Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C@@H:3]1([C:14]2[CH:15]=[C:16]([CH2:26][C:27]3[CH:36]=[C:35]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=[CH:34]4)[C:28]=3C(OC)=O)[C:17]3[C:22]([C:23]=2[O:24][CH3:25])=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[OH:5].Cl>CO>[CH:28]1[C:29]2[C:35]([CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:36][C:27]=1[CH2:26][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]([O:24][CH3:25])=[C:14]([C@@H:3]2[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]2[OH:5])[CH:15]=1
Reactant: COC(=O)c1c(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(OC)c3ccccc23)cc2cccccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc(Cc2cc3cccccc-3c2)c2ccccc12
Yield: 39.2 %

Procedure:
A 1 M aqueous solution of sodium hydroxide (12 ml) was added dropwise to a solution of methyl 2-[3-[(1S)-1,5-anhydro-D-glucitol-1-yl]-4-methoxy-1-naphthyl]methylazulene-1-carboxylate (0.23 g) in methanol (8.0 ml) and the mixture was refluxed with heating for three hours. A 1 M aqueous solution of hydrochloric acid (12 ml) was added to the reaction mixture under cooling with ice and the solvent was evaporated. The resulting residue was suspended in acetonitrile (15 ml). A 4 M 1,4-dioxane solution of hydrochloric acid (0.4 ml) was added dropwise to the suspension and the mixture was refluxed with heating for 15 minutes. The insoluble matter was removed by filtration and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography and reverse phase column chromatography in that order to obtain (1S)-1,5-anhydro-1-[4-(azulen-2-ylmethyl)-1-methoxy-2-naphthyl]-D-glucitol (0.08 g).
Reaction SMILES: C(N(CC)CC)C.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13](Cl)=[O:14].[C:16]1([CH3:45])[CH:21]=[CH:20][C:19]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][C:31]3([CH2:37][CH2:38][N:39]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:25][CH2:24]2)=[CH:18][CH:17]=1>C(Cl)Cl>[O:42]1[CH2:43][CH2:44][N:39]([CH2:38][CH2:37][C:31]2([CH2:30][CH2:29][N:26]3[CH2:27][CH2:28][CH:23]([N:22]([C:19]4[CH:20]=[CH:21][C:16]([CH3:45])=[CH:17][CH:18]=4)[C:13]([C:9]4[O:8][CH:12]=[CH:11][CH:10]=4)=[O:14])[CH2:24][CH2:25]3)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:40][CH2:41]1
Reactant: Cc1ccc(NC2CCN(CCC3(CCN4CCOCC4)CCCCC3)CC2)cc1
Reactant: O=C(Cl)c1ccco1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCN4CCOCC4)CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.4 %

Procedure:
After adding triethylamine (0.21 mL, 1.50 mmol) and 2-furoyl chloride (0.10 mL, 1.00 mmol) in that order to a solution of 4-[2-[1-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]cyclohexyl]ethyl]morpholine (319 mg, 0.77 mmol) in methylene chloride (5 mL) while cooling on ice, the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (20 g Merck Art 9385, chloroform:methanol=20:1-chloroform:methanol:ammonia water=10:1:0.1) to obtain the title compound as a colorless oil (283 mg) (72% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([OH:26])[CH2:10][CH2:11][CH:12]2[CH2:16][CH2:15][C:14](=[O:17])[N:13]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25])=[CH:4][CH:3]=1.[N:27]([Si](C)(C)C)=[N+:28]=[N-:29].C([Sn](=O)CCCC)CCC.Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([OH:26])[CH2:10][CH2:11][CH:12]2[N:13]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[N:27]=[N:28][NH:29][N:25]=3)[C:14](=[O:17])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CCCCCCCN1C(=O)CCC1CCC(O)Cc1ccc(F)cc1
Agent: CCCC[Sn](=O)CCCC
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C1CCC(CCC(O)Cc2ccc(F)cc2)N1CCCCCCc1nn[nH]n1
Yield: 49.1 %

