Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:37]([N:39]1[N:59]=C2C3OC(C4C=CC=CC=4)=C(I)C(=O)C=3C=C[C:41]2=[CH:40]1)C>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[CH:25]=[CH:24][C:23]5[C:22](=[N:59][N:39]([CH2:40][CH3:41])[CH:37]=5)[C:21]=4[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Reactant: CCn1cc2ccc3c(=O)c(I)c(-c4ccccc4)oc3c2n1
Product: CCn1cc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c2n1
Yield: 89 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 2-ethyl-7-iodo-8-phenyl-2H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one was reacted to give the title compound as a colourless gum (43.2 mg, 89%). LCMS (Method H): RT=4.24 min, [M+H]+=536.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C[O-].[Na+].[CH:17](OCC)=[O:18]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH:17]=[O:18])[C:12]#[N:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: CCOC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: COc1ccc(C(C#N)C=O)cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 78 %

Procedure:
To a stirred solution of 3,4-dimethoxyphenyl acetonitrile (8.86 g, 50 mmol) in diethyl ether (150 mL) was added sodium methoxide (2.97 g, 55 mmol) and ethyl formate (4.04 mL, 50 mmol) in diethyl ether (50 mL) solution. The reaction mixture was stirred at room temperature for 24 hrs. A solid was precipitated. The mixture was filtered and the solid was collected and washed with diethyl ether. The solid was dissolved in water (50 mL). 10% acetic acid was then added dropwise to the solution. A white precipitation was formed and the mixture was filtered again. The while solid was washed with water and collected to afford 2-(3,4-dimethoxy-phenyl)-3-oxo-propionitrile (8.0 g, 78% yield).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]([CH3:19])[CH:9]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1.O[N:26]1[C:30](=[O:31])[CH2:29][CH2:28][C:27]1=[O:32].C(N=C=NCCCN(C)C)C>C(Cl)Cl>[OH:1][C:2]1[C:7]2[CH:8]([CH3:19])[CH:9]([CH2:14][CH2:15][C:16](=[O:18])[O:17][N:26]3[C:30](=[O:31])[CH2:29][CH2:28][C:27]3=[O:32])[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)C(CCC(=O)O)C2C
Reactant: O=C1CCC(=O)N1O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CCCCCc1cc(O)c2c(c1)OC(C)(C)C(CCC(=O)ON1C(=O)CCC1=O)C2C
Reaction time: 0.25 h
Yield: 78.2 %

Procedure:
To a solution of 297 mg (0.88 mmol) of 3,4-Dihydro-5-hydroxy-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3-propanoic acid in 20 mL of anhy. CH2Cl2 under argon was added 246 mg (2.14 mmol) of N-hydroxysuccinimide (Aldrich) and the reaction stirred for 15 min. 408 mg (2.14 mmol) of 1-ethyl-3-(dimethylaminopropyl)carbodiimide (Sigma) was then added and the reaction stirred at RT for 3 hr. The reaction was diluted to five times the volume with CH2Cl2, washed with 0.1N aq. HCl that had been saturated with NaCl, followed by sat. aq. NaCl, followed by sat. aq. NaHCO3 (×3), dried and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with 1:1 EtOAc-CH2Cl2. The product fractions were combined and evaporated under reduced pressure and dried under high vacuum to give 297 mg (78%) of 1-[3-(3,4-Dihydro-5-hydroxy-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3-yl)-1-oxopropoxy]-2,5-pyrrolidinedione as a white foam. HR (+) FAB MS: Calc (M+H), 432.2386; Observed, 432.2413.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:26]=[CH:25][C:11]([O:12][C:13]2[C:18]([C:19]3[CH2:23][CH2:22][CH:21]([OH:24])[CH:20]=3)=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:10][CH:9]=1>O1CCCC1.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[C:18]([CH:19]3[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20]3)=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:25][CH:26]=1
Reactant: OC1C=C(c2cccnc2Oc2ccc(Nc3ccccn3)cc2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: OC1CCC(c2cccnc2Oc2ccc(Nc3ccccn3)cc2)C1
Temperature: 23 °C
Reaction time: 5 h
Yield: 49.2 %

