Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C1C[O:8][CH2:7][CH2:6]1>>[C:1]([O:4][C:7](=[O:8])[CH3:6])(=[O:3])[CH3:2].[C:1]([O-:4])(=[O:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(=O)O
Product: CC(=O)OC(C)=O
Product: CC(=O)[O-]

Procedure:
The particularly preferred PTHF acetates or THF copolymer acetates may be worked up by methods known per se. For example, after distillative removal of unconverted THF and any acetic anhydride, acetic acid and comonomer, the PTHF acetate or THF copolymer acetate obtained is transesterified under base catalysis with methanol to give PTHF or THF copolymer and methyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[NH2:15][OH:16]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8](=[N:15][OH:16])[NH2:9]
Reactant: NO
Reactant: CS(=O)(=O)Nc1ccc(C#N)c(Cl)c1
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(C(N)=NO)c(Cl)c1
Temperature: 90 °C

Procedure:
To a stirred solution of the product from Step A (0.13 g, 0.565 mmol) in ethanol (3 mL) was added hydroxylamine (50% in water, 1.0 mL). The reaction was heated at 90° C. for 2 h. The reaction was then concentrated to give the desired product.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])CN[C:6](=[O:9])[C:5]2[S:10][C:11]([N:13]3[C:18]4[CH:19]=[C:20](O)[CH:21]=[CH:22][C:17]=4[O:16][CH2:15][CH2:14]3)=[N:12][C:4]=2[CH2:3]1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[CH3:31]C(C)([O-])C.[Na+]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:24][C:2]1([CH3:31])[CH2:3][C:4]2[N:12]=[C:11]([N:13]3[C:18]4[CH:19]=[C:20]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[CH:21]=[CH:22][C:17]=4[O:16][CH2:15][CH2:14]3)[S:10][C:5]=2[C:6](=[O:9])[CH2:1]1
Reactant: C1COCCN1
Reactant: CC(C)(C)[O-]
Reactant: CC1(C)CNC(=O)c2sc(N3CCOc4ccc(O)cc43)nc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CC(=O)c2sc(N3CCOc4ccc(N5CCOCC5)cc43)nc2C1
Temperature: 140 °C
Yield: 8.9 %

Procedure:
Using Example 7 (50 mg, 0.14 mmol), morpholine (1.2 mL, 1.15 mmol), sodium tert-butoxide (41 mg, 0.43 mmol), palladium(II) acetate (2 mg, 0.007 mmol) and (But)3PBF4 (0.004 g, 0.014 mmol) in THF (3 mL) heated to 140° C. under microwave irradiation, for 60 min. The crude material was purified by prep HPLC to give the title compound as an off-white solid (5 mg, 11%). δH (CDCl3) 1.15 (6H, s), 2.43 (2H, s), 2.75 (2H, s), 3.04-3.12 (4H, m), 3.83-3.91 (4H, m), 4.20-4.25 (2H, m), 4.26-4.31 (2H, m), 6.70 (1H, dd, J 9.0, 2.8 Hz), 6.89 (1H, d, J 9.0 Hz), 7.41 (1H, d, J 2.6 Hz). LCMS (ES+) 400 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][O:7][C:8]1[C:16]([CH3:17])=[N:15][C:14]([CH:18]2[CH2:20][CH2:19]2)=[CH:13][C:9]=1[C:10]([OH:12])=O)#[N:2].[NH2:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29]>>[C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][O:7][C:8]1[C:16]([CH3:17])=[N:15][C:14]([CH:18]2[CH2:20][CH2:19]2)=[CH:13][C:9]=1[C:10]([NH:24][C:25]1[CH:32]=[CH:31][CH:30]=[C:27]([C:28]#[N:29])[CH:26]=1)=[O:12])#[N:2]
Reactant: N#Cc1cccc(N)c1
Reactant: Cc1nc(C2CC2)cc(C(=O)O)c1OCc1cccc(C#N)c1
Product: Cc1nc(C2CC2)cc(C(=O)Nc2cccc(C#N)c2)c1OCc1cccc(C#N)c1
Yield: 24.1 %

