Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[CH:23]=[O:24])[CH:13]=1.CO.[BH4-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][CH2:10][NH:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([C:20]2[CH:21]=[C:22]([CH2:23][OH:24])[CH:25]=[CH:26][CH:27]=2)[CH:13]=1
Reactant: COc1nc(NCCc2c(F)cccc2Cl)cc(-c2cccc(C=O)c2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1nc(NCCc2c(F)cccc2Cl)cc(-c2cccc(CO)c2)n1
Reaction time: 1 h
Yield: 72.7 %

Procedure:
A solution of 3-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzaldehyde [150 mg, 0.39 mmol, Example 35(v)], in DCM (4 mL) and MeOH (1 mL) is treated with sodium borohydride (74 mg, 1.95 mmol) at 0° C. After 1 hour at 20° C., the mixture is concentrated, and extracted twice with EtOAc (10 mL). The combined extracts are dried over magnesium sulfate and filtered through a plug of silica to afford (3-{6-[2-(2-chloro-6-fluoro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-methanol [110 mg, 73%, Example 9(d)]. LCMS: RT=2.79 minutes, MS: 388 (M+H). IC50=2.4 nM
Reaction SMILES: [CH2:1]([S:8]([C:11]1[N:15]=[CH:14][NH:13][N:12]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([N:18]([CH2:22][CH3:23])[C:19](Cl)=[O:20])[CH3:17].Cl>N1C=CC=CC=1>[CH2:1]([S:8]([C:11]1[N:15]=[CH:14][N:13]([C:19](=[O:20])[N:18]([CH2:22][CH3:23])[CH2:16][CH3:17])[N:12]=1)(=[O:10])=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cc1ccccc1)c1nc[nH]n1
Reactant: CCN(CC)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCN(CC)C(=O)n1cnc(S(=O)(=O)Cc2ccccc2)n1
Reaction time: 8 h

