Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C([N:18]1[CH:22]=[CH:21]N=C1)(N1C=CN=C1)=O.O>CN(C)C=O>[CH3:4][C:3]1[CH:2]=[C:22]([NH:18][C:4]([C:3]2[C:2](=[S:1])[NH:10][CH:9]=[CH:8][CH:7]=2)=[O:6])[CH:21]=[C:8]([CH3:9])[CH:7]=1
Reactant: O=C(O)c1cccnc1S
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)cc(NC(=O)c2ccc[nH]c2=S)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
2-Mercaptonicotinic acid (90 g, 0.58 mol) was suspended in N,N-dimethylformamide (660 mL) under ice-cooling, then carbonyldiimidazole (110 g, 0.70 mol) was added thereto, and the whole was stirred for 2 hours at room temperature. Water (5.4 mL) was added thereto, and the whole was stirred for 40 minutes, and then 3,5-xylydine (76 mL, 0.61 mol) was added thereto and the resulting mixture was stirred at 60° C. for 16 hours. The mixture was allowed to stand, and then water (1.3 L) was added, and the precipitated solid was filtered off. The solid was dried at 45° C. under reduced pressure to give 130 g of the title Reference Compound as a yellow solid (Yield: 89%).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23](OC)=[O:24])=[CH:18][C:17]=3[Cl:27])=[CH:12][CH:11]=2)[C:7]([CH3:28])=[N:6][C:5]=1[CH3:29])(=[O:3])[NH2:2].[NH3:30]>>[NH2:30][C:23](=[O:24])[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([C:8]3[N:9]=[C:4]([C:1]([NH2:2])=[O:3])[C:5]([CH3:29])=[N:6][C:7]=3[CH3:28])=[CH:11][CH:12]=2)=[C:17]([Cl:27])[CH:18]=1
Reactant: N
Reactant: COC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(Cl)c1
Product: Cc1nc(C)c(-c2ccc(-c3ccc(CC(N)=O)cc3Cl)cc2)nc1C(N)=O
Temperature: 140 °C
Yield: 27.4 %

Procedure:
Methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetate (Intermediate 1-1; 60 mg, 0.15 mmol) and ammonia (7M in methanol) (2091 μL, 14.64 mmol) were sealed into a microwave tube. The reaction was heated to 140° C. for 1 hour in the microwave reactor and cooled to RT. Removal of the solvent under reduced pressure gave crude product. The crude product was purified by preparative HPLC (Waters—Xbridge Prep C18 5 μm), using decreasingly polar mixtures of water (containing 0.1% formic acid) and {MeOH(3):MeCN(1)} as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-(4′-(2-amino-2-oxoethyl)-2′-chlorobiphenyl-4-yl)-3,5-dimethylpyrazine-2-carboxamide (16.20 mg, 28.0%) as a colourless solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]#N)[CH:9]=2)[CH:2]=1.[OH-:16].[Na+].Cl.C[OH:20].C(Cl)Cl>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([OH:20])=[O:16])[CH:9]=2)[CH:2]=1
Reactant: N#Cc1cc(Oc2cccnc2)ccn1
Reactant: [OH-]
Reactant: CO
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: O=C(O)c1cc(Oc2cccnc2)ccn1

Procedure:
Compound 1 (1.5 g, 7.6 mmol, 1.0 eq) was dissolved in ethanol (30 mL) and 1N NaOH (15 mL) was added. The mixture was refluxed for 18 h and after cooling the reaction was neutralized with 1N HCl (15 mL) and the reaction was concentrated in vacuo. The crude reaction was dissolved in 10% MeOH/CH2Cl2 and the undissolved salt was filtered off and the solvents were removed in vacuo to afford the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ 8.46 (d, J=2.7 Hz, 1H), 8.39-8.36 (m, 2H), 8.06 (ddd, J=8.7, 2.7, 1.1 Hz, 1H), 7.88 (dd, J=8.7, 5.4 Hz, 1H), 7.40 (d, J=2.2 Hz, 1H), 7.12 (dd, J=5.7, 2.4 Hz, 1H); ES-MS [M+1]+: 217.1.
Reaction SMILES: C(CCSC(C1C=CC=CC=1OCCCCCCC1C=CC=CC=1)CC(O)=O)(O)=O.C(C1C=CC=CC=1/C=C/CCC(OCC)=O)CCCCCCCCCCC.[F:58][C:59]([F:74])([F:73])[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][Mg]Br.CO[C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][C:78]=1[C:83]1[O:84][CH2:85][C:86]([CH3:89])([CH3:88])[N:87]=1>O1CCCC1>[F:58][C:59]([F:74])([F:73])[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][C:78]=1[C:83]1[O:84][CH2:85][C:86]([CH3:89])([CH3:88])[N:87]=1
Reactant: FC(F)(F)CCCCCCCCCCC[Mg]Br
Reactant: COc1ccccc1C1=NC(C)(C)CO1
Agent: CCCCCCCCCCCCc1ccccc1/C=C/CCC(=O)OCC
Agent: O=C(O)CCSC(CC(=O)O)c1ccccc1OCCCCCCc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccccc2CCCCCCCCCCCC(F)(F)F)=N1

