Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([CH:15]2[CH2:20][CH2:19][CH2:18][O:17][CH2:16]2)[C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:17]1[CH2:18][CH2:19][CH2:20][CH:15]([N:14]2[C:13]3[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=3[N:11]=[C:10]2[C@@H:8]([NH2:7])[CH3:9])[CH2:16]1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccccc2n1C1CCCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2ccccc2n1C1CCCOC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.8 %

Procedure:
To a solution of {(S)-1-[1-(tetrahydropyran-3-yl)-1H-benzoimidazol-2-yl]ethyl}carbamic acid tertbutyl ester (720 mg, 2.08 mmol) in DCM (5 mL) was added TFA (15 mL) and the mixture was stirred at RT for 20 min. Volatiles were removed under reduced pressure and the resulting residue was partitioned between DCM and a saturated solution of NaHCO3. The aqueous phase was further extracted with DCM (×2) and the combined organic layers were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM). The product containing fractions were concentrated in vacuo affording (S)-1-[1-(Tetrahydropyran-3-yl)-1H-benzoimidazol-2-yl]ethylamine as an oil (305 mg, 60%). LCMS: RT 1.85 min [M−NH2]+ 229.1.
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].Cl.N1C=CC=CC=1.[CH2:21]([O:23][C:24]([C:26]1[CH:37]=[CH:36][C:29]([O:30][CH2:31][CH:32]([OH:35])[CH2:33][CH3:34])=[CH:28][CH:27]=1)=[O:25])[CH3:22]>>[C:7]([O:35][CH:32]([CH2:33][CH3:34])[CH2:31][O:30][C:29]1[CH:36]=[CH:37][C:26]([C:24]([O:23][CH2:21][CH3:22])=[O:25])=[CH:27][CH:28]=1)(=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CCOC(=O)c1ccc(OCC(O)CC)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(OCC(CC)OC(=O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
In pyridine (10ml) 1.2 g (5 mmol) of 1-(p-ethoxycarbonyl-phenoxy)-butan- 2-ol was dissolved and to this solution was gradually added 0.6 g (5 mmol) of pivaloyl chloride cooling in an ice bath. The mixture was stirred at room temperature for 3 hours after the addition was completed. During the course of the reaction pyridine hydrochloride precipitated. The reaction mixture was then poured in ice water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated to afford 1.6g of 1-(p-ethoxycarbonyl-phenoxy)-butan-2-ol pivalate (compound No. 1) in a yield of 89% as a light yellow viscous oily substance.
Reaction SMILES: O(CCSCC1C=CC(C2C=CC=C(C(O)=O)C=2)=CC=1)C1C=CC=CC=1.C([O:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][S:45][CH2:46][CH2:47][O:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[CH:39]=2)=[CH:34][CH:33]=1)=[O:31])C.[OH-].[Li+]>C1COCC1>[O:48]([CH2:47][CH2:46][S:45][CH2:44][C:40]1[CH:39]=[C:38]([C:35]2[CH:34]=[CH:33][C:32]([C:30]([OH:31])=[O:29])=[CH:37][CH:36]=2)[CH:43]=[CH:42][CH:41]=1)[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: CCOC(=O)c1ccc(-c2cccc(CSCCOc3ccccc3)c2)cc1
Agent: O=C(O)c1cccc(-c2ccc(CSCCOc3ccccc3)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2cccc(CSCCOc3ccccc3)c2)cc1
Yield: 90.4 %