Procedure:
To a solution of 3-benzylsulfonyl-1,2,4-triazole, 4.8 g (0.022 m) in 25 ml dry pyridine, 3.3 g (0.024 m) diethylcarbamoyl chloride is added dropwise. Let it stir overnight and pour into ~100 ml cold dilute hydrochloric acid. The product is extracted with ethyl acetate. Dry the organic layer and evaporate to give the desired product. Recrystallize from toluene-hexane to give white crystals, 5.8 g (81%) m.p. 87°-88° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[C:12](Br)[C:11](=[O:15])[C:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:28]([O:30]CC)=[CH2:29])CCC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:28]([C:12]1[C:11](=[O:15])[C:10]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]=1)(=[O:30])[CH3:29]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=c1c(Br)cn(Cc2ccccc2)cc1Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)c1cn(Cc2ccccc2)cc(Cc2ccccc2)c1=O
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A mixture of 1,3-dibenzyl-5-bromo-1H-pyridin-4-one 13 (1.31 g, 2.70 mmol), tributyl-(1-ethoxyvinyl)tin (1.80 mL, 5.18 mmol) and dichlorobis(triphenylphosphine)-palladium(II) (0.26 g, 0.37 mmol) in anhydrous DMF (20 mL) was stirred under nitrogen atmosphere at 95° C. for 8 h. The reaction mixture was extracted with ethyl acetate (3×50 mL), washed with 1N HCl (3×50 mL), and solvent distilled off. The residue was purified by flash column chromatography on silica gel (dichloromethane:methanol, 98:2). Yield 1.06 g (90%), yellow oil. 1H NMR (CDCl3, 500 MHz): δ 8.19 (d, 1H, J=2.6), 7.39-7.10 (m, 10H), 6.90 (d, 1H, J=2.5), 4.89 (s, 2H), 3.81 (s, 2H), 2.74 (s, 3H). HRMS (M+H)+ calcd for C21H19NO2 318.1494, found 318.1493.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[OH:33][C@H:34]1[CH2:38][NH:37][C@@H:36]([C:39]([OH:41])=[O:40])[CH2:35]1>>[OH:33][CH:34]1[CH2:38][N:37]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([S:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[O:21][CH3:22])=[C:10]([C:23]([F:25])([F:24])[F:26])[CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:36]([C:39]([OH:41])=[O:40])[CH2:35]1
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Agent: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CC(O)CC3C(=O)O)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with cis-4-hydroxy-D-proline. A yellow solid 109 was obtained (0.030 g, 63%). MS (APCI) m/z 491 (M+H)+.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14]([O:16][CH2:22][CH3:23])=[O:15])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCO
Reactant: CCCCCCc1ccc(CC(=O)O)cc1
Agent: O=S(=O)(O)O
Product: CCCCCCc1ccc(CC(=O)OCC)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
5.5 g (25 mmol) of 2-(4-hexylphenyl)acetic acid was dissolved in 11 mL of ethanol and mixed with 1.1 g (11.2 mmol) of sulfuric acid and stirred at 60° C. for 1 hour. The reaction was quenched with cold saturated aqueous sodium carbonate (100 ml), and the reaction solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give 5.68 g of the desired product as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.CN(C)C=[O:23].[N-]=[N+]=[N-].[Na+]>O>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[C:7]([OH:23])=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: Nc1ccc(O)c2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
127 parts of 1-nitroanthraquinone are suspended at room temperature in 1000 parts of dimethyl formamide. To this suspension are then added 35 parts of sodium azide. The reaction mixture is then stirred for 8 hours at room temperature and, after addition of 1000 parts of a mixture of ice and water, filtered. The filter cake is washed with water and the moist product (28% paste) is added in the course of 2 hours to 1000 parts of conc. sulfuric acid, taking care that the temperature does not rise above 85° C. The suspension is then heated to 95° C., stirred for 3 hours at 95°-100° C. and, after the dropwise addition of 400 parts of ice-water, filtered hot. The filtrate is then poured into 4000 parts of ice-water and filtered. The filter cake is washed neutral with water, affording 100 parts of 1-amino-4-hydroxyanthraquinone.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[C:24]([O:28][C:29]([NH:31][CH2:32][CH2:33][NH2:34])=[O:30])([CH3:27])([CH3:26])[CH3:25].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.C(Cl)(Cl)Cl.CO>[NH:11]([C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[C@H:12]([C:20]([NH:34][CH2:33][CH2:32][NH:31][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 86.4 %

Procedure:
N-carbobenzoxy-L-phenylalanine (Cbz-Phe: 7.16 g, 25.4 mmol), N-t-butoxycarbonyl-ethylenediamine hydrochloride (5.00 g, 25.4 mmol), 1-hydroxybenzotriazole hydrate (HOBT: 4.28 g, 28.0 mmol), and N-methylmorpholine (NMM: 3.07 mL, 28.0 mmol) were dissolved in 100 mL of dimethylformamide (DMF), to which 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC: 5.36 g, 28.0 mmol) was then added under stirring and cooling with ice, followed by stirring at room temperature for one day. A 10% citric acid aqueous solution was added to the reaction solution, and the precipitated solid was dissolved in chloroform and a small amount of methanol, followed by washing the solution with a saturated sodium bicarbonate solution and a saturated saline solution before drying with sodium sulfate. It was concentrated under reduced pressure, followed by purifying the resultant residue using silica gel column chromatography (elution solvent: chloroform:methanol=95:5) to provide 9.69 g of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[N:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[C:5]([O:18][CH3:19])=[CH:4][C:3]=1[CH2:20][NH2:21].F[C:23]1[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=1[N+:30]([O-:32])=[O:31].C(N(CC)C(C)C)(C)C>C(#N)C.O>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[N:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[C:5]([O:18][CH3:19])=[CH:4][C:3]=1[CH2:20][NH:21][C:23]1[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=1[N+:30]([O-:32])=[O:31]
Reactant: COc1ccc(COc2cc(F)c(CN)cc2OC)cn1
Reactant: O=[N+]([O-])c1cc(I)ccc1F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(COc2cc(F)c(CNc3ccc(I)cc3[N+](=O)[O-])cc2OC)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.2 %

