyl)-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (300 mg, 0.854 mmol) obtained in Step 1 was dissolved in ethanol (10 mL), and the mixture was stirred at 70° C. for 3 hours after adding hydroxylamine hydrochloride (65.0 mg, 0.939 mmol) and N,N-diisopropylethylamine (0.164 mL, 0.939 mmol). The mixture was concentrated, diluted with chloroform, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in pyridine (4 mL), and stirred therein at 90° C. for 5 hours after adding propionyl chloride (0.103 mL, 1.19 mmol). The mixture was cooled to room temperature, and diluted with ethyl acetate. The organic layer was washed with 1 mol/L hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give (S)-5-[3-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl]-9-methylthio-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (252 mg, 70%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[OH:28][CH2:29][C:30]([NH:33][S:34]([C:37]1[S:38][C:39]([Cl:43])=[C:40]([NH2:42])[CH:41]=1)(=[O:36])=[O:35])([CH3:32])[CH3:31]>>[Cl:43][C:39]1[S:38][C:37]([S:34](=[O:36])(=[O:35])[NH:33][C:30]([CH3:32])([CH3:31])[CH2:29][OH:28])=[CH:41][C:40]=1[NH:42][C:25]([C:24]1[CH:23]=[N:22][N:15]2[C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:12]([C:4]3[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:9])[F:10])=[C:2]([CH3:1])[CH:3]=3)=[N:13][C:14]=12)=[O:26]
Reactant: CC(C)(CO)NS(=O)(=O)c1cc(N)c(Cl)s1
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cc(S(=O)(=O)NC(C)(C)CO)sc4Cl)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.8) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (example B.2) according to general procedure II. Yellow solid. MS (ISP) 654.2 [(M−H)−]; mp 207° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:10][C:9]([CH2:33][C:34]#[N:35])([N:11]3[CH:15]=[C:14]([C:16]4[C:17]5[CH:24]=[CH:23][N:22](COCC[Si](C)(C)C)[C:18]=5[N:19]=[CH:20][N:21]=4)[CH:13]=[N:12]3)[CH2:8]2)[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[N:45]([CH:48]([CH3:50])[CH3:49])=[C:46]=[O:47].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:34]([CH2:33][C:9]1([N:11]2[CH:15]=[C:14]([C:16]3[C:17]4[CH:24]=[CH:23][NH:22][C:18]=4[N:19]=[CH:20][N:21]=3)[CH:13]=[N:12]2)[CH2:10][N:7]([CH:4]2[CH2:3][CH2:2][N:1]([C:46]([NH:45][CH:48]([CH3:50])[CH3:49])=[O:47])[CH2:6][CH2:5]2)[CH2:8]1)#[N:35]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Reactant: CC(C)N=C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)N1CCC(N2CC(CC#N)(n3cc(-c4ncnc5[nH]ccc45)cn3)C2)CC1
Reaction time: 2 h

Procedure:
To a solution of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (0.075 g, 0.15 mmol, prepared as described in Example 1, Step H, except worked up to provide the free base) in methylene chloride (2 mL) was added N,N-diisopropylethylamine (0.026 mL, 0.15 mmol) followed by 2-isocyanatopropane (20 μL, 0.2 mmol, Aldrich). The reaction was continued for 2 hours. The crude product was deprotected by the addition of 1 mL TFA to the solution, which was stirred for 1 hour and evaporated. The deprotection was completed by stirring with ethylenediamine (0.2 mL) in methanol for 30 minutes. The product was purified by preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Fractions containing desired product were frozen and lyophilized. Yield: 0.025 g (37%); LC-MS: 448.2 (M+H)+. 1H NMR (300 MHz, CDCl3): δ 10.21 (br s, 1H), 8.85 (s, 1H), 8.41 (s, 1H), 8.32 (s, 1H), 7.41 (dd, 1H), 6.79 (dd, 1H), 4.22 (d, 1H), 4.04-3.87 (m, 1H), 3.81-3.69 (m, 4H), 3.61 (d, 2H), 3.40 (s, 2H), 3.00-2.86 (dq, 2H), 2.44-2.31 (m, 1H), 1.76-1.64 (m, 2H), 1.40-1.22 (m, 2H), 1.15 (d, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH2:19][OH:20])(=[O:11])=[O:10].CS(C)=O.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[O:16][CH2:17][CH2:18][CH:19]=[O:20])(=[O:11])=[O:10]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2c(C)nn(C)c2Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2c(C)nn(C)c2Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.5 %