Procedure:
A solution of 3-(2-(4-(pyridin-2-ylamino)phenoxy)pyridin-3-yl)cyclopent-2-enol (190 mg, 0.550 mmol) in Tetrahydrofuran (10 mL) was treated with palladium, 10% wt. on activated carbon (58.5 mg, 0.055 mmol, 0.1 equiv). The reaction mixture was purged with vacuum-hydrogen cycles (3×), and stirred at 23° C. under hydrogen. After 5 h, the reaction was heated to 45° C. After 24 h, the reaction was cooled to 23° C., and filtered through celite. The filter cake was washed with tetrahydrofuran (100 mL), the filtrates combined, concentrated in vacuo, and purified by silica gel chromatography (eluant: 0.5-4% methanol/dichloromethane), affording 3-(2-(4-(pyridin-2-ylamino)phenoxy)pyridin-3-yl)cyclopentanol (94 mg, 49% yield). MS (ESI, pos. ion) m/z: 348.1 (M+1). IC50 (uM) 0.010.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:21])[C:16]([O:18]CC)=[O:17])=[CH:11][C:10]=1[CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].S(=O)(=O)(O)O>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:21])[C:16]([OH:18])=[O:17])=[CH:11][C:10]=1[CH2:22][CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(O)c1ccc(OCc2ccccc2)c(CCOCc2ccccc2)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C(O)c1ccc(OCc2ccccc2)c(CCOCc2ccccc2)c1
Yield: 94.7 %

Procedure:
Ethyl 2-[4-benzyloxy-3-(2-benzyloxyethyl)phenyl]-2-hydroxyacetate (39.7 g) was suspended in 40 ml of ethanol, 57 ml of 2 N aqueous sodium hydroxide solution was added to the suspension with stirring under ice-cooling, and the mixture was subjected to 1 hour of reaction at room temperature. Then, 57 ml of 2 N aqueous sulfuric acid solution was added to the reaction solution with stirring under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with water and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was evaporated under reduced pressure to give 35.1 g of 2-[4-benzyloxy-3-(2-benzyloxyethyl)phenyl]-2-hydroxyacetic acid in an oily form.
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH:7][CH2:8][CH:9]=[CH2:10])=S)[CH:2]=[CH2:3].C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>C(#N)C>[CH2:1]([N:4]=[C:5]=[N:7][CH2:8][CH:9]=[CH2:10])[CH:2]=[CH2:3]
Reactant: C=CCNC(=S)NCC=C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=CCN=C=NCC=C

