Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)N[C@H:8]([C:13](=O)[NH:14][CH:15]1[CH2:21][CH2:20][CH2:19]NC[CH:16]1[OH:22])[CH2:9][CH:10]([CH3:12])C)(C)(C)C.S(Cl)(Cl)(=O)=[O:26]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[N:14]1[C:13]2[C:19](=[CH:12][CH:10]=[CH:9][CH:8]=2)[CH:20]=[CH:21][C:15]=1[C:16]([OH:22])=[O:26]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1CCCNCC1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)c1ccc2ccccc2n1

Procedure:
To a solution of [(S)-1-(3-hydroxy-azepan-4-ylcarbamoyl)-3-methyl-butyl]-carbamic acid tert butyl ester of Example 1g (2.5 g, 7.28 mmol) in CH2Cl2 (100 mL) and sat. NaHCO3 (400 mL) was added the solution of 2-pyridinesulfonyl chloride-N-oxide (27 mL, 102 mg/mL) dropwise in portions. As the addition proceeds additional sat. NaHCO3 is added in order to maintain the pH at approximately 8-9. Upon complete addition of the sulfonylchloride the reaction is stirred for an additional hour whereupon the organic layer was removed and washed with brine. The organic layer was evaporated and the residue chromatographed (5% methanol:dichloromethane) to provide 2.5 g of the title compound: MS (El) 500 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[S:23]1[CH:27]=[CH:26][N:25]=[CH:24]1.CC([O-])=O.[K+]>CC([O-])=O.CC([O-])=O.[Pd+2]>[F:22][C:21]1[CH:20]=[CH:19][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[C:27]1[S:23][CH:24]=[N:25][CH:26]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(F)c(Br)c1
Reactant: c1cscn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(F)c(-c2cncs2)c1
Temperature: 130 °C
Reaction time: 20 h