Procedure:
Following the procedure described for Example 3, Step D, 7-{2-[4-(4-fluoro-phenyl)-3-hydroxy-butyl]-5-oxo-pyrrolidin-1-yl}-heptanenitrile (71 mg, 0.197 mmol) was reacted with azidotrimethylsilane (45 mg, 0.394 mmol) and dibutyltin oxide (5 mg, 0.02 mmol) in toluene (10 mL) heated under reflux for 16 h. Additional azidotrimethylsilane (200 mg) and dibutyltin oxide (50 mg) were added and the reaction mixture was heated under reflux for 5 h. The reaction mixture was acidified with 1N HCl to pH=2 (5 mL) and the aqueous solution was washed with EtOAc (4×10 mL). The combined organic solutions were dried (MgSO4), filtered, and concentrated. Purification by medium pressure chromatography (EtOAc to 39:1 EtOAc:MeOH to 19:1 EtOAc:MeOH) provided the title compound of Example 5A (39 mg). 1H NMR (CDCl3) δ7.16 (m, 2H), 7.00 (m, 2H), 3.81 (m, 1H), 3.68 (m, 1H), 3.53 (m, 1H), 2.99 (m, 3H), 2.80 (m, 1H), 2.68 (m, 1H), 2.47 (m, 2H), 2.20 (m, 1H), 1.88-1.22 (m, 14H); MS 404.3 (M+1); 402.3 (M−1).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([O:25][C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1.[CH2:31]([O:33][C:34]([CH:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1)=[O:35])[CH3:32]>>[CH2:31]([O:33][C:34]([CH:36]1[CH2:41][CH2:40][CH:39]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:20]4[CH:21]=[C:22]([O:25][C:26]([F:28])([F:27])[F:29])[CH:23]=[CH:24][C:19]=4[O:18][N:17]=3)[CH2:11]2)[CH2:38][CH2:37]1)=[O:35])[CH3:32]
Reactant: O=C(CNc1noc2ccc(OC(F)(F)F)cc12)NC1CNC1
Reactant: CCOC(=O)C1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCC(N2CC(NC(=O)CNc3noc4ccc(OC(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethoxy-benzo[d]isoxazol-3-ylamino)-acetamide TFA salt (as prepared in Example 1, Step D) and 4-oxo-cyclohexane carboxylic acid ethyl ester using the procedure described in Step E of Example 1.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:20]([Br:24])(Br)(Br)Br.[F:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31](CO)[CH:32]=[CH:33][CH:34]=1>C(Cl)Cl>[Br:24][CH2:20][C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([O:28][CH2:27][CH2:26][F:25])[CH:34]=1
Reactant: OCc1cccc(OCCF)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FCCOc1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
PPh3 (3.08 g, 11.8 mmol) and CBr4 (2.93 g, 8.82 mmol) were added to a solution of 37 (1.00 g, 5.88 mmol) in DCM (20 mL) under nitrogen and stirred at room temperature for 1 h. The reaction mixture was filtered, concentrated and chromatographed to isolate the 49 as a colorless solid (0.85 g, 62% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[F:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:26]=1>CCCCCC.C(OCC)(=O)C>[F:20][C:21]1[CH:26]=[C:25]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:3]=2)[CH:24]=[N:23][CH:22]=1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Fc1cncc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)c1
Yield: 31 %