Procedure:
To a stirred solution of (2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)methanamine (0.89 g, 3.04 mmol) in acetonitrile (15 mL) was added 1-fluoro-4-iodo-2-nitrobenzene (0.89 g, 3.35 mmol) and N,N-diisopropylethylamine. The resulting yellow solution was heated to reflux. After 16 h, the mixture was allowed to cool to room temperature and was diluted with water. The mixture was extracted with ethyl acetate (3×25 mL). The combined organic phases were washed with brine, dried over magnesium sulfate, filtered, and concentrated. Chromatographic purification (Combi-Flash, 40 g SiO2 column, 0-33% ethyl acetate/hexanes elute) afforded 0.38 g (23%) of N-(2-fluoro-5-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-4-iodo-2-nitroaniline as a solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:5]([CH2:12][O:13][CH2:14][O:15][CH3:16])=[N:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)[CH3:2].[CH:17]1([CH:22]=O)[CH2:21][CH2:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH:17]1([CH2:22][N:3]([CH2:1][CH3:2])[C:4]2[C:5]([CH2:12][O:13][CH2:14][O:15][CH3:16])=[N:6][C:7]([O:10][CH3:11])=[CH:8][CH:9]=2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=CC1CCCC1
Reactant: CCNc1ccc(OC)nc1COCOC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCN(CC1CCCC1)c1ccc(OC)nc1COCOC
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.5 %

Procedure:
A solution of N-ethyl-6-methoxy-2-[(methoxymethoxy)methyl]pyridin-3-amine (7.20 g, 31.8 mmol) and cyclopentanecarbaldehyde (3.75 g, 38.2 mmol) in 1,2-dichloroethane (240 mL) was added with sodium triacetoxyborohydride (8.75 g, 41.3 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was added with water, and extracted with chloroform. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to obtain N-(cyclopentylmethyl)-N-ethyl-6-methoxy-2-[(methoxymethoxy)methyl]pyridin-3-amine (8.39 g, 86%) as pale yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:11](=[O:13])[CH2:10][CH2:9][C:8]([CH3:15])([CH3:14])[C:7]=2[CH:6]=[C:5](OS(C(F)(F)F)(=O)=O)[CH:4]=1)[CH3:2].C(N(CC)CC)C.CN(C)C=O.[CH3:36][Si:37]([C:40]#[CH:41])([CH3:39])[CH3:38]>CCCCCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([C:3]1[CH:4]=[C:5]([C:41]#[C:40][Si:37]([CH3:39])([CH3:38])[CH3:36])[CH:6]=[C:7]2[C:12]=1[C:11](=[O:13])[CH2:10][CH2:9][C:8]2([CH3:15])[CH3:14])[CH3:2]
Reactant: CCc1cc(OS(=O)(=O)C(F)(F)F)cc2c1C(=O)CCC2(C)C
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCc1cc(C#C[Si](C)(C)C)cc2c1C(=O)CCC2(C)C
Reaction time: 8 h
Yield: 106.9 %