Procedure:
Following the procedures of Example 1(a), (b) and (c), 12,12,12-trifluorododecylmagnesium bromide (from 29.19 mmoles of 12,12,12-trifluorododecyl bromide and 25.71 mmoles of magnesium) was reacted with 2-(2-methoxyphenyl)-4,4-dimethyloxazoline (20.17 mmoles) in tetrahydrofuran to give 2-[2-(12,12,12-trifluorododecyl)phenyl]-4,4-dimethyloxazoline. The oxazoline (14.39 mmoles) was converted to the methiodide salt and then reduced with sodium borohydride (13.43 mmoles) to yield the desired product as an oil.
Reaction SMILES: Cl.C(O[C:7]([NH:9][C@@H:10]([CH2:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=1)[CH2:11][NH:12][C@H:13]([C:15]([NH:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16])[CH3:14])=[O:8])(C)(C)C.C(O)(C(F)(F)F)=O.[CH2:38]([N:41]([CH2:54][CH2:55][CH3:56])[C:42]([C:44]1[CH:45]=[C:46]([CH:50]=[C:51]([CH3:53])[CH:52]=1)C(O)=O)=[O:43])[CH2:39][CH3:40].C(Cl)C[Cl:59].C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.ClCCl>[ClH:59].[F:29][C:27]1[CH:28]=[C:23]([CH2:22][C@H:10]([NH:9][C:7](=[O:8])[C:46]2[CH:50]=[C:51]([CH3:53])[CH:52]=[C:44]([C:42]([N:41]([CH2:38][CH2:39][CH3:40])[CH2:54][CH2:55][CH3:56])=[O:43])[CH:45]=2)[CH2:11][NH:12][C@H:13]([C:15]([NH:17][CH2:18][CH:19]([CH3:20])[CH3:21])=[O:16])[CH3:14])[CH:24]=[C:25]([F:30])[CH:26]=1
Reactant: CC(C)CNC(=O)[C@H](C)NC[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Reactant: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)O)c1
Reactant: ClCCCl
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1cc(C)cc(C(=O)N[C@H](CN[C@@H](C)C(=O)NCC(C)C)Cc2cc(F)cc(F)c2)c1
Reaction time: 1 h
Yield: 40 %

Procedure:
N2-[(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propyl]-N1-isobutyl-L-alaninamide hydrochloride (238 mg, 0.53 mmol) is stirred with 2 mL of TFA and 3 mL of dichloromethane for 1 h. The mixture is concentrated, neutralized with 3 mL of 1 N NaHCO3, and extracted into ethyl acetate containing 2% methanol. The organic phase is washed with brine, dried over Na2SO4, and concentrated to a yellow oil (400 mg) which includes TFA. The residue is dissolved in 2 mL of DMF. To 1 mL of the resulting solution is added a solution of 3-[(dipropylamino)carbonyl]-5-methylbenzoic acid, (80 mg, 0.3 mmol), EDC (58 mg, 0.3 mmol) and HOBT (40 mg, 0.3 mmol) in 3 mL of DMF which has been stirred together under nitrogen for 1 h. The combined mixture is stirred for 5 days, and is then quenched with 20 mL of water and dissolved in 120 mL of ethyl acetate containing 5 mL of methanol. The organic phase is washed with water, 1 N NaHCO3, and brine, and dried over Na2SO4. It is concentrated and chromatographed over silica gel, eluting with 3% to 5% methanol in chloroform to afford the free base of the title compound as a sticky solid (65 mg, 0.12 mmol, 45%). To a portion of this material is added ether and ethereal HCl, affording the title compound as an off-white solid. MS (CI) m/z 559 (MH+). HRMS (ESI) calcd for C31H44F2N4O3+H1 559.3459, found 559.3455
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:16][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[C:12]([F:13])([F:14])[F:15]
Reactant: Cc1ccc(C(C)(C)O)cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(O)c1ccc(CBr)c(C(F)(F)F)c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 75.7 %