Procedure:
3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid was synthesized as described for 4′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-3-carboxylic acid. 3′-(2-Phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid ethyl ester (2.0 g, 5.1 mmol, 1 eq.) in 30% aqueous THF was treated with lithium hydroxide (0.37 g, 15.3 mmol, 3 eq.). When complete, the reaction was worked up as described leaving 3′-(2-phenoxy-ethylsulfanylmethyl)-biphenyl-4-carboxylic acid (1.68 g, 90% yield) as a white solid.
Reaction SMILES: C(S)C.[H-].[Na+].C[O:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]=2[CH:18]=1.O>CN(C)C=O>[CH3:16][C:13]1([CH3:17])[C:12]2[CH:18]=[C:8]([OH:7])[CH:9]=[CH:10][C:11]=2[O:15][CH2:14]1
Reactant: COc1ccc2c(c1)C(C)(C)CO2
Agent: [H-]
Agent: [Na+]
Solvent: CCS
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)COc2ccc(O)cc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of ethanethiol (12.6 parts) in dimethyl formamide (60 parts) was added with stirring under nitrogen over a period of 20 minutes to a mixture of sodium hydride (6.6 parts of 80% dispersion in oil) and dry dimethyl formamide (60 parts) cooled to 0° C. After 10 minutes, a solution of 2,3-dihydro-5-methoxy-3,3-dimethylbenzofuran (18 parts) in dimethyl formamide (40 parts) was added and the mixture boiled under reflux in a nitrogen atmosphere for 3 hours. The mixture was then added to water and the aqueous phase washed with chloroform, acidified with hydrochloric acid and extracted into ether. The ether was evaporated off to yield 2,3-dihydro-3,3-dimethyl-benzofuran-5-ol (5.4 parts) as a brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]=[CH:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N-]>>[CH2:23]([O:22][C:20]([CH:19]1[CH:15]2[CH:14]1[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:16]2)=[O:21])[CH3:24]
Reactant: O=C(OCc1ccccc1)N1CC=CCC1
Reactant: CCOC(=O)C=[N+]=[N-]
Product: CCOC(=O)C1C2CCN(C(=O)OCc3ccccc3)CC21

Procedure:
Alternatively, 1-benzyloxycarbonyl-1,2,5,6-tetrahydropyridine can be subjected to reaction with ethyl diazoacetate under rhodium acetate catalysis, to provide ethyl-3-benzyloxycarbonyl-3-azabicyclo[4.1.0]heptane-7-carboxylate. Ester hydrolysis with sodium hydroxide then provides the corresponding carboxylic acid, which can be converted as described in Section VIII to give amino or substituted amino derivatives.
Reaction SMILES: C(OC(=O)[C@H:5]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:6][C:7](=[O:17])[CH2:8][NH:9][C:10](OC(C)(C)C)=[O:11])C.FC(F)(F)C(O)=O>ClCCl>[CH2:18]([C@@H:5]1[NH:6][C:7](=[O:17])[CH2:8][NH:9][C:10]1=[O:11])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CNC(=O)[C@H](Cc2ccccc2)N1
Reaction time: 1.5 h
Yield: 65.9 %

Procedure:
To a solution of Boc-glycylphenylalanine ethyl ester (5.96 g) in dichloromethane (20 ml) was added trifluoroacetic acid (20 mL) at room temperature. After stirring 1.5 h, the resulting solution was concentrated in vacuo. The residue was dissolved in water, into which sodium bicarbonate was added until the pH was 9. After the solution was stirred for several hours, the resulting white crystals were collected and dried in vacuo to afford (S)-3-benzyl-2,5-dioxopiperazine (2.29 g, 70% in 2 steps) as a white powder.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[CH2:26][CH2:25][C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][C@H:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[C:13]=3[CH2:12]2)=[CH:7][C:6]=1[C:27]([F:30])([F:29])[F:28].Br[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1.C(N(CC)C(C)C)(C)C>>[CH3:3][O:4][C:5]1[N:10]=[CH:9][C:8]([N:11]2[CH2:26][CH2:25][C:14]3[N:15]=[CH:16][N:17]=[C:18]([O:19][C@H:20]4[CH2:24][CH2:23][N:22]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=5)[CH2:21]4)[C:13]=3[CH2:12]2)=[CH:7][C:6]=1[C:27]([F:30])([F:28])[F:29]
Reactant: Brc1ccccn1
Reactant: COc1ncc(N2CCc3ncnc(O[C@H]4CCNC4)c3C2)cc1C(F)(F)F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(N2CCc3ncnc(O[C@H]4CCN(c5ccccn5)C4)c3C2)cc1C(F)(F)F
Temperature: 160 °C
Yield: 25.1 %