Procedure:
Following General Procedure D and using trifluoro-methanesulfonic acid 4-ethyl-8,8-dimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2yl ester (Intermediate 178, 0.9 g, 2.57 mmol), triethyl amine (6 mL), anhydrous N,N-dimethylformamide (5 mL), dichlorobis(triphenylphosphine)palladium(II) (0.144 g, 0.2 mmol) and (trimethylsilyl)acetylene (2 mL, 13.64 mmol), the reaction was conducted overnight in a sealed tube at 90° C. Work-up followed by flash column chromatography over silica gel (230–400 mesh) using 2–3% ethyl acetate in hexane as the eluent to afforded the title compound as an orange oil (0.82 g, quantitative).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:35])[C:18]([OH:34])([C:23]3[CH:24]=[CH:25][C:26]4[O:30][C:29](=[O:31])[N:28]([CH3:32])[C:27]=4[CH:33]=3)[C:19]([F:22])([F:21])[F:20])=[C:13]([Cl:36])[CH:12]=2)=[CH:7][C:6]=1[F:37])=[O:4].[Li+].[OH-].Cl>C1COCC1>[Cl:36][C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[C:6]([F:37])[CH:7]=2)[CH:16]=[CH:15][C:14]=1[CH:17]([CH3:35])[C:18]([OH:34])([C:23]1[CH:24]=[CH:25][C:26]2[O:30][C:29](=[O:31])[N:28]([CH3:32])[C:27]=2[CH:33]=1)[C:19]([F:22])([F:21])[F:20]
Reactant: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(c1ccc(-c2ccc(C(=O)O)c(F)c2)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3′-Chloro-3-fluoro-4′-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl)-propyl]-biphenyl-4-carboxylic acid methyl ester (435 mg, obtained in Example 117) was dissolved in THF (15 mL) followed by the addition of aqueous LiOH solution (1.0M, 1.21 mL). The mixture was stirred at r.t. for 6 hours. The reaction mixture was poured into ice/water and acified with 1M aqueous HCl to pH 1. The aqueous layer was extracted two times with ethylacetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, CH2Cl2:MeOH:CH3COOH=100:0:0 to 97:3:0.5) to give the title compound as a white solid. The residual acetic acid was removed by co-evaporation with toluene (250 mg, 59%). MS (neg. ion, m/e)=522.4 [(M−H)−].
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:7]2[CH:8]=[CH:9][C:10]([OH:15])=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][N:4]=1.[Br:18][CH2:19][CH2:20]Br.[OH-].[Na+]>O>[Br:18][CH2:19][CH2:20][O:15][C:10]1[CH:9]=[CH:8][C:7]2[C:3]([C:2]([F:1])([F:16])[F:17])=[N:4][O:5][C:6]=2[C:11]=1[CH2:12][CH2:13][CH3:14]
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)noc12
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCc1c(OCCBr)ccc2c(C(F)(F)F)noc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.1 %

Procedure:
3-Trifluoromethyl-7-propyl-6-hydroxy-benzisoxazole (1 g, 4.1 mmol) prepared in Example 24, 1,2-dibromoethane (3.7 g, 18.3 mmol) and NaOH (6 M aqueous solution, 1 mL, 6.0 mmol) were combined and stirred under reflux for 4.5 h. A second portion of NaOH (6 M aqueous solution, 0.43 mL, 2.6 mmol) was added, and stirring under reflux was continued for 4 h. Upon cooling to rt, water (10 mL) was added and the mixture was extracted with CH2Cl2 (3×). The combined organic phases were washed with NaOH (5 M aqueous solution, 2×) and water (3×). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (EtOAc/hexanes (v/v) 1:9) to obtain 550 mg (38%) of the title compound as colorless crystals. 1H NMR (300 MHz, CDCl3): δ 0.99 (t, 3H), 1.72 (dt, 2H), 2.94 (t, 2H), 3.70 (t, 2H), 4.42 (t, 2H), 7.03 (d, 1H), 7.58 (d, 1H).
Reaction SMILES: [CH2:1]([NH:8][S:9]([CH2:12][C:13]1[CH:26]=[CH:25][C:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:28]1[NH:29][CH2:30][CH2:31][N:32]=1.C(=O)([O-])[O-].[K+].[K+]>CC(O)C>[CH2:1]([NH:8][S:9]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:28]3[NH:32][CH2:31][CH2:30][N:29]=3)=[CH:22][CH:23]=2)=[CH:25][CH:26]=1)(=[O:11])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cc2ccc(CS(=O)(=O)NCc3ccccc3)cc2)cc1
Reactant: ClC1=NCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=S(=O)(Cc1ccc(Cc2ccc(NC3=NCCN3)cc2)cc1)NCc1ccccc1