Procedure:
A mixture of 2-(4-Methyl-3-trifluoromethyl-phenyl)-propan-2-ol (0.436 g, 2 mmol), N-Bromosuccinimide (356 mg, 2 mmol) and benzoyl peroxide (15 mg) in CCl4 (8 mL) was stirred at 85° C. for 16 hrs. The reaction mixture was then partitioned between saturated aqueous NaHCO3 and DCM. DCM layer was dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid which was purified via flash chromatography (15% EtOAc in n-heptane) to yield the title compound as a solid (450 mg, 76%)
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C@@H:15]2[C@:10]([CH3:22])([CH2:11][CH2:12][C:13]3[C:20](Br)=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:29][C:30]1(C)[C:34](C)(C)OB(C(C)=C)O1>COCCOC.C(O)C.O>[CH2:1]([N:8]1[CH2:16][C@@H:15]2[C@:10]([CH3:22])([CH2:11][CH2:12][C:13]3[C:20]([C:30]([CH3:34])=[CH2:29])=[CH:19][CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: C[C@]12CCc3c(Br)cccc3[C@@H]1CN(Cc1ccccc1)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: C=C(C)c1cccc2c1CC[C@]1(C)CN(Cc3ccccc3)C[C@@H]21
Temperature: 160 °C
Yield: 75.2 %

Procedure:
trans-2-Benzyl-6-bromo-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (0.561 mmol, 200 mg) was dissolved in DME (1 ml) and Ethanol (0.5 ml). 2 N sodium carbonate solution (1 ml) was added along with 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.842 mmol, 141 mg) and tetrakis(triphenylphosphine)Pd(0) (0.028 mmol, 32.4 mg). The reaction mixture was heated at 160° C. for 15 minutes in a microwave reactor and then diluted with water. The resulting mixture was extracted with DCM and the combined organic extracts were concentrated in vacuo to give a crude residue that was purified by silica column chromatography (eluting with 10% EtOAc in heptane) to afford trans-2-benzyl-3a-methyl-6-(prop-1-en-2-yl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (134 mg), m/z: 318.2 [M+H]+.
Reaction SMILES: C=CC=C.[CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[CH2:6].O1[C:17](=[O:18])[CH:16]=CC1=O.CC(C)=C.C(OCC1CO1)C(OCC1CO1)COCC1CO1>>[O:18]1[CH:17]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:7][CH:5]=[CH2:6])[CH2:16]1
Reactant: C=Cc1ccccc1
Reactant: O=C1C=CC(=O)O1
Agent: C(OCC1CO1)C(COCC1CO1)OCC1CO1
Agent: C=C(C)C
Agent: C=CC=C
Product: C=CCCCCCCC1CO1

Procedure:
2-Butenedioic acid (2Z)-sodium salt, polymer with 1,3-butadiene, ethenylbenzene, 2,5-furandione, 2-methyl-1-propene and 2,2′,2″-[1,2,3-propanethyltris(oxymethylene)]tris[oxirane], block (9Cl)
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][NH:9][C:10]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)=[CH:13][C:11]=1[NH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:26](=O)[CH3:27].OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[C:14]1[CH:15]=[CH:16][C:10]2[N:9]([CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:26]([CH3:27])=[N:12][C:11]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)CNc1ccc(-c2nc3ccccc3o2)cc1N
Reactant: CC=O
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.9 %

