Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([C:9]1[CH:27]=[CH:26][C:12]([CH2:13][O:14][C:15]([N:17]2[CH2:24][C@H:23]([OH:25])[CH2:22][C@H:18]2[C:19]([NH2:21])=[O:20])=[O:16])=[CH:11][CH:10]=1)([O-:8])=[O:7].C(N(CC)CC)C>O1CCCC1>[N+:6]([C:9]1[CH:27]=[CH:26][C:12]([CH2:13][O:14][C:15]([N:17]2[CH2:24][C@H:23]([O:25][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:22][C@H:18]2[C:19]([NH2:21])=[O:20])=[O:16])=[CH:11][CH:10]=1)([O-:8])=[O:7]
Reactant: NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]1C[C@@H](C(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h

Procedure:
A solution of 1.89 g of methanesulfonyl chloride in 10 ml of dried tetrahydrofuran was added dropwise to a suspension of 2.32 g of trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-prolineamide and 1.67 g of triethylamine in 40 ml of dried tetrahydrofuran at room temperature. After stirring for 1 hour, the reaction mixture was concentrated under reduced pressure, and to the residue were added 30 ml of water and 30 ml of diethyl ether. After cooling, the resulting white crystals were separated by filtration, washed successively with cool water and cool diethyl ether and dried under reduced pressure to obtain trans-1-(p-nitrobenzyloxycarbonyl)-4-methanesulfonyloxy-L-prolineamide.
Reaction SMILES: [F:1][C:2]1([F:19])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@@:3]21[C:17]1[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=1)[O:11][CH2:10][CH2:9]2.[C:20]([C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1)#[N:21]>>[NH2:8][C:5]1[O:6][CH2:7][C:2]([F:1])([F:19])[C@@:3]2([C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH:18][C:28](=[O:29])[C:25]4[CH:24]=[CH:23][C:22]([C:20]#[N:21])=[CH:27][N:26]=4)[CH:16]=3)[O:11][CH2:10][CH2:9]2)[N:4]=1
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: NC1=N[C@@]2(CCOc3ccc(N)cc32)C(F)(F)CO1
Product: N#Cc1ccc(C(=O)Nc2ccc3c(c2)[C@@]2(CCO3)N=C(N)OCC2(F)F)nc1
Yield: 74 %

Procedure:
The condensation of (R)-5′,5′-difluoro-5′,6′-dihydrospiro[chroman-4,4′-[1,3]oxazine]-2′,6-diamine (intermediate B7.1) and 5-cyanopicolinic acid yielded the title compound (74% yield) as a yellow solid. MS (ISP): m/z=400.2 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@@H:7]2[CH2:12][CH2:11][N:10](C(OC)=O)[C@@H:9]([CH2:17][C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=3)[CH2:8]2)[O:4][NH:3]1.Br>>[F:26][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([F:24])[C:21]=1[F:25])[CH2:17][C@H:9]1[CH2:8][C@H:7]([C:5]2[O:4][NH:3][C:2](=[O:1])[CH:6]=2)[CH2:12][CH2:11][NH:10]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(F)c(F)c(F)c1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](Cc3cc(F)c(F)c(F)c3)C2)o[nH]1
Yield: 21.5 %

Procedure:
Trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3,4,5-trifluorobenzyl)piperidine-1-carboxylate (111 mg, 0.3 mmol) was stirred in hydrogen bromide (33% in AcOH, 2 mL, 86.51 mmol) for 18 h. The reaction mixture was evaporated in vacuo and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-(3,4,5-trifluorobenzyl)piperidin-4-yl)isoxazol-3(2H)-one (20.17 mg, 21.5%). 1H NMR (600 MHz, dmso) δ 1.43-1.49 (m, 1H), 1.65-1.79 (m, 3H), 2.33-3.75 (m, 6H), 5.75 (s, 1H), 7.12-7.19 (m, 2H). HRMS Calculated for [C15H15F3N2O2+H]+: 313.1164. Found: 313.1147
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:7][CH:6]=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([O:32][CH3:33])=[C:27]([CH:31]=1)[C:28](Cl)=[O:29]>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([O:32][CH3:33])=[C:27]([CH:31]=1)[C:28]([NH:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:9][CH:10]=1)=[O:29]
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Reactant: CCOC(=O)CCCCCCc1ccc(CCN)cc1
Agent: Cl
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(CCCCCCC(=O)O)cc1

