Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21](O)=[O:22])[C:12]=3[CH:13]=[N:14][CH:15]=2)=[CH:6][CH:5]=1.[CH:26]([N:29](CC)C(C)C)(C)C.CN.CCO.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C1COCC1>[CH3:26][NH:29][C:21](=[O:22])[CH2:20][O:19][CH:16]1[C:12]2[CH:13]=[N:14][CH:15]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([F:25])([F:24])[F:2])=[CH:9][CH:8]=3)[C:11]=2[CH2:18][CH2:17]1
Reactant: O=C(O)COC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Reactant: CCN(C(C)C)C(C)C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CNC(=O)COC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.6 %

Procedure:
To a solution of (rac)-2-(4-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yloxy)acetic acid hydrochloride (example 99) (70 mg, 0.19 mmol) in THF (0.6 mL) was added N,N-diisopropylethylamine (131 μL, 0.75 mmol), 8M methylamine in EtOH (47 μL, 0.38 mmol) and 1-propanephosphonic acid cyclic anhydride (284 μL, 0.47 mmol). The reaction was stirred at room temperature for 16 h. The mixture was evaporated and purified by flash chromatography (20 g SiO2, Telos-cartridge, 2 to 10% 2-propanol in CH2Cl2) to give the title compound (41 mg, 63%) as light yellow oil. MS: 351.5 (M+H+).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([OH:9])[CH2:7][Cl:8])(=[O:3])[CH3:2].[CH:10]([O:12][CH2:13][CH3:14])=[CH2:11].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[C:1]([O:4][CH2:5][CH:6]([O:9][CH:10]([O:12][CH2:13][CH3:14])[CH3:11])[CH2:7][Cl:8])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(O)CCl
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(C)OC(CCl)COC(C)=O
Yield: 97.9 %

Procedure:
A solution of 30.5 g (0.20 mol) of 3-chloro-2-hydroxy-1-propyl acetate (prepared in Example 1), 22 g (0.30 mol) of ethyl vinyl ether, and 7.5 g (0.030 mol) of pyridinium p-toluenesulfonate in 150 mL of methylene chloride was stirred at room temperature for 6 hours. The solution was then washed with 75 mL of water, dried and stripped of solvent in vacuo to give 44.0 g (98.0%) of 3-chloro-2-(1-ethoxyethoxy)-1-propyl acetate: 1H NMR (CDCl3) δ1.05-1.37 (overlapping t and d, 6H, --CH2CH3 and --CHCH3); 2.07 (s, 3H, --COCH); 3.53 and 4.12 (m. 7H, --CH2CHCH2 and --CH2CH3); 4.72 (q, J=4 Hz, 1H, --CHCH3); IR (film) 1740 cm-1 (--COCH3 ). The unpurified product was used in the next step.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:11][CH:10]2[CH:5]3[CH2:6][CH:7]4[CH:9]2[CH:8]4[CH:4]13.[CH:12](OCC)=[O:13]>>[CH:12]([NH:1][CH2:2][CH:3]1[CH2:11][CH:10]2[CH:5]3[CH2:6][CH:7]4[CH:9]2[CH:8]4[CH:4]13)=[O:13]
Reactant: CCOC=O
Reactant: NCC1CC2C3CC4C2C4C13
Product: O=CNCC1CC2C3CC4C2C4C13