Procedure:
To a solution of 2-(2-(tert-butoxycarbonylmethylamino)anilin-5-yl)benzoxazole (see Working Example 91-1) (120 mg, 0.353 mmol) in dimethylformamide (2 mL) was added an aqueous solution of acetaldehyde (approx. 90%, 66 μL, 1.06 mmol) and oxone (217 mg, 0.353 mmol), and this was stirred at room temperature for 2 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (30.7 mg, 24% yield) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:29])=[C:16]([N:19]3[CH2:23][CH2:22][CH:21]([N:24]4[CH:28]=[CH:27][N:26]=[N:25]4)[CH2:20]3)[N:17]=2)[C:12](=[O:30])[C:11]([C:31]([O:33]CC)=[O:32])=[CH:10]1.C1COCC1.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:29])=[C:16]([N:19]3[CH2:23][CH2:22][CH:21]([N:24]4[CH:28]=[CH:27][N:26]=[N:25]4)[CH2:20]3)[N:17]=2)[C:12](=[O:30])[C:11]([C:31]([OH:33])=[O:32])=[CH:10]1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCC(n4ccnn4)C3)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCC(n4ccnn4)C3)c(F)cc2c1=O

Procedure:
A mixture of crude ethyl 1-(2,4-difluorophenyl) -6-fluoro-7-[3-(1,2,3-triazol-1-yl)pyrrolidin-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (150 mg, 0.31 mmol), THF (15 ml), NaOH (20 mg, 1.5 mmol) and water (15 ml) was heated under reflux for 3 h, cooled and the THF was evaporated. The residue was diluted with water, aqueous solution was acidified and the precipitated yellow solid was filtered, washed with water, dried in vac-oven at 50° C. This solid was washed with ether to get the pure compound. Yield: 50 mg (35.7%), m.p. 253° C. (dec). 1H NMR (TFA) δ: 2.85 (m, 2H), 3.70-4.50 (m, 4H), 5.80 (m, 1H), 7.20 (m, 2H), 7.60 (m, 1H), 8.25 (s, 1H), 8.57 (s, 1H), 8.62 (s, 1H), 9.20 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:19])[NH:10][C:11](=[O:18])[N:12]([CH2:14][CH2:15][CH:16]=O)[CH:13]=1.[F:20][C:21]([F:35])([F:34])[C:22]1[CH:27]=[CH:26][C:25]([C@:28]23[CH2:33][C@H:32]2[CH2:31][NH:30][CH2:29]3)=[CH:24][CH:23]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+].[Cl:52]C(Cl)C>CC(O)=O>[ClH:52].[ClH:52].[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:19])[NH:10][C:11](=[O:18])[N:12]([CH2:14][CH2:15][CH2:16][N:30]2[CH2:31][C@H:32]3[C@:28]([C:25]4[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:35])[F:34])=[CH:27][CH:26]=4)([CH2:33]3)[CH2:29]2)[CH:13]=1
Reactant: Cc1ccncc1-c1cn(CCC=O)c(=O)[nH]c1=O
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: CC(Cl)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1ccncc1-c1cn(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)c(=O)[nH]c1=O
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
A solution of 3-[5-(4-Methyl-pyridin-3-yl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl]-propionaldehyde (Prep113, 84 mg, 0.32 mmol), (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 74 mg, 0.32 mmol), and AcOH (23 μl) in dichloroethane (4 ml) was cooled to 0° C. NaBH(AcO)3 (72 mg, 0.34 mmol) was added portionwise. The mixture was stirred at 0° C. for 2 hours and at room temperature for 30 minutes and then basified with 1N NaOH. The product was extracted with DCM, the organic phase was dried (Na2SO4) and evaporated. The residue was redissolved in DCM and stirred for 5 hours in presence of PS-isocyanate. The mixture was filtered and the solvent was evaporated. The crude was purified by flash chromatography eluting with DCM-MeOH—NH4OH (98:2:0.2) to give 41 mg of the free base of title compound (27% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH2:10][CH2:11][CH2:12][CH3:13])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH2:35])=[CH:24][C:23]=2[F:38])[C:17]([CH2:39][CH3:40])=[N:16]1.Cl[C:42]([O:44][CH:45]([CH3:47])[CH3:46])=[O:43]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH2:10][CH2:11][CH2:12][CH3:13])=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:37])(=[O:36])[NH:35][C:42]([O:44][CH:45]([CH3:47])[CH3:46])=[O:43])=[CH:24][C:23]=2[F:38])[C:17]([CH2:39][CH3:40])=[N:16]1
Reactant: CCCCC(=O)Nc1ccc(Br)c(-n2nc(CC)n(Cc3ccc(-c4ccccc4S(N)(=O)=O)cc3F)c2=O)c1
Reactant: CC(C)OC(=O)Cl
Solvent: C1CCOC1
Product: CCCCC(=O)Nc1ccc(Br)c(-n2nc(CC)n(Cc3ccc(-c4ccccc4S(=O)(=O)NC(=O)OC(C)C)cc3F)c2=O)c1

