Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][C:6](=[O:32])[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:17][CH:16]=1)[CH2:8][CH2:9][C:10]([O:12]C)=O)[CH3:2].[O-]CC.[Na+].O.Cl>C1C=CC=CC=1>[CH2:25]([O:24][C:22]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:7]2[CH2:8][CH2:9][C:10](=[O:12])[CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:33])[C:6]2=[O:32])=[CH:16][CH:17]=1)=[O:23])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)CC(=O)N(CCC(=O)OC)Cc1ccc(NC(=O)OCc2ccccc2)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C1C(=O)CCN(Cc2ccc(NC(=O)OCc3ccccc3)cc2)C1=O
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
A solution of ethyl[N-(p-(N-benzyloxycarbonylamino)benzyl)-N-(methoxycarbonylethyl)carbamoyl]acetate (967 mg) in benzene (15 ml) is added dropwise to a solution of sodium ethoxide (prepared from sodium (60 mg) and ethanol (2 ml)) at room temperature. The mixture is stirred at the same temperature for 30 minutes. The mixture is poured into water. The aqueous solution is neutralized with 10% HCl, and extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and then distilled to remove the solvent to give ethyl 1-(p-(N-benzyloxycarbonylamino)-benzyl)-2,4-dioxopiperidine-3-carboxylate (841 mg, 93.5%) as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:9])=[CH:5][C:6]=1[C:7]#[N:8].O=[C:11]([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].Cl[Sn](Cl)(Cl)Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[NH2:8][C:7]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([CH3:18])[N:1]=[C:2]2[S:3][C:4]([CH3:9])=[CH:5][C:6]=12
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1cc(C#N)c(N)s1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)nc2sc(C)cc2c1N
Yield: 71.5 %

Procedure:
To a solution of 2-amino-5-methyl-3-thiophenecarbonitrile (5 g, 36.2 mmol), ethyl 3-oxobutanoate (5.49 mL, 43.4 mmol) in toluene (200 mL) was added SnCl4 (5.10 mL, 43.4 mmol). The resulting mixture was refluxed for 2 h after which the heater was switched off. SnCl4 (2.123 mL, 18.09 mmol) was added and the mixture refluxed for another 4 h. The solution was cooled and aqueous NaOH (5M) was added until the solution turned basic. Ethyl acetate (100 mL) was added and washed with water (3×30 mL). The organic layer was dried over MgSO4, filtered and solvent removed in vacuo. Purification by chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate in cyclohexane afforded the title compound (6.48 g). LCMS (A) m/z: 251 [M+1]+, Rt 0.74 min (acidic).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].Cl.[NH3:13]>>[NH2:13][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: N
Reactant: O=C(O)CCCCCCCBr
Agent: Cl
Product: NCCCCCCCC(=O)O
Temperature: 15 °C
Reaction time: 10 h
Yield: 86 %

Procedure:
A 500-ml three-necked flask equipped with stirrer, thermometer and dropping funnel was charged with 400 ml of 25% aqueous ammonia, and the flask contents were maintained at 15° C. Thereto was added 50 g (0.22 mole) of molten 8-bromocaprylic acid over 30 minutes. After the addition, stirring was continued for further 10 hours. Thereafter, the ammonia was removed by warming the liquid reaction mixture. The mixture was then cooled and adjusted to pH 6.0 with 0.1N hydrochloric acid. The resulting crystalline precipitate was collected by filtration. The precipitate and the second crop obtained by concentration the mother liquor were combined and recrystallized from water to give 30 g of 8-aminocaprylic acid (m.p. 193°-195° C.). The yield was 86% based on the charged 8-bromocaprylic acid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][OH:8])[CH:3]=[N:2]1.[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:9][S:10]([O:8][CH2:7][CH2:6][C:4]1[CH:5]=[N:1][N:2]([S:10]([CH3:9])(=[O:12])=[O:11])[CH:3]=1)(=[O:12])=[O:11]
Reactant: OCCc1cn[nH]c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1cnn(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-(1H-pyrazol-4-yl)ethanol (50 mg, 0.45 mmol) in dichloromethane (3 mL) at 0° C. was added methanesulfonyl chloride (0.104 mL, 1.39 mmol) followed by N,N-diisopropylethylamine (0.312 mL, 1.78 mmol) dropwise. The ice bath was removed and the mixture warmed to ambient temperature and stirred for 1 h. The solvent was removed in vacuo and the residue purified by column chromatography (silica gel Biotage 25S) eluting with ethyl acetate/hexane (gradient from 0% to 100%) to give the title compound as a colorless solid. LC/MS 269.2 (M+1).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:28])=[C:4]([O:29][CH3:30])[CH:3]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[C:36]([F:38])[CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>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>[O:25]1[CH:26]=[CH:27][C:23]([NH:22][S:19]([C:15]2[CH:14]=[C:13]3[C:18](=[CH:17][CH:16]=2)[N:9]([C:5]2[C:4]([O:29][CH3:30])=[CH:3][C:2]([C:34]4[CH:33]=[C:32]([F:31])[CH:37]=[C:36]([F:38])[CH:35]=4)=[C:7]([F:8])[CH:6]=2)[C:10](=[O:28])[CH:11]=[CH:12]3)(=[O:21])=[O:20])=[N:24]1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: COc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(-c2cc(F)cc(F)c2)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 90 °C