Procedure:
To a glass vial was added 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine dihydrochloride (prepared using step 1 of example 91 from intermediate 13) (75 mg, 0.16 mmol), 2-bromopyridine (1 mL, 10.25 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.80 mmol). The vial was capped and the mixture heated in the microwave at 160° C. for 20 min. Purification by reverse phase Gilson HPLC (Method A) and subsequent neutralization of the combined fractions over PL-HCO3 MP to give 6-(6-methoxy-5-trifluoromethyl-pyridin-3-yl)-4-((S)-1-pyridin-2-yl-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine as a light brown solid (19 mg, 25% yield) 1H NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.24-2.44 (m, 2 H) 2.92 (t, 2 H) 3.47-3.69 (m, 5 H) 3.77-3.85 (m, 1H) 3.88-3.93 (m, 3 H) 4.12-17 (m, 2 H) 5.73-5.81 (m, 1 H) 6.40-6.52 (d, 1 H) 6.56-6.58 (m, 1 H) 7.43-7.54 (m, 1 H) 7.77-7.84 (m, 1 H) 8.02-8.09 (m, 1 H) 8.13-8.20 (m, 1 H) 8.61-8.66 (m, 1 H) LCMS: [M+H]+=473.0, Rt(4)=0.85 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:17]([N:19]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:20]3=[O:30])=[O:18])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:37][C:38]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[CH:40][N:39]=1>O1CCOCC1.O.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>[CH3:15][C:14]1[N:13]=[C:12]([NH:16][C:17]([N:19]2[CH2:23][CH2:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:20]2=[O:30])=[O:18])[CH:11]=[CH:10][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:42]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:37])[CH:43]=2)[CH:7]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: Cc1nc(NC(=O)N2CCN(C3CCOCC3)C2=O)ccc1Oc1ccnc(Cl)c1
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: C1COCCO1
Solvent: O
Product: Cc1cc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCOCC5)C4=O)nc3C)ccn2)ccn1
Temperature: 80 °C
Yield: 35.4 %

Procedure:
A mixture of Example C3 (0.377 g, 0.873 mmol) and K2CO3 (0.362 g, 2.62 mmol) in dioxane (4 mL) and water (1 mL) was sparged with Ar, treated with 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.201 g, 0.917 mmol) and Pd(Ph3P)4 (0.101 g, 0.087 mmol), sparged again with Ar and heated at 80° C. overnight. The mixture was cooled to RT, diluted with EtOAc, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/EtOAc). The material was treated with Et2O, stirred at RT and the resulting solid collected via filtration and dried to afford N-(6-methyl-5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (151 mg, 35%). 1H NMR (400 MHz, DMSO-d6): δ 10.90 (s, 1 H), 8.56 (d, J=5.6 Hz, 1 H), 8.52 (d, J=5.2 Hz, 1 H), 7.93-7.88 (m, 2 H), 7.79 (dd, J=5.3, 1.6 Hz, 1 H), 7.66-7.63 (m, 2 H), 6.86 (dd, J=5.6, 2.4 Hz, 1 H), 3.93-3.77 (m, 5 H), 3.49-3.34 (m, 4 H), 2.52 (s, 3 H), 2.26 (s, 3 H), 1.78-1.66 (m, 2 H), 1.63-1.57 (m, 2H); MS (ESI) m/z: 489.2 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[Ca+2:5].C1(C)C(C)=CC=CC=1.[B:14]([OH:17])([OH:16])[OH:15]>O>[B:14]([O-:17])([O-:16])[O-:15].[Ca+2:5].[B:14]([O-:17])([O-:16])[O-:15].[Ca+2:5].[Ca+2:5]
Reactant: OB(O)O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: Cc1ccccc1C
Solvent: O
Product: [O-]B([O-])[O-]
Temperature: 95 °C

Procedure:
A solution of 200 g of a calcium carbonate overbased alkylsalicylate (TBN 280 mgKOH/g, calcium content; 10.0 wt. %) and 200 g of xylene were put in a 1000-ml four-necked flask fitted with a condenser and heated to 95° C. while agitating. To this mixture was added 20 g of orthoboric acid, and the temperature was gradually increased to 145° C., while the reaction water was removed by azeotropic distillation by spending time for 1.5 hours. Subsequently, the reactor contents were filtered to obtain a filtrate (solution) which was cooled and then centrifuged to remove any residual solids present. Finally, the xylene was removed in vacuo to obtain a calcium borate overbased alkylsalicylate.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:14][CH:12]=[N:1]2)=[CH:7][CH:8]=1
Reactant: NC=O
Reactant: Nc1cc(F)ccc1C(=O)O
Product: O=c1[nH]cnc2cc(F)ccc12
Temperature: 0 °C
Yield: 82 %