Procedure:
A mixture of 3-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.2, 100 mg, 0.264 mmol), thiazole (113 mg, 1.322 mmol), KOAc (130 mg, 1.322 mmol) and Pd(OAc)2 (0.297 mg, 1.322 μmol) were added to a vial, which was sealed and evacuated/purged with argon. DMA (0.81 mL) was added and the mixture was stirred at 130° C. for 20 h. The RM was diluted with THF (3 mL), treated with Si-Thiol (Silicycle, 1.44 mmol/g, 9.18 mg, 0.013 mmol) and filtered off. The filtrate was poured onto 1 M HCl (40 mL) and extracted 3 times with TBME. The combined extracts were washed 3 times with 1M HCl, sat. NaHCO3 and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a crude product which was purified by flash chromatography (RediSep® Silica gel column, 4 g, cyclohexane/EtOAc from 10% to 40% EtOAc) to yield the title compound as an off-white solid. UPLC-MS (Condition 1) tR=2.80 min, m/z=383.0 [M+H]+, m/z=381.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.40 (m, J=8.31 Hz, 2H) 7.58 (dd, J=10.76, 8.80 Hz, 1H) 7.83-7.97 (m, 2H) 8.02 (ddd, J=8.62, 4.95, 2.32 Hz, 1H) 8.40 (dd, J=7.21, 2.32 Hz, 1H) 8.49 (s, 1H) 9.28 (s, 1H) 10.54 (s, 1H).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[Br:15][C:16]1[CH:21]=[C:20]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[O:23])[CH:19]=[CH:18][C:17]=1[NH:31][C:32]([CH2:34][C:35](O)=[O:36])=[O:33]>[Cl-].[Na+]>[Br:15][C:16]1[CH:21]=[C:20]([C:22]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)=[O:23])[CH:19]=[C:18]2[C:17]=1[NH:31][C:32](=[O:33])[CH:34]=[C:35]2[OH:36]
Reactant: O=C(O)CC(=O)Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1Br
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Cl-]
Agent: [Na+]
Product: O=C(c1ccc(Cl)cc1)c1cc(Br)c2[nH]c(=O)cc(O)c2c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Into a 250-mL 3-necked round-bottom flask, was placed P2O5 (8.95 g, 63.03 mmol, 1.00 equip), and MSA (80.55 g). The resulting solution was stirred for 1 h at 80° C. and then the temperature was raised to 99° C. To the resulting mixture was then added 2-([2-bromo-4-[(4-chlorophenyl)carbonyl]phenyl]carbamoyl) acetic acid (25 g, 63.03 mmol, 1.00 equip) in several batches. The resulting solution was stirred for 3 h at 99° C. The resulting solution was cooled to room temperature and added dropwise into saturated sodium chloride (500 mL). The solids were collected by filtration and then dissolved in ethyl acetate (200 mL). And the un-dissolved solids were collected by filtration to yield 8-bromo-6-[(4-chlorophenyl)carbonyl]-4-hydroxy-1,2-dihydroquinolin-2-one as a yellow solid. The filtrate was concentrated under vacuum and was applied onto a silica gel column with ethyl acetate first and then dichloromethane/methanol (8:2) to yield additional 8-bromo-6-[(4-chlorophenyl)carbonyl]-4-hydroxy-1,2-dihydroquinolin-2-one as a yellow solid. LCMS (ES, m/z) 378 [M+H]+
Reaction SMILES: [Br:1]Br.[C:3]([CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:7])#[N:4].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[C:3]([CH2:5][CH:6]([C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][C:13]=1[Br:1])[CH3:7])#[N:4]
Reactant: BrBr
Reactant: COc1ccc(C(C)CC#N)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C(C)CC#N)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Bromine (17.9 ml) is added dropwise over a period of 1.5 hours to a solution of 1-cyano-2-(p-methoxyphenyl)-n-propane (61.2 g) and sodium acetate (34.4 g) in glacial acetic acid (350 ml), and the solution is stirred for 30 min. at RT. The reaction mixture is poured into H2O, extracted with diethyl ether, and the etheral extract is washed with H2O, sat'd NaHCO3, 10% NaOH, sat'd NaCl, dried, filtered, and the filtrate evaporated in vacuo. The residue is distilled affording the product as a cloudy oil, B.P.=162° C. (2 mm).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@@H:13]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[C:23]2=[O:38])[O:11][CH:10]1[C@H:39]([OH:68])[C@@H:40]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[NH:41][CH2:42][CH2:43][CH2:44][NH:45][C:46](=[O:60])[C@H:47]([CH3:59])[NH:48]C(=O)OCC1C=CC=CC=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[Pd]>[NH2:48][C@@H:47]([CH3:59])[C:46]([NH:45][CH2:44][CH2:43][CH2:42][NH:41][C@@H:40]([C@H:39]([CH:10]1[C@@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[C@@H:13]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:16])[CH3:17])[C@H:12]([N:22]2[CH:27]=[CH:26][C:25](=[O:28])[N:24]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)[C:23]2=[O:38])[O:11]1)[OH:68])[C:61]([O:63][C:64]([CH3:66])([CH3:67])[CH3:65])=[O:62])=[O:60]
Reactant: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@H](C)NC(=O)OCc4ccccc4)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(Cn2c(=O)ccn([C@@H]3OC([C@H](O)[C@H](NCCCNC(=O)[C@H](C)N)C(=O)OC(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]3O[Si](C)(C)C(C)(C)C)c2=O)cc1
Yield: 93.6 %

Procedure:
By using an analogous procedure to that described in Example 2, tert-butyl (5S,12S)-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl](hydroxy)methyl]-5-methyl-3,6-dioxo-1-phenyl-2-oxa-4,7,11-triazatridecan-13-oate (43 mg, 0.044 mmol, obtained from Example 14) was hydrogenated in methanol (1.5 ml) using 10% palladium on carbon (10 mg) to provide tert-butyl (2S,3R)-2-[(3-{[(2S)-2-aminopropanoyl]amino}propyl)amino]-3-[(3R,4R,5R)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-(3-(4-methoxybenzyl)-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)tetrahydro-2-furanyl]-3-hydroxypropanoate (35 mg, 94%) as a white amorphous solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2.[C:28](OC(=O)C)(=[O:30])[CH3:29].N1C=CC=CC=1>ClCCl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[CH:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]3[O:20][C:19]([C:21]4[CH:22]=[CH:23][C:24]([NH:27][C:28](=[O:30])[CH3:29])=[CH:25][CH:26]=4)=[N:18][C:17]=13)=[O:11])[CH2:2]2
Reactant: Nc1ccc(-c2nc3c(C(=O)NC4CN5CCC4CC5)cccc3o2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(-c2nc3c(C(=O)NC4CN5CCC4CC5)cccc3o2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.3 %

