Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](/[C:10](/[C:20]3[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=3)=[C:11](/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)\[CH2:12][CH3:13])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[H][H]>[Pd].CCO.CCOC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6](/[C:10](/[C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:24][CH:25]=3)=[C:11](/[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)\[CH2:12][CH3:13])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccccc2)c2ccc3[nH]ncc3c2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC/C(=C(/c1ccc(CCC(=O)O)cc1)c1ccc2[nH]ncc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 48 %

Procedure:
A 10-mL recovery flask equipped with a magnetic stir bar and a rubber septum was charged with Compound 1 (50 mg, 0.126 mmol) and EtOH-EtOAc (1:1, 2.5 mL). To this solution, palladium on carbon (13 mg, 10% Pd/C) was added in one portion. The flask was equipped with a hydrogen balloon, and the resulting mixture was stirred at room temperature 36 h. This mixture was filtered through Celite, concentrated, and purified on a RP-C18 column using 30-100% acetonitrile in water in the presence of 0.1% TFA to afford the title compound (24 mg). 1H NMR (300 MHz, Acetone-d6): 6; 7.94 (s, 1H), 7.58 (br, 1H), 7.44 (d, 1H), 7.17-6.97 (m, 6H), 6.8-6.73 (m, 4H), 2.64 (t, 2H), 2.39-2.32 (m, 4H), 0.80 (t, 3H), (NH and CO2H protons not observed). LCMS: 397 (M+H)+.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH:3]([O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([CH:23]=O)[CH:17]=[CH:16]3)[CH2:2]1.[NH2:25][CH2:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].C(O)C.C([BH3-])#N.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[F:31][C:27]([F:32])([CH2:26][NH:25][CH2:23][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([O:12][CH:3]3[CH2:2][CH2:1][C:6]4([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]4)[CH2:5][CH2:4]3)[CH:14]=2)[CH:19]=1)[C:28]([OH:30])=[O:29]
Reactant: O=Cc1ccc2cc(OC3CCC4(CCCCC4)CC3)ccc2c1
Reactant: NCC(F)(F)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C(F)(F)CNCc1ccc2cc(OC3CCC4(CCCCC4)CC3)ccc2c1
Temperature: 25 °C
Yield: 41.4 %

Procedure:
A solution of 6-(spiro[5.5]undec-3-yloxy)-naphthalene-2-carbaldehyde (150 mg, 0.46 mmol) and 3-amino-2,2-difluoro-propionic acid (58.2 mg, 0.465 mmol) in ethanol (0.7 mL, 10 mmol) was heated to reflux for 2 h. The yellow solution was then cooled to room temperature and sodium cyanoborohydride (35.1 mg, 0.558 mmol) was added portionwise. The resulting mixture was heated to reflux for 1 h. The reaction was then cooled to room temperature, and citric acid was added. The solution was stirred for several minutes and the solvent removed under vacuum. The resulting solid was suspended in water and filtered, and the collected solid was washed thoroughly with water (4×), ether (5×), and hexane (5×) to give (82.1 mg, 41%) of 2,2-difluoro-3-((6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)methylamino)propanoic acid. 1H NMR (400 MHz, CDCl3) δ: 7.93 (s, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.83 (d, J=9.1 Hz, 1H), 7.52 (dd, J=8.4, 1.8 Hz, 1H), 7.30 (d, J=2.2 Hz, 1H), 7.22 (dd, J=9.0, 2.4 Hz, 1H), 4.52 (m, 1H), 4.45 (s, 2H), 3.60 (t, J=15.9 Hz, 2H), 1.76-1.35 (m, 18H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:21][Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[CH:16]=3)[NH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32]C(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.IC.N1C2C(=CC=CC=2)C=C1>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:21][Si:22]([CH:23]([CH3:24])[CH3:25])([CH:26]([CH3:28])[CH3:27])[CH:29]([CH3:31])[CH3:30])[CH:16]=3)[N:11]([CH3:32])[C:10]=2[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CC(C)[Si](Oc1ccc2[nH]c3c(c2c1)CCN(C(=O)OC(C)(C)C)C3)(C(C)C)C(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: c1ccc2[nH]ccc2c1
Solvent: CI
Solvent: CCOCC
Product: CC(C)[Si](Oc1ccc2c(c1)c1c(n2C)CN(C(=O)OC(C)(C)C)CC1)(C(C)C)C(C)C
Reaction time: 0.17 h
Yield: 41.9 %