Procedure:
By the reaction of ethyl 6-[4-(2-aminoethyl)-phenyl]-hexane-carboxylate hydrochloride (m.p. 182°-185° C.) with 5-chloro-2-methoxybenzoyl chloride to give 6-{4-[2-(5-chloro-2-methoxybenzamido)-ethyl]-phenyl}-hexane-carboxylic acid; m.p. 36° C., after recrystallisation from toluene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[C:13]1([O:19][CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Al+3].[Cl-].[Cl-].[Cl-]>S(Cl)(Cl)=O.ClCCl.O>[CH3:20][O:19][C:13]1[CH:18]=[CH:17][C:16]([C:10](=[O:12])[CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:15][CH:14]=1
Reactant: COc1ccccc1
Reactant: COc1ccc(CC(=O)O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CC(=O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
A solution of 2-(4-methoxyphenyl)acetic acid (5.0 g, 30.12 mmol) in thionyl chloride (50 mL) was stirred for 3 hr at reflux and then concentrated in vacuo to give a residue, which was dissolved in dichloromethane (10 mL) and then added dropwise to a solution of anisole (6.51 g, 60.28 mmol) and AlCl3 (11.97 g, 90.00 mmol) in dichloromethane (120 mL). The resulting solution was stirred for 3 h at room temperature, then diluted with water (100 mL), extracted with dichloromethane (3×80 mL), dried over magnesium sulfate, and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography with (1%˜2% ethyl acetate in petroleum ether) to afford 1,2-bis(4-methoxyphenyl)ethanone as a white solid (6.5 g, 84%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].Br[C:13]1[CH:18]=[C:17]([F:19])[C:16]([OH:20])=[C:15]([F:21])[CH:14]=1>>[F:19][C:17]1[CH:18]=[C:13]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:14]=[C:15]([F:21])[C:16]=1[OH:20]
Reactant: Oc1c(F)cc(Br)cc1F
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2cc(F)c(O)c(F)c2)cc1
Yield: 48 %

Procedure:
4-Cyanophenylboronic acid and 4-bromo-2,6-difluorophenol were processed as described in Example 167A to provide the title compound (48% yield). 1HNMR (300 MHz, CDCl3) δ5.30 (bs, 1H), 7.20 (m, 2H), 7.60 (m, 2H), 7.78 (m, 2H); MS (CDI) m/z 232(M+H)+.
Reaction SMILES: [Br:1][CH2:2][C@@:3]([OH:16])([CH3:15])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][CH:8]=1)=[O:5].B(Br)(Br)Br>C(Cl)Cl>[Br:1][CH2:2][C@@:3]([OH:16])([CH3:15])[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)=[O:5]
Reactant: COc1ccc(NC(=O)[C@@](C)(O)CBr)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C[C@](O)(CBr)C(=O)Nc1ccc(O)cc1
Temperature: 0 °C
Yield: 97.9 %

Procedure:
(R)-3-bromo-2-hydroxy-N-(4-methoxyphenyl)-2-methylpropanamide (6b) (0.55 g, 1.91 mmol) was dissolved in 25 mL of anhydrous methylene chloride in a dry 250 mL round-bottomed flask fitted with a stirring bar, anitrogen inlet and rubber stopper. BBr3 solution (16.0 mL of 0.5 M CH2Cl2 solution, 8.0 mmol) was added dropwise with stirring at 0° C. The reaction solution was stirred at room temperature overnight. The reaction was quenched by adding 20 mL of water and extracted with EtOAc (3×30 mL). The EtOAc layers were separated and dried over anhydrous MgSO4. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography (silica gel, EtOAc/hexanes=1/1 v/v) to give a white solid product, (R)-3-bromo-2-hydroxy-N-(4-hydroxyphenyl)-2-methylpropanamide (6e), 0.51 g, 97.9% yield.
Reaction SMILES: [ClH:1].CO[C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[NH:5].[NH3:19]>CO>[ClH:1].[ClH:1].[CH2:12]([N:9]1[CH2:10][CH2:11][CH:6]([C:4]([NH2:19])=[NH:5])[CH2:7][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N
Reactant: COC(=N)C1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CO
Product: N=C(N)C1CCN(Cc2ccccc2)CC1
Reaction time: 18 h
Yield: 97 %

