Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH:37]([NH:41][CH2:42][CH2:43][OH:44])[CH2:36]1>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:35]4[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41][CH2:42][CH2:43][OH:44])[CH2:36]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: OCCNC1CCCNC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCC[C@H](NCCO)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-{(3S)-3-[(2-hydroxyethyl)amino]piperidin-1-yl}-1,3-thiazol-4(5H)-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-(Piperidin-3-ylamino)-ethanol following General Procedure C.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:26]([N:29]1[CH2:33][CH2:32][NH:31][C:30]1=[O:34])(=[O:28])[CH3:27]>>[C:26]([N:29]1[CH2:33][CH2:32][N:31]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH:23]5[CH2:25][CH2:24]5)=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:6][N:7]=2)[C:30]1=[O:34])(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCNC1=O
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C)CC3)cn2)C1=O
Yield: 56.1 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (241 mg) described in Preparation Example 144 and 1-acetylimidazolidin-2-one (115 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (151 mg) was obtained.
Reaction SMILES: CC(=NO)C(C)=NO.[BH4-].[Na+].[CH:11]1([CH2:16][CH2:17][O:18][C:19]2[CH:32]=[CH:31][C:22]([CH:23]=[C:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:21][CH:20]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1.C(O)(=O)C>O.[OH-].[Na+].C1COCC1.CN(C=O)C>[CH:11]1([CH2:16][CH2:17][O:18][C:19]2[CH:32]=[CH:31][C:22]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:21][CH:20]=2)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=C1NC(=O)C(=Cc2ccc(OCCC3CCCC3)cc2)S1
Agent: CC(=NO)C(C)=NO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1NC(=O)C(Cc2ccc(OCCC3CCCC3)cc2)S1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To the suspension containing CoCl2.6H2O (4.77 mg, 0.016 mmol) and dimethylglyoxime (73.14 mg, 0.63 mmol) in 10 ml of water, 4 drops of 1.0N NaOH and NaBH4 (409.4 mg, 10.65 mmol) were subsequently added. The mixture was cooled to 0° C., and 5-(4-(2-cyclopentylethoxy)benzylidene)thiazolidine-2,4-dione (1 g, 3.13 mmol) in 15 ml of THF-DMF (2:1) was added thereto over 20 minutes. The mixture was stirred at room temperature for 18 hours, to which acetic acid was then added until the pH thereof reached about 6. The mixture was diluted with water and extracted with ethyl acetate and water. The organic layer was washed with water several times, dried with anhydrous magnesium sulfate, filtered and solvent-evaporated. The residual oil was chromatographed on silica gel to afford 5-(4-(2-cyclopentylethoxy)benzyl)thiazolidine-2,4-dione (Derivative 118 of the above formula) as white solid (0.8 g, yield: 79%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[CH:5]=O.[CH3:14][NH:15][CH3:16].O1CCCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][N:15]([CH3:16])[CH3:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1
Reactant: O=Cc1cc(Br)cc(C(F)(F)F)c1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)Cc1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)benzaldehyde (2.0 g, 7.9 mmol, Combi-blocks) in methylene chloride (10 mL) was added a solution of 2.0M dimethylamine in tetrahydrofuran (7.9 mL, 16 mmol) and the reaction was stirred for 15 minutes at room temperature. The reaction was then cooled to 0° C. and sodium triacetoxyborohydride (2.5 g, 12 mmol) was added. The resulting mixture was warmed to room temperature and was stirred for 24 hours. The solvents were removed in vacuo. Saturated sodium bicarbonate solution was added and the resulting mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel column chromatography, eluting with a gradient from 10-40% ethyl acetate in hexanes afforded product as a colorless oil (1.58 g, 71%). 1H NMR (300 MHz, CDCl3) δ 7.68 (s, 1H), 7.65 (s, 1H), 7.57-7.46 (m, 1H), 3.45 (s, 2H), 2.25 (s, 6H); 19F NMR (282 MHz, CDCl3) δ−63.10 (s); LCMS (M+H)+: 282.0, 284.0.
