Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl(O)(=O)(=O)=O.[O:6]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[C:17]([CH:23]([OH:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:18]([CH3:22])[S:19][C:20]=3[CH3:21])=[CH:15][C:10]=2[CH2:9][CH2:8][CH2:7]1>C(OC(C)(C)C)(=O)C>[O:6]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]3[C:17]([CH:23]([O:29][C:10]([CH3:15])([CH3:11])[CH3:9])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:18]([CH3:22])[S:19][C:20]=3[CH3:21])=[CH:15][C:10]=2[CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)C(O)c1c(C)sc(C)c1-c1ccc2c(c1)CCCO2
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)OC(C)(C)C
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(C)c1-c1ccc2c(c1)CCCO2
Reaction time: 1 h
Yield: 88 %

Procedure:
Under a nitrogen atmosphere, perchloric acid (70%, 1.5 mL) was added at −10° C. to a solution of ethyl 2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-2,5-dimethyl thiophen-3-yl]-2-hydroxyacetate (17e) (88 mg, 0.25 mmol) in tert-butyl acetate (10 mL). After 1 hour, the reaction was quenched with a saturated aqueous solution of sodium carbonate and extracted with dichloromethane (2×30 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (dichloromethane)) to afford the desired product (17f) as a white solid (43 mg, 0.11 mmol, 43%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[C:28](O)(=[O:33])[CH2:29]/[CH:30]=[CH:31]/[CH3:32]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:33])[CH2:29]/[CH:30]=[CH:31]/[CH3:32])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: C/C=C/CC(=O)O
Agent: Cl
Product: C/C=C/CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (95 mg, 92%), MS (ISP) m/z=413.5 [(M+H)+], mp 175.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and (E)-pent-3-enoic acid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][N:5]1[CH2:13][C@H:12]([OH:14])[CH2:11][C@H:6]1[C:7]([O:9]C)=O)#[N:2].N1C=CN=C1.[CH2:20]([Si:22](Cl)([CH2:25][CH3:26])[CH2:23][CH3:24])[CH3:21]>CN(C)C=O>[CH2:20]([Si:22]([CH2:25][CH3:26])([CH2:23][CH3:24])[O:14][C@H:12]1[CH2:13][N:5]2[CH2:4][CH2:3][CH2:1][NH:2][C:7](=[O:9])[C@@H:6]2[CH2:11]1)[CH3:21]
Reactant: CC[Si](Cl)(CC)CC
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1CCC#N
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)O[C@@H]1C[C@H]2C(=O)NCCCN2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product from Example 1, Part B (0.33 g, 1.94 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added imidazole (0.264 g, 3.88 mmol) and triethylsilyl chloride (0.488 mL, 2.91 mmol). The resulting solution was stirred at room temperature for 16 hours. The mixture was partitioned between ethyl acetate (50 mL) and water (2×50 mL), and the organic extract was dried over Na2SO4. The drying agent was removed by filtration, and the filtrate was concentrated in vacuo to give a crude product that was purified by column chromatography on silica gel using a solvent gradient of 0-10% methanol in dichloromethane. The title compound was obtained as a colorless solid (0.28 g, 51%).
Reaction SMILES: [C:1]([OH:7])([C:3](F)(F)F)=O.[N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3([C:21]4[N:25]5[N:26]=[C:27]([C:30]6[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=6)[CH:28]=[N:29][C:24]5=[N:23][CH:22]=4)[CH2:20][CH2:19]3)=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1>>[N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3([C:21]4[N:25]5[N:26]=[C:27]([C:30]6[CH:38]=[CH:37][C:33]([C:34]([NH:8][CH:9]7[CH2:3][CH2:1][O:7][CH2:11][CH2:10]7)=[O:35])=[CH:32][CH:31]=6)[CH:28]=[N:29][C:24]5=[N:23][CH:22]=4)[CH2:20][CH2:19]3)=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1
Product: O=C(NC1CCOCC1)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3n2)cc1