Procedure:
A mixture of 4-(4-benzylaminosulfonylmethylbenzyl)-phenylamine (39 mg) and 2-chloro-imidazoline base (1 eq ) in 2-propanol was heated under reflux for 16 hours. A dilute solution of potassium carbonate was poured into the mixture and extracted with dichloromethane (4×15 mL). Solvents were evaported to give 2-[4-(4-benzylaminosulfonylmethylbenzyl)-phenyl]amino-imidazoline as a solid (41.7 mg), m.p. 115-118° C.; Analysis for C24H25CIN4O2S.H2O: Calc.: C, 58.94; H, 5.98; N, 11.46; Found: C, 59.01; H, 5.91; N, 11.30.
Reaction SMILES: O.C(O)(=O)C.Br.[O:7]=[C:8]([OH:20])[C@@H:9]([C@H:11]([C@@H:13]([C@@H:15]([C:17]([OH:19])=[O:18])O)O)O)O>C(O)(=O)C>[C:17]([OH:19])(=[O:18])[CH2:15][CH2:13][CH2:11][CH2:9][C:8]([OH:20])=[O:7]
Reactant: O=C(O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(=O)O
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CCCCC(=O)O
Temperature: 160 °C
Reaction time: 1.5 h

Procedure:
20 mg catalyst (1.7% Pt-0.6% Rh/Davisil 635) was dispensed into a 1.2 mL vial. Glacial acetic acid was added followed by a 10% water/acetic acid solution according to Table 1. 50 μL of an acetic acid solution containing 1.2 M HBr and 1.6 M D-glucaric acid was added bringing the final solution volume to 100 μL. The vials were transferred to a pressure reactor which was then sealed, purged with nitrogen and pressurized with hydrogen to 820 psig at room temperature. The reactor was agitated and heated to 160° C. for 90 minutes. After 90 minutes, the reactor was cooled to room temperature, vented, and purged with nitrogen prior to being unsealed. Adipic acid yields were determined by mass spectrometry relative to a d8-adipic acid internal standard.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[S:11])[CH:6]=[CH:7][CH:8]=1.Br.Br[CH2:16][CH2:17][NH2:18].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)(Cl)Cl>O>[F:13][C:2]([F:12])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:18]2[CH2:17][CH2:16][S:11][C:10]2=[N:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:4]=2)=[S:11])[CH:6]=[CH:7][CH:8]=1
Reactant: NCCBr
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: FC(F)(F)c1cccc(N=C2SCCN2C(=S)Nc2cccc(C(F)(F)F)c2)c1

Procedure:
A mixture of 6.1 g. of m-trifluoromethylphenyl isothiocyanate, 6.8 g. of 2-bromoethylamine hydrobromide, 3.5 g. of sodium carbonate, and about 100 ml. of chloroform was stirred at ambient temperature for about 14 hours. To the reaction mixture was added about 50 ml. of water. The aqueous phase was washed with chloroform which was added to the organic phase. The organic phase then was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After filtering, the solvent was removed under reduced pressure. The residue was recrystallized from petroleum ether to give N-(3-trifluoromethylphenyl)-2-(3-trifluoromethylphenylimino)-3-thiazolidinecarbothioamide, m.p. 116°-7°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([CH:8]=[CH:9][C:10](Cl)=[O:11])[CH:7]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].N1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([CH:8]=[CH:9][C:10]([N:16]([O:17][CH3:18])[CH3:15])=[O:11])[CH:7]=1
Reactant: CNOC
Reactant: O=C(Cl)C=Cc1cc(Br)ccc1F
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)C=Cc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.2 %