Procedure:
A RBF was charged with 1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (272 mg, 0.550 mmol), (3,5-difluorophenyl)boronic acid (130 mg, 0.825 mmol), potassium carbonate (228 mg, 1.651 mmol), and Pd(Ph3P)4 (63.6 mg, 0.055 mmol). The vial was sealed with a septum cap and flushed with N2 (g), then Dioxane (2064 μl) and Water (688 μl) were added via syringe. The mixture was heated at 90° C. for 40 min. The mixture was diluted with HCl (8 mL, 1M aq) then extracted with EtOAc (2×20 mL). The organic layers were combined and concentrated. The residue was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0%-3% MeOH in DCM, to provide N-(isoxazol-3-yl)-2-oxo-1-(2,3′,5′-trifluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-1,2-dihydroquinoline-6-sulfonamide. The racemic N-(isoxazol-3-yl)-2-oxo-1-(2,3′,5′-trifluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-1,2-dihydroquinoline-6-sulfonamide was subjected to chiral separation by SFC on an AS-H column (25% MeOH/75% CO2) to give (P)—N-(isoxazol-3-yl)-2-oxo-1-(2,3′,5′-trifluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-1,2-dihydroquinoline-6-sulfonamide as peak 1 and (M)-N-(isoxazol-3-yl)-2-oxo-1-(2,3′,5′-trifluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-1,2-dihydroquinoline-6-sulfonamide as peak 2. Data for peak 1: 1H NMR (500 MHz, DMSO-d6) δ 11.65 (br. s., 1H), 8.72 (d, J=1.66 Hz, 1H), 8.38 (d, J=1.98 Hz, 1H), 8.16-8.31 (m, 1H), 7.86 (dd, J=2.08, 8.98 Hz, 1H), 7.56 (d, J=10.47 Hz, 1H), 7.47 (t, J=6.79 Hz, 3H), 7.33-7.43 (m, 1H), 6.84-6.91 (m, 1H), 6.77-6.84 (m, 1H), 6.41-6.49 (m, 1H), 3.70-3.83 (s, 3H). m/z (ESI) 528.0 (M+H)+. Data for peak 2: 1H NMR (500 MHz, DMSO-d6) δ 11.65 (br. s., 1H), 8.72 (d, J=1.66 Hz, 1H), 8.38 (d, J=1.98 Hz, 1H), 8.16-8.31 (m, 1H), 7.86 (dd, J=2.08, 8.98 Hz, 1H), 7.56 (d, J=10.47 Hz, 1H), 7.47 (t, J=6.79 Hz, 3H), 7.33-7.43 (m, 1H), 6.84-6.91 (m, 1H), 6.77-6.84 (m, 1H), 6.41-6.49 (m, 1H), 3.70-3.83 (s, 3H). m/z (ESI) 528.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([OH:11])[C:9]#[N:10].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.CN(C)C1C=CC=CC=1.Cl>C(OCCCC)(=O)C>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([O:11][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]#[N:10])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: N#C[C@@H](O)c1ccccc1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCCCOC(C)=O
Solvent: CN(C)c1ccccc1
Product: Cc1ccc(S(=O)(=O)OC(C#N)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
(s)-2-(2-chlorophenyl)-2-hydroxyacetonitrile (16.8 g, 0.1 mol) and 4-toluene sulfonyl chloride (21 g, 0.11 mol) was dissolved in butyl acetate (100 mL) in a suitable reaction flask. N,N-dimethyl aniline (10 mL) was added dropwise to the mixture at 0-5° C. and the reaction continued at 20-25° C. for 3 hours, and then refluxed till the reaction was completed by TLC monitoring. Cold down the reaction mixture, 5% HCl (50 mL) was added and stirred at room temperature. Butyl acetate layer was separated and washed with water (50 ml×2). After removal of the solvent under reduced pressure, the target product was obtained (31 g, yield 96.9%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].C(=O)([O-])[O-].[K+].[K+].[CH3:32][S:33]([CH2:36][CH2:37][N:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[CH:40][C:39]1=[O:53])(=[O:35])=[O:34].FC(F)(F)C(O)=O>ClCCl.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.COCCOC>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[CH:5]=[CH:4][C:3]([CH3:25])=[C:2]([C:42]5[CH:41]=[CH:40][C:39](=[O:53])[N:38]([CH2:37][CH2:36][S:33]([CH3:32])(=[O:34])=[O:35])[CH:43]=5)[N:7]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: CC1(C)OB(c2ccc(=O)n(CCS(C)(=O)=O)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COCCOC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(=O)n(CCS(C)(=O)=O)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 3.5 %