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 3-fluoropyridine-5-boronic acid pinacol ester with reaction time of 15 h. Chromatography (hexane/ethyl acetate 1:1) gave the 31% of the title compound.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][O:14][CH:15]([C:17]3[CH:18]=[C:19]([C:28]([F:31])([F:30])[F:29])[CH:20]=[C:21]4[C:25]=3[NH:24][N:23]=[C:22]4[C:26]#[N:27])[CH3:16])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:34]([BH3-])#N.[Na+]>C(#N)C.C(O)(=O)C>[CH3:34][N:10]1[CH2:11][CH2:12][C:7]([CH2:13][O:14][CH:15]([C:17]2[CH:18]=[C:19]([C:28]([F:29])([F:30])[F:31])[CH:20]=[C:21]3[C:25]=2[NH:24][N:23]=[C:22]3[C:26]#[N:27])[CH3:16])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9]1
Reactant: [BH3-]C#N
Reactant: CC(OCC1(c2ccccc2)CCNCC1)c1cc(C(F)(F)F)cc2c(C#N)n[nH]c12
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(OCC1(c2ccccc2)CCN(C)CC1)c1cc(C(F)(F)F)cc2c(C#N)n[nH]c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(±)-7-(1-((4-Phenylpiperidin-4-yl)methoxy)ethyl)-5-(trifluoromethyl)-1H-indazole-3-carbonitrile (24 mg, 0.06 mmol) and formaldehyde (37 wt. % solution in water, 77 μL) were combined in acetonitrile (2 mL) and cooled to 0° C. The reaction was treated with sodium cyanoborohydride (18 g, 0.28 mmol) and a few drops of acetic acid. The reaction was stirred at 0° C. for 30 min and at room temperature for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvents were evaporated and the compound purified by flash chromatography on silica gel (1% aq. methanolic ammonia/8% methanol/methylene chloride) to afford 15 mg (59%). 1H-NMR (CDCl3, 500 MHz) δ 8.05 (s, 1H), 7.37-7.40 (m, 2H), 7.31-7.34 (m, 2H), 7.22-7.23 (m, 2H), 4.66 (q, J=6.7 Hz, 1H), 3.36-3.43 (m, 2H), 3.34 (q, J=9.2 Hz, 1H), 3.17 (d, J=9.2 Hz, 1H), 2.73-2.84 (m, 2H), 2.59 (s, 3H), 2.53-2.58 (m, 2H), 2.13-2.29 (m, 2H), 1.59 (m, 3H). Mass spec.: 442.48 (MH)+.
Reaction SMILES: Br[C:2]1[C:3]([CH3:22])=[C:4]2[CH2:20][CH2:19][N:18]([CH3:21])[C:5]2=[N:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].CN(C)CCN(C)C.[Li]CCCC.COB(OC)OC.[C:43]([O:46]O)(=[O:45])[CH3:44].C(N(CC)CC)C.C(OC(=O)C)(=O)C>C1COCC1.CN(C1C=CN=CC=1)C.O>[C:43]([O:46][C:2]1[C:3]([CH3:22])=[C:4]2[CH2:20][CH2:19][N:18]([CH3:21])[C:5]2=[N:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:45])[CH3:44]
Reactant: CC(=O)OO
Reactant: CCCCCCCCCCc1nc2c(c(C)c1Br)CCN2C
Agent: CN(C)CCN(C)C
Agent: CN(C)c1ccncc1
Agent: COB(OC)OC
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCc1nc2c(c(C)c1OC(C)=O)CCN2C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 43.0 mg (0.12 mmol) of 5-bromo-1,4-dimethyl-6-decyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine in 1 mL of THF was added 17.4 μL (0.12 mmol) of tetramethylethylenediamine (TMEDA) at −78° C. followed by 146.3 μL (0.23 mmol, 1.6 M in hexanes) of n-BuLi. After 30 min, 28.7 μL (0.26 mmol) of trimethoxy boron was added and the resulting mixture was stirred for another 1 h. To the reaction mixture was added slowly 54.2 μL (0.26 mmol, 32 wt %) of peracetic acid and the solution was then warmed to 0° C. over a period of 30 min. The mixture was diluted by 5 mL of H2O and extracted with three 5-mL portions of EtOAc. The combined organic layer was washed with brine, dried (MgSO4) and the solvent was concentrated under diminished pressure. The resulting oil was dissolved in 2 mL of CH2Cl2 at 0° C., followed by the addition of 97.9 μL (0.70 mmol) of triethylamine, 1.4 mg (0.01 mmol) of DMAP and 33.1 μL (0.35 mmol) of acetic anhydride. The reaction was stirred at room temperature for 1 h and quenched by the addition of 2 mL of sat aq NH4Cl. The solution was then extracted with three 5-mL portions of EtOAc. The combined organic layer was washed with brine, dried (MgSO4) and the solvent was concentrated under diminished pressure. The residue was purified by flash chromatography on a silica gel column (20 1.7 cm). Elution with 100:1 hexanes/ethyl acetate gave 2b as a yellow oil: yield 28.0 mg (68%); silica gel TLC Rf 0.15 (3:7 EtOAt/hexanes); 1H NMR (CDCl3) δ 0.86 (t, 3H, J=6.8 Hz), 1.24-1.28 (m, 16H), 1.60 (quint, 2H, J=7.6 Hz), 1.92 (s, 3H), 2.28 (s, 3H), 2.44 (t, 2H, J=8.0 Hz), 2.82 (t, 2H, J=8.4 Hz), 2.87 (s, 3H) and 3.41 (t, 2H, J=8.4 Hz); 13C NMR (CDCl3) δ 12.9, 14.1, 20.5, 22.7, 24.6, 28.7, 29.3, 29.5, 29.6, 28.6, 31.9, 32.5, 33.3, 52.8, 120.1, 134.7, 136.5, 149.7, 161.2 and 169.9; mass spectrum, m/z 346.3 (M)+ (theoretical 246.3); mass spectrum (APCI), m/z 347.2696 (M+H)+ (C21H35N2O2 requires 347.2699).
Reaction SMILES: [CH3:1][C:2]([CH3:23])([O:4][C:5]([NH:7][C@H:8]1[CH2:12][CH2:11][N:10](C(OCC2C=CC=CC=2)=O)[CH2:9]1)=[O:6])[CH3:3].[H][H]>CO.[Pd]>[CH3:3][C:2]([CH3:23])([O:4][C:5]([NH:7][C@H:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CCNC1
Yield: 98.2 %