Reaction SMILES: [CH2:1]([N:8]([CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[S:9]([CH2:12][C@H:13]([CH3:18])[C:14]([O:16]C)=[O:15])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].CO.OS([O-])(=O)=O.[K+]>C1COCC1.C(OCC)(=O)C>[CH2:1]([N:8]([CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[S:9]([CH2:12][C@H:13]([CH3:18])[C:14]([OH:16])=[O:15])(=[O:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](C)CS(=O)(=O)N(Cc1ccccc1)C(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@@H](CS(=O)(=O)N(Cc1ccccc1)C(c1ccccc1)c1ccccc1)C(=O)O
Yield: 80.7 %

Procedure:
A 50 mL round bottom flask equipped with magnetic stir bar was charged with 320 mg of methyl 3-[N-(benzyl)-N-(diphenylmethyl)aminosulfonyl]-2(R)-methylpropionate and 120 mg LiOH (4 eq) in 4 mL 50% aq THF. After 5 minutes 2 mL MeOH added to get homogeneous solution, after 1 hour the reaction was partioned between ethyl acetate and 5% aq KHSO4. The organic phase was washed with brine, dried, and concentrated in vacuo to yield 250 mg of 3-[N-(benzyl)-N-(diphenylmethyl)aminosulfonyl]-2(R)-methylpropionic acid as a clear semi-solid. HRMS (M+Li): calcd. 430.1664, obs. 430.1698.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[OH-:12].[Na+]>[Cu].O>[OH:12][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: [OH-]
Reactant: O=C(O)Cc1ccccc1Cl
Agent: [Cu]
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1ccccc1O
Temperature: 25 °C
Yield: 93 %

Procedure:
`Isopar M` (500 ml), (2-chlorophenyl)acetic acid (51.3 g, 0.3M), copper II sulphate hexahydrate (2.88 g, 10 mM) and sodium hydroxide pellets (84 g, 2.1M) were changed to a 1.5 litre hastalloy vessel equipped with a stirrer and condenser. The temperature of the vessel was increased from ambient using an oil bath, while stirring the reaction mixture. The oil bath was maintained at between 210° C. and 220° C. for 6 hours and then heating was ceased and the vessel was allowed to cool to ambient temperature. Water (500 ml) was added (exothern) and the reaction mixture was stirred for a further 30 minutes. After filtering off some insoluble material (about 600 mg) the phases were separated and the upper organic phase set aside (480-490 ml). The aqueous phase was acidified to pH1 (by test paper) by adding 36% hydrochloric acid (125-155 ml, exothern), and then extracted with isopropyl acetate (2×250 ml). The combined isopropyl acetate extracts were evaporated at 60° C. and about 20 mm Hg on a rotary evaporator to give (2-hydroxyphenyl)acetic acid as brown solid (44-45 g, purity by gas chromatography 94-99%, yield 93-96%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[CH3:17][NH2:18]>C1COCC1.C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH2:16])[N:9]=[C:10]([NH:18][CH3:17])[C:11]=1[I:12]
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Reactant: CN
Solvent: C1CCOC1
Solvent: CCO
Product: CNc1nc(N)nc(-c2ccco2)c1I

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine and methylamine in THF/ethanol. ES-MS m/e (%): 317 (M+H+, 100).
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C=O)C.[CH3:10][C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[N:12]=1>C1(C)C=CC=CC=1>[CH3:10][C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([Cl:3])=[O:21])=[CH:18][CH:17]=2)[N:12]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(-c2ccc(C(=O)O)cc2)no1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(C(=O)Cl)cc2)no1

Procedure:
46 ml of thionyl chloride and 1 ml of DMF are added to a solution of 10.0 g of 4-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid in 150 ml of toluene. The solution is heated under reflux for 5 hours. The solvent is removed, giving 4-(5-methyl-1,2,4-oxadiazol-3-yl)-benzoyl chloride, EI 222. Subsequent reaction with 9.3 g of 1-tert-butoxycarbonylpiperazine in 150 ml of dichloromethane and 48 ml of triethylamine gives, after customary work-up, tert-butyl 4-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)benzoyl]piperazine-1-carboxylate, FAB 373.
