Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].O[N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12])[C:8]([O:10][N:16]1[C:20](=[O:21])[CH2:19][CH2:18][C:17]1=[O:22])=[O:9]
Reactant: O=C1CCC(=O)N1O
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)ON2C(=O)CCC2=O)cc1Cl
Temperature: 10 °C
Reaction time: 8 h
Yield: 112.3 %

Procedure:
A 3-neck 1 L round-bottom flask equipped with a magnetic stirrer, ice cooling bath, thermometer and an argon inlet tube was set up and charged with 2-chloro-1,4-benzenedicarboxylic acid, 1-methyl ester (Example 1; 21.5 g, 0.1 mol) in tetrahydrofuran (250 mL). The solution was cooled to 10° C. under argon and was treated in succession with N-hydroxysuccinimide (12.66 g, 0.11 mol) and 1,3-dicyclohexylcarbodiimide (21.66 g, 0.105 mol). These reagents were washed in with additional tetrahydrofuran (100 mL). A precipitate started to form immediately. The cooling bath was removed and the reaction mixture was stirred at ambient temperature overnight, and then diluted with diethyl ether (400 mL) and stirred for another 30 min. The precipitate was collected by filtration, and the filter cake was washed with diethyl ether (3×50 mL). The dried solids (DCU) weighed 22.2 g (>99% of theory). The combined filtrates were diluted with hexane (100 mL) then were transferred to a 2 L separatory funnel and were washed in turn with cold saturated sodium bicarbonate solution (150 mL) and brine (150 mL). Each aqueous layer was back-extracted in turn with diethyl ether (200 mL), then the combined organic extracts were dried (MgSO4), and evaporated to give crude 1-[[3-chloro-4-(methoxycarbonyl)benzoyl]oxy]-2,5-pyrrolidinedione (˜35 g) as a colorless solid. This material was used directly in the next step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][CH2:12][Mg+].[Br-]>C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:7]([OH:8])[CH2:11][CH3:12])[CH:9]=1
Reactant: CC[Mg+]
Reactant: O=Cc1cc(Br)ccc1F
Agent: [Br-]
Solvent: CCOCC
Product: CCC(O)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.9 %

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (10 g, 49 mmol) in diethyl ether (20 mL) at 15° C., was added drop wise at 15° C. EtMgBr (7.22 g, 54.2 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with cold water and NH4Cl solution. It was extracted with diethyl ether and the ether layer was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4 and concentrated under vacuum to afford 1-(5-bromo-2-fluorophenyl)propan-1-ol (12.1 g, 98%) as a syrup. 1H NMR (CDCl3): δ 7.6-7.7 (m, 1H), 7.2-7.3 (m, 1H), 6.9 (t, 1H), 4.9 (brs, 1H), 1.8 (m, 2H), 1.0 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[Al].S(=O)(=O)(O)[OH:13].C(=O)([O-])O.[Na+]>O>[F:1][C:2]1[CH:7]=[C:6]([OH:13])[CH:5]=[CH:4][C:3]=1[NH2:8]
Reactant: O=S(=O)(O)O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])O
Agent: [Al]
Agent: [Na+]
Solvent: O
Product: Nc1ccc(O)cc1F
Reaction time: 0.67 h
Yield: 86 %