Procedure:
A solution of 17.7 g (55.2 mmol) of (S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-pyrrolidinecarboxylic acid, phenylmethyl ester, in 400 ml of methanol was treated with 2.0 g of 20% palladium on carbon and shaken in an atmosphere of hydrogen at temperatures of 22°-26.5° and pressures of 45-50.5 psi for one hour. The solvent was removed in vacuo to give 10.1 g of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:15][C:16]2[CH:21]=[C:20]([CH3:22])[C:19]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)=[C:18]([CH3:33])[CH:17]=2)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>CO>[C:29]([C:26]1[CH:25]=[CH:24][C:23]([C:19]2[C:18]([CH3:33])=[CH:17][C:16]([O:15][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:34])=[O:2])=[CH:9][CH:8]=3)[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:21][C:20]=2[CH3:22])=[CH:28][CH:27]=1)([CH3:30])([CH3:31])[CH3:32]
Reactant: COC(=O)c1ccc(C(CC(C)C)Oc2cc(C)c(-c3ccc(C(C)(C)C)cc3)c(C)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(OC(CC(C)C)c2ccc(C(=O)O)cc2)cc(C)c1-c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.7 %

Procedure:
4-[1-(4′-tert-Butyl-2,6-dimethyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoic acid methyl ester (2.90 g) is dissolved in MeOH (20 mL) and treated with 5N NaOH (3 mL). The reaction is stirred at room temperature for 5 h, acidified with 5N HCl and extracted with ethyl acetate. The combined organic portion is dried and concentrated to provide 2.69 g of the titled compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13](F)[CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][CH:19]2[CH2:21][CH2:20]2)[C:7]=1[C:22]([O:24]CC)=[O:23])[CH2:2][CH2:3][CH3:4].[OH-:27].[Na+].Cl.[H-].[Na+]>O1CCCC1.C(O)C.C(O)C1C=CC=CC=1.O>[CH2:9]([O:27][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:17])[N:8]([CH2:18][CH:19]1[CH2:21][CH2:20]1)[C:7]([C:22]([OH:24])=[O:23])=[C:6]2[O:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCOc1c(C(=O)OCC)n(CC2CC2)c(=O)c2ccc(F)cc12
Reactant: [OH-]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CCCCOc1c(C(=O)O)n(CC2CC2)c(=O)c2ccc(OCc3ccccc3)cc12
Temperature: 150 °C
Reaction time: 12 h
Yield: 138.7 %