Procedure:
To a solution of N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-aminophenyl)benzoxazole-4-carboxamide (22 mg, 0.06 mmol) in dichloromethane was added acetic anhydride (10 μL, 0.12 mmol), pyridine (15 μL, 0.18 mmol) and DMAP (1.5 mg, 0.01 mmol). The reaction mixture was stirred at room temperature for 3 h. Acetic anhydride (2 equiv) and pyridine (3 equiv) were re-filled and the reaction was stirred at room temperature for an additional 1.5 h. The mixture was diluted with ethyl acetate (20 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) and then recrystallized from acetonitrile to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-acetylaminophenyl)benzoxazole-4-carboxamide (11 mg, 44%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.59-9.58 (m, 1H), 8.17-8.16 (m, 3H), 7.77-7.69 (m, 4H), 7.46-7.43 (m, 1H), 7.39 (t, J=8.0 Hz, 1H), 4.40-4.33 (m, 1H), 2.26 (s, 3H), 3.58-3.53 (m, 1H), 3.19-2.88 (m, 3H), 2.13-1.70 (m, 6H); MS (ESI+) m/z 405 (M+H); HPLC 97.3% (AUC), tR=13.85 min.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])=[CH2:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[N+:19](=[CH:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23])=[N-:20]>CCOCC>[CH2:16]([O:15][P:11]([C:9]1([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH2:10][C:21]([C:22](=[O:23])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:19][NH:20]1)(=[O:18])[O:12][CH2:13][CH3:14])[CH3:17]
Reactant: [N-]=[N+]=CC(=O)c1ccccc1
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Solvent: CCOCC
Product: CCOP(=O)(OCC)C1(P(=O)(OCC)OCC)CC(C(=O)c2ccccc2)=NN1
Reaction time: 20 h

Procedure:
Ethenylidene bisphosphonic acid tetraethyl ester (II, PREPARATION 1, 6.00 g) in ether (20 ml) is treated with solid 2-diazo-1-phenylethanone (2.92 g) and stirred at 22° for 20 hrs. The precipitate is collected and washed with ether to give the title compound. An analytical sample is obtained by recrystallization from methylene chloride/hexane, mp 133.5°-134°; MS (m/e) 446, 327, 309, 281, 271, 253, 243, 215, 175; IR (mineral oil mull) 3183, 1631, 1600, 1578, 1548, 1433, 1260, 1242, 1161, 1067, 1043, 1020, 1001, 995, 976 and 962 cm-1 ; NMR (CDCl3) 8.10, 7.50, 6.90, 4.27, 3.69 and 1.34 δ.
Reaction SMILES: C([O:3][CH:4]1[CH:8]([NH:9][C:10]([C@H:12]2[N:23]3[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH:25][C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:22]3=[O:24])[CH2:15][N:14]([C:34](=[O:36])[CH3:35])[CH2:13]2)=[O:11])[CH2:7][C:6](=[O:37])[O:5]1)C.FC(F)(F)C(O)=O>C(#N)C.O>[OH:3][CH:4]1[CH:8]([NH:9][C:10]([C@H:12]2[N:23]3[C@@H:16]([CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([NH:25][C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:22]3=[O:24])[CH2:15][N:14]([C:34](=[O:36])[CH3:35])[CH2:13]2)=[O:11])[CH2:7][C:6](=[O:37])[O:5]1
Reactant: CCOC1OC(=O)CC1NC(=O)[C@@H]1CN(C(C)=O)C[C@@H]2CCCC[C@H](NC(=O)c3ccccc3)C(=O)N21
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)N1C[C@@H]2CCCC[C@H](NC(=O)c3ccccc3)C(=O)N2[C@H](C(=O)NC2CC(=O)OC2O)C1
Reaction time: 0.5 h