Procedure:
This compound was prepared as a TFA salt starting from 4-[7-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzoic acid using procedures analogous to those for Example 105. LCMS: (M+H)=491.1.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:25])[NH:9][N:10]=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.[OH-].[Na+].Cl[CH2:34][CH2:35][OH:36]>O>[OH:36][CH2:35][CH2:34][N:9]1[C:8](=[O:25])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:10]1
Reactant: OCCCl
Reactant: O=c1[nH]nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(-c2ccccc2)c(-c2ccccc2)c(-c2ccccc2)nn1CCO
Temperature: 25 °C
Yield: 25 %

Procedure:
To 4,5,6-triphenyl-2H-pyridazin-3-one (6.0 g) were added 50 ml of dimethylformamide and a solution of sodium hydroxide pellets (0.7 g) dissolved in 5 ml of water. The resultant slurry was stirred at room temperature, while adding dropwise, 1.5 g of 2-chloroethanol. The mixture was heated to 110° C. for 1 hour and then allowed to heat for 16 hours at 90° C., after which time, the dimethylformamide was removed by evacuation. The residue was redissolved in methanol from which the compound was triturated, filtered and washed with petroleum ether to obtain the title compound (25 percent yield), m.p. 189° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=O)[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8].[S:14]1[CH2:20][C:18](=[O:19])[NH:17][C:15]1=[S:16].C(O)(=O)C.C([O-])(=O)C.[Na+]>O>[C:7]([C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:12]=[C:20]1[S:14][C:15](=[S:16])[NH:17][C:18]1=[O:19])([OH:9])=[O:8]
Reactant: COc1ccc(C(=O)O)c(C=O)c1
Reactant: O=C1CSC(=S)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(C(=O)O)c(C=C2SC(=S)NC2=O)c1

Procedure:
To a stirred hot solution of 4.23 g. (23.5 mM) of 4-methoxyphthalaldehydic acid and 3.13 g. (23.5 mM) of rhodanine in 16.5 ml. of acetic acid is added 6.33 g. (77.2 mM) of anhydrous sodium acetate. The resulting hot solution is refluxed for 0.5 hour, whereupon a solid yellow mass forms. The mixture is cooled, poured into water, to yield 5-(2-carboxy-5-methoxybenzylidene) rhodanine.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9]([NH2:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>CN(C=O)C>[CH3:14][N:15](/[CH:17]=[N:11]/[C:9]([C:7]1[S:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:10])[CH3:16]
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1ccc([N+](=O)[O-])s1
Solvent: CN(C)C=O
Product: CN(C)/C=N/C(=O)c1ccc([N+](=O)[O-])s1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
5-Nitrothiophene-2-carboxamide (5.80 g, 33.7 mmol) was combined with N,N-dimethylformamide dimethyl acetal (75 mL, 560 mmol) and stirred at 120° C. overnight (added 10 mL DMF to help dissolve the starting material). The red-brown solution was cooled to room temperature, at which point a solid precipitated from solution. The solid was isolated by filtration, washed with Et2O, and dried to provide the title compound as tan crystals.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[N:8]([C:16]([CH3:21])([CH3:20])[C:17]([O-:19])=O)=[N:9][C:10]([CH3:15])([CH3:14])[C:11]([O-:13])=O.C[O-].[Na+].O>CO.CCCCCC>[N:9]([C:10]([CH3:14])([CH3:15])[C:11]([NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:13])=[N:8][C:16]([CH3:21])([CH3:20])[C:17]([NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[O:19]
Reactant: CC(C)(N=NC(C)(C)C(=O)[O-])C(=O)[O-]
Reactant: CCCCCCN
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CO
Product: CCCCCCNC(=O)C(C)(C)N=NC(C)(C)C(=O)NCCCCCC
Reaction time: 8 h
Yield: 95 %