Procedure:
To 227 mg (0.660 mmol) of 3-[3-(5-chloro-1,3-dimethyl-pyrazole-4-sulfonyloxy)-5-methylphenoxy]propanol, as prepared in the preceding step, in dichloromethane (2 mL) containing 61 μL (0.79 mmol) of anhydrous dimethyl sulfoxide and 275 μL (1.58 mmol) of N,N-diisopropylethylamine was added 124 mg (0.78 mmol) of sulfur trioxide pyridine complex. The reaction mixture was stirred at ambient temperature for 60 min and then purified by flash chromatography (dichloromethane then 20% ethyl acetate/dichloromethane) to give 75 mg of the title compound as an unstable oil. TLC clearly showed 3-(5-chloro-1,3-dimethylpyrazole-4-sulfonyloxy)-5-methylphenol as the major byproduct. 1H-NMR (300 MHz, CDCl3) δ 9.85 (t, 1H, J=1.5 Hz), 6.64 (s, 1H), 6.51-6.57 (m, 2H), 6.46 (t, 1H, J=2 Hz), 6.42 (t, 1H, J=2 Hz), 4.23 (t, 2H, J=6 Hz), 3.82 (s, 3H), 2.89 (td, 2H, J=1, 6 Hz), 2.29 (s, 3H), 2.26 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10](=[O:21])[CH:11]([CH3:20])[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.[F:23][C:24]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:25]=1[NH2:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:26]([C:25]2[C:24]([F:23])=[CH:30][CH:29]=[CH:28][C:27]=2[F:31])[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:11]([CH3:20])[C:10](=[O:21])[CH:9]=1
Reactant: Nc1c(F)cccc1F
Reactant: CC(C(=O)CC(=O)c1ccccc1Cl)C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: Cc1c(-c2ccccc2)n(-c2c(F)cccc2F)c(-c2ccccc2Cl)cc1=O
Yield: 24.5 %

Procedure:
In 200 ml of xylene were dissolved 6.3 g (0.020 mole) of 5-(2-chlorophenyl)-2-methyl-1-phenyl-1,3,5-pentanetrione, 20.0 g (0.155 mole) of 2,6-difluoroaniline, 4,6 g (0.024 mole) of para-toluenesulfonic acid and 50.0 g of Molecular Sieves 5A, followed by reflux for 8 hours. Solid matter was filtered off from the reaction mixture and 300 ml of chloroform was added to the filtrate. The mixture obtained was washed first with 50 ml of 10% aqueous solution of sodium hydroxide. After washing the chloroform layer further with water, it was dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was subjected to column chromatography (eluent: ethyl acetate) to afford crystals. The crystals were recrystallized from a 2:1 mixed solvent of acetone and hexane, thereby yielding 2.0 g of 6-(2-chlorophenyl)-1-(2,6-difluorophenyl)-3-methyl-2-phenyl-4(1H)-pyridinone having a melting point of 213°-215° C.
Reaction SMILES: [NH2:1][C:2]1[C:31](I)=[CH:30][C:5]([CH2:6][C@H:7]2[C@H:15]3[C@@H:11]([N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:19]=4)C(=O)[O:14]3)[CH2:10][S:9](=[O:29])(=[O:28])[CH2:8]2)=[CH:4][C:3]=1[F:33].[NH:34]1[CH2:37][CH2:36][C:35]1=[O:38]>>[NH2:1][C:2]1[C:3]([F:33])=[CH:4][C:5]([CH2:6][C@H:7]2[C@H:15]([OH:14])[C@@H:11]([NH:12][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([CH3:27])([CH3:25])[CH3:26])[CH:19]=3)[CH2:10][S:9](=[O:28])(=[O:29])[CH2:8]2)=[CH:30][C:31]=1[N:34]1[CH2:37][CH2:36][C:35]1=[O:38]
Reactant: CC(C)(C)c1cccc(CN2C(=O)O[C@H]3[C@H](Cc4cc(F)c(N)c(I)c4)CS(=O)(=O)C[C@@H]32)c1
Reactant: O=C1CCN1
Product: CC(C)(C)c1cccc(CN[C@H]2CS(=O)(=O)C[C@@H](Cc3cc(F)c(N)c(N4CCC4=O)c3)[C@@H]2O)c1