Procedure:
A solution of 6-triisopropylsilanyloxy-1,3,4,9-tetrahydro-β-carboline-2-carboxylic acid tert-butyl ester (175 mg, 0.39 mmol) in 3 mL of ethyl ether was added to a vigorously stirring solution of potassium tert-butoxide (263 mg) and 18-crown-6 (16 mg) in 10 mL ethyl ether. After 10 min, iodomethane (73 uL) in 0.5 mL of ethyl ether was added to the indole solution and the resulting mixture was stirred for 2 h. The solids were removed by filtration and the solvent was evaporated. Silica gel chromatography (10% ethyl acetate in hexanes) gave 9-methyl-6-triisopropylsilanyloxy-1,3,4,9-tetrahydro-β-carboline-2-carboxylic acid tert-butyl ester (75 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.[Cu][C:12]#[N:13].[C-]#N.[K+]>CN(C=O)C>[C:12]([C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1)#[N:13]
Reactant: COC(=O)c1cc(Br)cs1
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C#N)cs1
Reaction time: 18 h
Yield: 57.7 %

Procedure:
To a solution of 3.82 g (17.3 mmol) methyl 4-bromothiophene-2-carboxylate (as prepared in the previous step) in 10 mL of anhyd DMF was added 3.10 g (34.6 mmol) of copper (I) cyanide. The mixture was heated to reflux with stirring for 18 h, cooled and poured into 100 mL of 10% (w/v) KCN. The mixture was extracted with EtOAc (3×60 mL) and the combined extracts were washed with 150 mL each of water and brine. The dark solution was dried over Na2SO4, treated with decolorizing carbon, filtered and the resulting colorless solution concentrated in vacuo. The resulting light yellow solid was recrystallized from MeOH to afford the title compound as a cream-colored solid (1.67 g, 58%). 1H-NMR (300 MHz, CDCl3) δ8.09 (d, 1H, J=1.4 Hz), 7.93 (d, 1H, J=1.4 Hz), and 3.93 (s, 3H). IR (film): 2235 and 1712 cm−1.
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][N:16]=1)[C:11]([OH:13])=[O:12].CO>C(Cl)Cl.CN(C=O)C>[CH3:1][O:12][C:11](=[O:13])[C:10]1[C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][N:16]=[C:8]([Cl:7])[CH:9]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(Cl)ncc1C(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Oxalyl chloride (0.5 ml) was added to a solution of 2-chloro-5-(trifluoromethyl)isonicotinic acid (CAS Reg. No. 505084-58-2, 68 mg) in DCM (5 ml). DMF (1 drop) was added and the resulting mixture was stirred overnight at room temperature. Methanol (5 ml) was added and the mixture was concentrated to dryness. The crude product was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][NH:8][C:7]2=O.O=P(Cl)(Cl)[Cl:15].CN(C)C1C=CC=CC=1.CCCCCC>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][N:8]=[C:7]2[Cl:15]
Reactant: Cc1cccc2c(=O)[nH]cnc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)c1ccccc1
Solvent: CCCCCC
Product: Cc1cccc2c(Cl)ncnc12

Procedure:
4 g of 8-methyl 4-quinazolinone, 5 ml POCl3 and 5 ml dimethyl aniline in 40 ml toluene were refluxed 3.5 hours. Workup and trituration with hexane gave 2.6 g of 8-methyl 4 chloro quinazoline, mp—122° C. NMR CDCl3 δ 9.07(1H, S), 8.12(1H, d, J=7.7 Hz), 7.8(1H, d, J=6.0 Hz), 7.60(1H, t), 2.78(3H, S).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])[CH3:4].Br[CH2:24][CH2:25][CH2:26][CH3:27]>CN(C=O)C>[CH2:3]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:24][CH2:25][CH2:26][CH3:27])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])[CH3:4]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ncccc23)CC1
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1cc(C2CCN(C(=O)OCC)CC2)c2cccnc21
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, over a suspension of 0.55 g (13.72 mmol) of sodium hydride 60% in paraffin oil in 10 ml of DMF, a solution of 2.5 g (9.1 mmol) of 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid ethyl ester in 10 ml of DMF was added. After 30 minutes, a solution of 1.2 ml of 4-bromobutane in 2 ml of DMF was added. The crude mixture was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure and the crude was partionated between ethyl acetate and water. The organic phase was dried over sodium sulphate, filtered and the solvent was removed under reduced pressure affording 3.1 g of 4-(1-butyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-piperidine-1-carboxylic acid ethyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([OH:33])[C:5]2[CH2:16][S:15][CH2:14][C@@H:13]([C:17]([O:19]C)=O)[NH:12][C:11](=[O:21])[C@@H:10]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:9][O:8][C:7](=[O:30])[C:6]=2[C:31]=1[CH3:32].CO.[NH3:36]>>[C:17]([C@H:13]1[NH:12][C:11](=[O:21])[C@@H:10]([NH:22][C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:9][O:8][C:7](=[O:30])[C:6]2[C:31]([CH3:32])=[C:2]([OH:1])[CH:3]=[C:4]([OH:33])[C:5]=2[CH2:16][S:15][CH2:14]1)(=[O:19])[NH2:36]
Reactant: N
Reactant: COC(=O)[C@@H]1CSCc2c(O)cc(O)c(C)c2C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Solvent: CO
Product: Cc1c(O)cc(O)c2c1C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(N)=O)CSC2
Reaction time: 7 h