Procedure:
To a solution of ethyl 4-butoxy-2-cyclopropylmethyl-6-fluoro-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (9.03 g, 25 mmol) in tetrahydrofuran (30 mL) and ethanol (30 mL) was added sodium hydroxide (3.00 g, 75 mmol). The obtained mixture was refluxed under heating for 12 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in benzyl alcohol (20 mL) and the obtained solution was added dropwise to a solution of sodium hydride (5.0 g, 125 mmol)(60% in oil) in benzyl alcohol (20 mL). The obtained mixture was stirred at 150° C. for 12 h. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-diisopropyl ether to give 6-benzyloxy-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylic acid (7.31 g, 69.4%) as crystals.
Reaction SMILES: [C:1]([NH:20][C@@H:21]([C:33]12[CH2:42][CH:37]3[CH2:38][CH:39]([CH2:41][C:35]([OH:43])([CH2:36]3)[CH2:34]1)[CH2:40]2)[C:22]([N:24]1[C@H:29]([C:30]([NH2:32])=O)[CH2:28][C@H:27]2[C@@H:25]1[CH2:26]2)=[O:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CO>[C:1]([NH:20][C@@H:21]([C:33]12[CH2:40][CH:39]3[CH2:38][CH:37]([CH2:36][C:35]([OH:43])([CH2:41]3)[CH2:34]1)[CH2:42]2)[C:22]([N:24]1[C@H:29]([C:30]#[N:32])[CH2:28][C@H:27]2[C@@H:25]1[CH2:26]2)=[O:23])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NC(=O)[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C12CC3CC(CC(O)(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: N#C[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C12CC3CC(CC(O)(C3)C1)C2
Temperature: 5 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
A solution of (1S,3S,5S)-2-[(2S)-2-tritylamino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carboxamide (15.0 g) in tetrahydrofuran (150 ml) was mixed with pyridine (12.3 g) and cooled to 0-10° C. Trifluoroacetic anhydride (19.1 g) was added to the reaction mixture slowly over 30 minutes. The reaction mixture was stirred at 0-10° C. for 3 hours. Completion of the reaction was confirmed by HPLC. Aqueous potassium carbonate solution (20%, 240 ml) was added to the reaction mixture over 30 minutes to obtain pH 10-11. Methanol (50 ml) was added, and the reaction mixture was stirred at 25° C. for 3 hours. Completion of the reaction was verified using TLC. The reaction mixture was cooled to 0° C. and stirred for 30 minutes. The solid was filtered and washed with water (2×15 ml). The solid was dried under vacuum at 50-60° C. for 8 hours to give the title compound (10.0 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[C:10](F)=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F-].[K+]>C1COCC1>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[NH:8][C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:4]=2[CH:3]=1
Reactant: Nc1cnc(Br)cc1-c1cccnc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Brc1cc2c(cn1)[nH]c1ncccc12
Reaction time: 2.5 h
Yield: 74.9 %

Procedure:
A solution of 6′-bromo-2-fluoro-[3,4′]bipyridinyl-3′-ylamine (7.22 g, 26.9 mmol) in THF (75 mL) was added dropwise over 10 minutes to sodium bis-(trimethylsilyl)amide (1N solution in THF, 54 mL, 53.9 mmol). The reaction mixture was left to stir for 2.5 h then 1N aqueous potassium fluoride solution (7 mL) was added and the solvent evaporated in vacuo. The residue was diluted with water (100 mL) and the resultant solid was collected by filtration, washed with water (20 mL) and diethyl ether:pentane (1:1, 20 mL) and left to air dry. The resultant solid was triturated with methanol (50 mL), collected by filtration, washed with methanol (10 mL) and diethyl ether (20 mL) and pentane (20 mL) and left to air dry to afford the title compound as a brown solid (5.0 g, 75%). 1H NMR (DMSO-D6, 300 MHz): 8.73-8.69 (m, 2H), 8.63 (dd, J=4.8, 1.7 Hz, 1H), 8.48 (dd, J=1.0 Hz, 1H), 7.33 (dd, J=7.8, 4.8 Hz, 1H). LCMS (Method B): RT=2.43 min, M+H+=248/250.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][N:21]=1>C(OCC)(=O)C>[Br:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]([CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[N:21]=1
Reactant: Brc1n[nH]c2ccccc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1nn(C2CCCCO2)c2ccccc12
Yield: 98.1 %

