Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[S:8][CH2:9][CH2:10][CH2:11][C:12](C(O)=O)([C:18]([OH:20])=[O:19])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CS(C)=O>[C:30]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[S:8][CH2:9][CH2:10][CH2:11][CH:12]([C:18]([OH:20])=[O:19])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(O)CCC(CCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)(C(=O)O)C(=O)O
Solvent: CS(C)=O
Product: O=C(O)CCC(CCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2.56 mmol of 6-[(triphenylmethyl)thio]-1,3,3,-hexanetricarboxylic acid (III) (1.36 g) was dissolved in 5 ml of dimethylsulfoxide and the solution was heated to 100° C. for 1 hour, evaporated to dryness, dissolved in water and precipitated by addition of 1 M sulfuric acid. The precipitated oil solidified after 1 hour treatment in an ultrasound bath. The solid was filtered off, washed with water and dried in a dessicator. Yield 1.1 g of 6-[(triphenylmethyl)-thio]-1,3-hexanedicarboxylic acid (IV) (89% two steps from II), 13C-NMR (MeOH) δ 27.9, 28.6, 33.0 (two carbons), 33.1, 45.9, 68.1, 128.1, 129.2, 131.2, 146.8, 177.1, 179.4.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:9]=2)[N:5]=[C:4]([C:22]([NH2:24])=[O:23])[CH:3]=1.[CH:25](B1OC(C)(C)C(C)(C)O1)=[CH2:26].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:10]2[CH:9]=[C:8]([C:6]3[N:5]=[C:4]([C:22]([NH2:24])=[O:23])[CH:3]=[C:2]([CH:25]=[CH2:26])[CH:7]=3)[CH:13]=[CH:12][CH:11]=2)=[CH:16][CH:17]=1
Reactant: NC(=O)c1cc(Cl)cc(-c2cccc(Oc3ccc(F)cc3)c2)n1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=Cc1cc(C(N)=O)nc(-c2cccc(Oc3ccc(F)cc3)c2)c1
Temperature: 120 °C
Yield: 49.8 %

Procedure:
A 5 ml sealed microwave tube was charged with 4-chloro-6-[3-(4-fluoro-phenoxy)-phenyl]-pyridine-2-carboxylic acid amide (0.267 g, 0.78 mmol), vinyl boronic acid pinacol ester (0.180 g, 1.17 mmol, Aldrich) in three equivalents of TBAF/THF. The mixture was heated to 120° C. by microwave for 45 minutes. The mixture was chromatographed without workup by combiflash using a 40-gram silica column with a gradient of methanol (30% max) in chloroform to provide 0.130 g of 6-[3-(4-fluoro-phenoxy)-phenyl]-4-vinyl-pyridine-2-carboxylic acid amide as a clear oil in good purity (50% yield).
Reaction SMILES: [CH3:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[CH:5][N:4]2[C:13](SC)=[N:14][N:15]=[C:3]12.[OH-:18].[K+]>>[CH3:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[CH:5][N:4]2[C:13](=[O:18])[NH:14][N:15]=[C:3]12
Reactant: [OH-]
Reactant: CSc1nnc2n1C=Cc1ccccc1C2C
Agent: [K+]
Product: CC1c2ccccc2C=Cn2c1n[nH]c2=O

Procedure:
11-Methyl-3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine was treated with potassium hydroxide and the reaction mixture was treated as described. By this procedure was obtained 2,11-dihydro-11-methyl-3H-s-triazolo[3,4-b][3]benzazepin-3-one as crystals. Pale brown needles (as recrystallized from ethanol), m.p. 119°-120° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][NH:22][CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:4][C:3]=1[OH:31].[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][N:40]=2)[CH:35]=[C:34]([CH:42]=O)[CH:33]=1>>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][N:22]([CH2:42][C:34]6[CH:33]=[N:32][C:41]7[C:36]([CH:35]=6)=[CH:37][CH:38]=[CH:39][N:40]=7)[CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:28])([F:29])[F:30])=[CH:4][C:3]=1[OH:31]
Reactant: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCNC5)n[nH]c3c2)cc1F
Reactant: O=Cc1cnc2ncccc2c1
Product: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCN(Cc4cnc6ncccc6c4)C5)n[nH]c3c2)cc1F