Procedure:
N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (325 mg, 0.886 mmol), tetrakis(triphenylphosphine)palladium (0) (51.20 mg, 0.044 mmol), potassium carbonate (1.1 mL of 2 M, 2.21 mmol), and 1-(2-(methylsulfonyl)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one (377 mg, 1.15 mmol) were combined in a scintillation vial containing 1,2-dimethoxyethane (8 mL). The reaction mixture was then stirred and heated to 80 degrees C. for 16 hours. The reaction was then allowed to cool to room temperature. The layers were then separated and the organic layer was evaporated to dryness, re-dissolved in 1 mL of N,N-dimethylformamide, and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile (containing 0.035% trifluoroacetic acid (v/v)) in water (containing 0.05% trifluoroacetic acid (v/v)) to yield the product. The resulting trifluoroacetic acid salt was then dissolved in a minimum of dichloromethane (5 mL). This solution was then washed two times with a saturated aqueous solution of sodium bicarbonate, followed by two washes of a saturated aqueous solution of sodium chloride, followed by two washes of water. The organic layer was dried over sodium sulfate and then evaporated to dryness. The product was then further purified on 4 g of silica utilizing a gradient of 0-10% methanol in dichloromethane to yield the pure product (16.7 mg, 3.5%). ESI-MS m/z calc. 531.1. found 532.1 (M+1)+. Retention time 1.52 minutes. 1H NMR (400 MHz, CD3CN) δ 7.94 (d, J=8.4 Hz, 1H), 7.77 (s, 1H), 7.65 (d, J=2.3 Hz, 1H), 7.62-7.55 (m, 2H), 7.36-7.32 (m, 2H), 7.22 (d, J=8.2 Hz, 1H), 6.42 (d, J=9.4 Hz, 1H), 4.29 (t, J=6.7 Hz, 2H), 3.49 (t, J=6.7 Hz, 2H), 2.90 (s, 3H), 2.32 (s, 3H), 1.62-1.58 (m, 2H), 1.19-1.15 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([OH:26])([CH3:25])[C:20]([O:22]CC)=[O:21])[CH:15]=3)[C:10]([CH3:27])=[N:9]2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+]>CO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[C:18][C:19]([OH:26])([CH3:25])[C:20]([OH:22])=[O:21])[CH:15]=3)[C:10]([CH3:27])=[N:9]2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)C(C)(O)C#Cc1ccc2c(C)nn(-c3ccnc(N)n3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nn(-c2ccnc(N)n2)c2cc(C#CC(C)(O)C(=O)O)ccc12
Reaction time: 15 h