Procedure:
The title compound was prepared in analogous manner as described for example 4 from (3aR*,7S*,7aS*)-7-(4-amino-3-fluoro-5-iodo-benzyl)-3-(3-tert-butyl-benzyl)-5,5-dioxo-hexa-hydro-1-oxa-5lambda*6*-thia-3-aza-inden-2-one (example 1k) and azetidin-2-one: HPLC RtC=2.99 min; ESIMS [M+H]+=504; NMR (400 MHz, CDCl3+0.5% D2O): δ 7.65 (m, 2H), 7.56 (t, 1H), 7.47 (m, 3H), 6.30 (m, 2H), 4.20 (q, 2H), 3.80 (m, 2H), 3.59 (m, 2H), 3.35, (m, 2H), 3.18 (m, 2H), 2.95 (m, 1H), 2.85 (m, 1H), 2.75 (m, 2H), 1.30 (s, 9H).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[I:7][C:8]1[N:15]2[C:11]([S:12][C:13]([S:16][CH3:17])=[N:14]2)=[N:10][CH:9]=1>CO.O>[I:7][C:8]1[N:15]2[C:11]([S:12][C:13]([S:16]([CH3:17])=[O:1])=[N:14]2)=[N:10][CH:9]=1
Reactant: O=S([O-])OO
Reactant: CSc1nn2c(I)cnc2s1
Agent: [K+]
Solvent: CO
Solvent: O
Product: CS(=O)c1nn2c(I)cnc2s1
Reaction time: 1 h

Procedure:
Oxone(r), monopersulfate compound (263.99 mg; 0.43 mmol; 1.00 eq.) was added to a solution of 5-iodo-2-methylsulfanyl-imidazo[2,1-b][1,3,4]thiadiazole (127.60 mg; 0.43 mmol; 1.00 eq.) in MeOH (1.50 ml) and water (1.50 ml) at room temperature. After 1 h, the reaction was finished. Water was added and the reaction was extracted 2 times with dichloromethane. The combined organic extracts were dried over magnesium sulphate, filtered and concentrated to give 106.9 mg of the desired product as a beige solid.
Reaction SMILES: [NH3:1].[CH3:2][C:3]1([CH3:18])[CH2:14][CH:13]=[CH:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH:6]([CH:15]([CH3:17])[CH3:16])[N:5]=[CH:4]1.[H][H]>[Ni].[OH-].[Na+]>[CH:15]([CH:6]([NH2:1])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:3]([CH3:18])([CH3:2])[CH2:4][NH2:5])([CH3:17])[CH3:16]
Reactant: CC(C)C1CC=CCCC=CCC(C)(C)C=N1
Reactant: N
Reactant: [H][H]
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: CC(C)C(N)CCCCCCCCC(C)(C)CN
Temperature: 175 °C

Procedure:
75 g of a 25% aqueous ammonia solution are placed together with 10 g of Raney nickel and 20 ml of 1N aqueous NaOH as well as 52.2 g (0.2 mol) of 3,3-dimethyl-12- isopropyl-1-aza-1,5,9-cyclododecatriene into an autoclave with magnetic stirrer. After the reaction mixture has been heated to 175° C., hydrogen gas is injected up to a total pressure of 50 bar. After a reaction time of 9 hours, the mixture is cooled and distilled. There is obtained 65% of the theoretical yield of 1-isopropyl-10,10-dimethyl-1,11-diaminoundecane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2Br)[CH:21]=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)CCC>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)[CH:21]=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc3ccncc3cc2Br)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc3ccncc3cc2-c2cccs2)CC1