Procedure:
28.2 Grams of n-hexylamine is mixed with 50 g of 2,2'-azobis (2-methyl propionate), and 20 g of 28% sodium methoxide solution in methanol and 10 ml of methanol are added thereto with stirring followed by conducting a reaction at room temperature with stirring for 6 hours and keeping standing overnight. 100 Milliliter of water is added to the reaction solution and extraction with 100 ml of n-hexane is conducted. The hexane layer is washed with water and dried over anhydrous sodium sulfate. The solvent is removed by distillation to give 76.3 g (yield 95%) of 2,2'-azobis (N-hexyl-2-methyl propionamide) as pale yellow sintering crystal. The solubility is shown in Table 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:12][C:13]([O:15]CC)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)CC(CCCCc1ccccc1)c1ccc(OC)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(C(CCCCc2ccccc2)CC(=O)O)cc1OC
Yield: 91.3 %

Procedure:
A solution of ethyl 3-(3,4-dimethoxyphenyl)-7-phenylheptanoate (0.3 g, 0.8 mmol) and 10% sodium hydroxide (5 mL) in ethanol (10 mL) is heated under reflux for 30 minutes. The mixture is cooled and is added to aqueous HCl and is extracted with ether. The organic layer is washed with water and is dried over MgSO4. The solvent is removed in vacuo to afford 3-(3,4-dimethoxyphenyl)-7-phenylheptanoic acid (0.25 g, 92%); MS (EI) m/e 342 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:64]([CH3:66])[CH3:65])[C:7]([N:9]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][C@H:10]1[C:15]1[NH:16][C:17]([C:20]2[CH:21]=[C:22]3[CH2:35][O:34][C:33]4[C:24]5=[C:25]([CH:30]=[C:31]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:45][C@H:44]([CH3:46])[CH2:43][N:42]7[C:47](=[O:63])[C@H:48]([NH:55]C(OC(C)(C)C)=O)[C:49]7[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=7)=[N:38][CH:37]=6)[CH:32]=4)[CH2:26][O:27][C:28]([CH:29]=2)=[C:23]35)=[CH:18][N:19]=1)=[O:8])=[O:4].Cl>C(O)C>[NH2:55][C@H:48]([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[C:47]([N:42]1[CH2:43][C@@H:44]([CH3:46])[CH2:45][C@H:41]1[C:39]1[NH:40][C:36]([C:31]2[CH:32]=[C:33]3[O:34][CH2:35][C:22]4[C:23]5[C:24]3=[C:25]([CH2:26][O:27][C:28]=5[CH:29]=[C:20]([C:17]3[NH:16][C:15]([C@@H:10]5[CH2:11][C@H:12]([CH3:14])[CH2:13][N:9]5[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:64]([CH3:65])[CH3:66])=[N:19][CH:18]=3)[CH:21]=4)[CH:30]=2)=[CH:37][N:38]=1)=[O:63]
Reactant: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1ncc(-c2cc3c4c(c2)OCc2cc(-c5cnc([C@@H]6C[C@H](C)CN6C(=O)[C@H](NC(=O)OC(C)(C)C)c6ccccc6)[nH]5)cc(c2-4)OC3)[nH]1)C(C)C
Agent: Cl
Solvent: CCO
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)C[C@H]1c1ncc(-c2cc3c4c(c2)OCc2cc(-c5cnc([C@@H]6C[C@H](C)CN6C(=O)[C@H](N)c6ccccc6)[nH]5)cc(c2-4)OC3)[nH]1)C(C)C
Reaction time: 1 h

Procedure:
(S)-2-(methoxycarbonylamino)-1-((2S,4S)-2-(5-(7-(2-((2S,4S)-1-((R)-2-(t-butoxycarbonylamino)-2-phenylacetyl)-4-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)-5,10-dihydrochromeno[5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl)-4-methylpyrrolidin-1-yl)-3-methylbutan-1-one, 86 mg, was treated with 0.76 mL 1.25N HCl in Ethanol at room temperature overnight, then at 50° C. for 1 hour. The mixture was concentrated under reduced pressure and further dried under high vacuum to give product (90 mg).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([CH2:12][C:13](=[O:15])[CH3:14])(=[O:11])[CH3:10].N1CCCCC1>C1CCCCC1>[CH:1](=[CH:14][C:13](=[O:15])[CH2:12][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)CC(C)=O
Solvent: C1CCCCC1
Solvent: C1CCNCC1
Product: CC(=O)CC(=O)C=Cc1ccccc1