Procedure:
The titled compound was prepared from 2-[2-bromo-5-(valerylamino)phenyl]-2,4-dihydro-5-ethyl-4-[(3-fluoro-2'-sulfamoyl -biphenyl-4-yl)methyl]-3H-1,2,4-triazol-3-one (from Example 1, Step J) as described in Example 1, Step K, except that isopropyl chloroformate was used in place of di-t-butyl dicarbonate, and THF was used as the solvent. After chromatographic purification, the titled compound was obtained in 15% yield; mass spectrum (FAB) m/e 716,718 (M+1)+.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1.[CH3:29][N:30]([CH2:32][CH2:33][CH2:34]Cl)[CH3:31]>>[F:28][C:2]([F:1])([F:27])[C:3]1[CH:26]=[CH:25][CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([O:15][CH2:34][CH2:33][CH2:32][N:30]([CH3:31])[CH3:29])[CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1
Reactant: Cc1cccc(-c2nc3ccc(O)cc3n2Cc2ccccc2C(F)(F)F)c1
Reactant: CN(C)CCCCl
Product: Cc1cccc(-c2nc3ccc(OCCCN(C)C)cc3n2Cc2ccccc2C(F)(F)F)c1

Procedure:
The title compound was prepared essentially as described in Example 106 except that the compound of Example 120 was reacted with 3-(N,N-dimethylamino)propyl chloride. mp 74° C., NMR, IR, MS 468.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].C(N(CC)CC)C.[N:21]1([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C1COCC1>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([N:30]2[CH2:31][CH2:32][CH:27]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:28][CH2:29]2)=[O:3])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(N2CCCCC2)CC1
Reaction time: 2 h

Procedure:
To a solution of 4-nitrophenyl chloroformate (31) (5.15 g, 25.6 mmol) in 150 mL of dry THF at −78° C. was added triethylamine (10.7 mL, 76.2 mmol), followed by a solution of 4-piperidinopiperidine (30) (4.51 g, 25.6 mmol) in 40 mL of THF. This solution was stirred for two hours, after which the solvent was removed, and the residue was taken up in AcOEt, filtered and evaporated. The crude yellow solid was passed through a pad of neutral alumina using AcOEt as an eluent to yield, after evaporation, 6.73 g (79%) of a white solid: IR (CHCl3, cm−1) 3046, 2937, 2859, 1704, 1620, 1513, 1466, 1242, 1197; 1H NMR (300 MHz, CDCl3) δ1.20-1.80 (m, 8 H), 1.90 (d, J=12.7 Hz, 2 H), 2.20-2.70 (m, 5 H), 2.87 (t, J=12 Hz, 1 H), 3.01 (t, J=12 Hz, 1 H), 4.30 (br s, 2 H), 7.29 (d, J=9 Hz, 2 H), 8.26 (d, J=9 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ24.6, 26.3, 27.5, 28.2, 40.1, 44.4, 50.1, 62.0, 122.2, 124.9, 144.8, 151.9, 156.3; HRMS (EI) m/z calcd for C17H23N3O4 (M+) 333.1676, found 333.1688; LRMS (EI) m/z 333 (M+), 195, 167, 124, 110, 96, 55.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=O.Cl.[NH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)=O.[OH-:33].[Na+]>O.C(O)C.O1CCCC1>[NH2:17][C:18]1[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)=[N:8][C:9]2[C:5]([C:6]=1[C:7]([OH:33])=[O:12])=[CH:4][C:3]([C:2]([F:15])([F:14])[F:1])=[CH:11][CH:10]=2
Reactant: [OH-]
Reactant: O=C1Nc2ccc(C(F)(F)F)cc2C1=O
Reactant: NCC(=O)c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1c(-c2ccc(-c3ccccc3)cc2)nc2ccc(C(F)(F)F)cc2c1C(=O)O