Procedure:
A solution of (4S,6S,10aS)-2-acetyl-6-benzoylamino-5-oxo-decahydro-2,4a-diaza-benzocyclooctene-4-carboxylic acid (2-ethoxy-5-oxo-tetrahydrofuran-3-yl)amide, 11, (70 mg, 0.14 mmol) in acetonitrile/water is treated with trifluoroacetic acid. After stirring for 30 minutes the solution is concentrated in vacuo and the crude product purified by preparative reverse phase HPLC to afford 36 mg of the desired product as a white solid. 1H NMR (CD3OD) δ 7.90 (d, J=6.9 Hz, 2H), 7.52 (m, 3H), 5.2–4.2 (series of m, 7H), 3.40 (m, 1H), 3.18 (m, 1H), 2.8–1.2 (series of m, 12H), 2.35 (s, 3H); MS 487 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[C:15]([N+:22]([O-])=O)[CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl-].[NH4+]>C(O)(C)C.O.[Fe]>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[C:15]([NH2:22])[CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cccc2ccc(-c3cc(F)cc(C(F)(F)F)c3)nc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: Nc1cccc2ccc(-c3cc(F)cc(C(F)(F)F)c3)nc12
Temperature: 90 °C
Yield: 49.3 %

Procedure:
Crude 2-(3-fluoro-5-(trifluoromethyl)phenyl)-8-nitroquinoline (2.78 mmol) was taken up in isopropyl alcohol (120 mL) and ammonium chloride (150 mg, 2.8 mmol) in water (20 mL) was added. The mixture was heated to 90° C., iron powder (550 mg, 9.85 mmol) was added and the reaction was continued stirring at 90° C. 18 hours. The reaction mixture was filtered over celite and the celite cake was washed with ethyl acetate (150 mL). The filtrate was concentrated and the residue was taken up in 1N aqueous NaOH (80 mL) and extracted with ethyl acetate (3×25 mL). The organic layers were combined, washed with brine, dried (MgSO4), and concentrated. The crude material was purified by flash chromatography (a gradient of 0 to 100% ethyl acetate in pentane) to obtain 2-(3-fluoro-5-(trifluoromethyl)phenyl)quinolin-8-amine (0.42 g, 1.37 mmol, 49% yield over two steps).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7](C(OCC3C4C=CC=CC=4C4C3=CC=CC=4)=O)[CH2:8][C@@H:9]([O:10][CH3:11])[C@H:5]2[O:4][CH2:3]1.[H][H]>[Pd].C(O)C>[CH3:11][O:10][C@@H:9]1[CH2:8][NH:7][C@@H:6]2[C@@H:2]([OH:1])[CH2:3][O:4][C@H:5]12
Reactant: [H][H]
Reactant: CO[C@@H]1CN(C(=O)OCC2c3ccccc3-c3ccccc32)[C@H]2[C@@H]1OC[C@@H]2O
Agent: [Pd]
Solvent: CCO
Product: CO[C@@H]1CN[C@H]2[C@@H]1OC[C@@H]2O
Reaction time: 2.5 h

Procedure:
(3R,3aR,6R,6aS)— (9H-Fluoren-9-yl)methyl 3-hydroxy-6-methoxytetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (5b). Ethanol (30 mL) was added dropwise to a mixture of 10% palladium on charcoal (200 mg) and syn-/anti-epoxides respectively (605 mg, 2.06 mmol) under an atmosphere of argon. The argon was replaced by hydrogen then the suspension was stirred for 2.5 hours then filtered through celite in vacuo. The filter cake was washed with ethanol then the solvents removed in vacuo from the filtrate to obtain the crude (3R,3aR,6R,6aS)-6-methoxyhexahydro-2H-furo[3,2-b]pyrrol-3-ol which was used without further purification.
Reaction SMILES: [Br-].[CH2:2]([PH3+])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CC(C)([O-])C.[K+].[Si:16]([O:23][C@@H:24]1[CH2:32][C@@H:27]2[O:28][C:29](=[O:31])[CH2:30][C@@H:26]2[C@H:25]1[CH:33]=O)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C1COCC1>[Si:16]([O:23][C@@H:24]1[CH2:32][C@@H:27]2[O:28][C:29](=[O:31])[CH2:30][C@@H:26]2[C@H:25]1[CH:33]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])([C:19]([CH3:20])([CH3:22])[CH3:21])([CH3:17])[CH3:18]
Reactant: CCCCCCC[PH3+]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H]2OC(=O)C[C@@H]2[C@H]1C=O
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCCC=C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 91.2 %

