Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:27]([O:28][CH3:29])=[CH:26][C:7]2[C:8]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)=[N:9][C@H:10]3[C@@H:15]([C:6]=2[CH:5]=1)[CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[CH3:2].[CH2:30]([O:37][CH2:38][C@@H:39]([NH2:41])[CH3:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][CH2:38][C@@H:39]([NH:41][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][C:17]([C:8]2[C:7]3[CH:26]=[C:27]([O:28][CH3:29])[C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=3[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][N:13]([CH3:16])[CH2:14]3)[N:9]=2)=[CH:18][CH:19]=1)[CH3:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C[C@H](N)COCc1ccccc1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCN(C)C[C@H]21
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N[C@@H](C)COCc3ccccc3)cc1)=N[C@@H]1CCN(C)C[C@H]21

Procedure:
Prepared from 4-((4aR,10bS)-9-ethoxy-8-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridin-6-yl)benzoic acid and N—((S)-2-benzyloxy-1-methyl-ethyl)-amine as described for example 1.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][C@H:5]1[CH2:9][CH2:8][C@@H:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]2)[CH2:6]1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([Cl:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1>ClCCl.[OH-].[Na+]>[ClH:26].[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:4]([CH3:3])[C@H:5]2[CH2:9][CH2:8][C@@H:7]([N:10]3[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]3)[CH2:6]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CN[C@H]1CC[C@@H](N2CCC(C)CC2)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N(C)[C@H]2CC[C@@H](N3CCC(C)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 89.5 %

Procedure:
A mixture of cis-1-methylamino-3-(4-methylpiperidin-1-yl)cyclopentane dihydrochloride (24.5 mg, 0.091 mmol) and 4-toluenesulfonyl chloride (27.9 mg, 0.146 mmol) in dichloromethane (2 ml) and 1M aqueous sodium hydroxide (2 ml) was rapidly stirred at room temperature overnight (22 hours). The phases were separated and the aqueous extracted with more dichloromethane (5 ml). The combined organics were dried (MgSO4) and evaporated. The residue was dissolved in methanol-ethyl acetate and treated with excess 1M hydrogen chloride in diethyl ether. Recrystallization of the resulting solid from methanol-ethyl acetate gave the title compound (31.5 mg, 89%) as a white solid; δH (400 MHz, CD3OD) 1.00 (3H, d, J 6.1 Hz), 1.43 (2H, m), 1.62-1.83 (5H, m), 1.91 (2H, m), 2.04-2.18 (2H, m), 2.43 (3H, s), 2.77 (3H, s), 2.89 (2H, m), 3.50 (3H, m), 4.41 (1H, m), 7.40 (2H, d, J 8.5 Hz), 7.71 (2H, d, J 8.5 Hz); m/z (ES+) 351 ([M+H]+, 100%).
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[CH3:13][N:14]1[CH:19]2[CH2:20][CH2:21][CH:15]1[CH2:16][CH:17]([O:22][C:23]1[N:28]=[C:27]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:26]=[C:25]([C:35]3[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=3)[N:24]=1)[CH2:18]2.[NH2:42][C:43]1[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=1.CCN(CC)CC>C(Cl)Cl>[CH3:13][N:14]1[CH:15]2[CH2:21][CH2:20][CH:19]1[CH2:18][CH:17]([O:22][C:23]1[N:28]=[C:27]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[N:26]=[C:25]([C:35]3[CH:36]=[CH:37][C:38]([NH:41][C:5]([NH:42][C:43]4[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=4)=[O:11])=[CH:39][CH:40]=3)[N:24]=1)[CH2:16]2
Reactant: CN1C2CCC1CC(Oc1nc(-c3ccc(N)cc3)nc(N3CCOCC3)n1)C2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C2CCC1CC(Oc1nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CCOCC3)n1)C2
Reaction time: 0.25 h
Yield: 27.1 %

