Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].CN1CCOCC1.Cl.[NH2:40][C@@H:41]([CH3:46])[C:42]([NH:44][CH3:45])=[O:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:40][C@@H:41]([CH3:46])[C:42]([NH:44][CH3:45])=[O:43])=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CNC(=O)[C@H](C)N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CNC(=O)[C@H](C)NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 41.3 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.031 mL, 0.278 mmol), (S)-2-amino-N-methylpropanamide-HCl (6.43 mg, 0.046 mmol), and HATU (31.7 mg, 0.083 mmol). The reaction mixture was stirred overnight and was then purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow rate=20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)-N-methyl(S)propanamide (9.6 mg, 0.019 mmol, 40.2% yield): LCMS=516.1 [M+H]+; 1H NMR (Mixture of Diastereomers, 400 MHz, methanol-d4) δ ppm 8.11-8.25 (4 H, m), 7.50-7.78 (14 H, m), 5.16 (2 H, d, J=3.08 Hz), 4.37 (2 H, qd, J=7.08, 1.43 Hz), 2.75 (3 H, s), 2.72 (3 H, s), 1.39 (3 H, d, J=7.26 Hz), 1.35 (3 H, d, J=7.04 Hz); Analytical LCMS: column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 90:10 acetonitrile:water with 10 mM ammonium acetate; Temperature: 45° C.; Gradient: 0-100% B over 4 minutes, flow rate=4 mL/min, product retention=2.3 min+2.4 min (mixture of diastereomers).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Cl:32])=[C:5]([C:7](=[N:30][OH:31])[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[CH:12]2[S:13][CH2:14][C:15]([S:23][C:24]2[S:25][C:26]([NH2:29])=[N:27][N:28]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1.C(=O)(O)[O-].[Na+:37]>O>[Na+:37].[NH2:1][C:2]1[S:3][C:4]([Cl:32])=[C:5]([C:7](=[N:30][OH:31])[C:8]([NH:10][C@@H:11]2[C:18](=[O:19])[N:17]3[CH:12]2[S:13][CH2:14][C:15]([S:23][C:24]2[S:25][C:26]([NH2:29])=[N:27][N:28]=2)=[C:16]3[C:20]([O-:22])=[O:21])=[O:9])[N:6]=1
Reactant: Nc1nnc(SC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)C(=NO)c4nc(N)sc4Cl)C3SC2)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1nnc(SC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)C(=NO)c4nc(N)sc4Cl)C3SC2)s1

Procedure:
(7R)-7-[2-(2-Amino-5-chlorothiazol-4-yl)-2-hydroxyiminoacetylamino]-3-(5-amino-[1,3,4]thiadiazol-2-ylsulfanyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid (85 mg, 0.11 mmol) was dissolved in water (2.0 mL) and the pH was adjusted to 6.0 with 1.0 M aqueous sodium bicarbonate. The solution was loaded onto an HP20 column and inorganics were removed by washing the column thoroughly with water. The title compound was isolated by eluting with 2:1 acetonitrile/water, removing acetonitrile under reduced pressure and lyophilizing the remaining mixture (60 mg, 63%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7](=[O:14])/[C:6]/2=[CH:15]/OC.[N:18]1([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15][NH:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:30][CH:29]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(OC)cc21
Reactant: Nc1ccc(CN2CCCCC2)cc1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(=CNc1ccc(CN3CCCCC3)cc1)C(=O)NC2=O
Temperature: 110 °C
Yield: 77.7 %

Procedure:
A mixture of (4E)-6-methoxy-4-methoxymethylene-4H-isoquinoline-1,3-dione (117 mg, 0.50 mmole), N,N-dimethylformamide (1 mL) and 4-piperidin-1-ylmethyl-phenylamine (95 mg, 0.50 mmole) is stirred and heated at 110° C. for one hour, cooled in the refrigerator overnight. The reaction mixture is evaporated to dryness, taken up in 7.5% methanol in chloroform and passed through a short pad of Florisil eluting with 7.5% methanol in chloroform. The eluate is evaporated in vacuo, treated with acetonitrile, filtered and dried to give a yellow solid 152 mg (78%), mp 272-5° C. dec; MS (ESI): m/z 392.4 (M+H).
Reaction SMILES: O1[CH:6]2[CH:2]1[C:3](=[O:15])[CH2:4][CH:5]2[O:7][Si:8]([C:11](C)(C)C)([CH3:10])C.[CH3:16][C:17]([CH3:27])([CH2:22][CH2:23][CH2:24][CH2:25][SH:26])[C:18]([O:20][CH3:21])=[O:19]>CO>[C:17]([CH:6]1[CH2:2][C:3](=[O:15])[C:4]([S:26][CH2:25][CH2:24][CH2:23][CH2:22][C:17]([C:18]([O:20][CH3:21])=[O:19])([CH3:27])[CH3:16])=[C:5]1[O:7][SiH:8]([CH3:10])[CH3:11])([CH3:22])([CH3:18])[CH3:16]
Reactant: COC(=O)C(C)(C)CCCCS
Reactant: CC(C)(C)[Si](C)(C)OC1CC(=O)C2OC12
Solvent: CO
Product: COC(=O)C(C)(C)CCCCSC1=C(O[SiH](C)C)C(C(C)(C)C)CC1=O
Reaction time: 3 h
Yield: 128.5 %