Procedure:
using compound 13 and tributyl-thiophen-2-yl-stannane as starting materials.
Reaction SMILES: [C-:1]#[N:2].[K+].Cl.[NH2:5][C:6]1[N:11]=[C:10]([OH:12])[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20]Cl)=[CH:16][CH:15]=2)=[C:8]([CH3:22])[N:7]=1>CN(C=O)C.CS(C)=O>[NH2:5][C:6]1[N:11]=[C:10]([OH:12])[C:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:1]#[N:2])=[CH:16][CH:15]=2)=[C:8]([CH3:22])[N:7]=1
Reactant: Cc1nc(N)nc(O)c1Cc1ccc(CCl)cc1
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: Cc1nc(N)nc(O)c1Cc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Potassium cyanide (2 g) was added to a solution of the product from step (ii) in DMF (20 ml) and DMSO (10 ml) and the mixture stirred at rt for 18 h. The mixture was flushed with nitrogen for 20 min, then diluted with brine (80 ml), stirred for 10 min and the precipitate filtered, washed with water then ether and dried to afford the subtitle compound, 2.46 g.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14][C:15]([CH3:17])=[O:16].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([CH:43]=[CH:44][CH:45]=[O:46])=[C:31]([CH:40]([CH3:42])[CH3:41])[S:32][C:33]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:25][CH:24]=1>C1COCC1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([CH:43]=[CH:44][CH:45]([OH:46])[CH2:17][C:15](=[O:16])[CH2:14][C:13]([O:19][CH2:20][CH3:21])=[O:18])=[C:31]([CH:40]([CH3:42])[CH3:41])[S:32][C:33]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)c1sc(-c2ccccc2)c(-c2ccc(F)cc2)c1C=CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CC(=O)CC(O)C=Cc1c(C(C)C)sc(-c2ccccc2)c1-c1ccc(F)cc1
Reaction time: 1 h
Yield: 121.5 %

Procedure:
To a solution of 2.6 g of diisopropylamine in 30 ml of THF at 0° was added 1.67 g of n-butyllithium (1.16 m in hexane). Then a solution of 1.7 g of ethyl acetoacetate in 10 ml of THF was added dropwise. After stirring at 0° for 1 hour, the mixture was cooled to -20°, then a solution of 3.3 g of the title product of Step 3, above, in 20 ml of THF was added dropwise. The reaction was stirred at -20° for 1 hour. Then was quenched with saturated aqueous ammonium chloride solution. The mixture was extracted with MTBE and then methylene chloride and the organic solutions were combined and dried, adn the solvent evaporated under reduced pressure to give 5.5 g of crude title product of this step as an oil. This was used without further purification in the next step (Step 5).
Reaction SMILES: CON(C)[C:4]([CH:6]1[CH2:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:7]1)=[O:5].[CH3:23][Mg]Br>C1COCC1>[C:4]([CH:6]1[CH2:7][N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=2)[C:9](=[O:11])[CH2:10]1)(=[O:5])[CH3:23]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)C1CC(=O)N(c2cccc(C(F)(F)F)c2)C1
Solvent: C1CCOC1
Product: CC(=O)C1CC(=O)N(c2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.5 %