Procedure:
A solution of 2-amino-4-fluorobenzoic acid (3 g, 19.3 mmol) in formamide (30 ml) was heated at 150° C. for 6 hours. The reaction mixture was poured onto ice/water 1/1 (250 ml). The precipitated solid was collected by filtration, washed with water and dried to give 7-fluoro-3,4-dihydroquinazolin-4-one (2.6 g, 82%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[CH:21][CH:20]=3)[C:11]=2/[CH:12]=[CH:13]/[C:14]2[NH:15][CH:16]=[CH:17][N:18]=2)=[O:6])[CH2:3][CH2:2]1.CI.[C:32](=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:24]=3)[C:11]=2/[CH:12]=[CH:13]/[C:14]2[N:18]([CH3:32])[CH:17]=[CH:16][N:15]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2/C=C/c2ncc[nH]2)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2/C=C/c2nccn2C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 12.9 %

Procedure:
N-Cyclopropyl-1-{4-[(ethylamino)carbonyl]phenyl}-5-[(E)-2-(1H-imidazol-2-yl)vinyl]-1H-1,2,3-triazole-4-carboxamide (150 mg) obtained in Example 322 was dissolved in acetone (3 ml) and DMF (3 ml), methyl iodide (72 μl) and potassium carbonate (300 mg) were added, and the mixture was stirred at room temperature for 3 days. After an insoluble material was removed by filtration, the reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in chloroform. The obtained chloroform solution was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-methanol (10:1) to give the title compound as a white powder (20 mg).
Reaction SMILES: ClC1C(Cl)=CC=CC=1N[C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18](=[O:31])[N:19]([C@H:22]3[CH2:24][C@@H:23]3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:20](=[O:21])[C@@H:14]2[CH2:13]1)=[O:11].Cl.[C:33]1([C@H:39]2[CH2:41][C@@H:40]2N2C(=O)[C@@H]3CNCCN3C2=O)C=CC=CC=1.CC1(C(O)=O)CC1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:33][C:39]1([C:10]([N:12]2[CH2:17][CH2:16][N:15]3[C:18](=[O:31])[N:19]([C@H:22]4[CH2:24][C@@H:23]4[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:20](=[O:21])[C@@H:14]3[CH2:13]2)=[O:11])[CH2:41][CH2:40]1
Reactant: O=C1[C@@H]2CNCCN2C(=O)N1[C@H]1C[C@@H]1c1ccccc1
Reactant: O=C(Nc1cccc(Cl)c1Cl)N1CCN2C(=O)N([C@H]3C[C@@H]3c3ccccc3)C(=O)[C@@H]2C1
Agent: CC1(C(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC1(C(=O)N2CCN3C(=O)N([C@H]4C[C@@H]4c4ccccc4)C(=O)[C@@H]3C2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 0.2 M solution of Example 4, D2 (1 eq) in DMF were added 1-methylcyclopropanecarboxylic acid (1.1 eq), DIPEA (2.5 eq) and TBTU (1.5 eq). The reaction mixture was stirred at RT for 12 h. The crude product was purified by preparative RP-HPLC using H2O (0.1% TFA) and MeCN (0.1% TFA) as eluents, affording the title compound. 1H NMR (300 MHz, DMSO-d6, 300K) δ: 7.27-7.09 (5H, m), 4.42-4.32 (1H, m), 4.19 (1H, d, J=9.3 Hz), 4.05-3.95 (1H, m), 3.91-3.82 (1H, m), 2.97-2.81 (3H, m), 2.65-2.57 (1H, m), 2.36-2.26 (1H, m), 1.49-1.40 (1H, m), 1.39-1.30 (1H, m), 1.18 (3H, s), 0.83-0.76 (2H, m), 0.54-0.48 (2H, m). MS (ES) C20H23N3O3 requires: 353, found: 354 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH:19]=[CH:18]3)[C:10]1=[O:26])[C:6](O)=[O:7])(=[O:3])[CH3:2].[NH2:27][C:28]1[CH:47]=[CH:46][C:31]2[C:32]([N:35]3[C:43](=[O:44])[C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:36]3=[O:45])=[N:33][O:34][C:30]=2[CH:29]=1>>[O:45]=[C:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43](=[O:44])[N:35]1[C:32]1[C:31]2[CH:46]=[CH:47][C:28]([NH:27][C:6](=[O:7])[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:9]3[O:14][CH2:13][CH2:12][N:11]([C:15]4[CH:16]=[C:17]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20](=[O:25])[CH:19]=[CH:18]5)[C:10]3=[O:26])=[CH:29][C:30]=2[O:34][N:33]=1
Reactant: Nc1ccc2c(N3C(=O)c4ccccc4C3=O)noc2c1
Reactant: CC(=O)O[C@@H](C(=O)O)[C@H]1OCCN(c2ccc3[nH]c(=O)ccc3c2)C1=O
Product: CC(=O)O[C@@H](C(=O)Nc1ccc2c(N3C(=O)c4ccccc4C3=O)noc2c1)[C@H]1OCCN(c2ccc3[nH]c(=O)ccc3c2)C1=O