Procedure:
8-Aminomethyltetracyclo[4,3,0,02,4,03,7 ]nonane (1.1 g.) was heated under reflux for 16 hours with ethyl formate. The solvent was removed in vacuo and the residue chromatographed on silica gel with ethyl acetate as eluant to give 8-(N-formylaminomethyl)tetracyclo[4,3,0,02,4,03,7 ]nonane. This product was reduced in ether solution with lithium aluminium hydride as in previous Examples and the resulting amine precipitated as its hydrochloride. There was thus obtained 8-(N-methylaminomethyl)tetracyclo[4,3,0,02,4,03,7 ]nonane hydrochloride, m.p. 225°-226° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH3:9][NH:10][CH3:11]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:10]([CH3:11])[CH3:9])[CH:5]=[CH:6][N:7]=1
Reactant: CNC
Reactant: Clc1ccnc(Cl)n1
Solvent: CO
Product: CN(C)c1ccnc(Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
2,4-dichloropyrimidine (104, 500 mg, 3.30 mmol) was dissolved in methanol (5 mL) having 2.0 M dimethylamine dissolved therein, stirred at room temperature for 3 hours. Then, the methanol solvent was removed under reduced pressure and water was added to the reaction mixture. Organic compounds were extracted with ethyl acetate, and the recovered organic solution was washed with a saturated aqueous solution of sodium chloride and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give the target compound 2-chloro-4-(N,N-dimethylamino)pyrimidine (106c, 426 mg, 80%) as a white solid.
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29]6[O:30][CH2:31][C:32]([CH3:35])([CH3:34])[N:33]=6)[CH:26]=5)[N:21]=[CH:20][N:19]=4)=[CH:13][C:12]=3[CH3:36])=[CH:6][C:5]=12.C(C1C=C(NC(NC(C)(C)CO)=[S:47])C=CC=1/N=C/N(C)C)#N.N1C=NN2C=CC(OC3C=CC(N)=CC=3C)=CC=12>C(OC(C)C)(=O)C.C(O)(=O)C>[N:1]1[CH:2]=[N:3][N:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([NH:28][C:29]([NH:33][C:32]([CH3:35])([CH3:34])[CH2:31][OH:30])=[S:47])[CH:26]=5)[N:21]=[CH:20][N:19]=4)=[CH:13][C:12]=3[CH3:36])=[CH:6][C:5]=12
Reactant: Cc1cc(Nc2ncnc3ccc(NC4=NC(C)(C)CO4)cc23)ccc1Oc1ccn2ncnc2c1
Reactant: CN(C)/C=N/c1ccc(NC(=S)NC(C)(C)CO)cc1C#N
Agent: Cc1cc(N)ccc1Oc1ccn2ncnc2c1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)C
Product: Cc1cc(Nc2ncnc3ccc(NC(=S)NC(C)(C)CO)cc23)ccc1Oc1ccn2ncnc2c1

Procedure:
The synthesis of N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine is described in WO 2007/059257. Generally, N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine may be prepared by coupling (E)-N′-(2-cyano-4-(3-(1-hydroxy-2-methylpropan-2-yl)thioureido)phenyl)-N,N-dimethylformimidamide with 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline in isopropyl acetate:acetic acid (65:35 v/v) at 45° C. to yield 1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea. The 1-(4-((4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)amino)quinazolin-6-yl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea may then be agitated in tetrahydrofuran under basic conditions (2.5N NaOH), followed by the addition of p-toluenesulfonyl chloride. Water may then be charged to yield N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine as a mixture of polymorphs (generally a mixture containing one or more of Form C, Form G hemi-THF, Form G mono-THF, Form M or Form P). The final crystallizations or isolations will determine the polymorphic form, which are further detailed in the Examples section.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([NH2:12])=[N:8][C:9]=2Cl)[N:4]([CH3:13])[N:3]=1.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[CH2:14]([NH:21][C:9]1[N:8]=[C:7]([NH2:12])[N:6]=[C:5]2[N:4]([CH3:13])[N:3]=[C:2]([Br:1])[C:10]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cn1nc(Br)c2c(Cl)nc(N)nc21
Reactant: NCc1ccccc1
Solvent: CN(C)C=O
Product: Cn1nc(Br)c2c(NCc3ccccc3)nc(N)nc21
Temperature: 40 °C