Procedure:
A solution of 291 mg of the product of Example 2 was dissolved in 6 ml of saturated methanolic ammonia which had been prepared by the introduction of dry ammonia into methanol at 10° C. The solution was kept at 20° C. for 7 hours, and then evaporated in vacuo. The residue was crystallized from ethyl acetate to yield 243 mg of tert-butyl (4R, 7S)-4-carbamoyl-1,3,4,5,6,7,8,10-octahydro-12,14-dihydroxy-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-7-carbamate as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]([C:19]1[C:28]([C:29]([O:31][CH3:32])=[O:30])=[C:27]2[C:22]([CH:23]3[CH2:33][CH:24]3[CH2:25][O:26]2)=[CH:21][CH:20]=1)[S:6]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[N+:16]([O-])=O)(=[O:8])=[O:7])=[O:4].C(O)(=O)C>C(O)C.[Zn]>[CH3:1][O:2][C:3]([N:5]([C:19]1[C:28]([C:29]([O:31][CH3:32])=[O:30])=[C:27]2[C:22]([CH:23]3[CH2:33][CH:24]3[CH2:25][O:26]2)=[CH:21][CH:20]=1)[S:6]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[NH2:16])(=[O:7])=[O:8])=[O:4]
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2[N+](=O)[O-])ccc2c1OCC1CC21
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2N)ccc2c1OCC1CC21
Yield: 80 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-[N-(methoxycarbonyl)-N-(4-fluoro-2-nitrobenzene-sulfonyl)amino]-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylate (Intermediate 111, 0.2 g), zinc (0.54 g) and acetic acid (0.5 g) in ethanol (20 mL) was stirred and heated at reflux for 1 hour. After cooling, the solid was filtered off and the filtrate was evaporated to dryness. The residue was treated with saturated aqueous sodium bicarbonate and extracted with ethyl acetate, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and petroleum ether with a gradient of 30-50% to give methyl (1aRS,7bSR)-5-[N-(methoxycarbonyl)-N-(2-amino-4-fluorobenzenesulfonyl)amino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.15 g) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH:15](C2C=CC=CC=2OC)[OH:16])=[CH:13][CH:12]=[CH:11][C:10]=1C1C=CC=CC=1)C1C=CC=CC=1.C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.O=[Mn]=O>[CH3:1][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=1[CH:15]=[O:16]
Reactant: COc1ccccc1C(O)c1cccc(-c2ccccc2)c1OCc1ccccc1
Agent: O=[Mn]=O
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Product: COc1ccccc1C=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of crude 21 (12.2 g, ˜25 mmol, 1.0 equiv), 4-methylmorpholine N-oxide (3.5 g, 30 mmol, 1.2 equiv) in DCM (150 mL) was cooled to ˜7° C. and tetrapropylammonium perruthenate (TPAP) (0.2 g, 0.5 mmol, 2 mole %) was added. The mixture was allowed to warm to room temperature and stirred. After 1 hr TLC showed the reaction was incomplete. Additional TPAP (0.2 g) was added and the mixture stirred overnight at room temperature. Although unoxidized 21 remained, the mixture was filtered through Celite, washing the Celite pad with DCM. The filtrate was concentrated under reduced pressure to give a brown oil. The crude product was absorbed onto silica gel using DCM and dry-loaded on a column of silica gel (125 g) packed in heptanes. The column was eluted with heptanes (750 mL), 5% EtOAc/heptanes (1000 mL), 10% EtOAc/heptanes (1000 mL) and 15% EtOAc/heptanes (1000 mL). Clean separation of 22 from 21 was not achieved. All fractions containing 22 and 21 were concentrated under reduced pressure to give a pale yellow oil. The mixture was dissolved in DCM (300 mL) and MnO2 (10.9 g, 125 mmol) was added. The mixture stirred overnight at room temperature, then refluxed the following day for 6 hr. The mixture was filtered through Celite, washing the Celite pad with DCM (300 mL). The filtrate was concentrated under reduced pressure to give a pale yellow oil. The crude product was absorbed onto silica gel using DCM and dry-loaded on a column of silica gel (125 g) packed in heptanes. The column was eluted with heptanes (500 mL) and 5% EtOAc/heptanes (3000 mL). Product fractions were concentrated under reduced pressure and the residue dried under high vacuum for 2 hr to give 7.5 g (77% for 2 steps from 1) of 22 as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14](=[O:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C:14](=[O:24])[CH2:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CCCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(=O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-butan-1-one and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:31]2[CH:42]=[CH:41][C:34]([O:35][CH:36]([CH3:40])[C:37]([NH2:39])=O)=[CH:33][CH:32]=2)[C:4](=[O:30])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][C:27](=[O:29])[O:26][N:25]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(OCC)(=O)C>C(#N)C.O>[CH3:1][C:2]1[N:3]([C:31]2[CH:32]=[CH:33][C:34]([O:35][CH:36]([CH3:40])[C:37]#[N:39])=[CH:41][CH:42]=2)[C:4](=[O:30])[C:5]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][C:27](=[O:29])[O:26][N:25]=3)=[CH:16][CH:17]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)C(N)=O)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Solvent: CCOC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC(C)C#N)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 12 h
Yield: 63.4 %

