Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.CCCCCC.[B:32](OC(C)C)([O:37]C(C)C)[O:33]C(C)C.Cl>O1CCCC1>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([C:9]2[C:10]3[C:15]([C:2]([B:32]([OH:37])[OH:33])=[C:3]4[C:8]=2[CH:7]=[CH:6][CH:5]=[CH:4]4)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:21][CH:20]=1)([CH3:24])([CH3:25])[CH3:23]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)c1ccc(-c2c3ccccc3c(Br)c3ccccc23)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(-c2c3ccccc3c(B(O)O)c3ccccc23)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
15.4 g of the above-mentioned 9-bromo-10-(4-tert-butylphenyl) anthracene was dissolved in 380 ml of tetrahydrofuran to drop 30 ml of n-butylithium (1.6 M-hexane solution) thereto under nitrogen atmosphere at a temperature of 0° C. The solution was stirred at a temperature of 0° C. for 30 minutes and thereafter cooled to a temperature of −80° C. to drop 18.2 ml of triisopropyl borate thereto. The solution was heated up to room temperature by standing at room temperature and thereafter stirred at room temperature for 3 hours. 400 ml of 10%-hydrochloric acid was dropped thereto and further stirred at room temperature for 2 hours to thereafter extract 300 ml of diethyl ether therefrom. The organic layer was washed in 100 ml of 5%-sodium carbonate aqueous solution, washed in 100 ml of water, then dried by magnesium sulfate and thereafter concentrated by evaporation. The organic layer was purified by silica gel column chromatography (developing solvent was in the order of dichloromethane/hexane=1/1, dichloromethane and dichloromethane/methanol=50/1) and vacuum dried to thereafter obtain 6.78 g of 9-(4-tert-butylphenyl)-10-anthraceneboronic acid.
Reaction SMILES: O/[CH:2]=[C:3](/[CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[N:14][CH:15]=1)\[C:4]([O:6]CC)=O.[NH2:16][C:17]([NH2:19])=[S:18].CC(C)([O-])C.[K+]>C(O)(C)C>[N:14]1[CH:15]=[C:10]([CH2:9][C:3]2[C:4](=[O:6])[NH:16][C:17](=[S:18])[NH:19][CH:2]=2)[CH:11]=[N:12][CH:13]=1
Reactant: CCOC(=O)/C(=C\O)Cc1cncnc1
Reactant: NC(N)=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=c1[nH]c(=S)[nH]cc1Cc1cncnc1
Temperature: 80 °C

Procedure:
To a solution of ethyl (2Z)-3-hydroxy-2-(5-pyrimidinylmethyl)-2-propenoate (3 g, 7.20 mmol) in isopropanol (30 ml) was added thiourea (1.1 g, 14.45 mmol) and potassium tert-butoxide (1 g, 8.91 mmol). The mixture was heated at 80° C. for 4 h. The solvent was evaporated and residue was dissolved in water, extracted with ether twice to remove impurity. The aqueous phase was acidified to PH 4 with AcOH, and white participate formed. The mixture was filtered to afford the title compound as a white solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:9])[CH2:7][OH:8])(=[O:3])[CH3:2].[O-:10][C:11]#[N:12].[Na+].FC(F)(F)C(O)=O.O>C1C=CC=CC=1>[C:1]([O:4][CH2:5][C:6](=[O:9])[CH2:7][O:8][C:11](=[O:10])[NH2:12])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)CO
Reactant: N#C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)OCC(=O)COC(N)=O
Reaction time: 3 h

Procedure:
To a stirred mixture of 1-acetoxy-3-hydroxy-2-propanone (10.8 g., 0.1 mole) and sodium cyanate (13.0 g., 0.2 mole) in benzene (50 ml.) is slowly added trifluoroacetic acid (15.5 ml., 0.21 mole). The reaction mixture is stirred for three hours, then water (15 ml.) is added. The organic layer is separated, dried and the solvent removed under reduced pressure to afford 1-acetoxy-3-carbamoyloxy-2-propanone.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][C:11]1[O:15][C:14]([CH:16]([NH:18][OH:19])[CH3:17])=[CH:13][CH:12]=1>C1COCC1>[OH:19][N:18]([CH:16]([C:14]1[O:15][C:11]([CH3:10])=[CH:12][CH:13]=1)[CH3:17])[C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9]
Reactant: O=C=Nc1ccccc1
Reactant: Cc1ccc(C(C)NO)o1
Solvent: C1CCOC1
Product: Cc1ccc(C(C)N(O)C(=O)Nc2ccccc2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.7 %