Procedure:
n-heptylphosphonium bromide (3.185 g, 7.22 mmol) was dried under vacuum for 3 days and was then taken into dry THF (22 mL). Potassium tert-butoxide (7.2 mL, 7.2 mmol, 1 M/THF) was added and the resulting red-orange solution was stirred for 45 min. at room temperature. A solution of (3aR,4R,5R,6aS)-5-(tert-butyldimethylsilyloxy)-2-oxohexahydro-2H-cyclopenta[b]furan-4-carbaldehyde (5-1, 502 mg, 1.78 mmol, Cayman) in 7 mL THF was added by cannula, rinsing with 3 mL THF. After 1.5 h, the reaction was quenched by addition of saturated NH4Cl solution. The resulting mixture was extracted with ethyl acetate (3×) and the combined ethyl acetate solution was dried (Na2SO4), filtered and evaporated. Purification of the residue by flash chromatography on silica gel (Isco Combiflash unit) gave the title compound (595 mg, 91%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([O:10]C)=[O:9])=[CH:4][CH:3]=1.[OH:12][C:13]([CH3:46])([CH3:45])[CH2:14][C@@:15]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:20][C:19](=[O:21])[N:18]([C@H:22]([C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)[CH3:23])[CH2:17][CH2:16]1.C([O-])(O)=O.[Na+]>COCCOC.CCO.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>[OH:12][C:13]([CH3:45])([CH3:46])[CH2:14][C@@:15]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:20][C:19](=[O:21])[N:18]([C@H:22]([C:24]2[CH:25]=[CH:26][C:27]([C:2]3[N:7]=[N:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=3)=[CH:28][CH:29]=2)[CH3:23])[CH2:17][CH2:16]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: COC(=O)c1ccc(Cl)nn1
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: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: C[C@@H](c1ccc(-c2ccc(C(=O)O)nn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
To a solution of methyl 6-chloropyridazine-3-carboxylate (36 mg, 0.2 mmol) in DME (6 mL) was added Pd(PPh3)4 (20 mg, 0.02 mmol) under N2. The mixture was stirred at room temperature for 1 h. (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-ethyl)-1,3-oxazinan-2-one (96 mg, 0.2 mmol) in EtOH (2 mL) and satd aq NaHCO3 (2 mL) were added. The mixture was stirred at 100° C. for another 2 h under N2. The reaction mixture was quenched by addition of H2O, and extracted by EtOAc. The combined organic phase was dried and concentrated to give the crude product, which was purified by preparative TLC to give 6-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)-ethyl)-phenyl)-pyridazine-3-carboxylic acid (63 mg, 60%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([OH:31])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:32][N:33]([CH3:37])[CH2:34][CH2:35]O.O1C2C=CC(C3(C(NC4C=CC(C(OCC(O)C)C5C=CC=CC=5OC)=CN=4)=O)CC3)=CC=2OC1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH:22]([O:31][CH2:35][CH2:34][N:33]([CH3:37])[CH3:32])[C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[CH:18][N:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN(C)CCO
Reactant: COc1ccccc1C(O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Agent: COc1ccccc1C(OCC(C)O)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1
Product: COc1ccccc1C(OCCN(C)C)c1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)nc1