Procedure:
The amide coupling of 3-(3-cyano-benzyloxy)-6-cyclopropyl-2-methyl-isonicotinic acid (189) (128 mg, 0.4 mmol) and 3-aminobenzonitrile (59 mg, 0.4 mol), as described in Example 67, gave 3-(3-cyano-benzyloxy)-N-(3-cyano-phenyl)-6-cyclopropyl-2-methyl-isonicotinamide (192) (39.4 mg, 23% yield).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13]CC(O)C[CH:9]=2)=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH:18]=C>[C].[Pd].C(C(CCCC)CO)C>[CH2:16]([CH:17]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18][OH:1])[CH3:15].[CH3:13][C:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)=[CH2:9].[C:5]1([CH:8]([CH3:13])[CH3:9])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: Oc1ccc(C2=CCC(O)CC2)cc1
Reactant: C=Cc1ccccc1C
Agent: [Pd]
Solvent: CCCCC(CC)CO
Product: C=C(C)c1ccccc1
Product: CC(C)c1ccccc1

Procedure:
A 300-ml four-necked glass flask was charged with 38.0 g (0.20 mole) of 4-(4-hydroxyphenyl)-3-cyclohexene-1-ol, 0.4 g of 5% palladium carbon, 59.1 g (0.50 mole) of o-methylstyrene and 100 ml of 2-ethylhexanol. The mixture was reacted at 160° C. for 4 hours in a nitrogen atmosphere. The reaction mixture was hot filtered at 150° C. to recover the palladium-carbon. 2-Ethylhexanol, α-methylstyrene and cumene formed were distilled off from the filtrate under reduced pressure. 37.2 g of white crystals of 4,4'-biphenol were obtained. The product had a purity of 98.6% based on liquid chromatography, a p-phenylphenol content of 0.9% and a yield converted to a purity basis of 98.5%.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[C:27]([O:32][CH2:33]I)(=[O:31])[CH:28]([CH3:30])[CH3:29]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:33][O:32][C:27](=[O:31])[CH:28]([CH3:30])[CH3:29])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CC(C)C(=O)OCI
Agent: [Na+]
Product: CC(C)C(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 92.8 %

Procedure:
In the same manner as in Example 81, 360 mg of the title compound was prepared from 325 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 220 mg of isobutyryloxymethyl iodide.
Reaction SMILES: [N:1]1[C:2]([C:10](OCC)=[O:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[N:1]1[C:2]([CH2:10][OH:11])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCOC(=O)c1cn2ccccc2n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cn2ccccc2n1
Temperature: 0 °C
Yield: 90.7 %