Procedure:
To a solution of phenyl isocyanate (0.87 mL, 8.0 mmol) in 10 mL THF was added N-(1-(5-methyl-fur-2-yl)ethyl) hydroxylamine (0.50 g, 4.0 mmol) in 3 mL THF. The reaction was stirred 1 h at room temperature and was quenched with saturated ammonium chloride solution (25 mL). The aqueous layer was extracted with ethyl acetate (3×10 mL) and the organic layer was washed with brine (1×20 mL). The solution was dried with MgSO4, filtered and evaporated. Chromatography (silica gel, 30% ether/hexanes) gave 0.32 g of desired product; m.p.=109°-110° C.; 1H NMR (300 MHz, DMSO-d6) 9.43 (bs, 1H), 8.97 (bs, 1H), 7.62 (dd, J=1.50, 8.71 Hz, 2H), 7.25 (m, 2H), 6.96 (m, 1H), 6.15 (d, J=3.00 Hz, 1H), 5.38 (q, J=6.9, 17.4 Hz, 1H), 2.19 (s, 3H), 1.39 (d, J=6.30 Hz, 3H); MS (M+H)+ =261; Analysis calc'd for C14H16N2O3 : C, 64.59; H, 6.20; N, 10.77. Found: C, 64.00; H, 6.12; N, 10.60.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5]([C:4]3[CH:3]=[C:2]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:29]=[CH:28][CH:27]=3)=[O:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: OB(O)c1ccccc1
Reactant: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(Br)c1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1cccc(-c2ccccc2)c1

Procedure:
Compound is prepared from 3-bromo-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-benzamide and phenyl boronic acid according to conditions described in general procedure K. 1H NMR 300 MHz (DMSO-d6) δ 10.4(s, 1H), 8.4(s, 1H), 8.2(m, 1H), 8.05(d, 1H, J=7.2 Hz), 7.9(m, 2H), 7.8(m, 2H), 7.4-7.7(m, 7H), 7.0(d, 1H, J=10.1 Hz), 4.3(m, 2H), 3.6(s, 4H), 2.9(m, 2H), 2.6(m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:19](Cl)=[O:20])=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25].C(N(CC)CC)C>ClCCl.O>[Cl:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH:25][C:19]([C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[N:13]=[C:14]([S:17][CH3:18])[N:15]=[CH:16][C:11]=2[CH:10]=1)=[O:20]
Reactant: CSc1ncc2cc(C(=O)Cl)n(-c3ccc(F)cc3)c2n1
Reactant: Nc1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CSc1ncc2cc(C(=O)Nc3ccccc3Cl)n(-c3ccc(F)cc3)c2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 7-(4-fluoro-phenyl)-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbonyl chloride, 25, (0.57 g, 1.77 mmol) in dichloromethane (10 mL) is added 2-chloroaniline (0.28 mL, 2.66 mmol) and triethylamine (0.74 mL, 5.3 mmol). The mixture is allowed to stir at ambient temperature for 16 hours. The reaction was diluted with H2O and extracted three times with EtOAc. The combined organic phases are rinsed with brine, dried (MgSO4), filtered and concentrated in vacuo wherein the crude residue is purified over silica (5% to 40% EtOAc/hexanes) to afford 365 mg the desired product: 1H NMR (300 MHz, CDCl3) δ 9.00 (s, 1H), 8.42 (d, J=8.2 Hz, 1H), 8.32 (br s, NH), 7.55-7.50 (m, 2H), 7.42 (d, J=8.2 Hz, 1H), 7.36-7.20 (m, 3H), 7.12 (t, J=8.7 Hz, 1H), 2.49 (s, 3H); ESI+ MS: m/z (rel intensity) 413.0 (100, M++H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:21]2[CH2:26][C:25](C)(C)[CH2:24][C:23](C)(C)[CH2:22]2)[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17](OC)=O)=CC=2)=[CH:4][CH:3]=1.[O:31]1[CH:35]=[CH:34][CH:33]=[C:32]1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C1COCC1.O>CCOCC.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:9]1(=[C:8]([C:21]2[CH:22]=[CH:23][C:24]([C:32]3[O:31][CH:35]=[CH:34][CH:33]=3)=[CH:25][CH:26]=2)[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH2:14][CH2:13][CH2:12][CH2:15][CH2:16][CH2:17]1
Reactant: COC(=O)CCc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Reactant: OB(O)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: Oc1ccc(C(=C2CCCCCC2)c2ccc(-c3ccco3)cc2)cc1
Temperature: 25 °C
Yield: 44 %

