Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([OH:14])=[O:13])[CH:5]=[CH:4][C:3]1=2.[CH3:15][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>ClCCl.CO.O1CCCC1>[CH3:15][O:13][C:12]([C:6]1[CH:5]=[CH:4][C:3]2[C:2](=[O:1])[CH2:11][CH2:10][CH2:9][C:8]=2[CH:7]=1)=[O:14]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc2c(c1)CCCC2=O
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CCCC2=O

Procedure:
A sample of commercially available 5-Oxo-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid (200 mg, 1.05 mmol) is dissolved in a mixture of dichloromethane and methanol (5:1, 10 mL). The solution is then treated with a solution of trimethylsilyl diazomethane in tetrahydrofuran (2M) until the yellow color persists. The reaction is then treated with a small amount of acetic acid to destroy excess reagent and the solvent is removed. The residue is purified on silica gel to afford the title material as a yellow solid. ESMS m/z 204.1 (M+H+).
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:5]=[N:6][C:7](Cl)=[N:8][CH:9]=1>CO>[Br:3][C:4]1[CH:5]=[N:6][C:7]([NH:2][CH3:1])=[N:8][CH:9]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CN
Solvent: CO
Product: CNc1ncc(Br)cn1
Yield: 100 %

Procedure:
40% Aqueous methylamine solution (35 ml) and methanol (20 ml) were added to 5-bromo-2-chloropyrimidine (3 μg, 15.5 mmol) and the resulting mixture was heated to reflux for 3 days. The mixture was cooled, then the solvent was evaporated under reduced pressure, the residue was partitioned with methylene chloride and 1 M sodium hydroxide, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.0 g, 100%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:25][CH3:26])[C:5]([NH:20][CH2:21][CH2:22][O:23][CH3:24])=[C:6]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)[CH:7]=1.C(OCC)(=O)C>CC(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([O:25][CH3:26])[C:5]2[N:20]([CH2:21][CH2:22][O:23][CH3:24])[C:9]([C:10]3[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=3)=[N:8][C:6]=2[CH:7]=1
Reactant: COCCNc1c(NC(=O)c2ccc(C(C)C)cc2)cc(Br)cc1OC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(Br)cc(OC)c21
Yield: 87.6 %

Procedure:
A solution of 748 mg (1.77 mmol) N-[5-bromo-3-methoxy-2-(2-methoxy-ethylamino)-phenyl]-4-isopropyl-benzamide in 10 ml AcOH is stirred at 100° C. for 2 h. The reaction mixture is cooled to room temperature 200 ml ethyl acetate is added. The solution is washed with 4N NaOH (2×) and with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=3:1) to afford 625 mg of the title compound as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:11](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH3:11])=[O:8]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.3 %

Procedure:
5-Bromonicotinic acid (15.0 g, 74.3 mmol) was dissolved in DMF (200 mL), and the mixture was stirred at room temperature for 3 hours after adding potassium carbonate (15.4 g, 0.111 mol) and methyl iodide (9.25 mL, 0.149 mol). The mixture was diluted with ethyl acetate, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give methyl 5-bromonicotinate (10.0 g, 63%).
Reaction SMILES: CO[C:3]1[C:4]2[C:9]([N:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.Br.[NH:18]([C:20]1[S:21][CH2:22][CH2:23][N:24]=1)[NH2:19]>C(O)C>[S:21]1[CH2:22][CH2:23][NH:24][C:20]1=[N:18][N:19]=[C:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[NH:10][C:11]2[C:16]1=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: COc1c2ccccc2nc2ccccc12
Reactant: NNC1=NCCS1
Agent: Br
Solvent: CCO
Product: c1ccc2c(=NN=C3NCCS3)c3ccccc3[nH]c2c1