Procedure:
Dissolve 1-benzyl-piperidine-4-carboximidic acid methyl ester hydrochloride (17.47 g 1.00 equiv; 65 mmoles) in 2M ammonia in methanol (˜350 mL). Saturate with ammonia gas for 15 min. Stir for 18 hours and evaporate. Co-evaporate with dry methanol. Dry under high vacuum to give 18.29 g (63.03 mmol, 97%) of 1-benzyl-piperidine-4-carboxamidine dihydrochloride as a light yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:36])[C@@H:4]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Br:33])[CH:30]=[CH:29][C:28]=1[OH:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Li+].[OH-]>C1COCC1.CO>[Br:33][C:31]1[CH:30]=[CH:29][C:28]([OH:34])=[C:27]([CH:32]=1)[C:26]([NH:25][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)[C:3]([OH:36])=[O:2])=[O:35]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(Oc3ccccc3)cc2)cc1)NC(=O)c1cc(Br)ccc1O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccc(-c2ccc(Oc3ccccc3)cc2)cc1)C(=O)O)c1cc(Br)ccc1O
Yield: 104.4 %

Procedure:
To a solution of the preceding compound, (2S)-(5-Bromo-2-hydroxy-benzoylamino)-3-(4′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester (10 mg, 18 μmol) in THF/MeOH was added aqueous LiOH, as described in General procedure C which, after work-up afforded the title compound, (2S)-(5-Bromo-2-hydroxy-benzoylamino)-3-(4′-phenoxy-biphenyl-4-yl)-propionic acid (10 mg ) LCMS for C28H22BrNO5: 531, 533.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(=O)C(Cl)=O.CO>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(Cl)ccc1Br
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)ccc1Br
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a suspension of 2-bromo-5-chloro-benzoic acid (2.5 g, 10.6 mmol) in dichloromethane (50 ml) was added a solution of oxalyl chloride in dichloromethane (2 M, 6 ml, 12 mmol) followed by N,N-dimethylformamide (5 drops). After stirring for 30 minutes, methanol (10 ml) was added. After stirring for 3 hours, the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate (150 ml) and saturated aqueous potassium carbonate solution (100 ml). The organic layer was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with dichloromethane-hexane (1:2) to provide methyl 2-bromo-5-chloro-benzoate (2.1 g, 79% yield).
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[CH3:10][NH:11][CH3:12]>CCO>[CH3:10][N:11]([CH3:12])[C:3]([S:2][CH3:1])=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: CNC
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: CSC(=C[N+](=O)[O-])N(C)C

Procedure:
In 50 ml of EtOH was dissolved 3.3 g of 1,1-bis-(methylthio)-2-nitroethylene and 2.2 ml of a 40% aqueous solution of dimethylamine was added dropwise in 2 portions at 30-minute intervals under refluxing. After completion of dropwise addition, the mixture was further refluxed for 30 minutes. Then, the EtOH was distilled off and the residue was subjected to silica gel column chromatography using CHCl3 --MeOH (20:1) as an eluent. The procedure gave 1.0 g of 1-dimethylamino-1-methylthio-2-nitroethylene as a yellow oil.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:16][CH:17]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:16]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([C:13](=[O:15])[CH3:14])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)[CH3:17]
Reactant: CC=O
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCN1CCN(c2ccc(C(C)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
A mixture of 1-(4-piperazin-1-yl-phenyl)-ethanone (500 mg, 2.45 mmol), CH3CHO (161 mg, 3.67 mmol) and NaBH(OAc)3 (778 mg, 3.67 mmol) in DCM (15 ml) was stirred at room temperature overnight. The resulting solution was partitioned between water and DCM and the organic phase was extracted with 1 M HCl. The aqueous layer was brought to basic conditions with NH4OH, extracted with AcOEt and then the organic phase was dried over Na2SO4 and evaporated in vacuo to give 250 mg of 1-[4-(4-ethyl-piperazin-1-yl)-phenyl]-ethanone.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH:3]=[CH:2]1.C(N(CC)C(C)C)(C)C.[F:19][C:20]1[CH:25]=[C:24]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:23]=[C:22]([F:32])[C:21]=1[NH2:33].C(OCC)(=O)C>CN(C)C=O>[CH:1]1([CH2:6][C:7]([NH:33][C:21]2[C:20]([F:19])=[CH:25][C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:23][C:22]=2[F:32])=[O:9])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: Nc1c(F)cc(N2CCOCC2)cc1F
Reactant: O=C(O)CC1C=CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CC1C=CCC1)Nc1c(F)cc(N2CCOCC2)cc1F
Reaction time: 0.03 h
Yield: 71 %