Procedure:
To a solution of ethyl 4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-hydroxy-2-methylbut-3-ynoate (120 mg, 0.33 mmol) in methanol (0.5 mL) was introduced sodium hydroxide (0.16 mL of a 2M aqueous solution, 0.33 mmol). After 15 hr at RT, the reaction mixture was concentrated in vacuo and the pH of the aqueous residue adjusted to 7 with 0.5M aqueous hydrochloric acid. The solution was extracted with 3:1 chloroform/isopropanol (5×5 mL extractions) and the combined organic extracts dried (Na2SO4), filtered and concentrated in vacuo to furnish the crude title compound as a yellow solid: 1H NMR (250 MHz, DMSO) delta 1.68 (3H, s), 2.59 (3H, s), 7.07-7.29 (3H, m), 7.37 (2H, dd, J=8.4, 1.2 Hz), 7.87 (1H, d, J=7.7 Hz), 8.28 (1H, d, J=5.9 Hz), 8.85 (1H, s); LC-MS: m/z=+338.00 (M+H)+. This compound, with LC-MS purity=100% UV, was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14](N)=[O:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[OH-:19].[K+]>C(O)CC.O>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:19])=[O:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: NC(=O)c1ccc(NCc2ccc(F)cc2)cn1
Agent: [K+]
Solvent: CCCO
Solvent: O
Product: O=C(O)c1ccc(NCc2ccc(F)cc2)cn1

Procedure:
0.245 g of 5-(p-fluorobenzylamino)-pyridine-2-carboxamide are dissolved in 2.5 ml of warm n-propanol, the solution is combined with 2.5 ml of 20% aqueous potassium hydroxide and the mixture is heated on a steam bath for 16 hours. It is diluted with water and most of the n-propanol removed with a stream of nitrogen. The hot solution is filtered and the pH of the filtrate adjusted to 4 with hydrochloric acid. The precipitate formed is collected, redissolved in aqueous sodium bicarbonate, the solution filtered and reacidified with hydrochloric acid to pH=4. The solid formed is collected and air-dried, to yield the 5-(p-fluorobenzylamino)-pyridine-2-carboxylic acid melting at 196°-198°.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)=[N:13][CH:14]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC(OC)OC.[CH2:31]([NH2:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[BH4-].[Na+]>CO>[CH2:31]([NH:39][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([O:15][C:12]2[N:13]=[CH:14][C:9]([C:7]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:8])=[CH:10][CH:11]=2)=[CH:17][CH:18]=1)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCCc1ccccc1
Reactant: O=Cc1ccc(Oc2ccc(C(=O)N3CCCCC3)cn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: O=C(c1ccc(Oc2ccc(CNCCc3ccccc3)cc2)nc1)N1CCCCC1
Reaction time: 72 h
Yield: 82.7 %

Procedure:
Combine 4-[5-(Piperidine-1-carbonyl)-pyridin-2-yloxy]-benzaldehyde (72.0 mg, 0.23 mmol), MeOH (2.3 mL), Trimethylorthoformate (1.6 mL), and Phenethylamine (26 uL, 0.21 mmol). After the reaction stirs for 72 hours at room temperature under a Nitrogen atmosphere, add NaBH4 (10.5 mg, 0.28 mmol). After 5 hours, concentrate the reaction under reduced pressure and add the mixture to a 2 g SCX column. Wash with MeOH and then 1N NH3MeOH to afford 72.2 mg (75% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 1.5-1.8 (6H, m), 2.8-3.0 (4H, m), 3.3-3.8 (4H, m), 3.85 (2H, s), 6.8 (1H, d), 7.1-7.4 (9H, m), 8.0 (1H, d), 8.2 (1H, s); MS m/z 416 (M+1).
Reaction SMILES: C([O:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:23]([NH:25][N:26]1[C:31](=[O:32])[NH:30][C:29](=[O:33])[NH:28][C:27]1=[O:34])=[O:24])[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11])C1C=CC=CC=1>CO.[Pd]>[OH:8][NH:9][C:10]([C@H:12]([C@@H:22]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:23]([NH:25][N:26]1[C:31](=[O:32])[NH:30][C:29](=[O:33])[NH:28][C:27]1=[O:34])=[O:24])[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:11]
Reactant: CC(C)C[C@@H](C(=O)Nn1c(=O)[nH]c(=O)[nH]c1=O)[C@H](CCCc1ccccc1)C(=O)NOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)Nn1c(=O)[nH]c(=O)[nH]c1=O)[C@H](CCCc1ccccc1)C(=O)NO
Yield: 23.3 %