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([O:22][C:23]2[CH:45]=[CH:44][C:26]3[C:27]4[N:31]([CH2:32][CH2:33][O:34][C:25]=3[CH:24]=2)[CH:30]=[C:29]([C:35]2[N:36]([CH:41]([CH3:43])[CH3:42])[N:37]=[C:38]([CH3:40])[N:39]=2)[N:28]=4)[C:18]([F:21])([F:20])[F:19])[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.CO.[CH3:48]CN(C(C)C)C(C)C.C(Cl)(=O)C>[Pd].CC(C)=O>[F:21][C:18]([F:19])([F:20])[CH:17]([CH:14]1[CH2:15][CH2:16][N:11]([C:9](=[O:10])[CH3:48])[CH2:12][CH2:13]1)[O:22][C:23]1[CH:45]=[CH:44][C:26]2[C:27]3[N:31]([CH:30]=[C:29]([C:35]4[N:36]([CH:41]([CH3:43])[CH3:42])[N:37]=[C:38]([CH3:40])[N:39]=4)[N:28]=3)[CH2:32][CH2:33][O:34][C:25]=2[CH:24]=1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C4CCN(C(=O)OCc5ccccc5)CC4)C(F)(F)F)cc2OCC3)n(C(C)C)n1
Reactant: CCN(C(C)C)C(C)C
Agent: [Pd]
Solvent: CC(C)=O
Solvent: CC(=O)Cl
Solvent: CO
Product: CC(=O)N1CCC(C(Oc2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 8.3 %

Procedure:
To a solution of 4-{2,2,2-trifluoro-1-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]ethyl}piperidine-1-carboxylic acid benzyl ester from Example 5 (210 mg, 0.34 mmol) in a 1:10 mixture MeOH:acetone (11 mL), was added 10% Pd/C (200 mg). The reaction mixture was stirred at RT under a hydrogen atmosphere for 18 h. The suspension was then filtered through a pad of Celite® and to the filtrate fresh 10% Pd/C (200 mg) was added. The reaction mixture was stirred at RT under a hydrogen atmosphere for 48 h. The suspension was then filtered through a pad of Celite® and the filtrate was concentrated in vacuo. The resulting residue was treated with DIPEA (0.79 mL, 4.42 mmol) and acetyl chloride (0.23 mL, 4.08 mmol) and stirred at RT for 18 h. The crude material was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18 on a 25 min gradient 10-90% 0.1% HCO2H in acetonitrile/water) affording 179 (15 mg, 8%). LCMS: RT 4.23 min [M+H]+ 533.2. 1H NMR (CDCl3, 400 MHz): δ 8.47 (1H, d, J=8.99 Hz), 7.61 (1H, s), 6.80 (1H, dd, J=9.00, 2.62 Hz), 6.64 (1H, d, J=2.49 Hz), 5.92-5.85 (1H, m), 4.78-4.69 (1H, m), 4.50-4.47 (2H, m), 4.46-4.35 (3H, m), 3.93-3.85 (1H, m), 3.16-3.02 (1H, m), 2.64-2.51 (1H, m), 2.42 (3H, s), 2.27-2.15 (1H, m), 2.10 (3H, d, J=2.36 Hz), 2.05-1.93 (1H, m), 1.89-1.75 (1H, m), 1.64-1.44 (8H, m)
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([NH:27][CH:28]2[CH2:34][CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=3[N:30]([CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])[C:29]2=[O:47])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[BrH:48].C(O)(=O)C>C(O)(=O)C.C(OCC)C>[NH:11]1[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([NH:27][CH:28]2[CH2:34][CH2:33][C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=3[N:30]([CH2:39][C:40]([OH:42])=[O:41])[C:29]2=[O:47])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:15][CH2:16]1.[BrH:48]
Reactant: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)NC1CCc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)C(CCCCC1CCNCC1)NC1CCc2ccccc2N(CC(=O)O)C1=O
Reaction time: 2 h

Procedure:
In 2 ml of acetic acid is dissolved 0.8 g of tert-butyl 3(RS)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(SR)-ethoxycarbonylpentyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate, and 2 ml of 30% aqueous hydrogen bromide-acetic acid solution is added to the solution, followed by standing at room temperature for 2 hours. The reaction solution is diluted with 200 ml of ethyl ether, and after the mixture is allowed to stand, the supernatant layer is removed by decantation. The precipitate is rinsed with 100 ml of ethyl ether and dried to give 3(RS)-[5-(4-piperidyl)-1(SR)-ethoxycarbonylpentyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid·hydrobromide. This product is dissolved in 20 ml of 1N aqueous sodium hydroxide and the solution is allowed to stand at room temperature for 1 hour, acidified with 2 ml of acetic acid and purified by XAD-2 column chromatography (methanol:water=1:1). The effluent is concentrated under reduced pressure, and the crystals, which separate out, are rinsed with 50 ml of acetone and collected by filtration to give 0.33 g of 3(RS)-[5-(4-piperidyl)-1(SR)-carboxypentyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-benzazepine-1-acetic acid as colorless prisms. m.p. 250°-260° C. (decomp.).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:8]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=3[CH3:25])[CH:9]=[C:10]([C:15](=[O:17])[CH:16]=2)[C:11]([O:13]C)=[O:12])[CH2:3][CH2:2]1.[CH:26](Br)([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+].[ClH:36]>CN(C)C=O>[ClH:36].[OH:24][C:21]1[CH:22]=[CH:23][C:18]([N:8]2[C:7]([CH:4]3[CH2:5][CH2:6][N:1]([CH:26]([CH3:28])[CH3:27])[CH2:2][CH2:3]3)=[CH:16][C:15](=[O:17])[C:10]([C:11]([OH:13])=[O:12])=[CH:9]2)=[C:19]([CH3:25])[CH:20]=1
Reactant: CC(C)Br
Reactant: COC(=O)c1cn(-c2ccc(O)cc2C)c(C2CCNCC2)cc1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)ccc1-n1cc(C(=O)O)c(=O)cc1C1CCN(C(C)C)CC1

Procedure:
In 4 ml of N,N-dimethylformamide was dissolved 0.24 g of methyl 6-(4-piperidinyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinate, and 0.17 g of isopropyl bromide and 0.06 g of potassium carbonate were added to the solution, after which they were reacted at 60° C. for 6 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was dissolved in a mixture of 20 ml of chloroform and 20 ml of water. The organic layer was separated, washed twice with 20-ml portions of water, and dried with anhydrous sodium sulfate. Then, the solvent was removed by distillation under reduced pressure, and the oily substance thus obtained was purified by a column chromatography (Wako Silica Gel C-200; eluent: chloroform/ethanol (20:1 by volume) mixture). The fraction containing the objective substance was concentrated, and to the oily substance thus obtained was added 5 ml of 6N hydrochloric acid, and they were refluxed for 2 hours. The solvent was removed by distillation under reduced pressure to obtain 0.11 g of 1-(4-hydroxy-2-methylphenyl)-6-(1-isopropyl-4-piperidinyl)-4-oxo-1,4-dihydronicotinic acid hydrochloride having a melting point of 195.5°-200.5° C.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([CH2:12][OH:13])[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)Cl.O=[Mn]=O>[C:1]1([N:7]2[CH:11]=[C:10]([CH:12]=[O:13])[N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1cn(-c2ccccc2)nn1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1cn(-c2ccccc2)nn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82 %

Procedure:
To a solution of (1-phenyl-1H-1,2,3-triazol-4-yl)methanol, 7, (1.03 g, 5.87 mmol) in CH2Cl2 (50 mL) was added MnO2 (2.05 g, 23.5 mmol). The reaction mixture was stirred for 3 days at room temperature. The reaction mixture was then filtered through Celite® and the resulting filtrate was concentrated in vacuo. The crude material was purified by silica gel chromatography (0-5% methanol/dichloromethane) yielding 0.83 g (82%) of 9: 1H NMR (400 MHz, CDCl3) δ 10.22 (s, 1H), 8.51 (s, 1H), 7.53, (d, J=9.6 Hz, 2H), 7.58-7.49, (m, 3H).