Procedure:
The title compound was prepared from 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol (100 mg, 0.21 mmol) and [1,8]naphthyridine-3-carbaldehyde (146.1 mg, 0.92 mmol) using the method of Example 51. The crude material was purified initially over silica and finally by Prep TLC (Mobile Phase: 10% MeOH-DCM) to afford the title compound as an off white solid in 9.0% yield, 22 mg.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=O.[NH2:15][C:16]([NH2:18])=[S:17]>CO>[F:12][C:11]([F:14])([F:13])[C:7]1[CH:6]=[C:5]([C:3]2[S:17][C:16]([NH2:18])=[N:15][CH:2]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Reactant: NC(N)=S
Solvent: CO
Product: Nc1ncc(-c2cccc(C(F)(F)F)c2)s1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 2-bromo-1-(3-(trifluoromethyl)phenyl)ethanone (2.5 g, 9.40 mmol, 1.00 equiv) in methanol (50 mL), and thiourea (710 mg, 9.33 mmol, 1.00 equiv). The resulting solution was stirred overnight at 75° C. in an oil bath. The reaction mixture was cooled with a water/ice bath. The solids were collected by filtration. The residue was dissolved in 200 mL of ethyl acetate. The resulting mixture was washed with 1×50 mL of sodium hydroxide (1 N) and 2×50 mL of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 2.2 g (96%) of 5-(3-(trifluoromethyl)phenyl)thiazol-2-amine as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([N:20]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:25][CH:26]=2)=[CH:10][C:11]=1[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])C.Cl>C(O)C.[OH-].[Na+].O>[CH2:13]([NH:12][C:11]1[CH:10]=[C:9]([N:20]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:25][CH:26]=2)[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cnc(N(Cc2ccc(OC)cc2)c2ccc(N3CCOCC3)nc2)cc1NCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(CN(c2ccc(N3CCOCC3)nc2)c2cc(NCc3ccccc3)c(C(=O)O)cn2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 119.4 %

Procedure:
3.0 mg of 4-benzylamino-6-[4-methoxybenzyl-(6-morpholinopyridin-3-yl)amino]pyridine-3-carboxylic acid ethylester was dissolved in 1 mL of ethanol, to which 1 mL of 2 mol/L sodium hydroxide in water was added, and stirred at 80° C. for 1 hour. After cooling, hydrochloric acid was added to neutralize the reaction mixture. It was extracted with chloroform, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated to obtain 3.4 mg of the title compound containing impurities as a brown oil. Without further purification, this was used in the next reaction as it was.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[CH:11][O:10][N:9]=2)=[N:6][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:55][CH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[O:59]1[CH2:60][CH2:61][CH:56]([NH:55][C:21]([C:17]2[S:16][C:15](/[CH:14]=[CH:13]/[C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][CH:11]=3)=[N:19][C:18]=2[CH3:20])=[O:23])[CH2:57][CH2:58]1
Reactant: Cc1nc(/C=C/c2conc2-c2ccc(F)cn2)sc1C(=O)O
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(/C=C/c2conc2-c2ccc(F)cn2)sc1C(=O)NC1CCOCC1
Reaction time: 1 h
Yield: 82.8 %

Procedure:
To a solution of 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (99 mg, 0.3 mmol) in DMF (1.5 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (106 mg, 0.33 mmol), N,N-diisopropyl ethyl amine (257 μL, 1.5 mmol) and 4-aminotetrahydropyran (33 mg, 0.33 mmol). The resulting reaction mixture was stirred for 1 h. The reaction mixture was then evaporated and purification by trituration from methanol/water afforded the title compound (103 mg, 83%) as an off white solid. MS: m/e=415.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[N+](C1C=CC([O:42][C:43](=O)[O:44][CH:45]2[CH:52]3[CH:48]([O:49][CH2:50][CH2:51]3)[O:47][CH2:46]2)=CC=1)([O-])=O.CCN(C(C)C)C(C)C>C(#N)C.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:21][CH2:22][CH:23]([NH:26][C:43]([O:44][CH:45]2[CH:52]3[CH:48]([O:49][CH2:50][CH2:51]3)[O:47][CH2:46]2)=[O:42])[CH2:24][CH2:25]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1COC2OCCC12
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(N)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCC(NC(=O)OC2COC3OCCC23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-[(4-amino-cyclohexyl)-(trans-4-methylcyclohexanecarbonyl)-amino]-5-(3,3-dimethyl-but-1ynyl)thiophene-2-carboxylic acid methyl ester (0.40 g, 0.873 mmol) in ACN (5.0 mL) was cooled to 0° C. and carbonic acid hexahydro-furo[2,3-b]furan-3-yl ester 4-nitro-phenyl ester (0.295 g, 1.0 mmol) was added, followed by DIEA (391 μL, 2.18 mmol) and DMAP (cat). The reaction mixture was warmed to rt, and stirred for 1 h. The solvent was removed under reduced pressure and the crude reaction mixture was partitioned between EtOAc and 2N K2CO3(aq). The layers were separated and the organics washed repeatedly with 2N K2CO3(aq). Both epimers of 5-(3,3-Dimethyl-but-ynyl)-3-[[4-(hexahydro-furo[2,3-b]furan-3-yloxycarbonylamino)-cyclohexyl]-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester were isolated by reverse phase HPLC and carried forward wet into the next reaction.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][N:27]=[N:26][CH:25]=1)CCC>O1CCOCC1>[CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([C:24]3[CH:29]=[CH:28][N:27]=[N:26][CH:25]=3)[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]=2[C:6]([CH3:14])=[CH:7]1)([CH3:13])[CH3:12]
Reactant: COC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnnc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnnc2)cc2c1c(C)cn2C(C)C
Temperature: 105 °C