Procedure:
1.21 g (5.3 mmoles) of 2,3-epoxy-4(RS)-t-butyl-dimethylsilyloxycyclopentan-1-one was dissolved in 2.5 ml of methanol and then under cooling, 1.0 g (5.3 mmoles) of methyl 2,2-dimethyl-6-mercaptohexanoate was added. The mixture was stirred for 3 hours. After stirring, the solvent was removed by evaporation, and after adding water, the residue was extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated. The resulting crude product was chromatographed on a silica gel column using ethyl acetate-hexane (1/9) as an eluent to give 1.364 g (yield 64%) of 4(RS)-t-butyldi-methylsilyloxy-2-(5-methoxycarbonyl-5,5-dimethylpentylthio)-2-cyclopentenone.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:15]3[C:20]([C:21]([O-:23])=O)=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[NH4+].S(Cl)(Cl)=O.[NH2:29][C:30]1[S:31][C:32]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:33]=2[N:34]=1>C(Cl)Cl.N1C=CC=CC=1>[Cl:39][C:37]1[CH:36]=[CH:35][C:33]2[N:34]=[C:30]([NH:29][C:21]([C:20]3[C:15]([NH:14][CH2:13][CH:10]4[CH2:9][CH2:8][N:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)[CH2:12][CH2:11]4)=[N:16][CH:17]=[CH:18][CH:19]=3)=[O:23])[S:31][C:32]=2[CH:38]=1
Reactant: Nc1nc2ccc(Cl)cc2s1
Reactant: O=C([O-])c1cccnc1NCC1CCN(c2ccncc2)CC1
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1nc2ccc(Cl)cc2s1)c1cccnc1NCC1CCN(c2ccncc2)CC1
Reaction time: 3 h
Yield: 11.1 %

Procedure:
A solution of ammonium 2-[[1-(4-pyridinyl)piperidin-4-ylmethyl]amino]pyridine-3-carboxylate (400 mg, 1.28 mmol) in methylene chloride (5 mL) was treated with thionyl chloride (0.112 mL, 1.54 mmol) and the mixture was heated at reflux. After 3 h, the mixture was cooled and then treated dropwise with a solution of 2-amino-6-chlorobenzothiazole (284 mg, 1.54 mmol) in pyridine (5 mL). After 1 h, the mixture was concentrated in the presence of silica gel. The residue was purified by column chromatography (SiO2: 1 to 4% [2 N ammonia in methanol]:chloroform) followed by recrystallization from methanol to yield 68 mg (11%) of the title compound.
Reaction SMILES: [C:1]1([NH:7][N:8]=[C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2F)[N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+]>O1CCCC1>[C:1]1([N:7]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:9]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:12][CH2:11]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Fc1ccccc1C(=NNc1ccccc1)N1CCN(c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc(N2CCN(c3nn(-c4ccccc4)c4ccccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.4 %

Procedure:
To a stirred solution, under nitrogen, of 9.1 g of 1-[(phenylhydrazono)(2-fluorophenyl)methyl]-4-phenylpiperazine in 100 ml of tetrahydrofuran was added, dropwise, a solution of 3.3 g of potassium t-butoxide in 35 ml of tetrahydrofuran. The reaction mixture was stirred at ambient temperature for 4 hours and concentrated. The concentrate was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated to a solid. The solid was flash chromatographed on silica gel utilizing hexane/ethyl acetate (30%) as the eluent. Concentration of the appropriate fractions followed by recrystallization from ethyl acetate/hexane gave 2.1 g (25%) of 1-phenyl-3-(4-phenyl-1-piperazinyl)-1H-indazole, mp 129°-130°.
Reaction SMILES: [C:1](/[C:4](=[CH:10]\[CH3:11])/[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].[NH2:12][C:13]1[N:17]=[CH:16][NH:15][N:14]=1>C(O)C>[CH2:8]([O:7][C:5]([C:4]1[CH:1]([CH3:2])[N:14]2[N:15]=[CH:16][N:17]=[C:13]2[NH:12][C:10]=1[CH3:11])=[O:6])[CH3:9]
Reactant: Nc1nc[nH]n1
Reactant: C/C=C(\C(C)=O)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C1=C(C)Nc2ncnn2C1C
Temperature: 50 °C
Yield: 63.1 %