Procedure:
Cyclopent-2-enylacetic acid (0.17 mL), N,N-diisopropyl-ethylamine (0.50 mL) and N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-yl-methylene]-N-methyl-methanaminium hexafluoro-phosphate N-oxide (0.55 g) were mixed in dry N,N-dimethylformamide (3 mL) and stirred under argon for 2 minutes. 2,6-Difluoro-4-morpholin-4-yl-phenylamine (0.20 g) dissolved in dry N,N-dimethylformamide (2 mL) was added to the reaction mixture, which was stirred at 25° C. under argon for 16 hours. Ethyl acetate (20 mL) was added and the organic phase was washed with saturated aqueous ammonium chloride/water (1:1, 20 mL), water (20 mL), brine/water (1:1, 20 mL), dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography to furnish 0.21 g (71% yield) of the title compound as a white solid. LC-MS (m/z) 323 (MH+); tR=2.49, (UV, ELSD) 96%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.48 (m, 1H), 2.02 (m, 1H), 2.29 (m, 4H), 3.03 (m, 1H), 3.14 (t, 4H), 3.71 (t, 4H), 5.71 (m, 1H), 5.76 (m, 1H), 6.68 (d, 2H), 9.25 (s, 1H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=4)=[CH:19][CH:18]=[C:17]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.B(Cl)(Cl)Cl.CCO.C(Cl)Cl>ClCCCl>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:20]([C:21]4[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=4)=[CH:19][CH:18]=[C:17]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:16]=3)=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(-c2ccc(-c3ccccc3)nc2-c2ccc(OCCN3CCCC3)cc2)cc1
Agent: Cl
Agent: ClB(Cl)Cl
Solvent: CCO
Solvent: ClCCCl
Solvent: ClCCl
Product: Oc1ccc(-c2ccc(-c3ccccc3)nc2-c2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
The 2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-3-(4-methoxyphenyl)-6-phenylpyridine as the HCl salt (1.9 g, 3.9 mmol) was slurried with 50 mL of DCE in a screw cap flask, cooled to 0° C., and stirred while the BCl3 (2.7 mL at 0° C., 32 mmol) in 5 mL DCE was added and the reaction flask sealed. After 2 h, TLC (EtOH/ CH2Cl2, 1:4) indicated that starting material remained, so an additional 1.7 mL of BCl3 (20 mmol) was added and reaction mixture stirred for 18 h. The reaction mixture was carefully quenched with 25 mL MeOH at 0° C., poured in 150 mL of aqueous NaHCO3, and extracted with CH2Cl2 (3×100 mL). The CH2Cl2 extracts were combined, washed with brine, dried (Na2SO4), concentrated, and recrystallised from EtOH to give 1.35 g (79 % yield) of product: mp 176°-178° C.; 1H NMR (CDCl3) d 1.86 (bs, 4H, pyrrolidine), 2.73(bs, 4H, pyrrolidine), 2.97-3.01 (t, 2H, J=5 Hz, CH2N), 4.12-4.16 (t, 2H, J=5 Hz, OCH2), 6.64-6.67 (m, 4H, ArH), 6.98-7.01 (d, 2H, J=8 Hz, ArH), 7.38-7.50 (m, 5H, ArH), 7.67 (s, 2H, ArH), 8.10-8.12 (d, 2H, J=8 Hz, ArH); MS(FD) 436 (M+). Anal. Calcd for C29H28N2O2 : C, 79.79; H, 6.46; N, 6.42. Found: C, 80.01; H, 6.55; N, 6.54.
Reaction SMILES: [OH:1][CH:2]([CH2:16][CH2:17][S:18][CH3:19])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:4].C1C=C(Cl)C=C(C(OO)=[O:28])C=1>ClCCl>[OH:1][CH:2]([CH2:16][CH2:17][S:18]([CH3:19])=[O:28])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:4]
Reactant: CCCCCCCCCCOC(=O)C(O)CCSC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCCCCCCCOC(=O)C(O)CCS(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.5 %