Procedure:
3,4-Dihydro-2H-pyran (0.232 mL, 2.54 mmol) and p-toluenesulfonic acid monohydrate (0.024 g, 0.127 mmol) were added to a solution of 3-bromo-1H-indazole (0.250 g, 1.269 mmol) in ethyl acetate (12.0 ml), and the mixture was heated at reflux for 48 h. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous phase was separated and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column. gradient elution with 0-25% ethyl acetate-hexane) to afford 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.350 g, 98%) as a colorless oil. MS (ESI, pos. ion) m/z 281, 283 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18]C)=[N:16][CH:17]=1>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:17]=[N:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COc1ccc(N)cn1
Solvent: ClCCl
Product: O=C(Nc1ccc(O)nc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chlorobenzoyl chloride (1.75 g, 10.0 mmol) was added carefully to a stirred solution of 5-amino-2-methoxypyridine (1.24 g, 10.0 mmol) in dichloromethane (10 mL). After stirring overnight at room temperature, the solvent is evaporated in vacuo and the residue is heated in a pre-heated kugelrohr oven at 200° C. for 5–10 minutes under house-vacuum (around 20 mbar) yielding the title compound, which was used without further purification.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[CH2:27]([N:34]1[CH2:39][CH2:38][CH:37](O)[CH2:36][CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH:37]2[CH2:36][CH2:35][N:34]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:39][CH2:38]2)=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1ccc(I)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccc(I)cc1[N+](=O)[O-]
Yield: 12.5 %

Procedure:
2.33 g (0.00795 mol) of 4-iodo-2-nitrobenzoic acid were boiled und reflux in 13.8 ml (0.16 mol) of oxalyl chloride for 3 hrs. After removal of the excess oxalyl chloride the mixture was concentrated twice with 30 ml of toluene each time. The residue was dissolved in 80 ml of toluene, treated with 1.94 ml (0.0139 mol) of triethylamine and 1.52 g (0.00795 mol) of 1-benzyl-4-hydroxypiperidine and boiled at reflux for 18 hrs. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane (1:3). 0.465 g (13%) of 1-benzyl-piperidin-4-yl 4-iodo-2-nitrobenzoate was obtained as a yellow oil. MS: me/e=467 (C19H20IN2O4 +).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[Cl:20][CH2:21][C:22](Cl)=[O:23]>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][C:3]=1[NH:4][C:22](=[O:23])[CH2:21][Cl:20]
Reactant: Nc1cc(C(F)(F)F)ccc1Br
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1cc(C(F)(F)F)ccc1Br
Temperature: 0 °C

Procedure:
To a solution of 2-bromo-5-trifluoromethylaniline (10.0 g) in methylene chloride (100 ml) was added triethylamine and the solution was cooled to 0° C. To this solution was slowly added choroacetyl chloride and the reaction mixture was allowed to cool to room temperature overnight. The solution was concentrated and the resulting solid was extracted with ethyl acetate. The organic extract was first washed with 10% HCl (2×2 ml), then with water (12×25 ml) and was collected, dried and evaporated to obtain the title compound (yield, 10.2 g). 1HNMR (250 MHz, CDCl3): 4.22 (s, 2 H), 7.26 (d, J=8 Hz, 1 H), 7.66 (d, J=8 Hz, 1 Hz), 8.68 (s, 1 H), 9.02 (br s, 1 H).