Procedure:
3-Bromo-4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (Intermediate 14) (160 mg, 0.61 mmol), benzylamine (0.2 ml, 1.83 mmol) and DMF (5 ml) are mixed together and heated at 40° C. overnight. After cooling to room temperature the solvent is removed in vacuo and the residue is dissolved in methanol (30 ml) and passed through an Isolute™ CBA column (silica based carboxylic acid sorbent). Silica gel is added to the filtrate, the solvent is removed in vacuo and the resulting residue is flash chromatographed eluting with EtOAc:iso-hexanes (4:6) and then increasing to EtOAc:iso-hexanes (1:1). The appropriate fractions are collected and concentrated in vacuo to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].C([Mg]Cl)(C)C.[C:15]([N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=[O:28])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:23](=[O:28])[CH2:24][CH2:25][CH2:26][CH2:27][NH:22][C:15](=[O:16])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4][C:3]=1[F:9]
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: Fc1cc(I)ccc1Br
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCC(=O)c1ccc(Br)c(F)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
To a solution of 1-bromo-2-fluoro-4-iodobenzene (44.22 g, 0.147 mol) in tetrahydrofuran (160 mL) was added isopropylmagnesium chloride (2.0 M solution in tetrahydrofuran, 73.5 mL) at 0° C. and the mixture stirred at 0° C. for 3 hours. This solution was cannulated into a solution of 1-BOC-2-piperidone (24.4 g, 0.122 mol) in tetrahydrofuran (240 mL) at −78° C. and the mixture stirred at −78° C. for 1 hour. The solution was warmed to ambient temperature and stirred for one hour before quenching with water. Hydrochloric acid (2N, 120 mL) was added and the mixture stirred at ambient temperature for 10 minutes. The mixture was concentrated and the residue partitioned between ethyl acetate and brine. The organic layer was washed with brine, dried over magnesium sulfate and filtered. Concentration afforded the crude product which was recrystallized from hexane and dichloromethane to give 33.95 g of the title compound as a white solid. 1HNMR (CDCl3) δ 1.44 (s, 9H), 1.52-1.63 (m, 2H), 1.70-1.83 (m, 2H), 2.96 (t, J=7.1 Hz, 2H), 3.16 (q, J=6.4 Hz, 2H), 4.58 (s, 1H), 7.59-7.71 (m, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH2:19][CH3:20])[C:3](=[O:18])[CH2:4][C:5](=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.CO[CH:23](OC)[N:24]([CH3:26])[CH3:25].Cl.CN>>[CH3:23][N:24]1[CH:26]=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=2)[C:5](=[O:17])[C:4]([C:3](=[O:18])[CH:2]([CH3:1])[CH2:19][CH3:20])=[CH:25]1
Reactant: COC(OC)N(C)C
Reactant: CCC(C)C(=O)CC(=O)Cc1cccc(C(F)(F)F)c1
Agent: CN
Agent: Cl
Product: CCC(C)C(=O)c1cn(C)cc(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
A 1.3 g. portion of impure 5-methyl-1-(3-trifluoromethylphenyl)-2,4-heptanedione was reacted with 50 ml. of N,N-dimethylformamide dimethyl acetal, and then with 2 g. of methylamine hydrochloride as described in Example 12. The impure product was purified as described in Example 12, except that the final product was subjected to an additional step of trituration under hexane to obtain 0.08 g. of the desired product, m.p. 109°-111°, showing the following nmr peaks in CDCl3 : δ7.3-8.1 (m, 6H, aromatic); 3.9-4.2 (m, 1H, COCH); 3.8 (s, 3H, N--CH3); 1.2-2.0 (m, 2H, CH2CH3); 1.1-1.2 (d, 3H, CHCH3); 0.8-1.1 (t, 3H, CH2CH3).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:39]2[CH:43]=[CH:42][S:41][CH:40]=2)[CH:38]=1)C(O)=O)=[O:5])C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.C(O[C:82]([N:84]1[CH2:89][CH2:88][NH:87][CH2:86][CH2:85]1)=[O:83])(C)(C)C.[OH-].[Na+]>C(Cl)Cl.C(OCC)(=O)C.C(O)C.CN(C=O)C>[C:4]([CH2:6][CH2:7][C:8]1[C:9]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:38]=[C:37]([C:39]3[CH:43]=[CH:42][S:41][CH:40]=3)[CH:36]=[C:32]([C:82]([N:84]3[CH2:85][CH2:86][NH:87][CH2:88][CH2:89]3)=[O:83])[CH:31]=2)=[CH:10][CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])([OH:5])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCNCC3)cc(-c3ccsc3)c2)c1CCC(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 3-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-5-thiophen-3-yl-benzoic acid (130 mg, 0.21 mmol), PyBroP (263 mg, 0.63 mmol) and diisopropylethylamine (0.11 mL, 0.63 mmol) in CH2Cl2 (4 mL)/DMF (1 mL) was added piperazine-1-carboxylic acid tert-butyl ester (63 mg, 0.63 mmol). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The total amount of the product obtained from the previous step was dissolved in ethanol (5 mL) and 1 M NaOH solution was added (2 mL) and the reaction mixture stirred for 3 h. Then the reaction mixture was diluted with ethyl acetate, washed with 10% aq. HCl and brine. The organic extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude oil was dissolved in 5 mL CH2Cl2 and 5 mL of TFA was added. The reaction mixture was stirred for 1 h and the solvents were evaporated. The crude oil was purified by preparative HPLC using acetonitrile/water gradient to afford the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C([O-])(O)=O.[Na+].[C:16](ON1C(=O)CCC1=O)([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17].Cl>CC(C)=O.O>[NH:1]([C:16]([O:18][CH2:19][CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2[C:32]1=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:17])[C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6]
Reactant: N[C@H](CCC(=O)O)C(=O)O
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)CC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 0 °C
Yield: 81 %