Procedure:
1.56 g of N,N'-bis(allyl)thiourea, 2.4 g of triethylamine and 3.07 g of 2-chloro-1-methylpyridinium iodide are reacted in 40 ml of acetonitrile and the reaction mixture is worked up as described in Example 4. The product is obtained as a faintly yellowish oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]([O:16]C(C)(C)C)=[O:15].O[N:22]1[C:26](=[O:27])[CH2:25][CH2:24][C:23]1=[O:28].Cl.C(N=C=NCCCN(C)C)C>FC(F)(F)C(O)=O.ClCCl>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]([O:16][N:22]1[C:26](=[O:27])[CH2:25][CH2:24][C:23]1=[O:28])=[O:15]
Reactant: O=C1CCC(=O)N1O
Reactant: COCCOCCOCCOCCC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 3-{2-[2-(2-Methoxyethoxy)ethoxy]ethoxy}propionate (131 mg, 0.45 mmol) was dissolved in trifluoroacetic acid and left at room temperature for 1 hour. The solvent was removed in vacuo and residual trifluoroacetic acid was removed by evaporation from dioxane. The deprotected intermediate was dissolved in dichloromethane and treated with N-hydroxysuccinimide (57 mg, 0.49 mmol) and ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg, 0.45 mmol) and stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed twice with water. The organic phase was dried over MgSO4 and concentrated in vacuo to provide 122 mg (82%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][S:14]([N:17]([C:19]1[N:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[C:26]([O:33]S(C2C=CC(C)=CC=2)(=O)=O)=[C:25]2[C:20]=1[CH:21]=[CH:22][CH:23]=[N:24]2)[CH3:18])(=[O:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].CO.C(O)(=O)C>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][S:14]([N:17]([C:19]1[N:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[C:26]([OH:33])=[C:25]2[C:20]=1[CH:21]=[CH:22][CH:23]=[N:24]2)[CH3:18])(=[O:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1nc(N(C)S(=O)(=O)CCCCCNC(=O)OC(C)(C)C)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1nc(N(C)S(=O)(=O)CCCCCNC(=O)OC(C)(C)C)c2cccnc2c1O
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
Methyl 5-(5-(tert-butoxycarbonylamino)-N-methylpentylsulfonamido)-8-(tosyloxy)-1,6-naphthyridine-7-carboxylate (Example 2.1; 8.68 mmol) was dissolved in DMF (17 ml) at 40° C. and transferred to a 33% solution of NaOMe in MeOH (4.1 ml; 21.7 mmol) over 1-2 min at 25° C. The resulting yellow homogenous mixture was heated to 50° C. Mixture was cooled to 25° C. over 15 min and aged at 25° C. for 15 min. Acetic acid (1 ml) was added over 1 min, then water was added. The slurry was aged for 30 min and filtered. The filter cake was washed with water, and dried to give the target compound in 61% yield.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([NH:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO>[C:25]1([CH2:24][CH2:23][CH2:22][NH:21][C@H:18]2[CH2:17][CH2:16][C@H:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[CH2:20][CH2:19]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc(CCCN[C@H]2CC[C@H](c3ccc(OCc4ccccc4)cc3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: Oc1ccc([C@H]2CC[C@H](NCCCc3ccccc3)CC2)cc1
Reaction time: 3 h

Procedure:
A mixture of trans-[4-(4-benzyloxy-phenyl)-cyclohexyl]-(3-phenyl-propyl)-amine (200 mg, 0.5 mmol), Pd/C 10% (20 mg) and MeOH (20 ml) was hydrogenated at RT for 3 h. Removal of the catalyst and evaporation of the solvent left a residue which after trituration with ether gave trans-4-[4-(3-phenyl-propylamino)-cyclohexyl]-phenol (130 mg, 84%) as a white crystalline material. MS: m/e=310.3 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:5][CH:4]=1.[C:15]([S:19][C:20](=[O:25])[CH2:21][C:22](=[O:24])[CH3:23])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([S:19][C:20](=[O:25])[CH:21]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:5][CH:4]=1)[C:22](=[O:24])[CH3:23])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)C(=O)c1ccc(CBr)cc1
Reactant: CC(=O)CC(=O)SC(C)(C)C
Product: CC(=O)C(Cc1ccc(C(=O)C(C)(C)C)cc1)C(=O)SC(C)(C)C

Procedure:
The title compound was prepared by the method of Preparation 11a using 1-(4-bromomethylphenyl)-2,2-dimethylpropan-1-one and 3-oxothiobutyric acid S-tert-butyl ester
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][CH2:29][C:30]([NH2:32])=O)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][CH2:29][C:30]#[N:32])([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[O:18][C:17]3=[O:33])[CH3:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCC(N)=O)(c2ccccc2)OC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCC#N)(c2ccccc2)OC1=O
Reaction time: 2 h
Yield: 7.5 %