Procedure:
To an ice-cold solution of ethyl imidazo[1,2-a]pyridine-2-carboxylate (6.1 g, 32 mmol) in dry THF (300 mL) was added lithium aluminium hydride (LAH) (2.4 g, 64 mmol) in portions, and the temperature was maintained at <5° C. for 2 h. THF and water (50 mL, 1:1 v/v) were added slowly and the mixture was filtered. The filtrate was evaporated to dryness. The residue was re-dissolved in EtOAc (60 mL), and washed with brine (10 mL×3). The organic layers were combined, and the solvent was removed to give the title compound (4.3 g, yield 90%). ESI MS: m/z 149 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[N:11]=[C:12]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28]Cl)=[CH:21][CH:20]=2)[O:13][C:14]=1[C:15]([O:17][CH3:18])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][CH:31]1[CH2:35][CH2:34][CH2:33][NH:32]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[CH2:1]([NH:8][CH2:9][C:10]1[N:11]=[C:12]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:32]3[CH2:33][CH2:34][CH2:35][CH:31]3[CH3:30])=[CH:21][CH:20]=2)[O:13][C:14]=1[C:15]([O:17][CH3:18])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1oc(-c2ccc(OCCCCl)cc2)nc1CNCc1ccccc1
Reactant: CC1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1oc(-c2ccc(OCCCN3CCCC3C)cc2)nc1CNCc1ccccc1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A suspension of methyl 4-[(benzylamino)methyl]-2-[4-(3-chloropropoxy)phenyl]-1,3-oxazole-5-carboxylate i94 (0.11 g, 0.27 mmol, 1 eq), 2-methylpyrrolidine (30 μl, 0.32 mmol, 1.2 eq) and potassium carbonate (0.15 g, 1.06 mmol, 4 eq) in acetonitrile (5 ml) is stirred at 110° C. overnight. The mixture is then poured into ethyl acetate (50 ml) and washed with water. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. Two successive purifications over silicagel (eluent: dichloromethane, methanol, ammonia 90/10/1) and one purification by preparative liquid chromatography (gradient: acetonitrile/water/trifluoroacetic acid 95:5:01 to 5:95:01) yield 6 mg of methyl 4-[(benzylamino)methyl]-2-{4-[3-(2-methyl-1-pyrrolidinyl)propoxy]phenyl}-1,3-oxazole-5-carboxylate 99.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21]([Cl:31])(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[ClH:31].[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:30])[CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCCCSc1ccncc1
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(C=Cc1ccccc1)NCCCSc1ccncc1
Yield: 79.2 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.78 ml (19.9 mmol) of triethylamine in 40 ml of methylene chloride was added 830 mg (4.98 mmol) of cinnamoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:10) to obtain the powder which was washed with ether and dried to obtain 1.10 g of the desired compound (free base) (88.8%, colorless powder), mp: 116.0°-117.0° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.[CH2:21]=[C:22]([CH3:24])[CH3:23].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>C(#N)C.C(OCC)(=O)C>[Br:12][C:13]1[CH:14]=[C:15]([CH:16]2[CH2:21][C:22]([CH3:24])([CH3:23])[C:5]3[C:6](=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=3)[NH:9]2)[CH:18]=[CH:19][CH:20]=1
Reactant: C=C(C)C
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=Cc1cccc(Br)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(C(F)(F)F)cc21
Temperature: 85 °C
Reaction time: 18 h
Yield: 40.2 %

Procedure:
To a stirred solution of 4-trifluoromethyl-phenylamine (12.6 g, 78.4 mmol) and 3-bromobenzaldehyde (9.2 mL, 78.4 mmol) in acetonitrile (150 mL) were added isobutene (21.0 mL, 313.5 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (5.8 g, 9.5 mmol). The resulting mixture was stirred at 85° C. for 18 h in sealed tube. The mixture was diluted with ethyl acetate (300 mL) and washed with water (100 mL×2) and brine (100 mL×2) and then dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 20-40% ethyl acetate in petroleum ether) to afford 2-(3-bromo-phenyl)-4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (12.1 g, 40%) as a light yellow oil: LC/MS m/e obsd. (ESI+) [(M+H)+] 383.9 & 385.9.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][C:7]([CH3:9])=[CH2:8]>C1CCCCC1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:7]([CH3:9])([CH3:8])[CH3:6]
Reactant: OCCCCl
Reactant: C=C(C)C
Solvent: C1CCCCC1
Product: CC(C)(C)OCCCCl
Temperature: 25 °C