Procedure:
A solution of 0.544 g of 2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenylbutyl]-4-methyl-N-(2,4,6-trioxo-1,3,5-triazin-1-yl)valeramide in 20 ml of methanol was hydrogenated in the presence of 0.05 g of 10% palladium-on-carbon for 5 hours. Filtration, evaporation, and trituration of the residue with diethyl ether gave 0.105 g of 2(R)-[1(S)-(Hydroxycarbamoyl)-4-phenylbutyl]-4-methyl-N-(2,4,6-trioxo-1,3,5-triazin-1-yl)valeramide in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][OH:12])[N:8]([CH3:13])[C:5]2=[N:6][CH:7]=1.O[C:15]1[CH:47]=[CH:46][C:18]([CH2:19][CH:20]2[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]2=[O:45])=[CH:17][CH:16]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][O:12][C:15]3[CH:47]=[CH:46][C:18]([CH2:19][CH:20]4[S:24][C:23](=[O:25])[N:22]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:21]4=[O:45])=[CH:17][CH:16]=3)[N:8]([CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: Cn1c(CO)nc2cc(Br)cnc21
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cc(Br)cnc21

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 1.35 g of 6-bromo-2-hydroxymethyl-3-methyl-3H-imidazo[4,5-b]pyridine (prepared as described in Preparation 59), 2.60 g of 5-(4-hydroxybenzyl) -3-triphenylmethylthiazolidine-2,4-dione, 1.39 ml of tributylphosphine, 1.41 g of 1,1'-(azodicarbonyl)dipiperidine and 35 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 1:1by volume mixture of hexane and ethyl acetate as the eluent, to give 3.43 g of the title compound, melting at 97°-100° C. (softening).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]#[N:29])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:17](=[O:32])[N:18]=[C:19]2[NH:30][NH2:31])=[N:14]1.[N:37]#[C:38]Br>O1CCOCC1>[NH2:37][C:38]1[N:18]2[C:17](=[O:32])[N:16]([CH2:33][CH:34]3[CH2:35][CH2:36]3)[C:15]3[C:20](=[C:21]([C:22]4[N:26]([CH3:27])[CH:25]=[C:24]([C:28]#[N:29])[CH:23]=4)[N:13]([CH2:12][C:5]4[C:4]5[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=5)[N:8]=[CH:7][CH:6]=4)[N:14]=3)[C:19]2=[N:30][N:31]=1
Reactant: Cn1cc(C#N)cc1-c1c2c(NN)nc(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Reactant: N#CBr
Solvent: C1COCCO1
Product: Cn1cc(C#N)cc1-c1c2c(nn1Cc1ccnc3ccc(Cl)cc13)n(CC1CC1)c(=O)n1c(N)nnc21
Temperature: 100 °C

Procedure:
To a solution of 5-[2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-4-hydrazino-6-oxo-6,7-dihydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]-1-methyl-1H-pyrrole-3-carbonitrile (0.13 g) in dioxane (3 mL) was added cyanogen bromide (0.15 mL). The reaction was heated by microwave at 100° C. for 5 min. The mixture was concentrated and purified by HPLC yielding 27 mg of yellow foam, 1H NMR (300 MHz, CHLOROFORM-D) d ppm 0.56 (m, 4 H) 1.44 (m, 1H) 3.7 (s, 3H) 3.94 (m, 2H) 5.84 (m, 2H) 6.54 (d, 1H) 6.86 (m, 1H) 7.71 (m, 2H) 7.87 (m, 1H) 8.12 (m, 1H) 8.85 (m, 1H); ES M+H+=525.
Reaction SMILES: [CH2:1]([C@H:4]1[N:7]([C:8](=[C:13]([CH3:15])[CH3:14])[C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:16])[C@@H:5]1[N:17]1C(=O)C2=CC=CC=C2C1=O)[CH:2]=[CH2:3].CN(C)CCCN>C(Cl)Cl.CO>[NH2:17][C@@H:5]1[C@@H:4]([CH2:1][CH:2]=[CH2:3])[N:7]([C:8](=[C:13]([CH3:15])[CH3:14])[C:9]([O:11][CH3:12])=[O:10])[C:6]1=[O:16]
Reactant: C=CC[C@@H]1[C@@H](N2C(=O)c3ccccc3C2=O)C(=O)N1C(C(=O)OC)=C(C)C
Agent: CN(C)CCCN
Solvent: ClCCl
Solvent: CO
Product: C=CC[C@@H]1[C@@H](N)C(=O)N1C(C(=O)OC)=C(C)C
Reaction time: 120 h
Yield: 84.4 %