Procedure:
The round-bottom flask was charged with 4-[(4-bromophenyl)(cycloheptylidene)methyl]phenol (9) (0.100 g, 0.28 mmol), PdCl2(PPh3)2, (0.020 g, 0.028 mmol), 2-furanylboronic acid (0.063 g, 0.56 mmol), aqueous 2 M Na2CO3, (0.06 g, 0.56 mmol), and THF/H2O mixture (4:1, 5 mL) under a nitrogen atmosphere. The reaction mixture was refluxed for 10 h. Reaction mixture was cooled to room temperature, diluted with Et2O (10 mL) and filtered. The filtrate was diluted with EtOAc (30 mL), washed with brine, dried (Na2SO4), and concentrated under reduced pressure to afford the crude product. The product was purified by silica gel chromatography using hexanes:EtOAc (19:1 to 4:1) as an eluent to give 0.0.42 g (44%) of compound 202 as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 69.28 (s, 1H), 7.70 (br s, 1H), 7.59 (d, J=6.0 Hz, 2H), 7.12 (d, J=6.0 Hz, 2H), 6.91 (d, J=6.3 Hz, 2H), 6.86 (d, J=2.4 Hz, 1H), 6.66 (d, J=6.3 Hz, 1H), 6.55 (br s, 1H), 2.37 (br s, 4H), 1.62 (br s, 8H). LCMS (ESI): m/z 343 (M−H)−.
Reaction SMILES: N[C:2]1[NH:3][C:4](=[O:19])[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:7]=[N:8][C:9]=2[N:10]=1.N([O-])=[O:21].[Na+]>C(O)(=O)C.O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:6]2[C:5]3[C:4](=[O:19])[NH:3][C:2](=[O:21])[NH:10][C:9]=3[N:8]=[CH:7]2)=[CH:13][CH:14]=1
Reactant: Nc1nc2ncn(Cc3ccc(Cl)cc3)c2c(=O)[nH]1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(=O)c2c(ncn2Cc2ccc(Cl)cc2)[nH]1
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a solution of 2-amino-7-(4-chlorobenzyl)-1H-purin-6(7H)-one (6.8 g, 24.7 mmol) in acetic acid (80 mL) and water (10 mL) was added a solution of sodium nitrite (3.4 g, 24.7 mmol) in water (10 mL) dropwise at 50° C. The reaction was stirred at 50° C. for 1 h. The mixture was cooled to room temperature and stirred for another 1.5 h. The precipitate was collected, washed with water and ethanol, and dried in vacuo to give 7-(4-chlorobenzyl)-1H-purine-2,6(3H,7H)-dione (6.5 g, 95.3% yield) as yellow solid. LCMS retention time 0.635 min; LCMS MH+ 277.
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)C.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:18]=[N:19][C:20]([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:32]([OH:34])=O)[CH:30]=3)[C:25]([CH3:35])=[CH:24]2)=[N:21][CH:22]=1.[OH:36][C:37]1SC2C=CC=[CH:42][C:40]=2[N:41]=1.C(=O)([O-])O.[Na+]>ClCCl>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:18]=[N:19][C:20]([N:23]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([C:32]([N:4]4[CH2:42][CH2:40][NH:41][C:37](=[O:36])[CH2:1]4)=[O:34])[CH:30]=3)[C:25]([CH3:35])=[CH:24]2)=[N:21][CH:22]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Oc1nc2ccccc2s1
Reactant: Cc1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)O)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CCNC(=O)C3)ccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
EDCxHCl (150 μmol) and N,N-diisopropylethylamine (380 μmol) were added to a solution of 1-(5-(2-fluorophenyl)pyrimidin-2-yl)-3-methyl-1H-indole-6-carboxylic acid (100 μmol) and hydroxybenzothiazol (30 μmol) in dichloromethane (4 mL) and the mixture was stirred for 15 min at room temperature. The appropriate amine (125 μmol) was added and the reaction mixture was stirred for 16 h at room temperature. The reaction was stopped by addition of saturated sodium hydrogen carbonate solution (2.5 mL) and the mixture was extracted with dichloromethane (3×3 mL). The solvent was removed under reduced pressure and the residue purified by preparative HPLC to furnish the desired compound.
Reaction SMILES: [NH2:1][C:2]1[N:32]=[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[CH:12]=[C:13]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:14]=[CH:15][C:16]=3[CH3:17])=[CH:9][N:4]2[N:3]=1.Cl[CH2:34][C:35](Cl)=[O:36].C(N(CC)CC)C.[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.C(=O)([O-])O.[Na+]>CN(C)C=O.O>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:13]1[CH:14]=[CH:15][C:16]([CH3:17])=[C:11]([O:10][C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[C:2]([NH:1][C:35](=[O:36])[CH2:34][N:49]4[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]4)[N:32]=3)[CH:9]=2)[CH:12]=1)=[O:31])([CH3:28])[CH3:27])#[N:30]
Reactant: O=C(Cl)CCl
Reactant: CN1CCNCC1
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)nn2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)CN3CCN(C)CC3)nn2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.4 %