Reaction SMILES: [N+]([O-])(O)=[O:2].[CH3:5][C:6]1([CH3:15])[CH2:11][CH2:10][CH2:9][C@H:8]([CH3:12])[C@H:7]1[CH:13]=[O:14]>>[CH3:15][C:6]1([CH3:5])[CH2:11][CH2:10][CH2:9][C@H:8]([CH3:12])[C@H:7]1[C:13]([OH:2])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: C[C@H]1CCCC(C)(C)[C@@H]1C=O
Product: C[C@H]1CCCC(C)(C)[C@@H]1C(=O)O
Temperature: 55 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
In a 300-ml 4-necked flask equipped with a condenser, a thermometer, a dropping funnel, and a stirrer was placed 42 g of nitric acid (aqueous 60% solution), and the temperature was raised to 55° C. by heating. To the solution was added dropwise 100 g (0.65 mole) of (1R,6S)-2,2,6-trimethylcyclohexanecarbaldehyde (10) [composition: 90% of the (1R,6S)-form, 10% of the (1S,6S)-form] synthesized in Synthetic Example 4-A) with stirring over a period of 2 hours. After carrying out the reaction for 3 hours at the same temperature, the reaction mixture was washed with water with 100 g of toluene and 100 g of water at room temperature, followed by separating an organic layer from an aqueous layer. The organic layer was washed thrice with 100 g of a saturated aqueous sodium chloride solution, followed by separating the organic layer from an aqueous layer. The toluene was distilled off from the organic layer by an evaporator under reduced pressure to provide 109 g of crude (1R,6S)-2,2,6-trimethylcyclohexanecarboxylic acid (11) [composition: 91% of the (1R,6S)-form, 9% of the (1S,6S)-form; melting point: 44° C. to 54° C⟧
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][NH:6][C:7]=1[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:11]([O:13]C)=[O:12].[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[N:5][NH:6][C:7]=1[C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:11]([OH:13])=[O:12]
Reactant: COC(=O)c1ccc(C)c(-c2[nH]ncc2OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cn[nH]c1-c1cc(C(=O)O)ccc1C
Temperature: 60 °C
Reaction time: 3 h
Yield: 208.2 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(4-methoxy-1H-pyrazol-5-yl)-4-methylbenzoate (compound 244.6, 180 mg, 0.73 mmol) in methanol (4 mL). Sodium hydroxide (117 mg, 2.92 mmol) in water (2 mL) was added and the resulting solution was stirred for 3 h at 60° C., then concentrated under reduced pressure. The pH of the residue was adjusted to 1 with aqueous hydrogen chloride (1 M), then concentrated under reduced pressure. Methanol (5 mL) was added to the residue and the solids were filtered from the solution. The filtrate was concentrated under reduced pressure to obtain the title compound as a limit yellow solid (353 mg, crude).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:24]([CH3:30])=[C:25]([C:28]#[N:29])[C:26]#[N:27])[CH:20]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[N:11]1([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[CH:20]=[C:19]([C:24](=[C:25]([C:26]#[N:27])[C:28]#[N:29])[CH3:30])[CH:18]=[CH:17]3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(=C(C#N)C#N)c1ccc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2c1
Solvent: O=C(O)C(F)(F)F
Product: CC(=C(C#N)C#N)c1ccc2cc(N3CCNCC3)ccc2c1

Procedure:
When tert-butyl-4-[6-(2,2-dicyano-1-methylvinyl)-2-naphthyl]-1-piperazinecarboxylate was treated with TFA (trifluoroacetic acid) at room temperature, TLC showed that the reaction was over in 5 minutes and gave a single product, 2-[1-(6-piperazino-2-naphthyl)ethylidene]malononitrile. The TFA was removed in vacuo at room temperature. 1H NMR: δ2.72 (s, 3H, CH3), 3.50 and 3.63 (broad, 8H, piperazine), 7.18 (broad s, 1H, 5-H), 7.29 (d, 1H, 7-H), 7.59 (d, 1H, 3-H), 7.79 (d, 1H, 4-H), 7.87 (d, 1H, 8-H), 8.04 (s, 1H, 1-H), 9.0 (broad, 1.5H, NH and acid); J7,8=8.8 Hz, J3,4=8.4 Hz. 19F NMR: δ−76.2 (CF3COO).