Procedure:
2.03 Grams of o-fluoronitrobenzene, 0.70 g of aluminum powder, 43 ml of water and 4.4 g of conc. sulfuric acid were added to a reactor and stirred at an inner temperature of from 90° to 95° C. for 40 minutes. After cooling the reaction solution, a 5% aqueous sodium hydrogencarbonate solution was added to make the reaction solution weakly alkaline. The reaction solution was then extracted with three 100-ml portions of diethyl ether. The ether layers were combined, dried and concentrated to obtain a crude product. This crude product was subjected to chromatography on silica gel to obtain 1.58 g of 3-fluoro-4-aminophenol.
Reaction SMILES: F[B-](F)(F)F.C([O+:8]([CH2:11][CH3:12])[CH2:9][CH3:10])C.[Cl:13][C:14]1[CH:22]=C2[C:17]([CH2:18][NH:19]C2=O)=[CH:16][CH:15]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:11]([O:8][C:9]1[C:10]2[C:17](=[CH:16][CH:15]=[C:14]([Cl:13])[CH:22]=2)[CH2:18][N:19]=1)[CH3:12]
Reactant: O=C1NCc2ccc(Cl)cc21
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC1=NCc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
A solution of 151 g of triethyloxonium tetrafluoroborate in 3200 ml of methylene chloride was stirred under argon at room temperature for 3.5 hours after the addition of 106.6 g of 6-chloro-2,3-dihydro-1H-isoindol-1-one. The mixture was then treated within 40 minutes with 1.28 l of saturated sodium hydrogen carbonate solution, the organic phase was separated and washed with 1.28 l of water. After drying over sodium sulphate the organic phase was filtered and evaporated. The residue was taken up in 1.3 l of diethyl ether, whereupon it was stirred at room temperature for about 30 minutes. After removing insoluble material by filtration the filtrate was evaporated. There was obtained 110.5 g of 1-ethoxy-6-chloro-3H-isoindole with a m.p. of 64°-66°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:25][O:26][C:27]1[C:32]2[N:33]=[C:34]([NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[CH3:43])[O:35][C:31]=2[CH:30]=[C:29]([CH2:44][C:45](O)=[O:46])[CH:28]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:25][O:26][C:27]1[C:32]2[N:33]=[C:34]([NH:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[CH3:43])[O:35][C:31]=2[CH:30]=[C:29]([CH2:44][C:45]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C@H:8]([CH3:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=2)=[O:46])[CH:28]=1
Reactant: COc1cc(CC(=O)O)cc2oc(Nc3ccccc3C)nc12
Reactant: CCOC(=O)C[C@@H](C)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](C)c1ccc(NC(=O)Cc2cc(OC)c3nc(Nc4ccccc4C)oc3c2)cc1
Reaction time: 20 h
Yield: 100.8 %

Procedure:
A stirred solution of with ethyl (R) 3-(4-aminophenyl)butanoate (0.107 g, Reference Example 1) in dimethylformamide (10 mL) was treated with diisopropylethylamine (0.4 g), 2-(4-methoxy-2-o-tolylaminobenzoxazol-6-yl)acetic acid [0.105 g, Reference Example 9(a)] and then with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.14 g). The mixture was left to stand for 20 hours and then partitioned between ethyl acetate and hydrochloric acid (1M). The organic phase was washed with water, then with aqueous bicarbonate solution (5%), then with water, then with brine, then dried and then evaporated to give the title compound (0.17 g) as a cream coloured solid.
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:20][C:12]2=[N:13][C:14](O)=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:22].P(Cl)(Cl)(Cl)=O>>[CH2:1]([S:8][C:9]1[S:20][C:12]2=[N:13][C:14]([Cl:22])=[C:15]([CH3:18])[C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(O)nc2sc(SCc3ccccc3)nn2c1=O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(Cl)nc2sc(SCc3ccccc3)nn2c1=O
Reaction time: 1.5 h
Yield: 72 %

Procedure:
A mixture of 18.3 g of the thus obtained 2-benzylthio-7-hydroxy-6-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one, 13.1 g of phosphorus pentachloride and 36.8 g phosphorus oxychloride was stirred at 85°-95° C. for 1.5 hours. Thereafter, the reaction mixture was concentrated under reduced pressure, and the residue was dissolved in toluene. The organic layer was washed with an aqueous potassium carbonate solution and water respectively, and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography using an ethyl acetate/toluene (3:7) mixture as an eluent. Then the solvent was distilled off, and thus 14.0 g of 2-benzylthio-7chloro-6-methyl-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained m.p. 102°-104° C. Yield 72%.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[CH:7][C:6]=2[NH:5][N:4]=1)=[O:2].[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[F:16][C:17]1[CH:22]=[CH:21][C:20]([N:5]2[C:6]3[CH:7]=[CH:8][CH:9]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:11]=3[C:3]([CH:1]=[O:2])=[N:4]2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1cccc2[nH]nc(C=O)c12
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc2c1c(C=O)nn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 9.5 %