Procedure:
To a solution of decyl 2-hydroxy-4-(methylthio)butanoate (20.05 g, 69.03 mmol) in dichloromethane (300 mL) at 0° C. was added mCPBA (77%, 14.7 g, 65.6 mmol) portionwise over 30 min. The resulting mixture was allowed to warm to room temperature with stirring overnight. Another portion of mCPBA (77%, 1.4 g, 6.25 mmol) was added to the solution at 0° C. and the resulting mixture was allowed to warm to room temperature with stirring over the weekend. The reaction was washed with 10% sodium bisulfite (2×100 mL), saturated sodium bicarbonate (3×150 mL), 1N HCl (1×150 mL), and brine (1×200 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated to give a crude oil. The oil was purified by silica gel chromatography with 0-6% methanol/dichloromethane to give a light yellow oil (20.61 g, 97%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.85 (t, J=6.83 Hz, 3 H) 1.10-1.37 (m, 14 H) 1.50-1.65 (m, 2 H) 1.80-1.93 (m, 1 H) 1.97-2.08 (m, 1 H) 2.52 (d, J=3.81 Hz, 3 H) 2.60-2.75 (m, 1 H) 2.75-2.91 (m, 1 H) 3.98-4.12 (m, 2 H) 4.12-4.20 (m, 1 H) 5.62 (dd, J=5.72, 2.54 Hz, 1 H). m/z 307 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:4][C:3]=1[C:12]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[CH3:25])[N:15]=[C:14]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=2[CH3:33])[N:13]=1.[C:34](Cl)(=[O:37])[CH:35]=[CH2:36]>O1CCCC1>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][O:11][C:34](=[O:37])[CH:35]=[CH2:36])[CH:5]=[CH:4][C:3]=1[C:12]1[N:13]=[C:14]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=2[CH3:33])[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[CH3:25])[N:17]=1
Reactant: C=CC(=O)Cl
Reactant: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(OCCO)cc3O)n2)c(C)c1
Solvent: C1CCOC1
Product: C=CC(=O)OCCOc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(C)cc3C)n2)c(O)c1
Temperature: 27.5 °C
Yield: 88.8 %

Procedure:
22.1 g (0.05 mol) of 2-(2-hydroxy-4-hydroxyethoxy-phenyl)-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine (prepared as described in U.S. Pat. No. 3,244,708, Example 18), are dissolved in 300 ml of tetrahydrofurane at 40° C. and 21 ml (0.15 mol) of triethylamnine are added. A solution of 5.05 ml (0.053 mol) of acrylic acid chloride in 20 ml THF is added dropwise with stirring and with cooling the reaction mixture to 25-30° C. After further stirring of two hours the precipitated ammonium salt is filtered off, the filtrate is evaporated and the residue recrystallized from toluene-hexane mixture to obtain 22 g (88.7% yield) of 2-(2-hydroxy-4-acryloyloxyethoxy-phenyl)-4,6-bis(2,4-dimethylphenyl)-1,3,5-triazine as slightly yellow crystals (compound No. 25), m.p. 128-129° C.
Reaction SMILES: [I-].ClC1C=CC(C[N:10]2[C:18]3[N:17]=[CH:16][NH+:15]([CH3:19])[C:14]=3[C:13](=[O:20])[N:12]3[CH2:21][CH2:22][N:23]([CH3:24])[CH:11]23)=CC=1>[Pd].CCO>[CH3:19][N:15]1[C:14]2[C:13](=[O:20])[N:12]3[CH2:21][CH2:22][N:23]([CH3:24])[C:11]3=[N:10][C:18]=2[N:17]=[CH:16]1
Reactant: CN1CCN2C(=O)C3=C(N=C[NH+]3C)N(Cc3ccc(Cl)cc3)C12
Agent: [Pd]
Agent: [I-]
Solvent: CCO
Product: CN1CCn2c1nc1ncn(C)c1c2=O