Procedure:
To a solution of 3-((R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide (110 mg, 0.25 mmol) and DIEA (170 mg, 1.05 mmol) in anhydrous CH2Cl2 (5 mL) was added TFAA (158 mg, 0.75 mmol) at 0° C. The mixture was stirred for 2 h. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to afford 3-((R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanenitrile (8 mg, yield 10%). LC-MS Method 3 tR=1.458, min, m/z=429.2; 1H NMR (CDCl3): 1.52 (d, 3H), 2.01 (m, 1H), 2.14 (m, 2H), 2.29 (m, 3H), 2.53 (m, 2H), 2.90 (m, 1H), 5.62 (m, 1H), 6.93 (m, 2H), 7.04 (m, 2H), 7.16-7.25 (m, 2H), 7.30-7.47 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)=[O:9])=[CH:6][CH:5]=[C:4]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[N:3]=1.[BH4-].[Na+]>CO>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][NH:19][C:4]2[N:3]=[C:2]([Cl:1])[C:7]([CH:8]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[OH:9])=[CH:6][CH:5]=2)=[CH:22][CH:23]=1
Reactant: O=C(c1ccc(NCc2ccc(Cl)cc2)nc1Cl)c1c[nH]c2ncccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(c1ccc(NCc2ccc(Cl)cc2)nc1Cl)c1c[nH]c2ncccc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To [2-Chloro-6-(4-chloro-benzylamino)-pyridin-3-yl]-(1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (P-0048, 0.045 g, 0.00011 mol, prepared as described in Example 27) was added methanol (10 mL) and sodium borohydride (0.00428 g, 0.000113 mol). The reaction was allowed to stir at 50° C. overnight. The volatiles were removed from the reaction, and the resulting material was extracted with ethyl acetate and 1M aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with dichloromethane followed by 1% methanol in dichloromethane to give the compound (P-0050, 31 mg, 68%). MS (ESI) [M+H+]+=399.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH2:17])[C:14]=1[O:15][CH3:16])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.C(OC([NH:25][CH:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[C:31](O)=[O:32])=O)(C)(C)C.Cl.O1CCOCC1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:17][C:31]([CH:27]3[CH2:28][CH2:29][CH2:30][CH:26]3[NH2:25])=[O:32])[C:14]=1[O:15][CH3:16])[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CC(C)(C)OC(=O)NC1CCCC1C(=O)O
Reactant: COc1c(Cl)cc2c([nH]c3cnccc32)c1N
Agent: Cl
Solvent: C1COCCO1
Product: COc1c(Cl)cc2c([nH]c3cnccc32)c1NC(=O)C1CCCC1N
Temperature: 25 °C

Procedure:
6-chloro-7-methoxy-9H-β-carboline-8-ylamine and 2-tert-butoxycarbonylamino-cyclopentanecarboxylic acid were reacted using Method A. To this product was added 5 ml of 4N HCl/dioxane and the resulting mixture was allowed to stir at RT. The reaction was followed by LC-MS until completion. Evaporation was allowed to remove all the solvent which gave a crude HCl salt. The desired product was then purified by preparative HPLC. 1H-NMR (300 MHz, DMSO-d6): δ 1.68 (m, 1H), 1.84 (m, 2H), 2.06 (m, 2H), 2.20 (m, 1H), 3.46 (m, 1H), 3.67 (m, 1H), 3.89 (s, 3H), 8.24 (d, 2H), 8.61 (d, 1H), 8.72 (s, 1H), 8.78 (d, 1H), 9.19 (s, 1H), 10.58 (s, 1H), 13.20 (s, 1H). Retention Time (LC, method: ammonium acetate standard): 1.54 min. MS (M+H+): 359.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:18])[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(O)(C1C=CC(C)=CC=1)(=O)=O>CC(C)=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:18])[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: OC1(c2ccc(Br)cc2)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCC(O)(c2ccc(Br)cc2)CC1
Temperature: 75 °C
Reaction time: 1 h
Yield: 104.5 %

Procedure:
To a mixture of 8-(4-bromophenyl)-1,4-dioxaspiro[4.5]decan-8-ol (0.99 g, 3.2 mmol) in acetone (10 mL) and water (5 mL) was added Ts-OH (12 mg, 0.063 mmol) and the reaction was let stir in at 75° C. oil bath for 1 hr. The resulting reaction mixture was cooled to rt and the acetone was removed by rotary evaporation in vacuo. The resulting aqueous mixture was extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated by rotary evaporation in vacuo to afford 0.9 g of a crude pale yellow solid which was used without further purification. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.84-1.98 (m, 2H), 2.06-2.29 (m, 4H), 2.76 (td, J=13.8, 6.3 Hz, 2H), 5.47 (s, 1H), 7.51 (s, 4H). ESI-MS m/z: not ionized [M+H]+, retention time 1.18 min (condition E).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>ClCCl>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[Br:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Brc1ccc(OC2CCNCC2)nc1
Reaction time: 1.5 h