Procedure:
A two liter, three-necked round bottom flask was fitted with a mechanical stirrer, a gas inlet tube, and a Claisen adapter equipped with a dry ice condenser, and a thermocouple. This apparatus was dried in an oven overnight at 125° C., assembled hot, and allowed to cool to room temperature in a stream of argon. The flask was charged with 141.81 grams (1.50 moles, 1.00 equivalent) of 3-chloro-1-propanol and 500 ml. of cyclohexane. The resultant two-phase solution was stirred at 400 RPMs. Amberlyst 15 resin catalyst, 35 grams, was added, followed by an additional 250 ml. of cyclohexane. A total of 93 grams (1.657 moles, 1.105 equivalents) of 2-methylpropene was discharged from the cylinder in two and a third hours. A modest exotherm was noted during the addition. The reaction mixture was stirred at 20°-25° C., and periodically monitored by gas chromatography (GC) for the disappearance of 3-chloro-1-propanol. After stirring at room temperature for twenty-eight hours, the conversion to the desired product was 94.7%. The catalyst was removed by filtration through a piece of fluted filter paper. The reaction flask was rinsed with fresh cyclohexane (2×100 ml.). The product was purified by distillation from 10.72 grams of potassium carbonate through a twelve inch Vigreux column, at atmospheric pressure. This afforded a clear, colorless oil, yield=158.42 grams (70.2%).
Reaction SMILES: CN1C(=O)N(C)CC1.[Br:9][C:10]1[CH:16]=[C:15]([C:17]([F:29])([C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[C:18]([F:21])([F:20])[F:19])[CH:14]=[C:13]([Br:30])[C:11]=1[NH2:12].[Cl:31][C:32]1[C:40]([N+:41]([O-:43])=[O:42])=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35].O>C(OCC)(=O)C>[Cl:31][C:32]1[C:40]([N+:41]([O-:43])=[O:42])=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([NH:12][C:11]1[C:10]([Br:9])=[CH:16][C:15]([C:17]([F:29])([C:22]([F:27])([F:28])[C:23]([F:24])([F:25])[F:26])[C:18]([F:19])([F:20])[F:21])=[CH:14][C:13]=1[Br:30])=[O:35]
Reactant: Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1Br
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1Cl
Solvent: CCOC(C)=O
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: O=C(Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc1Br)c1cccc([N+](=O)[O-])c1Cl
Temperature: 140 °C
Reaction time: 4 h
Yield: 39.9 %

Procedure:
To 27 ml of DMI were added 9.90 g (21.1 mmol) of 2,6-dibromo-4-(perfluorobutan-2-yl)aniline and 4.60 g (20.9 mmol) of 2-chloro-3-nitrobenzoyl chloride, followed by stirring at 140° C. for 4 hours. To the reaction solution were added water and ethyl acetate, and the organic phase was extracted, and washed with 1 mol/L of an aqueous sodium hydroxide solution, saturated brine, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent solvent; hexane:ethyl acetate=20:1→10:1→5:1→3:1) to prepare 5.44 g (yield 40%) of a target compound.
Reaction SMILES: [CH:1]([C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7](=S)[C:6]=2[N:5]=1)([CH3:3])[CH3:2].O(C)S(C(F)(F)F)(=O)=O.[CH3:28][O:29][CH2:30][CH2:31][CH2:32][C@H:33]1[CH2:38][NH:37][CH2:36][CH2:35][NH:34]1.N1C=CC=CC=1>ClCCl>[CH3:28][O:29][CH2:30][CH2:31][CH2:32][C@@H:33]1[NH:34][CH2:35][CH2:36][N:37]([C:7]2[C:6]3[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[S:13][C:12]=3[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=2)[CH2:38]1
Reactant: COCCC[C@H]1CNCCN1
Reactant: CC(C)c1nc2c(s1)Nc1ccccc1NC2=S
Agent: COS(=O)(=O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C(C)C)nc32)CCN1

Procedure:
Combine 2-isopropyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione (0.5 g, 1.816 mmol), methyl triflate (0.306 mL, 2.723 mmol) in dichloromethane (4 mL) and stir at ambient temperature for 2 hours. Evaporate the mixture uner reduced pressure and then combine the residue with (S)-2-(3-methoxy-propyl)-piperazine (0.287 g, 1.816 mmol) and pyridine (4 mL) and reflux for 8 hours. Concentrate the reaction mixture under reduced pressure and dilute the residue with ethyl acetata. Wash the organic with brine twice, dry over sodium sulfate, filter and concentrate under reduced pressure to give a residue. Purify the residue by flash chromatography, eluting with 2M ammonia in methanol:dichloromethane (5:95) to give the title compound: mass spectrum (m/e):400.03 (M+1).
Reaction SMILES: C([O:4][C:5]1[C:10](=[O:11])[N:9]([CH:12]([CH3:14])[CH3:13])[C:8](=[O:15])[N:7]2[CH:16]([CH2:29][CH2:30][NH:31][CH3:32])[CH2:17][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:19](=[O:20])[C:6]=12)(=O)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:18]2[CH2:17][CH:16]([CH2:29][CH2:30][N:31]([CH3:32])[S:34]([CH3:33])(=[O:36])=[O:35])[N:7]3[C:8](=[O:15])[N:9]([CH:12]([CH3:14])[CH3:13])[C:10](=[O:11])[C:5]([OH:4])=[C:6]3[C:19]2=[O:20])=[CH:23][CH:24]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNCCC1CN(Cc2ccc(F)cc2)C(=O)c2c(OC(C)=O)c(=O)n(C(C)C)c(=O)n21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1c(=O)c(O)c2n(c1=O)C(CCN(C)S(C)(=O)=O)CN(Cc1ccc(F)cc1)C2=O