Procedure:
To 50 ml of ethanol are added 7.8 g of ethyl α-acetylcrotonate and 4.2 g of 3-amino-1,2,4-triazole, stirred at 50° C. for an hour and then heated under reflux for an hour. The ethanol is evaporated under reduced pressure, and the obtained crystals are recrystallized from ethanol to give 7 g of 6-ethoxycarbonyl-5,7-dimethyl-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine, melting at 155°-157° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]=[C:11]2[CH2:16][CH2:15][CH:14]([C@H:17]3[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)[CH:5]=[CH:6][C:7]=1[F:8].B1C2CCCC1CCC2.[OH-:37].[Na+].OO.Cl>C1COCC1.C1(C)C=CC=CC=1.O.C(O)C>[OH:37][CH:10]([C@H:11]1[CH2:12][CH2:13][C@H:14]([C@H:17]2[CH2:22][CH2:21][C@H:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH2:18]2)[CH2:15][CH2:16]1)[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1
Reactant: [OH-]
Reactant: CCCCC[C@H]1CC[C@H](C2CCC(=CCc3ccc(F)c(F)c3)CC2)CC1
Agent: B1C2CCCC1CCC2
Agent: Cl
Agent: OO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(O)Cc3ccc(F)c(F)c3)CC2)CC1
Temperature: 25 °C

Procedure:
To a solution of 11.24 g (30 mmol) of 1-(3,4-difluorophenyl)-2-[4-(trans-4-pentylcyclohexyl) cyclohexylidene]ethane in 30 ml of THF were added 300 ml (150 mmol) of 0.5 M-9-BBN (THF solution) over a period of 35 minutes, at room temperature under stirring in an argon atmosphere and the mixture was stirred as such overnight. 90 ml of ethanol and 30 ml of an aqueous 6M-NaOH solution were added, and 60 ml of an aqueous 30% H2O2 solution were added over a period of 40 minutes (during this period, refluxed spontaneously). The mixture was stirred at 50° C. for 1 hr. After cooling, 180 ml of an aqueous 1M-HCl solution, water and toluene were added and the precipitate was filtered through Celite. An organic layer and an aqueous layer were separated, the aqueous layer was extracted with toluene, an extract combined with the organic layer was washed with an aqueous 5% Na2S2O3 solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the solution was condensed. The concentrate was purified by column chromatography (elution solvent: heptane:ethyl acetate=5:1). The eluate was recrystallized from 50 ml of heptane-5 ml of solmix to obtain 6.86 g of the title compound (58%, Cr 108.4-109.2 N 143.1-144.1 Iso).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])[CH:6]=[CH:5][C:4]=1[Cl:14].C[N+]1([O-])CC[O:19]CC1>O1CCOCC1>[Cl:14][C:4]1[CH:5]=[CH:6][C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:8][C:3]=1[CH:2]=[O:19]
Reactant: C[N+]1([O-])CCOCC1
Reactant: COCCOc1ccc(Cl)c(CBr)c1
Solvent: C1COCCO1
Product: COCCOc1ccc(Cl)c(C=O)c1

Procedure:
2-(Bromomethyl)-1-chloro-4-(2-methoxyethoxy)benzene (1 eq.) from the previous step and NMO (3 eq.) were stirred in dioxane (0.3 M) at 90° C. for 6 h. The reaction mixture was then quenched with saturated aqueous sodium bicarbonate and extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound.
Reaction SMILES: C([O:5][C:6](=[O:53])[CH2:7][O:8][C:9]1[CH:14]=[C:13]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:34])[N:21]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=3)[CH:22]=[CH:23][CH:24]=2)=[O:18])[CH:12]=[C:11]([C:35]2[C:43]3[C:38](=[N:39][CH:40]=[CH:41][CH:42]=3)[N:37](S(C3C=CC=CC=3)(=O)=O)[CH:36]=2)[CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O.C(Cl)Cl>>[F:33][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][C:29]=1[F:32])[CH2:25][N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]([NH:16][CH2:15][C:13]2[CH:14]=[C:9]([CH:10]=[C:11]([C:35]3[C:43]4[C:38](=[N:39][CH:40]=[CH:41][CH:42]=4)[NH:37][CH:36]=3)[CH:12]=2)[O:8][CH2:7][C:6]([OH:53])=[O:5])=[O:18])[C:20]1=[O:34]
Reactant: CC(C)(C)OC(=O)COc1cc(CNC(=O)c2cccn(Cc3ccc(F)c(F)c3)c2=O)cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)COc1cc(CNC(=O)c2cccn(Cc3ccc(F)c(F)c3)c2=O)cc(-c2c[nH]c3ncccc23)c1
Reaction time: 8 h
Yield: 36.7 %