Reaction SMILES: C([O:8][CH2:9][C@H:10]([NH:41][C:42](=[O:50])[CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)[C:11]([NH:13][C@@H:14]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=1)[C:15]([NH:17][C@@H:18]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:19]([C@@:21]1([CH3:24])[CH2:23][O:22]1)=[O:20])=[O:16])=[O:12])C1C=CC=CC=1>[Pd].CO>[OH:8][CH2:9][C@H:10]([NH:41][C:42](=[O:50])[CH2:43][N:44]1[CH2:45][CH2:46][O:47][CH2:48][CH2:49]1)[C:11]([NH:13][C@@H:14]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=1)[C:15]([NH:17][C@@H:18]([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:19]([C@@:21]1([CH3:24])[CH2:23][O:22]1)=[O:20])=[O:16])=[O:12]
Reactant: COc1ccc(C[C@H](NC(=O)[C@H](COCc2ccccc2)NC(=O)CN2CCOCC2)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C[C@H](NC(=O)[C@H](CO)NC(=O)CN2CCOCC2)C(=O)N[C@@H](Cc2ccccc2)C(=O)[C@@]2(C)CO2)cc1
Temperature: 40 °C
Reaction time: 16 h
Yield: 41550 %

Procedure:
To (S)-3-(benzyloxy)-N-((S)-3-(4-methoxyphenyl)-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)-2-(2-morpholinoacetamido)propanamide (330 mg, 0.480 μmol) was added methanol (20 mL) and Pd/C (10%, 500 mg). The reaction mixture was stirred under a hydrogen atmosphere (balloon) for 16 h at 40° C. before it was cooled to ambient temperature and filtered through Celite. Purification by column chromatography (3:1 DCM/ethyl acetate+0-10% methanol) provided (S)-3-hydroxy-N-((S)-3-(4-methoxyphenyl)-1-(((S)-1-((R)-2-methyloxiran-2-yl)-1-oxo-3-phenylpropan-2-yl)amino)-1-oxopropan-2-yl)-2-(2-morpholinoacetamido)propanamide (119 mg, 42%) as a colorless amorphous solid. 1H NMR (400 MHz,) δ 7.89 (d, J=7.7 Hz, 1H), 7.26-7.19 (m, 3H), 7.10-7.06 (m, 2H), 7.01-6.96 (m, 2H), 6.82-6.79 (m, 2H), 6.73 (d, J=8.0 Hz 1H), 6.50 (d, J=7.8 Hz, 1H), 4.80 (td, J=7.7, 7.7, 5.4 Hz, 1H), 4.64-4.48 (m, 1H), 4.45-4.31 (m, 1H), 3.92 (dd, J=11.0, 3.9 Hz, 1H), 3.79-3.74 (m, 5H), 3.73-3.67 (m, 3H), 3.54 (dd, J=11.0, 6.7 Hz, 1H), 3.27 (d, J=4.9 Hz, 1H), 3.15-2.84 (m, 6H), 2.72 (dd, J=14.0, 7.8 Hz, 1H), 2.55-2.39 (m, 4H), 1.48 (s, 3H). MS (EI) for C31H40N4O8, found 597.1 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)=[CH:11][CH:10]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.C(N(CC)CC)C.[C:35]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>CN(C)C=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][N:21]4[C:35](=[O:41])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:11][CH:10]=2)=[C:4]([O:26][CH3:27])[CH:3]=1
Reactant: O=C1CCC(=O)O1
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3[nH]ccc23)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3c2ccn3C(=O)CCC(=O)O)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
To 4-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indole (37 mg, 0.10 mmol, 1 eq.) was added dimethylformamide (1 mL), triethylamine (0.154 ml, 1.1 mmol, 10 eq.) and succinic anhydride (30 mg, 0.3 mmol, 3 eq.) the reaction was stir at 80° C. for 8 hr and allowed to cool to room temperature. Lithium bis(trimethylsilyl)amide (1 M in THF, 1.2 mL, 1.2 mmol, 12 eq) was added and the reaction was allowed to proceed at room temperature for 24 hr. The reaction was purified by HPLC with a 30-100% acetonitrile in water gradient and dried from dichloromethane/hexanes mixture to yield 4-[4-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-4-oxo-butyric acid as a white solid (16 mg, 34%). LC-MS (ES) calculated for C26H21F2NO5, 465.1; found m/z 466 [M+H]+.