Procedure:
A mixture of methyl 3-formyl-1H-indazole-4-carboxylate (B1) (3.3 g, 16.1 mmol), 4-fluorophenylboronic acid (4.5 g, 32.3 mmol) and copper(II) acetate (3.99 g, 21.9 mmol) was degassed under nitrogen (3×). Anhydrous dichloromethane (240 ml) and triethylamine (4.5 ml, 13.5 mmol) were added. The mixture was degassed under nitrogen (2×) and stirred at ambient temperature for 21 h. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 0-30% ethyl acetate in hexanes) to afford methyl 1-(4-fluorophenyl)-3-formyl-1H-indazole-4-carboxylate (454 mg, 9%) as a brown solid. 1H NMR (500 MHz, CDCl3) δ 10.38 (s, 1H), 8.01 (d, J=8.3 Hz, 1H), 7.91-7.88 (m, 2H), 7.80 (d, J=7.1 Hz, 1H), 7.69 (dd, J=8.4, 7.3 Hz, 1H), 7.53 (t, J=8.7 Hz, 2H), 3.93 (s, 3H); MS (ESI+) m/z 299 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8]([CH:11]=O)=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[S:13]([NH2:17])([NH2:16])(=[O:15])=[O:14].[BH4-].[Na+].O>C(O)C>[Br:1][C:2]1[C:7]2[C:8]([CH2:11][NH:16][S:13]([NH2:17])(=[O:15])=[O:14])=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NS(N)(=O)=O
Reactant: O=Cc1csc2cccc(Br)c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)NCc1csc2cccc(Br)c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Bromobenzothiophene (1.80 g, 8.45 mmol) and dichloromethyl methyl ether (1.46 g, 12.7 mmol) were dissolved in anhydrous DCM (100 mL). Titanium tetrachloride (2.40 g, 12.7 mmol) was added, turning the solution dark. After 30 minutes at room temperature, the reaction was poured into a mixture of saturated aqueous NaHCO3 and ice. The mixture was stirred for about 30 minutes and then was extracted with DCM (2×150 mL). The extracts were concentrated and chromatographed (0 to 15% ethyl acetate in hexane) to yield 4-bromobenzothiophene-3-carboxaldehyde (0.910 g). The 4-bromobenzothiophene-3-carboxaldehyde (0.910 g, 3.77 mmol) and sulfamide (3.0 g, 31 mmol) were combined in anhydrous ethanol (25 mL) and heated to reflux for three days. The reaction was cooled to room temperature and sodium borohydride (0.157 g, 4.15 mmol) was added. After five hours, water (50 ml) was added and the solution was extracted with chloroform (3×50 mL). The extracts were concentrated, suspended in a minimal amount of DCM, and filtered to yield the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:23]#[N:24])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10](B3OC(C)(C)C(C)(C)O3)[CH:9]=2)=[CH:6][CH:7]=1.Br[C:26]1[N:30]2[N:31]=[CH:32][C:33]([C:35]([OH:38])([CH3:37])[CH3:36])=[N:34][C:29]2=[N:28][CH:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:23]#[N:24])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:26]3[N:30]4[N:31]=[CH:32][C:33]([C:35]([OH:38])([CH3:36])[CH3:37])=[N:34][C:29]4=[N:28][CH:27]=3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(O)c1cnn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2cccc(-c3ccc(F)cc3C#N)c2)OC1(C)C
Product: CC(C)(O)c1cnn2c(-c3cccc(-c4ccc(F)cc4C#N)c3)cnc2n1