Procedure:
A mix of [3-(1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-({[1-(3,4-difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenoxy]-acetic acid tert-butyl ester (20 mg, 0.00003 mol) and Trifluoroacetic Acid (20 mg, 0.0001 mol;) in Methylene chloride (8 mL, 0.1 mol) was stirred for overnight. LC-MS showed only formation of the des-phSO2 and saponified product C (1.24 min, ES+/545.64). Evaporated off the solvents and dissolved in DMSO and water and purified on Gilson HPLC to give the desired product (6 mg, 40%) MS (ES+) m/z 545.64 (M+1). 1H NMR (DMSO, 400 MHz): δ 8.41 (dd, 1H), 8.26 (d, 2H), 8.24 (dd, 1H), 7.88 (s, 2H), 7.45-7.35 (m, 2H), 7.30 (s, 2H), 7.18 (m, 1H), 7.10-7.07 (m, 2H), 6.77 (s, 2H), 6.60 (t, 1H), 5.22 (s, 2H), 4.75 (s, 2H), 4.55 (d, 2H),
Reaction SMILES: [O-]Cl=O.[Na+].[OH2:5].[CH2:6]([C:13]1([CH2:19][CH:20]=[O:21])[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CS(C)=O.CCOCC>[CH2:6]([C:13]1([CH2:19][C:20]([OH:5])=[O:21])[CH2:18][CH2:17][CH2:16][CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=CCC1(Cc2ccccc2)C=CCCC1
Reactant: O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CCOCC
Solvent: CS(C)=O
Product: O=C(O)CC1(Cc2ccccc2)C=CCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of NaH2PO4 (55.3 g), NaClO2 (36.3 g), DMSO (200 mL) and water (375 mL) was added a solution of 3-benzyl-3-formylmethylcyclohexene (57 g) in DMSO (150 mL) during a 3 hour period. After addition, the mixture was stirred overnight and diluted with ether (200 mL). This was extracted with saturated NaHCO3 (3×100 mL). The combined aqueous layer was cooled to 0° C. and acidified to PH=1 with conc. HCl. This was extracted with CH2Cl2 (3×300 mL). The combined organic layer was dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel to give the title compound as thick oil (50 g). MS (MH+=231).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:27])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][Br:27])=[CH:15][CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2nsc(-c3ccc(F)cc3)n2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(-c2nc(-c3ccc(CBr)cc3)ns2)cc1
Temperature: 25 °C
Yield: 106.8 %

Procedure:
To a solution of 5-(4'-fluorophenyl)-3-(p-tolyl)-1,2,4-thiadiazole (0.16 g, 0.59 mmol) in CCl4 (20 ml) is added NBS (0.11 g, 0.59 mmol) and the mixture is heated to reflux for 36 hours. The mixture is cooled to room temperature and filtered through celite. The mother liquor is concentrated. The residue is taken up in chloroform (30 ml) amd washed with water (30 ml). The organic layer is dried over MgSO4 and concentrated to yield 5-(4'-fluorophenyl)-3-(p-bromomethylphenyl)-1,2,4-thiadiazole, (0.22 g) as crude product which is used as is without further purification.
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[OH:23])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[F:25].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.O>CC#N>[C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20]([F:25])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[OH:23])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccccc2c1O
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)c(F)c2ccccc2c1O
Temperature: 23 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
A solution of ethyl 2-tert-butoxy-2-(1-hydroxy-3-methylnaphthalen-2-yl)acetate (1.50 g, 4.74 mmol) in CH3CN (37.5 mL) was cooled to 0° C. Selectfluor (1.70 g, 4.74 mmol) was added, and the reaction was allowed to warm to 23° C. After 2 h, the reaction was added slowly to a mixture of saturated Na2HPO4 (70 mL) and H2O (30 mL) at 23° C. More H2O (40 mL) was added, and the system was extracted with DCM (3×40 mL). The combined organic phases were treated with hexane (20 mL). The phase that separated was removed. The remaining organic phase was dried (Na2SO4), filtered, and concentrated. The filtrate was concentrated and dissolved in benzene. The solution was wet-loaded onto a 24 g “gold” ISCO silica gel column and purified by flash chromatography (ethyl acetate/hexanes) giving the desired product (1.26 g, 79%). 1H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H), 8.23 (d, J=8.2 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.51 (dd, J=6.9, 6.9 Hz, 1H), 7.45 (dd, J=6.9, 6.9 Hz, 1H), 5.46 (s, 1H), 4.23-4.14 (m, 2H), 2.49 (d, JHF=3.2 Hz, 3H), 1.31 (s, 9H), 1.20 (t, J=7.1 Hz, 3H). 19F NMR (377 MHz, CDCl3) δ−137.3 (app. s).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH2:18]([NH2:23])[CH2:19][CH2:20][CH2:21][CH3:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.CO>CO>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][CH:14]([NH:23][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C1CCC(Nc2ccc3[nH]ncc3c2)CC1
Reactant: CCCCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCCNC1CCC(Nc2ccc3[nH]ncc3c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 13.4 %