Procedure:
According to the Step 15-1 in the synthetic method for Example aa15, (2R)-2-acetyloxy-2-[(2R)-3-oxo-4-(2-oxo-1H-quinolin-6-yl)morpholin-2-yl]acetic acid (compound aa3-3) and 6-amino-3-(1,3-dioxoisoindol-2-yl)-1,2-benzisoxazole can be used to obtain [(1R)-2-[[3-(1,3-dioxoisoindol-2-yl)-1,2-benzisoxazol-6-yl]amino]-2-oxo-1-[(2R)-3-oxo-4-(2-oxo-1H-quinolin-6-yl)morpholin-2-yl]ethyl]acetate (compound ap1-1), then further treatment can be achieved according to the Step 15-2 to obtain the title compound ap1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[N:13][C:14]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[N:17](COCC[Si](C)(C)C)[C:15]=4[N:16]=3)=[N:9][N:8]([CH2:31][CH2:32][C:33]([F:38])([F:37])[CH:34]([F:36])[F:35])[C:5]2=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[N:13][C:14]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=4[N:16]=3)=[N:9][N:8]([CH2:31][CH2:32][C:33]([F:38])([F:37])[CH:34]([F:35])[F:36])[C:5]2=[N:6][CH:7]=1
Reactant: CC1(C)C(=O)N(COCC[Si](C)(C)C)c2nc(-c3nn(CCC(F)(F)C(F)F)c4ncc(F)cc34)nnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)F)c4ncc(F)cc34)nnc21
Temperature: 45 °C
Reaction time: 3 h
Yield: 41.9 %

Procedure:
96 mg (0.173 mmol) of the compound from Example 37A were stirred in dichloromethane (4 ml) and trifluoroacetic acid (1 ml) at room temperature for 4.5 h. The mixture was then concentrated to dryness. The residue was stirred in ethanol/2N hydrochloric acid (4:1, 15 ml) at 45° C. for 3 h. This was followed by concentration to dryness. Purification by preparative HPLC (methanol:water (+1% trifluoroacetic acid) gradient) gave 31 mg of the title compound (42% of theory).
Reaction SMILES: C1C=C2O[C@@H](CO)COC2=C(N2CCN(CCN[C:22]([C:24]3[CH:25]=[CH:26][C:27](F)=[CH:28][CH:29]=3)=[O:23])CC2)C=1.C(Cl)[Cl:32]>>[C:22]([Cl:32])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClCCl
Reactant: O=C(NCCN1CCN(c2cccc3c2OC[C@H](CO)O3)CC1)c1ccc(F)cc1
Product: O=C(Cl)c1ccccc1

Procedure:
Preparation of flesinoxan from R-(+)-BDA ##STR13## (a). Benzoylation of R-(+)-BDA(1) with benzoyl chloride in methylene chloride as the solvent, to produce compound (2).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:15]([NH:17][C:18](=[O:31])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH3:16])=[N:13][CH:14]=1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:15]([NH:17][C:18](=[O:31])[CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=2)[CH3:16])=[N:13][CH:14]=1
Reactant: C[C@@H](NC(=O)COc1ccc(C(F)(F)F)cc1)c1ccc(OCc2ccccc2)cn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@@H](NC(=O)COc1ccc(C(F)(F)F)cc1)c1ccc(O)cn1
Reaction time: 6 h
Yield: 92.7 %