Procedure:
In an ice-water bath, a solution of D-glutamic acid (H-D-Glu-OH, 29.4 g, 1.0 eq) in a mixture of acetone and H2O (V/V=1:1) was stirred. After the solid was fully dissolved, NaHCO3 (23.3 g, 1.1 eq) was added in portions, then Fmoc-OSu (67.4 g, 1.0 eq) were added slowly and the reaction was stirred for additional 3 days at r.t. The mixture was then cooled in ice-water bath again, and pH was adjusted to 2-3 with 2.0N HCl. After removal of acetone under reduced pressure, the remaining solution was extracted with AcOEt (400 mL×4). The organic layer was separated and combined, dried with MgSO4 overnight, and concentrated to a small volume under reduced pressure. Then residue was recrystallized with ethylacetate-cyclohexane system. After filtration, 59.8 g of target product was obtained as a white solid with a yield of 81%.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([O:18]C)=[O:17])[CH:14]=2)[C:9]([CH3:21])([CH3:20])[C:8]1=[O:22].[OH-].[Na+].CO>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([OH:18])=[O:17])[CH:14]=2)[C:9]([CH3:20])([CH3:21])[C:8]1=[O:22]
Reactant: COCCCCN1C(=O)C(C)(C)c2ccc(C(=O)OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCCCCN1C(=O)C(C)(C)c2ccc(C(=O)O)cc21
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To methyl 1-(4-methoxybutyl)-3,3-dimethyl-2-oxoindoline-6-carboxylate (480 mg) were added 2N aqueous NaOH solution (5 ml), MeOH (5 ml), and THF (5 ml), and the mixture was stirred at 65° C. for one hour. After the reaction was complete, the solvent was concentrated, and to the resultant was added dropwise 2N aqueous hydrochloric acid solution. The precipitated crystals were extracted with ethyl acetate, and this ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated. The obtained residue (400 mg) was used in the subsequent reaction without further treatment.
Reaction SMILES: [O:1]=[O+][O-].[CH:4]([CH:6]1[C:10]2([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:9][CH2:8][C:7]1=[O:23])=C>CO>[CH:4]([CH:6]1[C:10]2([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:14][CH2:15]2)[CH2:9][CH2:8][C:7]1=[O:23])=[O:1]
Reactant: O=[O+][O-]
Reactant: C=CC1C(=O)CCC12CCN(C(=O)OC(C)(C)C)CC2
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CCC(=O)C2C=O)CC1
Temperature: 25 °C

Procedure:
Ozone was bubbled into a solution of tert-butyl 1-vinyl-2-oxo-8-azaspiro[4.5]decane-8-carboxylate (0.168 g, 0.599 mmol) from Step B in methanol (6 mL) at −70° C. until a blue color persisted. Excess ozone was removed with a stream of nitrogen and then dimethyl sulfide (0.5 mL) was added. The mixture was allowed to warm to room temperature for 1 h and was then concentrated in vacuo without heating to afford the crude title compound which was used directly in the next step.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:29]=[CH:28][C:27]([NH:30][C:31](=[O:50])[C:32]4[CH:37]=[C:36]([NH:38][C:39](=[O:48])[C:40]5[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=5)[CH:35]=[CH:34][C:33]=4[Cl:49])=[CH:26][N:25]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]>C(Cl)Cl>[Cl:49][C:33]1[CH:34]=[CH:35][C:36]([NH:38][C:39](=[O:48])[C:40]2[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=2)=[CH:37][C:32]=1[C:31]([NH:30][C:27]1[CH:26]=[N:25][C:24]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([S:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)(=[O:15])=[O:16])=[CH:22][CH:21]=2)=[N:29][CH:28]=1)=[O:50].[C:51]([OH:57])([C:53]([F:56])([F:55])[F:54])=[O:52]
Reactant: COc1ccc(C(=O)Nc2ccc(Cl)c(C(=O)Nc3cnc(Nc4ccc(S(=O)(=O)C5CCN(C(=O)OC(C)(C)C)CC5)cc4)nc3)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccc(Cl)c(C(=O)Nc3cnc(Nc4ccc(S(=O)(=O)C5CCNCC5)cc4)nc3)c2)cc1
Reaction time: 18 h