Procedure:
2.09 g of 9-methoxyacridine are dissolved in 50 ml of dry ethanol, treated with a solution of 1.98 g of 2-hydrazino-2-thiazoline hydrobromide in 50 ml of dry ethanol, heated to boiling under reflux for 1 hour and the solvent is removed in vacuo. The residue is treated with aqueous ammonia (1:5) and extracted with ethyl acetate. After drying the extract over sodium sulfate and evaporation, the material obtained is crystallized by the addition of pentane. There is obtained 9-acridanone (2-thiazolidinylidene)hydrazone of melting point 214°-215° (decomposition).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[C:12]3[S:13][CH:14]=[CH:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([Li])CCC.[CH2:23]([O:30][C@@H:31]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:36]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@@H:35]([CH2:54][O:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[O:34][C:32]1=[O:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:23]([O:30][C@@H:31]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:36]([O:46][CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C@@H:35]([CH2:54][O:55][CH2:56][C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[O:34][C:32]1([C:14]1[S:13][C:12]2[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:17][CH:16]=3)=[CH:8][CH:9]=[CH:10][C:11]=2[CH:15]=1)[OH:33])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: Cc1ccc(Cc2cccc3ccsc23)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(Cc2cccc3cc(C4(O)O[C@H](COCc5ccccc5)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)sc23)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
To a solution of 7-(4-methylbenzyl)benzo[b]thiophene (0.57 g) in tetrahydrofuran (10 mL) was added n-butyllithium (2.71 mol/L tetrahydrofuran solution, 0.88 mL) at −78° C. under an argon atmosphere. The mixture was stirred at the same temperature for 30 minutes and a solution of 2,3,4,6-tetra-O-benzyl-D-glucono-1,5-lactone (1.2 g) in tetrahydrofuran (5 mL) was added to the mixture. The reaction mixture was warmed to 0° C. and stirred for 10 minutes. The reaction mixture was poured into a saturated ammonium chloride aqueous solution, and the mixture was extracted with diethyl ether. The organic layer washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1) to give the title compound (1.2 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].I[C:27]1[S:31][C:30]([NH:32][C:33](=[O:35])[CH3:34])=[N:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[S:31][C:30]([NH:32][C:33](=[O:35])[CH3:34])=[N:29][CH:28]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: CC(=O)Nc1ncc(I)s1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(=O)Nc1ncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and N-(5-iodo-thiazol-2-yl)-acetamide [CAS-No. 252662-43-4] (268 mg, 1.0 mmol) according to general procedure II. Obtained as an orange solid (240 mg, 48%). MS (EI) 495.1 [(M)+]; mp 302° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C(O)C>[C:19]([C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][NH:1][C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1)([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1nc(N)sc1C
Solvent: CCO
Product: CCOC(=O)C(=CNc1nc(C)c(C)s1)C(=O)OCC
Yield: 70.6 %

Procedure:
2-Amino-4,5-dimethylthiazole (2.56 g., 20 mmoles), diethyl ethoxymethylenemalonate (4.8 g., 22 mmoles) and ethanol (5 ml.) were refluxed for 1 hour. The reaction mixture was cooled and the crude product precipitated with hexane. Purified 2-(2,2-dicarbethoxyethenylamino)-4,5-dimethylthiazole (4.21 g., m.p. 82°-83.5° C.) was obtained by recrystallization from hexane.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].[CH:10](OCC)(OCC)[O:11][CH2:12][CH3:13]>C1(C)C=CC=CC=1>[CH2:12]([O:11][CH:10]1[O:2][C:1]2[CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=2[O:4]1)[CH3:13]
Reactant: CCOC(OCC)OCC
Reactant: Oc1cccc(O)c1O
Solvent: Cc1ccccc1
Product: CCOC1Oc2cccc(O)c2O1
Yield: 92.9 %

Procedure:
Pyrogallol (0.50 g, 3.96 mmol), triethyl orthoformate (0.80 cm3, 4.81 mmol) and amberlyst-IR-120(plus), (0.11 g, 5% weight alcohol) were combined in dried toluene (40 cm3) and heated to reflux under nitrogen for 28 hours. Any low boiling solvents were removed by distillation through a 10 cm Vigreux column, and the reaction vessel was recharged with toluene as required. The cooled solution was filtered through a pad of celite, and the filtrate was evaporated under reduced pressure. The residue was filtered through a pad of silica with ethyl acetate (20% in heptane), and the filtrate was evaporated under reduced pressure to give the protected pyrogallol, (0.67 g, 92%) as clear oil.
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:4][NH:3][CH2:2]1.[H-].[Na+].O.[CH3:23]N(C=O)C>>[CH2:18]([O:17][C:15]([C:5]1[C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH2:1][CH2:2][N:3]([CH3:23])[CH:4]=1)=[O:16])[CH3:19]
Reactant: CN(C)C=O
Reactant: CCOC(=O)C1=CNCCc2c1[nH]c1ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C1=CN(C)CCc2c1[nH]c1ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate (0.15 g, 0.6 mmol) in DMF (2 mL) was added sodium hydride (60%, 28 mg, 0.7 mmol) at 0° C. and a solution of Mel (38 μL, 0.7 mmol). The mixture was stirred for 30 min at 0° C. Water was added to the reaction mixture, which was then extracted by DCM. The combined organic layer was washed with water and dried over magnesium sulfate. Evaporation of solvent gave a crude product, which was purified by column chromatography on silica gel eluting with MeOH-DCM (5:95) and then further purified by preparative HPLC to afford the title compound (86 mg); 1H-NMR (CDCl3): δ 10.50 (1H, s), 8.26 (1H, m), 7.77 (1H, s), 7.40 (1H, d), 7.31 (1H, d), 7.05 (2H, m), 5.35 (1H, s), 4.28 (2H, q), 3.54 (2H, t), 3.26 (3H, s), 3.14 (2H, m), 1.36 (3H, t). MS (ES): 271 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[C:8]1([Mg]Br)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C1COCC1.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ni]Cl>[C:8]1([C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1cnccn1
Reactant: Br[Mg]c1ccccc1
Agent: Cl[Ni]Cl
Agent: Cl
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(-c2cnccn2)cc1
Reaction time: 1.33 h
Yield: 39 %