Procedure:
A mixture of (R)-N-(1-(5-(benzyloxy)pyridin-2-yl)ethyl)-2-(4-(trifluoromethyl)phenoxy)acetamide (Example 63, 550 mg, 1.3 mmol) and palladium hydroxide on carbon (20 wt. %, 50 mg) in methanol (30 mL) was hydrogenated for 6 hours. The mixture was filtered through a pad of celite, washed with methanol, the filtrate was concentrated gave 410 mg (94% yield) of (R)-N-(1-(5-hydroxypyridin-2-yl)ethyl)-2-(4-(trifluoromethyl)phenoxy)acetamide as a white crystalline solid;
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:2]2[S:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:14][CH:13]=1
Reactant: Clc1nc2ccccc2s1
Reactant: Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Nc1ccc(Sc2nc3ccccc3s2)cc1
Yield: 88.4 %

Procedure:
2-Chlorobenzothiazole (0.06 moles, 10.1 g), 4-aminothiophenol (0.06 moles, 7.5 g) and potassium carbonate (0.06 moles, 8.3 g) were stirred for 3 days at room temperature in 250 ml ethanol, filtered, and concentrated. Ethyl acetate was added and the solution washed with water, dried over sodium sulfate and concentrated. The product was purified by HPLC over silica gel eluted with 40-60% ethyl acetate in hexane to yield 2-(4-aminophenylthio)benzothiazole 13.7 g, 88%. Mass spec (FD) 258. Calculated for C11H10N2S2 : C, 60.44; H, 3.90; N, 10.84. Found: C, 60.63; H, 3.98; N, 11.01.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl.[Cl:15][C:16]1[C:22]([Cl:23])=[CH:21][C:19]([NH2:20])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1>C(O)C>[Cl:15][C:16]1[C:22]([Cl:23])=[CH:21][C:19]([NH:20][C:8](=[O:10])[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: O=C(O)Cc1ccccc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: O=C(Cc1ccccc1)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
A mixture of phenylacetic acid (10 mmol) in SOCl2 (4 ml, apr. 50 mmol) was stirred for 16 h at room temperature, then evaporated and kept at 2 mm Hg for 0.5 h to remove residual SOCl2. A suspension of 4,5-dichloro-2-nitroaniline (1.035 g, 5 mmol) in ethanol-free CHCl3 (10 mL) was added to the residue and the mixture was stirred at 50° C. for 4 h. It was then cooled to room temperature and evaporated. The residue was treated with ether (100 mL). Precipitated crude product was filtered, washed with ether (5×20 mL) and dried on air to give the title compound. Yield 90%; mp 116°-118° C. (from EtOH); (Lit., 118° C., Ahmad, Yu., et al., Tetrahedron 21:861 (1965)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1I)[NH2:5].[CH2:10](C([Sn])=C(CCCC)CCCC)[CH2:11]CC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:5])[CH:6]=[CH:7][C:8]=1[CH:10]=[CH2:11]
Reactant: Nc1ccc(I)c(Cl)c1
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Solvent: C1CCOC1
Product: C=Cc1ccc(N)cc1Cl
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a deoxygenated solution of 3-chloro-4-iodo-aniline (6.95 g) triphenyl arsine (0.67 g), and tris(dibenzylideneacetone)palladium(0) (0.50 g) in tetrahydrofuran (120 mL) at 50° C. is added tributylvinyltin (10 g) and the mixture is stirred for approximately 15 hours at 50° C. under an atmosphere of argon. The reaction is then cooled, filtered through diatomaceous earth, and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in hexanes and then extracted three times with 5% aqueous hydrochloric acid. These aqueous acidic extracts are then basified with solid potassium carbonate and extracted three times with ethyl acetate. These pooled organic extracts are then washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the solvent is removed under reduced pressure. The resulting residue is chromatographed over silica gel (hexanes and then 10% ethyl acetate in hexanes is used as the eluant) to provide the desired product as an amber oil.