Procedure:
4-Fluoro-3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile was coupled to 2-(7-bromoimidazo[1,2-b][1,2,4]triazin-3-yl)-propan-2-ol in 32% yield using a similar procedure to that described in Example C, step f, to give a yellow solid: mp 175° C.; 1H NMR (360 MHz, CDCl3) δ1.71 (6H, s), 3.25 (1H, br s), 7.41-7.67 (5H, m), 8.01 (1H, m), 8.24 (1H, s), 8.31 (1H, s), 8.78 (1H, s); MS (ES+) m/z 374 [M+H]+. Anal. Found: C, 67.38; H, 4.27; N, 18.51%. Required for C21H16FN5O; C, 67.55; H, 4.32; N, 18.76%.
Reaction SMILES: B(F)(F)F.CCOCC.[OH:10][C:11]1[C:20]([CH3:21])=[C:19]2[C:14]([CH:15]=[C:16]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17](=[O:22])[O:18]2)=[CH:13][C:12]=1[O:34][CH2:35][CH2:36][CH3:37].ClC(Cl)(Cl)C(=N)O[C@H:42]1[C@@H:47]2[O:48][C:49](=[O:51])[O:50][C@@H:46]2[C@@H:45]([O:52][CH3:53])[C:44]([CH3:55])([CH3:54])[O:43]1.C(N(CC)CC)C>C(Cl)Cl>[CH3:53][O:52][C@H:45]1[C:44]([CH3:55])([CH3:54])[O:43][C@@H:42]([O:10][C:11]2[C:20]([CH3:21])=[C:19]3[C:14]([CH:15]=[C:16]([NH:23][C:24](=[O:33])[O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:17](=[O:22])[O:18]3)=[CH:13][C:12]=2[O:34][CH2:35][CH2:36][CH3:37])[C@@H:47]2[O:48][C:49](=[O:51])[O:50][C@H:46]12
Reactant: CCCOc1cc2cc(NC(=O)OCc3ccccc3)c(=O)oc2c(C)c1O
Reactant: CO[C@@H]1[C@H]2OC(=O)O[C@H]2[C@H](OC(=N)C(Cl)(Cl)Cl)OC1(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOc1cc2cc(NC(=O)OCc3ccccc3)c(=O)oc2c(C)c1O[C@@H]1OC(C)(C)[C@H](OC)[C@H]2OC(=O)O[C@@H]12
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.8 %

Procedure:
Boron trifluoride etherate (16.7 μL, 0.13 mmol) was added to 23b (170 mg, 0.44 mmol) and (3aR,4S,7R,7aR)-7-methoxy-6,6-dimethyl-2-oxo-tetrahydro-3aH-[1.3]dioxolo[4,5-c]pyran-4-yl 2,2,2-trichloroacetimidate (643 mg, 1.77 mmol) in anhydrous CH2Cl2 (11.1 mL). After stirring at room temperature for 48 hours, triethylamine (150 μL) was added and the solvent was concentrated. The residue was purified via column chromatography (SiO2, 100:1→40:1 CH2Cl2:Acetone) to give 25b as a colorless foam (246 mg, 95%): 1H NMR (CDCl3, 500 MHz) δ 8.17 (s, 1H), 7.35-7.27 (m, 5H), 6.84 (s, 1H), 5.96 (s, 1H), 5.15 (s, 2H), 4.99 (d, J=7.5 Hz, 1H), 4.59 (d, J=9.7 Hz, 1H), 4.23 (d, J=9.6 Hz, 1H), 3.97 (t, J=6.6 Hz, 1H), 3.82-3.75 (m, 2H), 3.37 (s, 3H), 1.84-1.79 (m, 2H), 1.51 (s, 3H), 1.41 (s, 3H), 1.18 (s, 3H), 1.00 (t, J=7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 157.8, 154.3, 152.2, 151.8, 146.7, 144.2, 142.9, 134.6, 127.8, 127.6, 127.5, 127.5, 127.2, 121.0, 120.9, 111.1, 105.3, 101.7, 91.6, 85.7, 82.8, 80.0, 69.8, 58.1, 54.8, 28.3, 28.2, 22.4, 21.3, 9.4; IR (film) νmax 2961, 2939, 2906, 2359, 2341, 1811, 1757, 1726, 1522, 1445, 1371, 1267, 1175, 1113, 1086, 825, 768 cm−1; HRMS (ESI+) m/z: [M+Na]+ calcd for C30H33NO11, 606.1952. found, 606.1950.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:10]=1[CH2:19][N:20]1[CH2:24][C@@H:23]([CH3:25])[C@@:22]([CH2:42][C:43]([O:45]C(C)(C)C)=[O:44])([C:26](=[O:41])[NH:27][CH:28]2[CH2:33][CH2:32][N:31]([CH2:34][C:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]=3)[CH2:30][CH2:29]2)[CH2:21]1>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:18])[F:17])[C:10]=1[CH2:19][N:20]1[CH2:24][C@@H:23]([CH3:25])[C@@:22]([CH2:42][C:43]([OH:45])=[O:44])([C:26](=[O:41])[NH:27][CH:28]2[CH2:33][CH2:32][N:31]([CH2:34][C:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]=3)[CH2:30][CH2:29]2)[CH2:21]1
Reactant: C[C@@H]1CN(Cc2c(Cl)cccc2C(F)(F)F)C[C@]1(CC(=O)OC(C)(C)C)C(=O)NC1CCN(CC2=CCCCC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(Cc2c(Cl)cccc2C(F)(F)F)C[C@]1(CC(=O)O)C(=O)NC1CCN(CC2=CCCCC2)CC1
Reaction time: 2 h
Yield: 67 %