Procedure:
The unpurified 3-(5-bromo-2-fluoro-phenyl)-acryloyl chloride (1.4 g, 5.0 mmol) prepared in Step 2, N,O-dimethylhydroxylamine hydrochloride (0.52 g, 5.3 mmol), and pyridine (0.9 mL, 11.1 mmol) were added at 0° C. to dichloromethane (10.0 mL). The reaction mixture was stirred at room temperature for 12 hours, quenched with a 1N hydrochloric acid solution, and then extracted with diethyl ether two times. The combined extract was washed with a saturated solution of sodium hydrogen carbonate and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was recrystallized from diethyl ether and n-hexane to give 1.3 g of the titled compound as a white solid.
Reaction SMILES: [OH:1][C@@H:2]([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[N:8]=[C:7]([C:25]([NH:27][C@@H:28]([CH3:33])[C:29]([O:31]C)=[O:30])=[O:26])[CH:6]=1)[CH2:3][OH:4].O[Li].O>C1COCC1.O>[OH:1][C@@H:2]([C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[CH:15][CH:16]=2)[N:8]=[C:7]([C:25]([NH:27][C@@H:28]([CH3:33])[C:29]([OH:31])=[O:30])=[O:26])[CH:6]=1)[CH2:3][OH:4]
Reactant: COC(=O)[C@H](C)NC(=O)c1cc([C@H](O)CO)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](NC(=O)c1cc([C@H](O)CO)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1)C(=O)O

Procedure:
To a solution of (S)-methyl 2-(6-((S)-1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamido)propanoate (0.100 g, 0.22 mmol) in 5:1 THF/water (5 mL) was added LiOH.H2O (0.009 g, 0.21 mmol). After stirring overnight additional LiOH.H2O (0.001 g, 0.02 mmol) was added. After 5 hours the reaction was evaporated in vacuo. To the residue was added 5 mL water and 0.22 mL 1N HCl. The resulting precipitate was filtered off, washed with water, and dried under vacuum. The solid was triturated with 2 mL 20% EtOAc/hexanes, isolated, and rinsed with additional hexanes. The material was dried under vacuum to give (S)-2-(6-((S)-1,2-dihydroxyethyl)-2-(4-(4-fluorophenoxy)phenyl)pyrimidine-4-carboxamido) propanoic acid (Compound Example No. 15) as an off-white powder (0.062 g, 0.14 mmol, 64% yield). 1H NMR (400 MHz, DMSO-d6): 12.82 (1 H, s), 9.23 (1 H, d, J=7.9 Hz), 8.62 (2 H, d, J=9.0 Hz), 8.00 (1 H, s), 7.33-7.25 (2 H, m), 7.23-7.16 (2 H, m), 7.13 (2 H, d, J=8.8 Hz), 5.82 (1 H, d, J=5.3 Hz), 4.83 (1 H, t, J=5.9 Hz), 4.70 (1 H, q, J=4.4 Hz), 4.55 (1 H, p, J=7.5 Hz), 3.84-3.76 (1 H, m), 3.71-3.63 (1 H, m), 1.48 (3 H, d, J=7.2 Hz); LC/MS: m/z=442.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH:18]1([O:23][C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=2[O:32][CH3:33])[CH:27]=O)[CH2:22][CH2:21][CH2:20][CH2:19]1.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:16]([NH:17][CH2:27][C:26]4[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:24]([O:23][CH:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)[CH:25]=4)=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc2nc(-c3cccc(Cl)c3)oc12
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNc2cccc3nc(-c4cccc(Cl)c4)oc23)cc1OC1CCCC1
Yield: 59.8 %

Procedure:
By employing a procedure similar to that in Example 33 and using 2-(3-chlorophenyl)-7-aminobenzoxazole (1.00 g, 0.0041 mol), 3-cyclopentyloxy-4-methoxybenzaldehyde (1.08 g, 0.0049 mol), sodium cyanoborohydride (0.41 g, 0.0065 mol) and 35 ml of methanol, a white, crystalline solid was isolated. This crude product (1.4 g) was recrystallized from 200 ml of methanol to yield the title compound (1.1 g), mp 133-134° C.