Procedure:
To a stirred solution of triphosgene (60 mg, 0.20 mmol) in CH2Cl2 (3 mL) was added 4-[4-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenylamine (100 mg, 0.25 mmol) at 25° C. The reaction mixture was stirred for 15 min and 4-aminopyridine (70 mg, 0.75 mmol) and NEt3 (346 μL, 2.5 mmol) were added and the reaction mixture was stirred for additional 1 hr. The solvents were removed and the crude mixture was purified by semi-prep-HPLC (NH3-method) to give 1-{4-[4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yloxy)-6-morpholin-4-yl-[1,3,5]triazin-2-yl]-phenyl}-3-pyridin-4-yl-urea (28 mg, 22% yield); MS (ESI) m/z 517.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.O.N1[C:23]2[C:14](=[CH:15][CH:16]=[C:17]3[C:22]=2N=CC=C3)[CH:13]=CC=1.O=O.[N:26]#N>[Cu]Br.C(#N)C1C=CC=CC=1>[Br:8][C:6]1[CH:5]=[CH:4][N:3]2[N:26]=[C:13]([C:14]3[CH:23]=[CH:22][CH:17]=[CH:16][CH:15]=3)[N:1]=[C:2]2[CH:7]=1
Reactant: Nc1cc(Br)ccn1
Reactant: c1cnc2c(c1)ccc1cccnc12
Reactant: N#N
Agent: [Cu]Br
Agent: O=O
Solvent: O
Solvent: N#Cc1ccccc1
Product: Brc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 130 °C
Yield: 64 %

Procedure:
A mixture of 2-amino-4-bromopyridine (5.00 g, 28.3 mmol), copper (I) bromide (207 mg, 1.44 mmol), 1,10-phenanthroline monohydrate (284 mg, 1.44 mmol) and benzonitrile (60 mL) was heated in a 380-mL autoclave to 130° C. and stirred for 23 h under 20 bar of O2/N2 (5:95). After the autoclave was vented and opened (100% conversion, HPLC method cf. example 1.3), the dark brown reaction suspension was then cooled to 0-5° C. and filtered. The filter cake was washed with TBME (40 mL) and dried to yield crude 7-bromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (5.12 g, 64%) as a green solid with 97.0% purity (HPLC area-%, HPLC method see example 1.3).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[H-].[Na+].[CH3:24]I.O>CN(P(N(C)C)(N(C)C)=O)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([N:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])[CH3:24])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CI
Reactant: COC(=O)c1nccnc1Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: COC(=O)c1nccnc1N(C)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3.1 g 3-(4-chloro-2-nitrophenylamino)-pyrazine-2-carboxylic acid methyl ester in 15 ml absolute hexamethylphosphorotriamide is treated portionwise with 0.3 g sodium hydride. The reaction mixture is stirred at room temperature for 1 hour and then treated dropwise with 2.8 g methyl iodide, and the temperature is maintained under 20° C. After the reaction mixture has been stirred for 1 hour at room temperature 10 ml water are added dropwise. The mixture is extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate and evaporated. The residue is recrystallised from ethyl acetate to give the heading compound, m.p. 111°-112°.
Reaction SMILES: O.NN.[Br:4][C:5]1[C:6]([C:24]#[N:25])=[N:7][N:8]([CH3:23])[C:9]=1[CH2:10][CH2:11][N:12]1C(=O)C2C(=CC=CC=2)C1=O>C(O)C>[NH2:12][CH2:11][CH2:10][C:9]1[N:8]([CH3:23])[N:7]=[C:6]([C:24]#[N:25])[C:5]=1[Br:4]
Reactant: Cn1nc(C#N)c(Br)c1CCN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: Cn1nc(C#N)c(Br)c1CCN
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A mixture of hydrazine hydrate (6.40 g, 127 mmol) and 4-bromo-5-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1-methyl-1H-pyrazole-3-carbonitrile (9.15 g, 25.5 mmol) in ethanol (200 mL) was heated at reflux for 80 minutes, then was allowed to cool to ambient temperature in a water bath. A precipitate formed and was isolated by filtration and washed with cold ethanol. The filtrate was concentrated under reduced pressure, and the resulting white solid was twice treated with toluene and concentrated under reduced pressure then dried under vacuum to provide 5.74 g of 5-(2-aminoethyl)-4-bromo-1-methyl-1H-pyrazole-3-carbonitrile as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])[C:10]([O:12]CC)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>CO.C1COCC1.O.[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C@@H:15]([CH3:20])[C:16]([F:19])([F:17])[F:18])[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C(c1ccc(Cl)c(Cl)c1)[C@@H](C)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](C(C(=O)O)c1ccc(Cl)c(Cl)c1)C(F)(F)F
Temperature: 40 °C
Reaction time: 6 h