Procedure:
Trifluoroacetic acid (1.5 ml, 20.3 mmol) was added to a solution of tert-butyl 2-[(3R*,4S*)-1-{[2-chloro-6-(trifluoromethyl)phenyl]methyl}-3-{[1-(cyclohex-1-en-1-ylmethyl)piperidin-4-yl]carbamoyl}-4-methylpyrrolidin-3-yl]acetate obtained in Example 4i (353 mg, 0.577 mmol) in dichloromethane (400 μl), which was stirred at mom temperature for two hours. The reaction mixture was concentrated under reduced pressure and purified by ODS column chromatography (elution solvent: methanol/water) to give the title compound (215 mg, yield 67%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:9]=[CH:8]2.[N+](=[CH:22][CH3:23])=[N-]>C(OCC)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:15]([CH3:19])[C:16]([O:18][CH2:22][CH3:23])=[O:17])[CH:9]=[CH:8]2
Reactant: CC=[N+]=[N-]
Reactant: COCOc1ccc2cc(C(C)C(=O)O)ccc2c1
Solvent: CCOCC
Product: CCOC(=O)C(C)c1ccc2cc(OCOC)ccc2c1
Reaction time: 0.25 h

Procedure:
To a solution of 26 g. of 6-methoxymethyloxy-2-naphthyl-α-methylacetic acid and 500 ml. of diethyl ether are slowly added a solution comprising of 5.6 g. of diazoethane and 50 ml. of diethyl ether. The reaction mixture is allowed to stand for 15 minutes and then is evaporated under reduced pressure to yield ethyl 6-methoxymethyloxy-2-naphthyl-α-methylacetate. By replacing diazoethane with diazopropane in the above process, propyl 6-methoxymethyloxy-2-naphthyl-α-methylacetate is obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])[O:3]1.C(N(CC)CC)C.[O:24]1[CH2:29][CH2:28][O:27][CH2:26][CH:25]1[C:30](Cl)=[O:31]>CN(C)C(=O)C.C(OCC)(=O)C>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:16])([CH3:1])[O:3][B:4]([C:9]2[CH:10]=[C:11]([NH:12][C:30]([CH:25]3[CH2:26][O:27][CH2:28][CH2:29][O:24]3)=[O:31])[CH:13]=[CH:14][CH:15]=2)[O:5]1
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Reactant: O=C(Cl)C1COCCO1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cccc(NC(=O)C3COCCO3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (220 mg) and triethylamine (0.182 mL) in N,N-dimethylacetamide (1.5 mL) chilled to 0° C. was added 1,4-dioxane-2-carbonyl chloride (prepared from 1,4-dioxane-2-carboxylic acid (159 mg) and oxalyl chloride (0.15 mL) in dichloromethane (2.5 mL)) dropwise. After being stirred at room temperature for 1 h, the reaction mixture was diluted with ethyl acetate and washed with 1 M citric acid aqueous solution (3 times) then brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (10-100% ethyl acetate in hexanes) gave the product (270 mg, 81%).
Reaction SMILES: [CH2:1]([C:3]1[S:4][C:5]([CH:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[CH:6][C:7]=1[CH:8]=[O:9])[CH3:2].[CH:16]1([Mg]Br)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.O1CCCC1.[Cl-].[NH4+]>O1CCCC1>[CH:16]1([CH:8]([C:7]2[CH:6]=[C:5]([CH:10]3[CH2:15][CH2:14][S:13][CH2:12][CH2:11]3)[S:4][C:3]=2[CH2:1][CH3:2])[OH:9])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Br[Mg]C1CCCCC1
Reactant: CCc1sc(C2CCSCC2)cc1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1sc(C2CCSCC2)cc1C(O)C1CCCCC1
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 2-ethyl-5-(tetrahydro-2H-thiopyran-4-yl)thiophene-3-carbaldehyde (1.85 g) synthesized above in tetrahydrofuran (20 mL) was added dropwise 1.0M cyclohexylmagnesium bromide-tetrahydrofuran solution (11.6 mL) at 0° C., and the mixture was stirred for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give the title compound (1.91 g, 76%) as a pale-yellow oil.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C12BC(CCC1)CCC2.C1COCC1.[Cl:29][C:30]1[N:31]=[N:32][C:33](Cl)=[CH:34][CH:35]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.CCOC(C)=O>[Cl:29][C:30]1[N:31]=[N:32][C:33]([CH2:1][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)=[CH:34][CH:35]=1
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Clc1ccc(Cl)nn1
Agent: B1C2CCCC1CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccc(Cl)nn2)CC1
Temperature: 65 °C
Yield: 49 %