Procedure:
2-(4-Fluorobenzyl)-7-isopropyl-4-[2-(methylamino)ethyl]-1,6,8-trioxo-1,3,4,6,7,8-hexahydro-2H-pyrazino[1,2-c]pyrimidin-9-yl acetate (Example 67, Step 2, 37 mg, 0.08 mmol) in CH2Cl2 (1.5 mL) was treated with a large excess of reagents (70 μL MsCl, 270 μL triethylamine and 20 mg DMAP). Stirring the reaction at ambient temperature over night gave complete conversion to the sulfonamide with exchange of the 9-acetate to the 9-mesylate. The solvent was removed under a steady nitrogen stream at 50° C. and the residue dissolved in MeOH (1 mL) and treated with a solution of sodium methoxide in MeOH (25 wt %, 2.5 mL). After four days of stirring at ambient temperature, cleavage of the 9-mesylate to the 9-hydroxy was complete. The mixture was quenched by the addition of TFA and water and was then concentrated under a steady stream of nitrogen at 50° C. The crude material was purified by reverse phase preparative HPLC to afford the title compound as an off-white solid. 1H NMR (500 MHz, CDCl3) δ 11.73 (s, 1 H), 7.38-7.27 (m, 2 H), 7.09-7.05 (m, 2 H), 5.22-5.15 (m, 1 H), 4.96 (d, J=14.5 Hz, 1 H), 4.78-4.76 (m, 1 H), 4.37 (d, J=14.0 Hz, 1 H), 3.72 (dd, J=1.5, 14.0 Hz, 1 H), 3.62 (dd, J=3.8, 14.0 Hz, 1 H), 2.83 (s, 3 H), 2.80-2.66 (m, 5 H), 1.90-1.83 (m, 1 H), 1.56-1.49 (m, 1 H), 1.47 (d, J=7.0 Hz, 6 H). HRMS (APCI) M+H: calcd for (C21H28FN4O6S)+ 483.1708. found 483.1729.
Reaction SMILES: F[C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1.O.[NH2:22][NH2:23]>C(O)C>[F:19][C:15]1[CH:14]=[C:13]([C:12]2[C:3]3[C:2](=[C:9]([O:10][CH3:11])[CH:8]=[C:5]([C:6]#[N:7])[CH:4]=3)[NH:23][N:22]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: NN
Reactant: COc1cc(C#N)cc(C(=O)c2cccc(F)c2)c1F
Solvent: O
Solvent: CCO
Product: COc1cc(C#N)cc2c(-c3cccc(F)c3)n[nH]c12
Temperature: 70 °C
Reaction time: 24 h