Procedure:
To a solution of N-{3-[(2-amino[1,2,4]triazolo[1,5-a]pyridin-6-yl)oxy]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (202 mg, 0.474 mmol) in N,N-dimethylformamide (5 mL) was added chloroacetyl chloride (76 μL, 0.948 mmol), and the mixture was stirred at room temperature for 4 hr. Water (15 mL) was added to the reaction mixture, and extracted with ethyl acetate (20 mL, 2×10 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL). Triethylamine (197 μL, 1.42 mmol) and 1-methylpiperazine (158 μL, 1.42 mmol) were added, and the mixture was stirred at 60° C. for 19 hr. A saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/methanol=100/0→94/6), and fractions containing the desired product were concentrated under reduced pressure. Diisopropyl ether was added to the obtained residue. The obtained precipitate was collected by filtration and dried to give the title compound (173 mg, 64%) as a colorless powder.
Reaction SMILES: [OH-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[C:22]([F:36])[CH:23]=[C:24]4[C:28]=3[NH:27][CH:26]=[C:25]4[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4].Cl>C1COCC1.O>[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[C:22]([F:36])[CH:23]=[C:24]4[C:28]=3[NH:27][CH:26]=[C:25]4[CH2:29][CH2:30][C:31]([OH:33])=[O:32])[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cc(F)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3cc(F)cc4c(CCC(=O)O)c[nH]c34)no2)cc1C#N
Temperature: 90 °C
Reaction time: 3 h
Yield: 62.5 %

Procedure:
Sodium hydroxide (100 mg) was added to a solution of ethyl 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoate (D138) (230 mg) in THF (4 mL) and water (4 mL). The reaction mixture was stirred at 90° C. for 3 hours. Then 0.5 M HCl was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitate was purified by MDAP and recrystallized in MeCN to afford 3-[7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-fluoro-1H-indol-3-yl]propanoic acid (E99) (135 mg) as an off-white solid. δH (DMSO-d6, 400 MHz): 1.39 (6H, d), 2.63 (2H, t), 2.97 (2H, t), 4.96-5.02 (1H, m), 7.36 (1H, d), 7.55 (1H, d), 7.64-7.69 (2H, m), 8.49 (1H, dd), 8.72 (1H, d), 10.97 (1H, s), 12.13 (1H, br s). δF (DMSO-d6, 376 MHz): −124.9. MS (ES): C23H19FN4O4 requires 434; found 435.2 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].O>Br.C(O)(=O)C>[C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(-c2cccc(C(C)=O)c2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1cccc(-c2ccc(O)cc2)c1
Yield: 75.7 %

Procedure:
A solution of 3'-acetyl-4-methoxybiphenyl (2.07 g) in hydrobromic acid (48%, 25 ml) and glacial acetic acid (25 ml) was heated at reflux under nitrogen for 1 hour. After cooling the mixture was poured into water and extracted with ether. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a crude yellow/brown solid The latter was purified by column chromatography over silica eluting with diethyl ether:hexane (2:3) to give the sub-title compound as a cream/orange solid (1.47 g).
Reaction SMILES: [CH:1]1([C@@H:4]2[O:15][CH2:14][C:7]3=[N:8][O:9][C@@H:10]([CH2:11][O:12][CH3:13])[C@@H:6]3[CH2:5]2)[CH2:3][CH2:2]1.C1([C@@H]2OC[C@]3([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=4[F:35])NOC[C@@H]3C2)CC1>>[CH:1]1([C@@H:4]2[O:15][CH2:14][C@:7]3([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=4[F:35])[NH:8][O:9][C@@H:10]([CH2:11][O:12][CH3:13])[C@@H:6]3[CH2:5]2)[CH2:2][CH2:3]1
Reactant: Fc1ccc([C@]23CO[C@@H](C4CC4)C[C@H]2CON3)c(F)c1
Reactant: COC[C@@H]1ON=C2CO[C@@H](C3CC3)C[C@H]21
Product: COC[C@@H]1ON[C@@]2(c3ccc(F)cc3F)CO[C@@H](C3CC3)C[C@@H]12