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((2-(dimethylamino)ethoxy)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide was prepared from 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-(hydroxy(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide and 2-(dimethylamino)ethanol in a manner analogous to that of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((2-hydroxypropoxy)(2-methoxyphenyl)methyl)pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.C(N(C(C)C)CC)(C)C.[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([F:41])[C:38]=1[O:39][CH3:40])[C:33](Cl)=[O:34]>ClCCl>[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([F:41])[C:38]=1[O:39][CH3:40])[C:33]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:34]
Reactant: COc1c(F)cc(C(=O)Cl)cc1F
Reactant: c1ccc2c(c1)NCS2
Agent: C=O
Agent: Nc1ccccc1S
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(F)cc(C(=O)N2CSc3ccccc32)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (316 mg) and 37% formalin (0.21 mL) in the same manner as in Example 1 was dissolved in dichloromethane (3 mL), and diisopropylethylamine (0.56 mL) and 3,5-difluoro-4-methoxybenzoyl chloride (347 mg) were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (c).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=1>>[C:7]([O:6][C:5](=[O:11])[NH:4][CH2:3][CH2:2][O:1][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=1)([CH3:8])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)NCCOc1ccc(C(F)(F)F)cn1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 36.8 %

Procedure:
Tert-Butyl (2-hydroxyethyl)carbamate (8.88 g, 55.08 mmol) was added to a solution of NaH (55%, 55.08 mmol, washed twice with petroleum ether) in DMF (150 ml) at −10° C. and stirred for 10 mins. 2-Chloro-5-(trifluoromethyl)pyridine (10.0 g, 55.08 mmol) was added and the reaction mixture was stirred at rt for 3 days, heated to 100° C. and cooled to rt. The reaction mixture was evaporated, the residue was washed with isopropylether, and the solution was decanted from insoluble salts and concentrated. The residue was dissolved in EtOAc, washed twice with water, dried over MgSO4 and concentrated. Recrystallisation from isobutylethyl ether gave the title compound (6.2 g, 37%). 1H-NMR (500 MHz, CDCl3) δ 1.46 (s, 9H), 3.56 (br.m, 2H), 4.45 (t, 2H), 6.84 (d, 1H), 7.79 (dd, 1H), 8.44 (s, 1H.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[C:21]([F:24])([F:23])[F:22]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:1]2[C:9]3[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=3)[CH:3]=[N:2]2)=[C:15]([C:21]([F:22])([F:23])[F:24])[CH:16]=1
Reactant: Fc1ccc(CBr)c(C(F)(F)F)c1
Reactant: O=Cc1ccc2[nH]ncc2c1
Product: O=Cc1ccc2c(cnn2Cc2ccc(F)cc2C(F)(F)F)c1

Procedure:
1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde was prepared from 1H-Indazole-5-carbaldehyde and 1-Bromomethyl-4-fluoro-2-trifluoromethyl-benzene following General Procedure A.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27](F)[CH:26]=3)[C:10]3[CH2:11][CH2:12][C@@H:13]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:14][C:15]=3[C:16]=2[CH:17]=1)=[O:4].[Li+].[OH-]>>[CH2:24]([N:9]1[C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:17][C:16]=2[C:15]2[CH2:14][CH:13]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH2:12][CH2:11][C:10]1=2)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)c1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CC[C@@H](NC(=O)C(C)C)C1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)C(=O)NC1CCc2c(c3cc(C(=O)O)ccc3n2Cc2ccccc2)C1
Temperature: 70 °C
Reaction time: 24 h
Yield: 100.1 %

Procedure:
Add (R)-9-(3-fluorobenzyl)-6-isobutyrylamino-6,7,8,9-tetrahydro-5H-carbazole-3-carboxylic acid methyl ester (2.54 g, 6.01 mmol) to a solution of excess LiOH in methanol/water/TBF (33:33:33) and stir for 24 h at 70° C. Concentrate in vacuo, partition between water and EtOAc/Et2O. Make the aqueous layer acidic with aqueous HCl and extract with EtOAc. Wash with brine, filter the solids from the EtOAc layer and slurry in hot EtOAc. Collect by filtration and dry to give 2.35 g (96%) of a white solid. MS (ES): m/z 409 (M+1), HPLC: Rt=1.93 (100%).