Procedure:
To a flask containing tert-butyl 4-methylenepiperidine-1-carboxylate (487 mg, 2.47 mmol) was added 0.5 M 9-borabicyclo[3.3.1]nonane in THF (5.4 mL, 2.72 mmol). The reaction was refluxed at 65° C. for 1 h then added to a degassed suspension of 3,6-dichloropyridazine (368 mg, 2.47 mmol), K2CO3 (1.0 g, 7.41 mmol), and PdCl2(dppf)CH2Cl2 (101 mg, 0.12 mmol) in 1,4-dioxane (5.2 mL) and water (0.88 mL). The resulting reaction mixture was heated at 60° C. for 3 h then cooled to RT and diluted with EtOAc. The suspension was filtered through celite and concentrated in vacuo. Silica gel chromatography, eluting with 0-100% EtOAc/heptane, afforded the product, tert-butyl 4-((6-chloropyridazin-3-yl)methyl)piperidine-1-carboxylate (376 mg, 1.21 mmol, 49% yield). 1H NMR (DMSO-d6) δ: 7.85 (d, J=8.8 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 3.74-4.05 (m, 2H), 2.85 (d, J=7.3 Hz, 2H), 2.54-2.79 (m, 2H), 1.82-2.01 (m, 1H), 1.48-1.62 (m, 2H), 1.38 (s, 9H), 0.97-1.18 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[O:4][C:3]=1[C:16]([O:18]CC)=[O:17].B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[O:4][C:3]=1[C:16]([OH:18])=[O:17]
Reactant: CCOC(=O)c1oc(-c2ccccc2Cl)cc(=O)c1Br
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1oc(-c2ccccc2Cl)cc(=O)c1Br

Procedure:
A stirred solution of ethyl 3-bromo-6-(2-chlorophenyl)-4-oxo-4H-pyran-2-carboxylate (2.3 g) and boron tribromide (2.5 ml) in dichloromethane (25 ml) was heated under reflux for 4 hours. A tan solid precipitated out. Water (25 ml) was added to the cooled mixture and the yellow solid was filtered off. Recrystallisation from glacial acetic acid yielded the title product as off-white needles (mp 205°-207° C. with decomposition).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([NH:21]C(=O)OC(C)(C)C)=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=1.C(=O)(OC(C)(C)C)[NH2:30].C([O-])([O-])=O.[Cs+].[Cs+].O>C1COCC1.C(Cl)Cl.C(O)(C(F)(F)F)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:21][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([CH2:10][CH2:9][O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:30])[CH:7]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCOc2ccnc(Cl)c2)c2ccccc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(OCCc2ccc(N)c3ccccc23)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.7 %

Procedure:
To a degassed suspension of tert-butyl 4-(2-(2-chloropyridin-4-yloxy)ethyl)naphthalen-1-ylcarbamate (33) (600 mg, 1.50 mmol), tert-butyl carbamate (176 mg, 1.50 mmol), Cs2CO3 (733 mg, 2.26 mmol) and Xathphos (43 mg, 0.075 mmol) in THF (10 mL) was added Pd2dba3 (34 mg, 0.038 mmol) and the reaction mixture was heated at reflux under nitrogen for 16 hr. Water was added and the reaction mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 0-50% hexane in ethyl acetate, gradient elution) to afford a mixture of the desired Boc protected product and starting material, which was dissolved in a mixture of DCM (2 mL) and TFA (2 mL) and stirred at RT for 1 hr. The solvent was evaporated in vacuo and the residue was dissolved in DCM and washed with saturated aqueous NaHCO3 solution and brine, then dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 5% MeOH in DCM, isocratic elution) to afford the title compound (34) (45 mg, 11%); m/z 280 (M+H)+, (ES+).