Procedure:
Theses compounds may be prepared by various methods but are most conveniently prepared by reacting a benzaldehyde with acetyl acetone in the presence of a suitable catalyst and reaction medium, preferably piperidine and cyclohexane, at reflux temperature under continuous azeotropic water removal. The benzaldehyde reactant will be that which corresponds to the desired substitution of the benzylidene derivative of the final benzylidene pentanedione. The crude product resulting from the foregoing reaction may then be purified by crystallization with methanol to produce the desired benzylidene 2,4-pentanedione. Suitable reactions and reaction conditions are set forth in the examples contained herein.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[C@H:24]4[C@H:19]([CH2:20][CH:21]=[CH:22][CH2:23]4)[C:18](=[O:25])[NH:17][N:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:26]1(Br)[CH2:30][CH2:29][CH2:28][CH2:27]1.COC1C=C(C2[C@H]3[C@H](CCCC3)C(=O)N(C)N=2)C=CC=1OC>>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[C@H:24]4[C@H:19]([CH2:20][CH:21]=[CH:22][CH2:23]4)[C:18](=[O:25])[N:17]([CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[N:16]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CC=CC[C@@H]23)cc1OC1CCCC1
Agent: COc1ccc(C2=NN(C)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(C3CCCC3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC1CCCC1

Procedure:
Prepared from compound 5 and cyclopentylbromide as described for compound 8. Crystallized from diethyl ether. M.p. 144-145° C.
Reaction SMILES: ClC(C)COO[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][N:10]([C:16]1[CH:17]=[C:18]([CH:25]=[CH:26][C:27]=1[CH3:28])[C:19]([NH:21][CH:22]1[CH2:24][CH2:23]1)=[O:20])[C:9]2=[O:29].[NH:31]1[CH2:36][CH2:35][S:34][CH2:33][CH2:32]1.[I-].[K+]>CC(N(C)C)=O>[CH:22]1([NH:21][C:19](=[O:20])[C:18]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:16]([N:10]3[C:9](=[O:29])[C:8]4[C:13](=[CH:14][CH:15]=[C:6]([O:20][CH2:19][CH2:18][CH2:17][N:31]5[CH2:36][CH2:35][S:34][CH2:33][CH2:32]5)[CH:7]=4)[N:12]=[CH:11]3)[CH:17]=2)[CH2:23][CH2:24]1
Reactant: C1CSCCN1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OOCC(C)Cl)cc2c1=O
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OCCCN3CCSCC3)cc2c1=O
Temperature: 120 °C
Yield: 147.7 %

Procedure:
3-[6-(2-Chloropropoxyoxy)-4-oxoquinazolin-3(4H)-yl]-N-cyclopropyl-4-methylbenzamide (0.23 g), thiomorpholine (0.37 g) and potassium iodide (0.2 g) were stirred in DMA (3 ml) and heated under microwave irradiation conditions (Personal Chemistry Emrys Optimizer with 300 W magnetron) for 30 mins at 120° C. The reaction mixture was filtered, washed with ethyl acetate and the filtrate concentrated. Purification by column chromatography on a silica column eluting with a 0% to 30% MeOH/EtOAc gradient gave the title compound (0.19 g) as a white solid; Mass Spectrum: M+H+ 479.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[CH:19][CH:18]=2)=[C:12]([C:14]#[N:15])[N:13]=1.C(=O)(O)[O-:32].[Na+].[OH-].[Na+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[O:24])=[CH:21][CH:22]=2)=[C:12]([C:14]([NH2:15])=[O:32])[N:13]=1
Reactant: O=C([O-])O
Reactant: N#Cc1nc(-c2c(F)cccc2F)oc1Nc1ccc(C(=O)N2CCOCC2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1Nc1ccc(C(=O)N2CCOCC2)cc1
Yield: 77 %