Procedure:
To a solution of 2-{4-[2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-propylpyrimidin-1(6H)-yl]phenoxy}propanamide (0.57 g) and triethylamine (0.42 mL) in acetonitrile (5 mL) was added trifluoroacetic anhydride (0.28 mL), and the mixture was stirred for 12 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.35 g, 64%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:57]([O:59][CH:60]([CH3:62])[CH3:61])=[O:58]>ClCCl>[Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([NH:39][C:57](=[O:58])[O:59][CH:60]([CH3:62])[CH3:61])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](N)CC4)cc3)nc2n1COCC[Si](C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N[C@H]1CC[C@H](c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O[Si](C)(C)C(C)(C)C)n4COCC[Si](C)(C)C)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(trans)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-Butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanamine (10 mg) and triethylamine (6 μL) are dissolved in dichloromethane (1 mL), treated with isopropyl chloroformate (28 μL, 1 M solution in toluene) and stirred for 12 hours at room temperature. The mixture is partitioned between ethylacetate and saturated aqueous NH4Cl solution. The organic phase is washed with brine, dried (MgSO4) and concentrated to give the title compound, which is used directly in the next step. LC (method 5): tR=1.27 min.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[Br:6][C:7]([Br:12])([Br:11])[C:8](O)=[O:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:8](=[O:9])[C:7]([Br:12])([Br:11])[Br:6])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)C(Br)(Br)Br
Reactant: CCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCOC(=O)C(Br)(Br)Br