Procedure:
To a 50 ml round bottom flask was added; methyl 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylate (150 mg, 0.484 mmol), PdCl2(dppf)-CH2C12 adduct (39.5 mg, 0.048 mmol) and 1,4-Dioxane (4836 μl) followed with 4-(tributylstannyl)pyridazine (179 mg, 0.484 mmol) and a magnetic stir bar. The flask was equipped with a reflux condenser and an exhaust bubbler and heated to 105° C. The reaction solution changed to a dark brown at 30 minutes. LCMS (105C-3 h) showed the reaction to be complete. The reaction solvent was removed in-vacuo and the remaining residue taken up with DMSO. (1.5 ml). The DMSO solution was purified by reverse phase HPLC using a Phenomenex Gemini 100×30 mm column, neutral acetonitrile and 0.1% formic acid in water, 40-70%, 10 min gradient. The desired fractions were dried in a Genovac EZ-2 evaporator and the solid residues combined. The product, methyl 1-isopropyl-3-methyl-6-(pyridazin-4-yl)-1H-indole-4-carboxylate, was obtained as a white solid. 1H NMR (400 MHz, METHANOL-δ4) 9.68 (δ, J=1.26 Hz, 1H), 9.19 (d, J=5.56 Hz, 1H), 8.20 (d, J=1.52 Hz, 1H), 8.13 (dd, J=2.53, 5.56 Hz, 1H), 7.98 (d, J=1.52 Hz, 1H), 7.48 (s, 1H), 4.96 (dt, J=6.60, 13.33 Hz, 1H), 4.00 (s, 3H), 2.39 (s, 3H), 1.56 (d, 6H). MS(ES) [M+H]+ 310.2.
Reaction SMILES: Cl.[F:2][C:3]([F:12])([F:11])[C:4]1[CH:5]=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1.[C:13](#[N:16])[CH:14]=[CH2:15].C(NCC)C.[OH-].[Na+]>>[F:2][C:3]([F:11])([F:12])[C:4]1[CH:5]=[C:6]([NH:10][CH2:15][CH2:14][C:13]#[N:16])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: C=CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCNCC
Product: N#CCCNc1cccc(C(F)(F)F)c1
Temperature: 180 °C
Reaction time: 2.5 h
Yield: 45 %

Procedure:
A mixture of 70 parts of 3-(trifluoromethyl)benzenamine hydrochloride, 26.5 parts of 2-propenenitrile and 36.5 parts of N-ethylethanamine was stirred for 2.5 hours at 180° C. After cooling to 0° C., the whole was treated with a sodium hydroxide solution. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated, yielding 34.5 parts (45%) of 3-[[3-(trifluoromethyl)phenyl]amino]propanenitrile as a residue (int. 105).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[N:19]1([C:24]2[CH:30]=[CH:29][C:27](N)=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[N:19]1([C:24]2[CH:30]=[CH:29][C:27]([NH:13][C:12]3[C:11]4[C:10](=[CH:9][CH:8]=[C:6]5[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]5=4)[N:14]=[CH:15][N:16]=3)=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Nc1ccc(N2CCCC2)cc1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(N5CCCC5)cc4)c3c2s1
Yield: 48 %