Procedure:
To a stirred solution of 5-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidine-3-carboxylic acid methoxy-methyl-amide (0.6 g, 1.89 mmol) in THF (6 mL) was added methylmagnesium bromide (1.6 ml, 4.74 mmol, 3.0M in ether) drop wise over a period of 10 min at 0° C. The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was quenched with saturated ammonium chloride solution (2 ml) and extracted with ethyl acetate (2×15 ml). The combined organic layer was washed with saturated brine solution (25 ml). The organic layer was dried over Na2SO4, evaporated to obtain 4-Acetyl-1-(3-trifluoromethyl-phenyl)-pyrrolidin-2-one as a brown oil (0.5 g, 97%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].[CH3:13]I.O>CN(C)C=O>[Cl:3][C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: CI
Reactant: O=Cc1ccc(O)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C=O)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To suspension of sodium hydride (2.6 g; 62.6% in oil) in dimethylformamide (80 ml), a solution of 2-chloro-4-hydroxybenzaldehyde (10.0 g) in dimethylformamide (50 ml) was dropped over 15 minutes. The mixture was stirred for 30 minutes. Methyl iodide (4.2 ml) was dropped into the reaction mixture over 10 minutes at 0° C., and stirred for 1 hour. The reaction mixture was poured into water and extracted with hexane/ethyl:acetate (1:1) The organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the title compound (10.7 g) having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[CH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=3)[C:10]2=[O:13])=[CH:5][CH:4]=1>O1CCCC1.CO.[Pd]>[NH2:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]1=[O:13]
Reactant: COc1ccc2c(c1)C(=O)C(=Cc1cccc([N+](=O)[O-])c1)CC2
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1)C(=O)C(Cc1cccc(N)c1)CC2
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
A mixture of 626 mg (2.02 mmol) of the product of Example 28 and 125 mg of 10% Pd/C in 15 mL tetrahydrofuran and 15 mL CH3OH was hydrogensted on a Parr (trademark) Hydrogenator under 25 psi H2 at room temperature. After 30 minutes, the reaction mixture was filtered through diatomaceous earth [Celite (trademark)], the filtrate concentrated in vacuo, and the residue purified by silica gel chromatography (5% ethyl acetate-CH2Cl2) to yield 369 mg of pure product, a yellow solid. m.p.: 159°-161° C. MS (LSIMS): 282 M+H, 155 Base; 1H NMR (AC 300, CDCl3): δ3.84 (s, 3H); 3.64 (br s, 2H, NH2); IR (cm31 1): 3360, 6450, 1665. Analysis calculated: C 76.85, H 6.81, N 4.98%; found: C 75.94, H 6.66, N 4.77%.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]([NH:32][S:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:29]=[N:30][CH:31]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.C(OCC)C>[CH3:17][N:15]1[CH:16]=[C:12]([C:8]2[CH:7]=[N:6][C:5]3[C:10]([N:9]=2)=[CH:11][C:2]([C:26]2[CH:27]=[C:28]([NH:32][S:33]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)(=[O:34])=[O:35])[CH:29]=[N:30][CH:31]=2)=[CH:3][CH:4]=3)[CH:13]=[N:14]1
Reactant: Cn1cc(-c2cnc3ccc(Br)cc3n2)cn1
Reactant: CC1(C)OB(c2cncc(NS(=O)(=O)c3ccccc3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cn1cc(-c2cnc3ccc(-c4cncc(NS(=O)(=O)c5ccccc5)c4)cc3n2)cn1
Temperature: 100 °C
Yield: 30.4 %

Procedure:
A mixture of 7-bromo-2-(1-methyl-1H-pyrazol-4-yl)quinoxaline (5.98 mmol), N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (6.78 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.18 mmol) in 2M aqueous sodium carbonate (15 mL) and 1,4-dioxane (40 mL) was heated at 100° C. for 22 h. Additional N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (0.83 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.09 mmol), and 2M aqueous potassium carbonate (3 mL) were added and the reaction mixture was heated at 100° C. for 22 h for complete consumption of starting material. The reaction mixture was cooled, diluted with diethyl ether (30 mL), and filtered through a pad of Celite while rinsing with (2×30 mL) diethyl ether. The organic layer was poured into a separatory funnel containing water (100 mL) and the layers were separated. The aqueous layer was acidified with 6N aqueous HCl until the pH was approximately 7 and then further extracted with (3×200 mL) ethyl acetate. The combined organic layers were dried over sodium sulfate with decolorizing activated carbon, filtered through a pad of Celite while rinsing with (2×100 mL) ethyl acetate, and concentrated in vacuo. The filtrate was separated and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Recrystallization of the residue from hot ethyl acetate afforded the title product as an ivory solid (804 mg, 30%). Additional product was obtained from the concentrated mother liquors after purification by silica gel chromatography (70-100% ethyl acetate/hexanes) followed by precipitation from cold ethyl acetate (534 mg, 20%). MS(ES)+ m/e 443 [M+H]+.