Procedure:
3.77 g (crude, about 11.5 mmol) of ethyl (3R)-2-(3,4-dichlorophenyl)-4,4,4-trifluoro-3-methylbutanoate (diastereomer mixture) were dissolved in a mixture of 14 ml of methanol, 14 ml of THF and 5 ml of water, and 9.16 g of 50% strength aqueous sodium hydroxide solution were added at 0° C. The reaction mixture was stirred at 40° C. for about 6 h. The mixture was then acidified with 1 N hydrochloric acid (pH about 2) and extracted three times with ethyl acetate. The combined organic phases were washed with sat. sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. This gave 3.94 g of the target compound as a crude product which could be used without further purification for subsequent reactions.
Reaction SMILES: [C:1]1(=O)[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C(O)(C(F)(F)F)=O>C(OCC)(=O)C.[Pd]>[C:4]1(=[O:6])[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:1][NH:5]1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCc2ccccc21
Reaction time: 48 h
Yield: 7.2 %

Procedure:
A solution of phthalimide (1.0 g, 6.8 mmol) and TFA (5 mL) in ethyl acetate (100 mL) was added 10% Pd—C (1 g). The reaction mixture was hydrogenated at 55 psi for 2 days. Catalyst was then filtered through diatomaceous earth (Celite®) and the filtrate was concentrated to give yellowish solid as crude product (0.37 g). 120 mg of them was then purified by Prep. TLC (eluted with dichloromethane) to give pure 2,3-dihydro-isoindol-1-one (65 mg).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:6][CH:7]=1.C(N)(=S)C1C=CC=CC=1.ClCC(CCl)=O.[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[CH:37]([OH:44])[CH2:38][N:39]1[CH:43]=[CH:42][N:41]=[CH:40]1>>[ClH:1].[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[CH:37]([O:44][CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:6][CH:7]=1)[CH2:38][N:39]1[CH:43]=[CH:42][N:41]=[CH:40]1
Reactant: OC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: NC(=S)c1ccccc1
Agent: O=C(CCl)CCl
Product: Cl
Product: Clc1ccc(C(Cn2ccnc2)OCc2csc(-c3ccccc3)n2)c(Cl)c1

Procedure:
Following the procedure of Example 1b, 4-chloromethyl-2-phenylthiazole (prepared according to Example 1a from thiobenzamide and 1,3-dichloroacetone, m.p. 134°-136° C. (absolute alcohol/ethylacetate), is reacted with 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol to obtain the title compound, m.p. 204°-205° C. (absolute alcohol/ethyl acetate).
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1/[CH:24]=[CH:25]/[N+:26]([O-:28])=[O:27].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:10]([N:4]1[CH2:5][CH:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH3:17])[CH:25]([N+:26]([O-:28])=[O:27])[CH2:3]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1ccccc1/C=C/[N+](=O)[O-]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1C1CN(Cc2ccccc2)CC1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.6 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (3.93 g, 16.55 mmol) in CH2Cl2 (60 ml) was added drop wise, over a 30 minutes period, to a stirred solution of 1-methyl-2-((E)-2-nitro-vinyl)-benzene (2.70 g, 16.55 mmol) and trifluoroacetic acid (0.13 ml, 1.65 mmol) in CH2Cl2 (30 ml) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 48 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/H 1:6) afforded 1.01 g (21%) of the title compound as a light yellow oil. ES-MS m/e: 297.4 (M+H+).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-:23].[K+].[K+]>CC(=O)CC>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:23][C:5]1[CH:6]=[CH:7][C:2]([C:1](=[O:8])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:3][CH:4]=1)[CH3:21]
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(C(=O)c2ccccc2)cc1