Procedure:
Prepared from VII and 4-(pyrrolidin-1-yl)aniline. Flash chromatography eluent (DCM-EtOAc, 8:2). Yield: 48%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3303, 2842, 2233, 1709, 1629, 1613, 1583, 1522, 1466, 1388, 1347, 1275, 1219, 1185, 1166, 1060, 1014, 989, 828, 809; 1H NMR (300 MHz, DMSO-d6) δ 8.54 (d, 1H, J=9.0 Hz), 8.15 (s, 1H), 7.88 (d, 1H, J=9.0 Hz), 7.35 (d, 2H, J=8.1 Hz), 6.73 (d, 2H, J=8.1 Hz), 3.17 (m, 4H), 1.99 (m, 4H); HRMS calcd for C20H17N6S (M+H+): 373.1235, found 373.1218.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[CH2:10]1.[O-]CC.[Na+].Cl[CH2:22][C:23](=O)[CH3:24]>C(O)C.CN(C=O)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[C:12]2[C:23]([CH3:24])=[CH:22][O:16][C:11]=2[CH2:10]1
Reactant: CC(=O)CCl
Reactant: O=C1CC(=O)CC(c2cccc(Cl)c2Cl)C1
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1coc2c1C(=O)CC(c1cccc(Cl)c1Cl)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-(2,3-dichlorophenyl)cyclohexane-1,3-dione(mp205-206° C.; 1.29 g) in ethanol (10 ml) was added sodium ethoxide (0.37 g), and the mixture was stirred, under argon atmosphere, at room temperature for 15 minutes. To the mixture was added a solution of chloroacetone (0.45 ml) in DMF (10 ml), and the mixture was stirred at 100° C. overnight (13 hours). The reaction solution was cooled and concentrated under reduced pressure. To the residue was added ice-water, and the mixture was extracted with ethyl acetate. The upper layer was washed with saturated brine, dried (anhydrous magnesium sulfate), and concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with ethyl acetate/hexane to give 6-(2,3-dichlorophenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.18 g).
Reaction SMILES: [Li].[F:2][C:3]1[CH:4]=[N:5][C:6]2[N:7]([N:9]=[CH:10][C:11]=2[C:12]([O-:14])=O)[CH:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:48][C@@H:49]1[NH:54][CH2:53][CH2:52][N:51]([S:55]([C:58]2[CH:63]=[CH:62][C:61]([C:64]([F:67])([F:66])[F:65])=[CH:60][CH:59]=2)(=[O:57])=[O:56])[CH2:50]1>CN(C=O)C>[F:2][C:3]1[CH:4]=[N:5][C:6]2[N:7]([N:9]=[CH:10][C:11]=2[C:12]([N:54]2[CH2:53][CH2:52][N:51]([S:55]([C:58]3[CH:59]=[CH:60][C:61]([C:64]([F:67])([F:65])[F:66])=[CH:62][CH:63]=3)(=[O:56])=[O:57])[CH2:50][C@@H:49]2[CH3:48])=[O:14])[CH:8]=1
Reactant: O=C([O-])c1cnn2cc(F)cnc12
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1cnn2cc(F)cnc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
The lithium salt of 6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylate (117 mg, 0.63 mmol) (may be prepared as described in Description 16) was weighed into a vial with HATU (247 mg, 0.65 mmol), suspended in DMF (2 ml) and treated with DIPEA (0.170 ml, 0.97 mmol). This mixture was stirred about 15 min at ambient temperature. (3S)-3-Methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Description 2) (100 mg, 0.32 mmol) was added and stirring was continued for 3 h at ambient temperature. The reaction mixture was partitioned between DCM and sat. aq. NaHCO3 solution (10 ml each). The layers were separated (hydrophobic frit) and the aqueous layer was washed with further DCM (2×5 ml). The combined organic layers were concentrated to leave an orange gum. Purification by MDAP gave the title compound (112 mg, 0.24 mmol, 73% yield) as an orange solid.
Reaction SMILES: C1(C)C=CC(S([O:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])(=O)=O)=CC=1.C(N(CC)C(C)C)(C)C.[N:31]12[C:37](=[O:38])[CH2:36][CH2:35][CH:34]1[C:33](=O)[CH:32]2[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41]>C(Cl)Cl>[C:17]1([CH3:20])[CH:16]=[CH:15][C:14]([S:11]([O:10][C:33]2[CH2:34][CH:35]3[N:31]([C:37](=[O:38])[CH2:36]3)[C:32]=2[C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])(=[O:12])=[O:13])=[CH:19][CH:18]=1
Reactant: O=C(OCc1ccccc1)C1C(=O)C2CCC(=O)N21
Reactant: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2=C(C(=O)OCc3ccccc3)N3C(=O)CC3C2)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 66.8 %