Procedure:
To a solution of methyl 2-[(3R,4R)-4-allyl-3-phthalimido-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (6.78 g) in a mixture of methylene chloride (46 ml) and methanol (23 ml) was added N,N-dimethyl-1,3-propanediamine (6.25 ml) at 0° C. and the mixture was left at room temperature for 5 days. The reaction mixture was evaporated and the residue was chromatographed on silica gel eluting with a mixture of methylene chloride and ethyl acetate (10:1-5) to give methyl 2-[(3R,4R)-3-amino-4-allyl-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (3.70 g) as an oil.
Reaction SMILES: [O:1]1[C@H:3]2[C:4]3[CH:13]=[C:12]([S:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=4)(=[O:16])=[O:15])[CH:11]=[CH:10][C:5]=3[O:6][C:7]([CH3:9])([CH3:8])[C@@:2]12[CH3:25].[NH3:26]>C(O)C>[NH2:26][C@H:3]1[C@@:2]([OH:1])([CH3:25])[C:7]([CH3:8])([CH3:9])[O:6][C:5]2[CH:10]=[CH:11][C:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)(=[O:16])=[O:15])=[CH:13][C:4]1=2
Reactant: N
Reactant: COc1cccc(S(=O)(=O)c2ccc3c(c2)[C@@H]2O[C@]2(C)C(C)(C)O3)c1
Solvent: CCO
Product: COc1cccc(S(=O)(=O)c2ccc3c(c2)[C@@H](N)[C@](C)(O)C(C)(C)O3)c1
Temperature: 50 °C

Procedure:
(3S,4S)-3,4-Dihydro-3,4-epoxy-6-(3-methoxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo[b]pyran (2.0 g) (see Preparation 17) was dissolved in ethanol (15 ml) and 35% aqueous ammonia solution (10 ml) was added. The mixture was heated at 50° C. for 48 hours before adding further ammonia solution (5 ml) and heating for another 8 hours. The solvent was removed under reduced pressure and the residue was chromatographed on silica using 5:95 methanol:dichloromethane as the eluent to yield (3S,4R)-4-amino-3,4-dihydro-3-hydroxy-6-(3-methoxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo[b]pyran (1.9 g) as a foam. Found: C,58.65; H,5.77; N,3.29. C19H23NO5S, 0.22 CH2Cl2 requires C,58.28; H,5.96; N,3.53%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][C:18](=O)[CH:19]([CH3:21])[CH3:20])[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.[CH3:23][NH2:24]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:18]([CH:19]([CH3:21])[CH3:20])[N:24]([CH3:23])[C:9]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)CC(C(=O)c1ccccc1)c1ccc(F)cc1
Reactant: CN
Solvent: CCO
Product: CC(C)c1cc(-c2ccc(F)cc2)c(-c2ccccc2)n1C

Procedure:
2.98 g (10 mmol) of 2-(4-fluorophenyl)-5-methyl1-phenyl-hexane-1,4-dione (Example 2) are heated at 80° C. in 10 ml of 40% strength aqueous methylamine solution, and about 14 ml of ethanol are added so that a clear solution forms. The solution is heated under reflux for a further 30 minutes and, after cooling, the precipitate is filtered off with suction. This is washed with a little ethanol and dried over phosphorus pentoxide in a vacuum desiccator.