Procedure:
A mixture of the quaternary salt of Procedure 94 and 10% palladium on carbon in abs. EtOH is subjected to hydrogenolysis at a pressure of about 50 psig. The spent catalyst is removed by filtration, the filtrate concentrated in vacuo, and the residue dissolved in water. Treatment with concentrated NH4OH liberates the free base which is collected and dried.
Reaction SMILES: C1(=O)OCCO1.[F-:7].[K+].Cl[C:10]([O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].ClC([O-])=O>>[F:7][C:10]([O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: [F-]
Reactant: O=C(Cl)OC1CCCCC1
Agent: O=C([O-])Cl
Agent: [K+]
Solvent: O=C1OCCO1
Product: O=C(F)OC1CCCCC1
Reaction time: 0.75 h
Yield: 83.9 %

Procedure:
The preparation was carried out as in Example 2 but using 250 g of ethylene carbonate, 90 g (1.55 mol) of potassium fluoride and 162.6 g (1.0 mol) of cyclohexyl chloroformate. After addition of the chloroformate, stirring of the mixture was continued for 45 minutes at 45° C. Evaporation under vacuum was carried out as above. By distillation under reduced pressure, 122.7 g (84% yield) of cyclohexyl fluoroformate with a boiling point of 55-56° C. at 22 mm Hg were obtained.
Reaction SMILES: C([O:5][C:6](=[O:34])[CH:7]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31](=[O:33])[CH3:32])[CH2:8][C:9]1([C:14](=[O:25])[NH:15][C@H:16]2[CH2:21][CH2:20][C@@H:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)(C)(C)C>FC(F)(F)C(O)=O>[C:31]([NH:30][CH2:29][CH2:28][CH2:27][CH2:26][CH:7]([CH2:8][C:9]1([C:14](=[O:25])[NH:15][C@H:16]2[CH2:21][CH2:20][C@@H:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]2)[CH2:10][CH2:11][CH2:12][CH2:13]1)[C:6]([OH:34])=[O:5])(=[O:33])[CH3:32]
Reactant: CC(=O)NCCCCC(CC1(C(=O)N[C@H]2CC[C@@H](C(=O)O)CC2)CCCC1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCCCCC(CC1(C(=O)N[C@H]2CC[C@@H](C(=O)O)CC2)CCCC1)C(=O)O
Yield: 44.7 %

Procedure:
2-(4-Acetamidobutyl)-3-{1-[(cis-4-carboxy-cyclohexyl)carbamoyl]cyclopentyl}propanoic acid t-butyl ester (270 mg, 0.58 mmole) was dissolved in trifluoroacetic acid (4 ml) at 0° C. After 20 hours the solvent was evaporated and the resulting oil azeotroped with dichloromethane (3×20 ml). The oil was taken up in ethyl acetate (20 ml) and washed with water (7×20 ml) until the washings were neutral. The organic layer was separated, dried over magnesium sulphate, and evaporated. The residue was dissolved in saturated sodium carbonate solution (20 ml) washed with ethyl acetate (2×20 ml), acidified with 2N hydrochloric acid and then extracted with ethyl acetate (3×20 ml). The organic layer was separated, dried over magnesium sulphate and evaporated. The residue was azeotroped with tetrahydrofuran to give the title product as a colourless foam (110 mg, 45%). Found: C,62.58; H,8.71; N,5.27. C22H36N2O5.C4H8O requires C,62.88; H,8.93; N,5.64%.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[O:11][C:12]4[CH:18]=[CH:17][C:16]([C:19]#N)=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.C[OH:31].O>C1COCC1.C1(C)C=CC=CC=1>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[O:11][C:12]4[CH:18]=[CH:17][C:16]([CH:19]=[O:31])=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: CO
Reactant: N#Cc1ccc2oc(N3CCN(C4CC4)CC3)nc2c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc2oc(N3CCN(C4CC4)CC3)nc2c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a solution of 2-(4-cyclopropylpiperazin-1-yl)benzooxazole-5-carbonitrile (1.5 g, 5.6 mmol) in THF-toluene (50 mL, 2:1) was added DIBAL (16.8 mL, 16.8 mmol) dropwise at −78° C. under a nitrogen atmosphere. Then the mixture was allowed to warm to 20° C. and then stirred for 1 h. Methanol (5 mL) was added dropwise, followed by water (20 mL). The mixture was extracted with ethyl acetate (3×20 mL) and the combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel (elute: 2% dichloromethane in methanol) to give 1.1 g (72%) of 2-(4-cyclopropylpiperazin-1-yl)benzooxazole-5-carboxaldehyde.