Procedure:
To a solution of 640 mg of 4-fluoro-3-(3-fluorobenzoyl)-5-methoxybenzonitrile in 6 ml ethanol was added 3 ml of hydrazine monohydrate at room temperature, followed by stirring at 70° C. for one day. The reaction mixture was evaporated, and the resulting crystals were collected by filtration. The crystals were sequentially washed with ethanol and diethyl ether, to give 590 mg of the title compound as colorless crystals.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[O:13]=[C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)=[C:18]([CH2:35][CH2:36][CH3:37])[N:17]2[N:38]=[CH:39][N:40]=[C:16]2[N:15]1[CH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>C(OCC)(=O)C>[O:7]=[C:4]1[O:5][N:3]=[C:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:24]2[CH:23]=[CH:22][C:21]([CH2:20][C:19]3[C:14](=[O:13])[N:15]([CH:41]4[CH2:42][CH2:43][O:44][CH2:45][CH2:46]4)[C:16]4[N:17]([N:38]=[CH:39][N:40]=4)[C:18]=3[CH2:35][CH2:36][CH3:37])=[CH:26][CH:25]=2)[NH:34]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2ncnn12
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCOCC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A mixture of hydroxylammonium chloride (0.69 g), sodium hydrogen carbonate (1.1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.3 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.13 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.19 g, 56%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1.[Br:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][OH:34]>>[Br:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][O:34][CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CCl)n1
Reactant: OCc1cccc(Br)c1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(COCc2cccc(Br)c2)n1
Yield: 61 %

Procedure:
As described for Example 157, 4-[2-chloromethyl-1-(4-nitro-phenyl)-1H-imidazol-4-yl]-5-methyl-3-phenyl-isoxazole (100 mg, 0.25 mmol), using 3-bromobenzyl alcohol instead of 3-chlorobenzyl alcohol, was converted to the title compound (84 mg, 61%) which was obtained as a light yellow gum. MS: m/e=545.3/547.3 [M+H]+.
Reaction SMILES: [CH:1]([N:14]1[CH2:17]C(O[Si](C)(C)C)(C#N)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:26].[O:30]1[CH2:35][CH2:34][O:33]CC1>>[CH:1]([N:14]1[CH2:15][C:34]([OH:33])([C:35]([OH:30])=[O:26])[CH2:17]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: C[Si](C)(C)OC1(C#N)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: O=S(=O)(O)O
Product: O=C(O)C1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 95 °C

Procedure:
1-Benzhydryl-3-(trimethylsilyloxy)azetidine-3-carbonitrile (2.85 g, 8.47 mmol) was taken up in a 1:1 mixture of 1,4-dioxane (30 mL) and 60% aqueous sulfuric acid (30 mL). The mixture was heated to 95° C. for 1 h. The solvent was removed and the residue was taken to pH 7 using 5N NaOH. The solid was isolated by filtration, rinsed with Et2O to give 1-benzhydryl-3-hydroxyazetidine-3-carboxylic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.36-7.47 (m, 4H), 7.22-7.33 (m, 4H), 7.13-7.23 (m, 2H), 4.52 (s, 1H), 3.46 (d, J=8.3 Hz, 2H), 3.02 (d, J=8.2 Hz, 2H). MS (ESI) m/z: Calculated; 283.1 Observed: 284.1 (M++1).
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].[CH2:8]([Li])CCC.[CH3:13][O:14][CH:15]([CH3:20])[C:16]([O:18][CH3:19])=[O:17].C(Br)C=C>C1COCC1>[CH3:13][O:14][C:15]([CH3:8])([CH2:20][CH:1]=[CH2:2])[C:16]([O:18][CH3:19])=[O:17]
Reactant: [Li]CCCC
Reactant: CC(C)NC(C)C
Reactant: COC(=O)C(C)OC
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC(C)(OC)C(=O)OC
Temperature: -15 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine (2.34 L, 16.4 mol) in THF (6 L) at −48° C. was added n-butyllithium (5.78 L, 14.5 mol) via additional funnel over 35 minutes, and the resulting mixture was warmed to −15° C. over 20 minutes, held at −15° C. for 10 minutes, then cooled down to −40° C. To this solution was added methyl 2-methoxypropionate (1.85 kg, 12.4 mol) via additional funnel over 1.75 hours. After stirring for 30 minutes, allyl bromide (1.4 L, 16.4 mol) was added via additional funnel. The resulting solution was stirred for 30 minutes, warmed to 0° C. over 1 hour, then quenched with 3NHCl (7 L), and extracted with MTBE (2×4 L). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was used in the next reaction without further purification.