Procedure:
rel-(3R,3aR,5R)-5-Cyclopropyl-3-(methoxymethyl)-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C38) was converted to the product using the method described for synthesis of rel-(3aR,5R,7aS)-5-cyclopropyl-7a-(2,4-difluorophenyl)hexahydro-1H-pyrano[3,4-c][1,2]oxazole (C19) in Example 2. The product was obtained as an oil. Yield: 0.85 g, 2.6 mmol, 55%. LCMS m/z 326.2 [M+H+].
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].ClCCl.[CH3:11][O:12][C:13]([C:15]1[C@H:16]2[CH2:33][C@@H:32]3[O:34][C@:31]3([CH3:35])[C@@H:17]2[C@H:18]([O:21][C:22](OC2C=CC=CC=2)=[O:23])[O:19][CH:20]=1)=[O:14]>CCCCCC.C(OCC)(=O)C>[CH3:11][O:12][C:13]([C:15]1[C@H:16]2[CH2:33][C@@H:32]3[O:34][C@:31]3([CH3:35])[C@@H:17]2[C@H:18]([O:21][C:22](=[O:23])[NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[O:19][CH:20]=1)=[O:14]
Reactant: COC(=O)C1=CO[C@@H](OC(=O)Oc2ccccc2)[C@@H]2[C@@H]1C[C@@H]1O[C@]21C
Reactant: CCCCCCN
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCCNC(=O)O[C@@H]1OC=C(C(=O)OC)[C@H]2C[C@@H]3O[C@]3(C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
0.11 ml of n-hexylamine were added to a dichloromethane solution containing 246 mg of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(phenoxycarbonyloxy) cyclopenta [c] pyrane-4-carboxylic acid methylester described in Example 10 followed by stirring for 1 hour at room temperature. The reaction mixture was then extracted with dichloromethane. After washing the organic phase with brine, it was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a colorless powder from the hexane-ethyl acetate eluate in the form of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1-(n-hexylcarbamoyloxy)-1,4a,5,6,7,7a-hexahydro-7-methylcyclopenta [c] pyrane-4-carboxylic acid methylester (87 mg, yield: 35%). The physicochemical properties of this compound are described in Table 7, Compound No. 33.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][O:12][C:11]2[CH:15]=[C:16]([S:19]([N:22](CC3C=CC(OC)=CC=3)[C:23]3[S:24][CH:25]=[CH:26][N:27]=3)(=[O:21])=[O:20])[CH:17]=[CH:18][C:10]1=2)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][O:12][C:11]2[CH:15]=[C:16]([S:19]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)(=[O:21])=[O:20])[CH:17]=[CH:18][C:10]1=2)[CH3:2]
Reactant: CCc1ccccc1N1CCOc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
To a solution of 4-(2-ethylphenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (400 mg, 0.77 mmol) in DCM (50 mL) was added TFA (2.0 mL) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h. After completion, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude product which was purified by prep HPLC purification to obtain 4-(2-ethylphenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (176 mg, 56.9%) as a white solid. MS (ESI, positive ion) m/z; 402.3 (M+1). 1H NMR (400 MHz, DMSO) δ 12.51 (s, 1H), 7.42-7.38 (m, 1H), 7.33 (dt, J=4.4, 2.0 Hz, 2H), 7.29-7.24 (m, 1H), 7.21 (d, J=4.6 Hz, 1H), 7.12 (d, J=2.0 Hz, 1H), 7.08 (dd, J=8.5, 2.0 Hz, 1H), 6.77 (d, J=4.4 Hz, 1H), 6.00 (d, J=8.5 Hz, 1H), 4.34 (dd, J=10.2, 3.1 Hz, 2H), 3.74 (dt, J=7.3, 3.8 Hz, 1H), 3.51 (d, J=12.5 Hz, 1H), 2.47-2.44 (m, 2H), 1.11 (t, J=7.5 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:9](=[O:12])[CH2:10][Cl:11])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C1COCC1.O>[C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C@@H:9]([OH:12])[CH2:10][Cl:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)CCl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)CCl
Temperature: 0 °C
Yield: 55.6 %

Procedure:
To a stirred solution of (R)-1-Benzyl-3-chloro-2-oxopropylcarbamic acid tert-butyl ester (8.0 g, 27 mmol) in THF/water (200 mL, 9/1, v/v) at 0° C. is added NaBH4 (1.23 g, 32 mmol). After 30 min the mixture is concentrated under reduced pressure and the residue is suspended in a mixture of water and ethyl acetate (1:1, v/v). This mixture is cooled to 0° C. and the pH is adjusted to ˜2 by the slow addition of 2M NaHSO4. The phases are separated and the organic layer is washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure to afford a white solid as a mixture of diastereomers (7.92 g, 27 mmol, ˜5:2 R,R:R,S), which is purified using General Purification Procedure C to afford the title compound as a white solid (4.45 g, 15 mmol).