Procedure:
A solution of 2-(2,6-difluorophenyl)-5-(4-(morpholine-4-carbonyl)phenylamino)oxazole-4-carbonitrile (0.009 g, 0.022 mmol) in concentrated sulfuric acid (0.5 mL) was stirred at room temperature for 1.5 hours. The solution was neutralised by pouring into saturated sodium bicarbonate solution. The aqueous phase was then basified to pH14 using 5M NaOH and extracted with EtOAc. The combined organic phase was dried over MgSO4 and the solvent removed in vacuo to afford 2-(2,6-difluorophenyl)-5-(4-(morpholine-4-carbonyl)phenylamino)oxazole-4-carboxamide (0.007 g, 0.017 mmol, 77%) as a yellow solid. 1H NMR (DMSO) δ 3.51 (4H, m), 3.58 (4H, m), 7.32-7.47 (8H, m), 7.64 (1H, m), 9.55 (1H, s). LCMS (2) Rt: 2.14 min; m/z (ES+) 429.
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH3:11])=[O:9].[NH2:12][CH2:13][CH2:14][O:15][C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[C:18]([CH2:26][N:27]([CH:35]2[CH2:37][CH2:36]2)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:17]=1.O>C(Cl)(Cl)Cl>[C:30]([O:29][C:28]([N:27]([CH2:26][C:18]1[CH:17]=[C:16]([O:15][CH2:14][CH2:13][NH:12][C:8](=[O:9])[O:10][CH3:11])[C:25]2[C:20]([CH:19]=1)=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:35]1[CH2:36][CH2:37]1)=[O:34])([CH3:31])([CH3:32])[CH3:33]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N(Cc1cc(OCCN)c2ccccc2c1)C1CC1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)NCCOc1cc(CN(C(=O)OC(C)(C)C)C2CC2)cc2ccccc12
Temperature: 25 °C

Procedure:
Pyridine (272 μL) and methyl chloroformate (130 μL) were added to a solution of tert-butyl {[4-(2-aminoethoxy)-2-naphthyl]methyl}cyclopropylcarbamate (400 mg) in chloroform (4.0 ml) under ice-cooling and the mixture was stirred at room temperature for an hour. Water was added to the reaction mixture and it was extracted with chloroform. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated brine successively, dried over sodium sulfate and concentrated in vacuo. The resulted residue was purified with NH-silica gel column chromatography (eluting solvent: n-hexane to n-hexane/ethyl acetate=2/1) to give methyl {2-[(3-{[(tert-butoxycarbonyl)(cyclopropyl)amino]methyl}-1-naphthyl)oxy]ethyl}carbamate (418 mg) as a colorless oil.
Reaction SMILES: Cl.[N:2]1([CH2:11][C:12]([OH:14])=O)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:15]([C@H:22]1[CH2:26][NH:25][C@H:24]([C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:32][CH:31]=2)=[O:28])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[N:2]1([CH2:11][C:12]([N:25]2[CH2:26][C@H:22]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][C@H:24]2[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:32][CH:31]=2)=[O:28])=[O:14])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: O=C(O)Cn1nnc2ccccc21
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)Cn1nnc2ccccc21
Yield: 12 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-benzo[d][1,2,3]triazol-1-yl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 176, (2S,4R)-1-(2-(1H-benzo[d][1,2,3]triazol-1-yl)acetyl)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (17 mg, 12%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.95 (s, 1H), 8.04 (d, 1H), 7.77-7.64 (m, 1H), 7.59-7.49 (m, 3H), 7.44-7.12 (m, 8H), 7.07-6.90 (m, 4H), 5.80 (q, 2H), 4.56-4.48 (m, 1H), 4.02-3.93 (m, 1H), 3.55-3.46 (m, 1H), 2.85-2.69 (m, 3H), 2.08-1.94 (m, 2H). MS (EI) for C32H28FN5O3. found 549.9 (MH+).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[CH:2]([CH3:4])[OH:3].[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]C.[H-].[Na+]>>[C:1]([O:6][CH2:7][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: CCCCCCCCCCCCCCCCCCCCCCO
Reactant: COC(=O)C(C)O
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCCCCCCCCCCCCCCCOC(=O)C(C)O
Temperature: 160 °C
Reaction time: 1 h