Procedure:
n-Butanol (7.4 g) and tribromoacetic acid (29.6 g) were dissolved in toluene (100 ml). p-Toluenesulfonic acid (0.7 g) was added, and the solution was heated under reflux in a Dean and Stark apparatus. After 90 minutes water (2 ml) had been collected. The solvent was spun off on a rotary evaporator and the residue was distilled under water pump vacuum, collecting the fraction boiling between 120°-130° C. The fraction was redistilled yielding a colorless oil b.p. 128° C./15-18 mm (31 g).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[C:4]([C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:3]=1[CH3:27].C(=O)=O.CC#N.[B]1OC2C(=CC=CC=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.CCOC(C)=O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][S:13]([C:16]([F:18])([F:17])[F:19])(=[O:14])=[O:15])=[C:4]([C@H:20]([OH:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:3]=1[CH3:27]
Reactant: CCOC(=O)C(=O)c1c(C)c(F)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)[C@@H](O)c1c(C)c(F)c2ccccc2c1OS(=O)(=O)C(F)(F)F
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
A solution of ethyl 2-(4-fluoro-3-methyl-1-(trifluoromethylsulfonyloxy)naphthalen-2-yl)-2-oxoacetate (1.08 g, 2.64 mmol) in PhMe (20 mL) was cooled to −40° C. (dry ice/CH3CN bath). (R) —CBS catalyst (146 mg, 0.528 mmol) was introduced. Distilled catecholborane (423 μL) was added dropwise over a 5 min period. After 30 min, the reaction was warmed to −20° C. and treated with EtOAc (20 mL). Then 15% Na2CO3 (10 mL) was added. The reaction was warmed to 23° C. and stirred vigorously. The organic phase was collected after 30 min. It was washed (vigorous stirring) with 10 mL portions of 15% Na2CO3 for 30 min each until the layer was colorless. (Early washes tended to be dark greenish-brown). After six such washings, the organic phase was treated with saturated NH4Cl (20 mL) for 30 min. The organic phase was dried (MgSO4), filtered, and concentrated. The residue was treated with hexanes and concentrated again. The material was dissolved in benzene. The solution was wet-loaded onto a 40 g “gold” ISCO silica gel column and purified by flash chromatography (hexane→ethyl acetate) giving the desired product (1.02 g, 94% yield). 1H NMR (400 MHz, CDCl3) δ 8.11-8.06 (m, 2H), 7.67-7.64 (m, 2H), 5.79 (s, 1H), 4.33-4.22 (m, 2H), 2.40 (d, JHF=3.2 Hz, 3H), 1.22 (t, J=7.4 Hz, 3H). 19F NMR (377 MHz, CDCl3) δ−122.6 (app. s, 1F), −73.1 (s, 3F).
Reaction SMILES: C(N)C1C=CC=CC=1.[NH2:9][CH2:10][CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[S:29][C:30]([C:34](O)=[O:35])=[C:31]([CH3:33])[N:32]=3)[C:24]2=[O:37])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[S:29][C:30]([C:34]([NH:9][CH2:10][CH2:11][N:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)=[O:35])=[C:31]([CH3:33])[N:32]=3)[C:24]2=[O:37])=[CH:20][CH:19]=1
Reactant: NCCN1CCCC1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Solvent: NCc1ccccc1
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCCN1CCCC1
Yield: 17 %

Procedure:
Following the procedure as describe in Example 8, making variations as required to replace benzylamine with 1-(2-aminoethyl)pyrrolidine to react with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white powder in 17% yield: mp 183-184° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.27-7.22 (m, 2H), 7.04-6.97 (m, 2H), 6.33 (br s, 1H), 4.43 (s, 2H), 4.07-4.01 (m, 2H), 3.47-3.32 (m, 4H), 2.64-2.50 (m, 9H), 1.85-1.70 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 162.6, 162.5 (d, JC-F=245.2 Hz), 157.3, 155.4, 152.0, 131.4 (d, JC-F=3.0 Hz), 130.0 (d, JC-F=8.2 Hz), 118.3, 115.8 (d, JC-F=21.0 Hz), 54.3, 53.8, 47.2, 42.0, 41.6, 38.4, 23.5, 17.1; MS (ES+) m/z 432.4 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=[C:7](Cl)[N:6]=1)=[O:4].[Br:16][C:17]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:18]=1[CH:19]=[O:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=[C:7]([O:25][C:22]2[CH:23]=[CH:24][C:17]([Br:16])=[C:18]([CH:19]=[O:20])[CH:21]=2)[N:6]=1)=[O:4]
Reactant: O=Cc1cc(O)ccc1Br
Reactant: COC(=O)c1ccc(Cl)nc1C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2ccc(Br)c(C=O)c2)nc1C(=O)OC
Temperature: 80 °C
Yield: 16.6 %

Procedure:
To a solution of 6-chloro-pyridine-2,3-dicarboxylic acid dimethyl ester (18, 4.0 g, 17.42 mmols) and 2-bromo-5-hydroxy-benzaldehyde (3.5 g, 17.42 mmol) in DMF (30 mL) was added cesium carbonate (11.35 g, 34.84 mmols). The resulting mixture was heated at 80° C. overnight. DMF was removed under reduced pressure, diluted with EtOAc (100 mL), washed with water (2×25 mL) and brine (50 mL) solution. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give crude product which was purified by column chromatography (Silica gel 20% EtOAc in hexane) to yield title compound 19 (1.14 g, 15%) as a light yellow oil. 1H NMR 400 MHz (DMSO-d6) δ: 10.18 (s, 1H), 8.38 (d, J=8.6 Hz, 1H), 7.90 (d, J=8.5 Hz, 1H), 7.66 (s, 1H), 7.55-7.52 (m, 1H), 7.36 (d, J=8.6 Hz, 1H), 3.86 (s, 3H), 3.84 (s, 3H); MS (ES) m/z: 394 (M+1)+, 396 (M+3)+.