Procedure:
4-(1H-5-Indazolylamino)-1-cyclohexanone (intermediate 3) (57 mg) and amylamine (44 mg) were dissolved in methanol (1 ml), and sodium triacetoxyborohydride (105 mg) was added by portions to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. Hydrochloric acid-methanol was then added thereto, and the reaction mixture was stirred and was then concentrated. The residue was purified by HPLC [0.5% aqueous trifluoroacetic acid solution/acetonitrile] to give an anti-form compound (10 mg) and a syn-form compound (10 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([NH:7][CH2:8][C:9]([OH:11])=O)=[O:6].C1(N=C=NC2CCCCC2)CCCCC1.[N:30]12[CH2:38][CH2:37][CH:34]([CH2:35][CH2:36]1)[NH:33][CH2:32][CH2:31]2.O>O1CCOCC1>[N:30]12[CH2:38][CH2:37][CH:34]([CH2:35][CH2:36]1)[N:33]([C:9](=[O:11])[CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:12]=[CH:13][CH:14]=[C:2]([Br:1])[CH:3]=1)[CH2:32][CH2:31]2
Reactant: O=C(O)CNC(=O)c1cccc(Br)c1
Reactant: C1CN2CCC(CC2)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCC(=O)N1CCN2CCC1CC2)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.77 g (3 mmol) of N-(3-bromobenzoyl)glycine dissolved in 30 ml of dioxane is placed in a 100 ml round-bottomed flask, 0.68 g (3.3 mmol) of dicyclohexylcarbodiimide is added and the mixture is stirred at room temperature for 30 minutes, 0.38 g (3 mmol) of 1,4-diazabicyclo[3.2.2]nonane is added and the mixture is stirred for a further two hours. 30 ml of water are added and the precipitate formed is filtered off, the filtrate is extracted with chloroform and the organic phase is then extracted with aqueous 0.1N hydrochloric acid solution. The aqueous extraction phase is basified to pH 10 by addition of concentrated aqueous sodium hydroxide solution and extracted with chloroform. The organic phase is dried over sodium sulfate and concentrated under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:10]1C(C(N)=O)=C(C)C=CN=1.[OH-].[Na+].BrBr>>[Cl:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccnc1Cl
Reactant: Cc1ccnc(Cl)c1C(N)=O
Agent: BrBr
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccnc(Cl)c1N
Yield: 90 %

Procedure:
In a manner similar to that described for 2-chloro-3-aminopyridine in Example 14, the title compound was prepared in 90% yield (m.p. 63°-66° C., uncorrected) from 2.57 g of 2-chloro-4-methyl-3-pyridinecarboxamide, 2.28 g of NaOH, and 3.1 g of bromine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:23]=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)=[CH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:23]=[N:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cnc3ccccc3n2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2cnc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 83.3 %

Procedure:
A mixture of 0.55 gm (1.8 mMol) 1-tert-butoxycarbon-yl-4-(quinoxalin-2-yl)-1,2,5,6-tetrahydropyridine and 0.1 gm 5% palladium on carbon in 10 mL methanol was stirred at room temperature for 45 minutes under a hydrogen atmosphere. The reaction mixture was then filtered and the filtrate concentrated under reduced pressure to provide 0.47 gm (84%) of 1-tert-butoxycarbonyl-4-(quinoxalin-2-yl)piperidine as a yellow oil.