Procedure:
To a solution of 6.45 g of 5-trifluoromethylisatin (J. Org. Chem., 1344, 42, 1977) in 70 ml of 2.5N sodium hydroxide at 90°-95° C. was added a warm solution of 10.55 g of 2-amino-4'-phenylacetophenone, hydrochloride in 75 ml of water, 75 ml of ethanol and 50 ml of tetrahydrofuran over 30 minutes. The mixture was refluxed 1.5 hours, then the organic solvents were boiled off, the mixture diluted with 125 ml of water and filtered while still warm. The recovered solid was dissolved in 500 ml of hot water and filtered twice through celite. The second filtrate was acidified to pH 5 with glacial acetic acid, heated to near boiling, then cooled and the solid collected. This solid was recrystallized from acetonitrile/tetrahydrofuran, giving 5.74 g of the desired product as green crystals mp 255°-260° C. (dec.).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].O1CCCC1.[C:10]12[CH2:16][C:13](=[CH:14][CH:15]=1)[C:12]1[CH:17]=[CH:18][CH:19]=[CH:20][C:11]2=1.[OH-].[Na+]>O.[BH4-].[Na+]>[NH2:1][C:15]1[CH:14]=[C:13]2[CH2:16][C:10]=1[C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]2=1
Reactant: C1=C2CC(=C1)c1ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC1=C2CC(=C1)c1ccccc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Sodium azide (2 g) was combined with water (40 ml) and tetrahydrofuran (40 ml) and cooled to 0° C. Mercuric acetate (4g) was added to the cold solution and the mixture was stirred for 20 minutes. Benzobicyclo[2.2.1]heptadiene (2 g) was added to the stirred mixture and the resulting mixture was heated to 75° C. for 24 hours. The solution was cooled to room temperature, treated with 10% sodium hydroxide in water (10 ml) and sodium borohydride (0.4 g), and stirred for 1 hour. The two layers were separated and the organic layer was dried over magnesium sulfate and the solvent removed on a rotary evaporator. The residue was combined with tetrahydrofuran (20 ml) and added to a suspension of lithium aluminum hydride (0.1 g) in tetrahydrofuran (20 ml). The mixture was stirred at room temperature for 3 hours, treated with water (1 ml) and filtered. The solvent was removed on a rotary evaporator to provide the product as a yellow oil.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:6]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:5]=[C:4]1[S:23][CH3:24])[CH3:2].OOS([O-])=O.[K+].S([O-])(O[O-])(=O)=O.[K+].[K+].[OH2:39].C[OH:41]>>[CH2:1]([N:3]1[C:8](=[O:9])[C:7]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:6]([C:17]2[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=2)[N:5]=[C:4]1[S:23]([CH3:24])(=[O:41])=[O:39])[CH3:2]
Reactant: CCn1c(SC)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Reactant: CO
Reactant: O
Agent: O=S(=O)([O-])O[O-]
Agent: O=S([O-])OO
Agent: [K+]
Product: CCn1c(S(C)(=O)=O)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O

Procedure:
A mixture of 3-ethyl-5-(4-fluorophenyl)-2-methylthio-6-(4-pyridyl)-4(3H)-pyrimidinone (300 mg, 0.88 mmol) and Oxone® (potassium peroxymonosulfate, 2.54 g, 4.14 mmol) in methanol (71 ml) and water (33 ml) was stirred for 14 h. The solvent was concentrated to about 35 ml, followed by extraction with dichloromethane, drying and evaporation. The resulting white solid was used without purification in the next step.
Reaction SMILES: C(O)(=O)C.[CH2:5]([N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:19]1[CH2:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[N:19]1([CH:15]2[CH2:16][CH2:17][N:12]([CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:13][CH2:14]2)[CH2:22][CH2:21][CH2:20]1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: c1ccc(CN2CCC(N3CCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.0 mL (17.5 mmol) glacial acetic acid were added to the stirred mixture of 3.0 mL (16.5 mmol) 1-benzyl-4-piperidone, 1.0 g (17.5 mmol) azetidine and 100 mL DCM. Then 6.0 g (39.5 mmol) sodium triacetoxy-borohydride was added batchwise within one hour while cooling with an ice bath and the mixture was stirred for a further 12 h at RT. The reaction mixture was extracted with 200 mL EtOAc, the organic phase was dried, evaporated down under reduced pressure and the residue was purified by chromatography.