Procedure:
Chloropyrazine (20.68 g, 177 mmol) and [1,2-bis(diphenylphosphino)ethane]nickel(II) chloride (41.08 g, 77.8 mmol) in dry THF (1.5 L) were mixed and stirred for 80 minutes in a flask (cooled with a water bath) under nitrogen. A solution of phenylmagnesium bromide (3M in Et2O) (103 mL, 309 mmol) was added slowly through a dropping funnel into the cooled brick-red slurry at room temperature under nitrogen over 3.5 hours. After stirring at room temperature overnight, TLC showed that the reaction was complete. 3N HCl (100 mL) was added slowly through a dropping funnel under nitrogen and the mixture was stirred for one hour. The THF layer was separated from the aqueous layer. The aqueous layer was adjusted to pH 12 with 6N NaOH and extracted with EtOAc (100 mL, 3×). The organic fractions (THF and EtOAc) were combined and dried over MgSO4, filtered and concentrated to give a solid. The product was purified by flash chromatography on 300 g of flash grade silica gel in 2.5% EtOAc/CH2Cl2 to give 10.79 gram (69 mmol, 39%) of 2-phenylpyrazine, m.p. 69°-70° C.; FAB MS [M+1]+ 157;
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12](SC)[N:11]=[C:10]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]3[CH3:22])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.ClC1N=C(N2CCOC[C@@H]2C)C=C(C2C=NC=C(F)C=2)N=1.[F:44][C:45]1[CH:46]=[C:47]([NH:60][C:61]([NH:63][CH2:64][CH2:65][F:66])=[O:62])[CH:48]=[CH:49][C:50]=1B1OC(C)(C)C(C)(C)O1>>[F:44][C:45]1[CH:46]=[C:47]([NH:60][C:61]([NH:63][CH2:64][CH2:65][F:66])=[O:62])[CH:48]=[CH:49][C:50]=1[C:12]1[N:13]=[C:8]([C:4]2[CH:5]=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:9]=[C:10]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]2[CH3:22])[N:11]=1
Reactant: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCCF)cc2F)OC1(C)C
Agent: C[C@H]1COCCN1c1cc(-c2cncc(F)c2)nc(Cl)n1
Product: C[C@H]1COCCN1c1cc(-c2cncc(F)c2)nc(-c2ccc(NC(=O)NCCF)cc2F)n1

Procedure:
Method as described for intermediate 5 using(S)-4-(2-chloro-6-(5-fluoropyridin-3-yl)pyrimidin-4-yl)-3-methylmorpholine (intermediate 7) and 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-fluoroethyl)urea (intermediate 14). Material was purified by prep HPLC (high pH) followed by purification using a TsOH cartridge (500 mg) to afford a brown solid, (10 mg, 6%).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:8][C:9]1[C:14]([C:15]2[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=2[F:23])=[C:13](Cl)[N:12]2[N:25]=[CH:26][CH:27]=[C:11]2[N:10]=1>C1COCC1.[Cu](I)I>[Cl:8][C:9]1[C:14]([C:15]2[C:20]([F:21])=[CH:19][C:18]([F:22])=[CH:17][C:16]=2[F:23])=[C:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[N:12]2[N:25]=[CH:26][CH:27]=[C:11]2[N:10]=1
Reactant: [Li]CCCCCC
Reactant: Fc1cc(F)c(-c2c(Cl)nc3ccnn3c2Cl)c(F)c1
Agent: I[Cu]I
Solvent: C1CCOC1
Product: CCCCCCc1c(-c2c(F)cc(F)cc2F)c(Cl)nc2ccnn12
Temperature: -70 °C
Reaction time: 0.75 h