Procedure:
This ester-linked benzophenone was prepared according to the method of PCT Patent Appln. No. WO 93/16131 (Everaerts et al.). In a first step, an ethyl-(4-benzoyl-phenoxy)acetate (EPBA) precursor was prepared by refluxing a mixture of 100.0 grams (0.51 moles) 4-hydroxybenizoplhenonie, 85.2 grams (0.51 moles) ethyl bromoacetate and 800 ml of 2-butanone (MEK) in the presence of an excess of potassium carbonate (209 grams or 1.5 moles). The carbonate was filtered off and the MEK removed on a rotovapor. The residue was crystallized from isopropyl alcohol to yield a white, flaky product with a sharp melting point of 82° C. The structure was confirmed by NoM.
Reaction SMILES: CO[C:3]1[CH:35]=[CH:34][C:6]2[NH:7][CH:8]([CH2:32][CH3:33])[N:9]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:19]([NH:21][S:22]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=4)(=[O:24])=[O:23])=[O:20])=[CH:12][CH:11]=3)[C:5]=2[CH:4]=1.[OH-:36].[Na+]>Br>[CH2:32]([C:8]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:19]([NH:21][S:22]([C:25]3[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=3)(=[O:24])=[O:23])=[O:20])=[CH:12][CH:11]=2)[C:5]2[CH:4]=[CH:3][C:35]([OH:36])=[CH:34][C:6]=2[N:7]=1)[CH3:33]
Reactant: CCC1Nc2ccc(OC)cc2N1c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: [OH-]
Agent: Br
Agent: [Na+]
Product: CCc1nc2cc(O)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture of 1-[4-(2-chloroethyl)phenyl]-2-ethyl-5-methoxy-1H-benzimidazole (step 5 of Example 71, 600 mg, 1.9 mmol) in 48% hydrobromic acid (60 mL) was stirred at 100° C. for 6 h. After cooling, the mixture was neutralized with 2N aqueous NaOH and extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL), dried (Na2SO4), and concentrated to afford 890 mg (quant.) of the title compound as pale yellow solids: 1H-NMR (CDCl3) δ 7.64 (4H, s), 7.16 (2H, m), 6.97-7.01 (1H, m), 3.86 (2H, t, J=7.1 Hz), 3.30 (2H, t, J=7.1 Hz), 2.92 (2H, q, J=7.8 Hz), 1.29 (3H, t, J=7.8 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[CH:4][C:3]=1[N:10]1[N:14]=[C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]2=[N:11]1.[NH:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22]>CC(C)=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:19]([CH2:23][CH2:24][OH:25])[CH2:20][CH2:21][OH:22])=[CH:4][C:3]=1[N:10]1[N:14]=[C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]2=[N:11]1
Reactant: OCCNCCO
Reactant: Oc1ccc(CBr)cc1-n1nc2ccccc2n1
Solvent: CC(C)=O
Product: OCCN(CCO)Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Temperature: 75 °C
Reaction time: 6 h

Procedure:
2-(2′-Hydroxy-5′bromomethylphenyl)benzotriazole (3.03 g. 0.01 mole), diethanol amine (3.14 g. 0.03 mole) were dissolved in 100 ml. of acetone. The reaction mixture was refluxed with constant stirring at 75° C. for 6 h. The solvent was then removed by rotary evaporation. Crude product was purified using silica gel column chromatography Product was identified by 1H-NMR.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([OH:43])=O)=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.O.C(O)(=O)C(O)=O.C(O)(=O)C(O)=O.[CH3:61][C:62]1[C:66]([CH2:67][NH2:68])=[C:65]([CH3:69])[NH:64][N:63]=1>>[CH3:61][C:62]1[C:66]([CH2:67][NH:68][C:41]([C:39]2[S:40][C:36]([N:33]3[CH2:34][CH2:35][N:31]([CH2:30][C:29]4[CH:46]=[CH:47][C:26]([F:25])=[CH:27][CH:28]=4)[C:32]3=[O:45])=[CH:37][C:38]=2[CH3:44])=[O:43])=[C:65]([CH3:69])[NH:64][N:63]=1
Reactant: Cc1n[nH]c(C)c1CN
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Agent: O=C(O)C(=O)O
Solvent: O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1c(C)n[nH]c1C
Yield: 24 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (3,5-dimethyl-1H-pyrazol-4-yl)methanamine dioxalate monohydrate, the title compound was obtained as a colorless solid in 24% yield: 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (m, 2H), 7.07-6.99 (m, 2H), 6.08 (s, 1H), 5.61 (t, J=4.6 Hz, 1H), 4.42 (s, 2H), 4.35 (d, J=4.6 Hz, 2H), 3.83-3.75 (m, 2H), 3.47-3.39 (m, 2H), 2.48 (s, 3H), 2.28 (s, 6H); MS (ES+) m/z 442.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[C:20]([C:25]([F:28])([F:26])[F:27])[CH:19]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCBr
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(O)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc(CCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Compound 1-1 (500 mg) was dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (494 mg) and 1-bromohexane (0.201 ml) were added, and the mixture was stirred at 80° C. for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (620 mg) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](OS(C2C=CC(C)=CC=2)(=O)=O)=[C:4]([N+:23]([O-:25])=[O:24])[C:3]1=[O:26].[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C=O)C>[N:27]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:2]([CH3:1])[C:3](=[O:26])[C:4]=1[N+:23]([O-:25])=[O:24])=[N+:28]=[N-:29]
Reactant: Cc1ccc(S(=O)(=O)Oc2c([N+](=O)[O-])c(=O)n(C)c3ccccc23)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c([N+](=O)[O-])c(N=[N+]=[N-])c2ccccc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 92 %