Procedure:
A stirred suspension of intermediate 28 (Example 41) (0.075 g, 0.104 mmol) in DCM (8 mL) was treated with TFA (0.200 mL) and stirred for 18 h. Solvents were then removed yielding desired product as TFA salt (0.064 g, 99%). 1H NMR (DMSO-d6): δ 1.64-1.70 (m, 2H), 2.01-2.04 (m, 2H), 2.86-2.88 (m, 2H), 3.44-3.48 (m, 1H), 3.84 (s, 3H), 7.08 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.9 Hz, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.90 (dd, J=8.7 Hz, J=2.5 Hz, 1H), 7.98 (d, J=8.9 Hz, 2H), 8.05 (d, J=8.8 Hz, 2H), 8.23 (d, J=2.5 Hz, 1H), 8.24 (br s, 1H), 8.68 (br s, 1H), 8.90 (s, 2H), 10.37 (s, 1H), 10.39 (s, 1H), 10.78 (s, 1H).
Reaction SMILES: C([O-])(=O)CCC.[C:7]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])(=[O:9])[CH3:8].C(=O)([O-])[O-].[K+].[K+].[CH2:26]([O:33][C:34](=[O:39])[CH2:35][CH2:36][CH2:37]Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C.CCOC(C)=O.CCCCCCC>[C:7]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([O:15][CH2:37][CH2:36][CH2:35][C:34]([O:33][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:39])=[O:14])(=[O:9])[CH3:8]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: O=C(CCCBr)OCc1ccccc1
Agent: CCCC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)Oc1ccccc1C(=O)OCCCC(=O)OCc1ccccc1
Temperature: 90 °C

Procedure:
Benzyl 4-{[2-(acetyloxy)phenyl]carbonyloxy}butanoate was synthesized from benzyl-4-bromo)butanoate, 2-(acetyloxy)benzoic acid and potassium carbonate. To a solution of benzyl-4-bromobutanoate (0.5 g, 1.9 mmol) in acetonitrile (5 ml) at ambient temperature was added potassium carbonate (0.28 g, 2.0 mmol) and 2-(acetyloxy)benzoic acid (0.35 g, 1.9 mmol). The reaction was heated to 90° C. for 18 hours and monitored by TLC (4:1 heptane:EtOAc) The mixture was allowed to cool to room temperature and concentrated in vacuo. The crude product was partitioned between water and EtOAc and the organic phase was separated, dried over Na2SO4, filtered and concentrated in vacuo. The title compound was purified by silica column chromatography eluting with heptane:EtOAc (4:1, v:v) and isolated as a clear, colorless oil (0.556 g, 81% yield). 1H NMR (250 MHz, DMSO-d6) δ 7.29-7.41 (5H, m), 5.09 (2H, s), 4.01 (2H, t, 6.5 Hz), 2.44 (2H, t, 7.3 Hz), 1.97 (3H, s), 1.85 (2H, quin, 6.9 Hz).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:30])/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)[CH:18]=3)=[CH:9][CH:8]=2)[CH:2]=1.ClC1C=CC=C(C(OO)=[O:39])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[O-:39][N+:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:30])/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=4)[CH:18]=3)=[CH:11][CH:12]=2)[CH:2]=1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(-c4cccnc4)cc3)c2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(-c4ccc[n+]([O-])c4)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.9 %

Procedure:
To a solution of (E)-N-[4-(3-pyridyl)phenyl]-3-(4-methylphenyl)cinnamamide (250 mg) in tetrahydrofuran (20 ml) was added 3-chloroperbenzoic acid (70%, 0.24 g) at 0° C., and the mixture was stirred at room temperature for 18 hours. To the reaction mixture was added sodium thiosulfate solution, and the mixture was stirred for a few minutes and extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was recrystallized from ethanol-tetrahydrofuran-acetone to give (E)-N-[4-(1-oxidopyridin-3-yl)phenyl]-3-(4-methylphenyl)-cinnamamide (Compound 193) (208 mg) as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH3:14])[CH:6]([NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:7])[CH3:2].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH3:14])[CH:6]([N:8]([C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)C(C)NC1CCCC1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(C)C(C)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
A solution of 1.07 g (0.005 mole) of (rac)-3-cyclopentylamino-2-methyl-butanoic acid ethyl ester in 30 mL of water was added dropwise to a solution of 0.97 g (0.005 mole) of 2,4-dichloro-5-nitro-pyrimidine in 30 mL of ethyl ether. At 0 degrees, 1.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-80:20) gave 1.4 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-2-methyl-butanoic acid ethyl ester (IV-41).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([O-:26])=O)=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.[Li+].[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][N:12]([C:15]2[C:23]3[O:22][C:21]([C:24]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:26])=[CH:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:14]1
Reactant: O=C([O-])c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Reactant: C1CCNC1
Agent: [Li+]
Product: O=C(c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1)N1CCCC1

Procedure:
The compound was prepared according to the procedure disclosed in Example 1 starting from lithium 7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxylate (90 mg, 0.24 mmol) and pyrrolidine (54 mg, 0.76 mmol). Yield: 68 mg (66%).