Procedure:
Copper iodide (5 mmol) was suspended in THF (25 ml) under an inert gas atmosphere. The suspension was cooled to −70° C. and n-hexyllithium (5 ml,2M in hexanes) was added by syringe. The mixture was stirred for 45 minutes and 5,7-dichloro-6-(2,4,6-trifluorophenyl)-pyrazolo[1,5-α]pyrimidine (5 mmol, obtained from Example 3) was added as a solution in THF (10 min). The reaction mixture was stirred for 15 minutes at −70° C. The reaction mixture was then quenched with a mixture of aqueous saturated ammonium chloride/concentrated ammonia (9:1). The two phase mixture was separated. An oil was isolated from the organic layer which was subjected to chromatographic purification which yields the product as a crystalline residue.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[NH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>O1CCOCC1>[NH2:16][C:8]1[N:9]=[C:10]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:11]([I:12])=[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Reactant: NCCc1ccc(O)cc1
Solvent: C1COCCO1
Product: Nc1nc(NCCc2ccc(O)cc2)c(I)c(-c2ccco2)n1

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-y-lamine and tyramine in dioxane. ES-MS m/e (%): 423 (M+H+, 100).
Reaction SMILES: OO.[CH2:3]([C:5]1[N:6]=[N+:7]([O-:25])[C:8]2[CH:17]=[C:16]3[C:12]([CH2:13][CH:14]([CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[CH2:15]3)=[CH:11][C:9]=2[N:10]=1)[CH3:4].C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:27].C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH2:3]([C:5]1[N:6]=[N+:7]([O-:25])[C:8]2[CH:17]=[C:16]3[C:12]([CH2:13][CH:14]([CH2:18][N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)[CH2:15]3)=[CH:11][C:9]=2[N+:10]=1[O-:27])[CH3:4]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCc1nc2cc3c(cc2[n+]([O-])n1)CC(CN1CCOCC1)C3
Agent: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CC(CN1CCOCC1)C3
Temperature: 20 °C
Reaction time: 7 h
Yield: 16.5 %

Procedure:
H2O2 (70%, 0.95 mL, ca 16 mmol) was added drop-wise (over 10 min) to a stirred solution of 1-oxide 143 (503 mg, 1.6 mmol), TFAA (2.56 mL, 16.0 mmol) and TFA (0.66 mL, 8.0 mmol) in DCM (60 mL) at 20° C. and the mixture was stirred at 20° C. for 7 h. Dilute Na2CO3 solution (40 mL) was added and the mixture was extracted with DCM (5×80 mL). The combined organic fraction was dried and the solvent evaporated to give an oil which was purified by chromatography, eluting with a gradient (0-2%) of MeOH/DCM, to give 1,4-dioxide 144 (87 mg, 21%) as a yellow solid: mp (MeOH/DCM) 164-165° C.; 1H NMR δ 8.31 (s, 1H, H-9), 8.25 (s, 1H, H-5), 3.72 (t, J=4.6 Hz, 4H, 2×CH2O), 3.17-3.34 (m, 4H, CH2), 2.80-2.95 (m, 3H, CH2, H-7), 2.45 (t, J=4.6 Hz, 4H, 2×CH2N), 2.38 (d, J=7.7 Hz, 2H, CH2), 1.43 (t, J=7.5 Hz, 3H, CH3); 13C NMR δ 155.7, 154.1, 149.5, 139.2, 134.0, 116.3, 114.3, 67.0 (2), 63.1, 53.9 (2), 37.7, 37.2, 36.6, 23.8, 9.2. Anal. calcd for C17H22N4O3: C, 61.8; H, 6.7; N, 17.0. Found: C, 62.1; H, 6.7; N, 16.8%.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13]([NH:15][C@H:16]1[C@H:19]([CH3:20])[N:18]([OH:21])[C:17]1=[O:22])=[O:14])([CH3:11])([CH3:10])[CH3:9].Cl[CH2:24][C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26]>CN(C)C=O>[C:8]([O:12][C:13]([NH:15][C@H:16]1[C@H:19]([CH3:20])[N:18]([O:21][CH2:24][C:25]([O:27][CH:28]([CH3:30])[CH3:29])=[O:26])[C:17]1=[O:22])=[O:14])([CH3:9])([CH3:11])[CH3:10]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1O
Reactant: CC(C)OC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)OC(=O)CON1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H]1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
11.3 g of Triethylamine was dropped into a solution of 19.5 g of (3S-trans)-3-(t-butyloxycarbonylamino)-1-hydroxy -4-methyl-2-azetidinone and 14.8 g of chloroacetic acid, 1-methylethyl ester in 400 ml of dry dimethylformamide. The whole was stirred at room temperature for 3 days. Triethylamine hydrochloride was filtered off and the solvent was stripped at 35° C. in vacuo. The residual oil was taken up in ether, the extract was allowed to stand in the refrigerator for about two hours, filtered and the ether again evaporated in vacuo. The resulting oily title compound (30 g) containing about 2 g of impurities was used in the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:14].[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][SH:24])[CH:19]=[CH:20][C:21]=1[Cl:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:23][S:24][CH2:2][C:3]1[C:12]([OH:13])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C:8]2=[O:14]
Reactant: O=C1CCCc2c1ccc(O)c2CCl
Reactant: SCc1ccc(Cl)c(Cl)c1
Product: O=C1CCCc2c1ccc(O)c2CSCc1ccc(Cl)c(Cl)c1
Temperature: 40 °C
Yield: 63.5 %