Procedure:
A solution of toluene-4-sulfonic acid 1-methyl-3-nitro-2-oxo-1,2-dihydro-quinolin-4-yl ester (20.0 g, 53.42 mmol) in DMF (70 mL) was treated with a small excess of sodium azide (3.8 g, 59.0 mmol) and stirred at room temp for 17 h. The solvent was evaporated under reduced pressure. Then the reaction mixture was poured into 500 mL of ice water and the resulting precipitate was collected by suction filtration and dried in vacuo. The pure 4-azido-1-methyl-3-nitro-1H-quinolin-2-one was obtained (12.0 g, 92% yield). 1H-NMR (CDCl3): δ 8.16 (d, 1H, J=8.8 Hz), 7.75 (t, 1H, J=7.6 Hz), 7.42 (d, 1H, J=8.4 Hz), 7.36 (t, 1H, J=7.6 Hz), 3.79 (s, 3H). MS: calculated for C10H7N5O3+H 246.1; found: 246.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([Cl:12])=[CH:5]2.C([Sn](CCCC)(CCCC)[C:18]1[S:22][CH:21]=[N:20][CH:19]=1)CCC>COCCOC.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:6]1[N:7]=[CH:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([C:18]1[S:22][CH:21]=[N:20][CH:19]=1)=[CH:11][CH:10]=2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Reactant: Clc1cc2cc(Br)ccc2cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: COCCOC
Product: Clc1cc2cc(-c3cncs3)ccc2cn1
Temperature: 120 °C
Reaction time: 1 h
Yield: 27.9 %

Procedure:
A suspension of 6-bromo-3-chloroisoquinoline (39 mg, 0.16 mmol), 5-(tributylstannyl)-thiazole (72 mg, 0.19 mmol) and Pd(PPh3)4 (18.6 mg, 0.016 mmol) in DME/MeOH (3/1 mL) was stirred at 120° C. under microwave irradiation for 60 minutes. The reaction mixture was filtered and concentrated in vacuo. The residue was purified using Biotage silica gel column chromatography eluting with 25% EtOAc in cyclohexane to afford the title compound (11 mg, 28%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC(C)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C:15](=[O:18])[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(N1CCC(O)C1)C1(c2ccc(Cl)cc2)CC1
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCN(C(=O)C2(c3ccc(Cl)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solutin of 1-{[1-(4-chlorophenyl)cyclopropyl]carbonyl}pyrrolidin-3-ol (2.70 g, 0.0102 mol) in acetone (50 mL, 0.7 mol) was added Jone's oxidant in water (8.00M, 1.90 mL) at 0° C. The solution was stirred at rt for 1 hour and then filetered, concentrated. The residue was dissolved in AcOEt, and the solution was washed with water and brine successively, dried over MgSO4, and concentrated. The crude product was purified using Combiflash eluting with 50% AcOEt in hexanes.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:34])[CH:17]([NH:21][CH:22]2[CH2:31][CH2:30][C:29]3[C:24](=[C:25]([F:33])[CH:26]=[C:27]([F:32])[CH:28]=3)[CH2:23]2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.C=O.[C:37]([BH3-])#N.[Na+]>CO>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:34])[CH:17]([N:21]([CH:22]2[CH2:31][CH2:30][C:29]3[C:24](=[C:25]([F:33])[CH:26]=[C:27]([F:32])[CH:28]=3)[CH2:23]2)[CH3:37])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CCCC(C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1)N(C)C1CCc2cc(F)cc(F)c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide (1 equiv) is dissolved in methanol and to the reaction is added formalin (4 equiv) and sodium cyanoborohydride (2.0 equiv). The reaction is stirred at rt for 3 h, quenched with water, and extracted with methylene chloride. The solvent is dried, concentrated and the residue purified by silica gel chromatography to provide the title compound: Diagnostic C13 NMR (100 MHz, CDCl3) 55.9, 57.0, 57.1, 56.0, 65.1, 67.2, 101.0, 104.5, 110.5, 110.7, 131.1; MS m/z 488.4 (M+1).