Procedure:
Behenyl Lactate was prepared by reacting methyl lactate (Aldrich Chemical Company, Inc. of Milwaukee, Wis.) with Lanette 22 (behenyl alcohol, 90%, Henkel Corp. of Ambler, Pa.) in a transesterification reaction according to the following method: 0.2 g sodium hydride (60% in mineral oil) was added to 32.6 grams Lanette 22 at 70° C. in a 3-neck 250 ml glass flask purged with nitrogen and inserted with overhead stirrer, Dean Stark trap, thermometer, and condenser. To this was slowly added 9.4 g of methyl lactate and the contents were slowly heated to 160° C. and held at that temperature for one hour. At this temperature over 2 ml of methanol was collected. The contents were heated to 200° C. with a nitrogen sweep to remove any volatile components. After approximately 15 minutes at 200° C. the contents were cooled. Upon cooling the product crystallized and had a melting point of approximately 57° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C(OC1C=CC(C([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:41][CH2:40][C:35]4([O:39][CH2:38][CH2:37][O:36]4)[CH2:34]3)=[C:29]([F:42])[CH:28]=2)=O)=CC=1)CCC>>[CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[O:36]1[C:35]2([CH2:40][CH2:41][N:33]([C:30]3[CH:31]=[CH:32][C:27]([NH2:26])=[CH:28][C:29]=3[F:42])[CH2:34]2)[O:39][CH2:38][CH2:37]1
Reactant: CCCCOc1ccc(C(=O)Nc2ccc(N3CCC4(C3)OCCO4)c(F)c2)cc1
Agent: CCCCOc1ccc(C(=O)O)cc1
Product: Nc1ccc(N2CCC3(C2)OCCO3)c(F)c1

Procedure:
4-Butoxy-N-[4-(3-oxopyrrolidin-1-yl)-phenyl]benzamide was obtained using 4-butoxybenzoic acid in an analogous way. Likewise, 4-butoxybenzoic acid and 4-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-3-fluorophenylamine initially resulted in 4-butoxy-N-[4-(1,4-dioxa-7-azaspiro[4.4]non-7-yl)-3-fluorophenyl]benzamide which, after methylation by method F and treatment with para-toluenesulfonic acid as described above, afforded 4-butoxy-N-[3-fluoro-4-(3-oxopyrrolidin-1-yl)phenyl]benzamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([NH:13][C@@H](C2C=CC=CC=2)C)[C@H:10]([C:22]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:25]2)=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[OH-].[Pd+2].[OH-].C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([C:22]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[CH2:25]2)=[O:23])[C@H:11]([NH2:13])[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)C1
Reaction time: 20 h
Yield: 94.8 %

Procedure:
(3R,4S)-3-[(S)-3-(4-fluorobenzyl)-piperidine-1-carbonyl]-4-[(R)-1-phenyl-ethylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (99 mg, 195 μmol), palladium hydroxide (20 weight % on carbon, dry basis; 40 mg) and ethanol (7 mL) were combined in a pressure bottle and shaken under hydrogen atmosphere (50-55 psig) for 20 h. The mixture was filtered through Celite, and the solids were rinsed with ethanol. The filtrate was concentrated to give the product as a glassy foam (75 mg, 95%), used without further purification. 1H NMR (300mHz, CDCl3) δ7.26 (m, 2H), 6.96 (m, 2H), 4.57-4.36 (1H), 3.84-2.41 (10H), 1.93-1.70 (6H), 1.44-1.39 (9H); mass spec. (ES+) m/z 406.4.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[N+:21]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]#[N:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C#N)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C#N)cc1N

Procedure:
The title compound was prepared from (4-cyano-2-nitro-5-pyrrolidin-1-yl-phenyl)-carbamic acid tert-butyl ester (Example C25) (1.82 g, 5.48 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as a pale brown solid (1.27 g, 77%).