Procedure:
5-Chloromethyl-6-hydroxy-1-tetralone (315 mg, 1.5 mmol) and (3,4-Dichloro-phenyl)-methanethiol (1.0 mL, 6.0 mmol) were sealed in a 16×120 mm screw capped tube and heated to 40° C. overnight. The excess (3,4-Dichloro-phenyl)methanethiol was removed in vacuo and the residue was purified by silica gel chromatography (hexanes/ethyl acetate/acetic acid, 58:40:2) to give 350 mg (63%) of the desired product as a tan powder: (LC-MS, APCI) m/z 367/369 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:20])([NH:6][S:7]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2)(=[O:9])=[O:8])[CH3:5].[CH3:22]I.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[C:4]([CH3:5])([N:6]([CH3:22])[S:7]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2)(=[O:9])=[O:8])[CH3:20]
Reactant: CI
Reactant: COC(=O)C(C)(C)NS(=O)(=O)c1cccc2cccnc12
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)N(C)S(=O)(=O)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.1 %

Procedure:
methyl-2-methyl-2-(quinoline-8-sulfonamido)propanoate (699 mg, 2.26 mmol) was dissolved in DMF (10 ml), added with MeI (0.49 ml, 7.93 mmol) at 0° C., and stirred at room temperature for 12 hours. The resultant solution was added with H2O and extracted with EA (×2). The organic solution was washed with H2O, dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed. The resultant mixture was purified with column chromatography so as to obtain methyl-2-methyl-2-(N-methylquinoline-8-sulfonamido)propanoate (694 mg, 2.15 mmol, 95%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.Cl.[O:24]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:17][C:10]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[C:7]([N:34]2[CH2:35][CH2:36][CH:31]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32][CH2:33]2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: c1ccc(OC2CCNCC2)cc1
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(Oc2ccccc2)CC1
Temperature: 65 °C
Yield: 18.2 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.12 g, 0.34 mmol, from Example 47, Step 2), 4-phenoxypiperidine hydrochloride (0.087 g, 0.41 mmol), palladium acetate (1.5 mg, 0.0067 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6.3 g, 0.010 mmol), and cesium carbonate (0.42 g, 1.3 mmol) in tetrahydrofuran (4 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over MgSO4, evaporated and purified on silica gel (eluting with 100% dichloromethane) to give the desired product (23.6 mg, 18%). LCMS calculated for C22H22ClN2O2 (M+H)+: m/z=380.1; Found: 381.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[C:11](C(O)=O)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CCOC(C)=O.CCCCCC>N1C2C(=CC=CC=2)C=CC=1.[Cu]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([NH:13][S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:11][CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)S(=O)(=O)Nc1c(C(=O)O)cnn1-c1ccc(Br)cc1
Agent: [Cu]
Solvent: CCCCCC
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)Nc1ccnn1-c1ccc(Br)cc1
Temperature: 180 °C
Reaction time: 0.25 h
Yield: 76.4 %

Procedure:
Dissolve 1-(4-Bromo-phenyl)-5-(propane-2-sulfonylamino)-1H-pyrazole-4-carboxylic acid (1.952 g, 5.03 mmol) in quinoline (2.79 mL) in a sealed tube. Add copper (0.16 g, 2.51 mmol) and immerse into a pre-heated (180° C.) oil bath and stir for 15 min. Cool to room temperature and remove the solvent under reduced pressure. Dilute with dichloromethane, wash with 1.0M HCl (2×50 mL), dry over sodium sulfate, filter, and concentrate to yield a residue. Subject to silica gel flash column chromatography (15-55% EtOAc/n-hexane) to yield the title compound (1.323 g, 76%).