Procedure:
p-Toluenesulfonic anhydride (326 mg, 1 mμol) and N,N-diisopropylethylamine (192 μl, 1.1 mμol) are added to an ice-cold, stirring solution of benzyl 1-azabicyclo[2.3.0]heptan-3,7-dione-2-carboxylate (259 mg, 1 mμol) in anhydrous methylene chloride (10 ml). The resulting solution is stirred in the cold and under a nitrogen atmosphere for 2.5 hours. The solution is diluted with methylene chloride (20 ml), washed with water (10 ml). 1 M pH3 phosphate buffer (10 ml) and 5% aqueous sodium bicarbonate (2×10 ml) dried with magnesium sulfate, filtered, and evaporated under vacuum to a semi-solid. This material is triturated with ice-cold ethyl acetate (2×2 ml) and diethyl ether (2×5 ml) to provide benzyl 3-(p-toluenesulfonyloxy)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (276 mg, 67%) as a white powder. Recrystallization from methylene chloridediethyl ether gives analytically pure product as small white needles: mp 103°-105°; IR (CH2Cl2) 1786, 1723, 1382, and 1190 cm-1 ; NMR (CDCl3) 8 2.44 (s, 3, ArCh3) 3.03 (dd,1,J=3.0 and 17.0,HGβ), 3.16 (dd,1,J=8.5 and 18.7,H4a), 3.32 (dd,1,J=10.0 and 18.7,H46), 3.55 (dd,1,J=5.5 and 17.0, HG), 4.21 (m,1,H5), 5.14 (ABq,2,J=12,CH2Ar), 7.35 (S,5, ArHO, 7.26 and 7.75 (two d's,4,J=9,ArH); UV(dioxane) 283 (E6600) and 277 (E6500) nm.
Reaction SMILES: C(O[C:6]([N:8]([CH2:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]#[N:22])=[O:15])[CH2:9][CH:10]([CH3:12])[CH3:11])=[O:7])(C)(C)C.C(N(CC)CC)C.C(Cl)(=O)[C:31]1[C:32]([O:37][CH3:38])=[CH:33][CH:34]=[CH:35][CH:36]=1>FC(F)(F)C(O)=O>[CH3:38][O:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[C:6]([N:8]([CH2:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[C:21]#[N:22])=[O:15])[CH2:9][CH:10]([CH3:11])[CH3:12])=[O:7]
Reactant: CC(C)CN(CC(=O)N1CCC[C@H]1C#N)C(=O)OC(C)(C)C
Reactant: COc1ccccc1C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: COc1ccccc1C(=O)N(CC(=O)N1CCC[C@H]1C#N)CC(C)C
Temperature: 0 °C
Yield: 64.2 %

Procedure:
(2S)-1-(2-(N-tert-Butyloxycarbonyl-N-(2-methylpropyl)amino)acetyl)pyrrolidine-2-carbonitrile (25 mg, 0.081 mmol) was treated with trifluoroacetic acid (50 ml). After 1 h at room temperature the solvent was removed in vacuo and the residue dissolved in CH2Cl2 (100 ml). The solution was cooled to 0° C., triethylamine (30 mg, 0.3 mmol) was added followed by 2-anisoyl chloride (15 mg, 0.088 mmol). After 18 h at 0° C. to room temperature the solvent was removed in vacuo and the residue dissolved in ethyl acetate (200 ml). This solution was washed with 0.3M KHSO4, sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography (eluant: 2% methanol, 98% chloroform) to give a colourless oil identified as the title compound (18 mg, 0.052 mmol, 66%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]Cl>>[Cl:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: O=C1CCNCC1
Reactant: ClCc1ccccc1Cl
Product: O=C1CCN(Cc2ccccc2Cl)CC1

Procedure:
1-(2-Chlorobenzyl)-4-piperidone is prepared from 4-piperidone and 2-chlorobenzyl chloride essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[C:7]([N+:17]([O-:19])=[O:18])=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl>CN(C)C1C=CC=CC=1>[C:1]([NH:5][C:6]1[C:7]([N+:17]([O-:19])=[O:18])=[C:8]([CH:14]=[CH:15][CH:16]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1cccc(N)c1[N+](=O)[O-]
Agent: Cl
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)c1cccc(NC(C)=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Acetyl chloride (13 ml) was added dropwise to a solution of 2.98 g of ethyl 3-amino-2-nitrobenzoate and 20 ml of N,N-dimethylaniline in an ice bath. The mixture was stirred at room temperature for 48 hours. The reaction solution was acidified with 10% hydrochloric acid, and was extracted twice with ethyl acetate. The organic layer was washed three times with water. The solvent was distilled off under reduced pressure, and the resulting residue was crystallized with hexane. The crystals were separated through filtration, washed with hexane, and dried to give 3.30 g of ethyl 3-acetylamino-2-nitrobenzoate.