Procedure:
2-[1-(t-Butyloxycarbonyl)-piperidin-4-yloxy]-5-bromopyridine was stirred in dichloromethane (8 ml). Trifluoroacetic acid (5 ml) was added and stirring continued at room temperature for 1.5 h. Volatile materials were removed in vacuo and the residue was triturated with ether and hexane, then collected by filtration to give the product as a white solid (0.86 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[CH:41]1([NH:44][C@H:45]2[CH2:50][CH2:49][C@H:48]([CH2:51][C:52]([O:54][CH3:55])=[O:53])[CH2:47][CH2:46]2)[CH2:43][CH2:42]1>C(Cl)Cl>[CH:41]1([N:44]([C@H:45]2[CH2:50][CH2:49][C@H:48]([CH2:51][C:52]([O:54][CH3:55])=[O:53])[CH2:47][CH2:46]2)[C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=2[F:1])[CH2:42][CH2:43]1
Reactant: COC(=O)C[C@H]1CC[C@H](NC2CC2)CC1
Reactant: Cc1ccc(C(=O)O)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C[C@H]1CC[C@H](N(C(=O)c2ccc(C)cc2F)C2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-fluoro-4-methylbenzoic acid (0.153 g, 0.994 mmol), 1-hydroxybenzotriazole (0.0639 g, 0.473 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.181 g, 0.947 mmol) in CH2Cl2 (5 mL) was added triethylamine (0.396 ml, 2.84 mmol) and methyl 2-(trans-4-(cyclopropylamino)cyclohexyl)acetate (0.200 g, 0.947 mmol). The mixture was stirred at room temperature overnight, diluted with CH2Cl2 (50 mL), and then washed with 10% Na2CO3 and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified through silica gel chromatography eluting with 18%-25% EtOAc-hexane. The desired amide product was obtained as a colorless oil (0.224 g). MS: 348 (M+1), C20H26FNO3.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[Cl:25])=[C:7]([Cl:16])[C:8]2[N:9]([C:11]([CH:14]=O)=[CH:12][N:13]=2)[CH:10]=1)=[O:4].C(O)(=O)C.[CH3:30][NH2:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][O:2][C:3]([C:5]1[C:6]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=2[Cl:25])=[C:7]([Cl:16])[C:8]2[N:9]([C:11]([CH2:14][NH:31][CH3:30])=[CH:12][N:13]=2)[CH:10]=1)=[O:4]
Reactant: CN
Reactant: COC(=O)c1cn2c(C=O)cnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CNCc1cnc2c(Cl)c(Nc3ccc(Br)cc3Cl)c(C(=O)OC)cn12
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
A suspension of 7-(4-bromo-2-chlorophenylamino)-8-chloro-3-formylimidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (58) (25 mg, 0.056 mmol), acetic acid (7 μL, 0.11 mmol), and methylamine (2.0 M solution in THF, 56 μL, 0.11 mmol) was stirred for 0.5 hours. Sodium triacetoxyborohydride (36 mg, 0.17 mmol) was added and the solution allowed to stir overnight. The reaction mixture was concentrated to dryness and flashed (dichloromethane followed by 10:1 dichloromethane/methanol) to provide the desired product as a yellow solid (12 mg, 46%). MS (APCI+) m/z 455, 457, 459 (M+; Cl, Br pattern) detected.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([C:11]1[S:12][CH:13]=[C:14]([C:16]([N:18]2[CH2:23][C:22]3([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[O:21][CH2:20][CH2:19]2)=[O:17])[N:15]=1)([CH3:10])[CH3:9].[Cl:29][C:30]1[C:37]([CH2:38][CH2:39][OH:40])=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1.C(O)(=O)C>[Cl:29][C:30]1[C:37]([CH2:38][CH2:39][OH:40])=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][N:26]1[CH2:25][CH2:24][C:22]2([O:21][CH2:20][CH2:19][N:18]([C:16]([C:14]3[N:15]=[C:11]([CH:8]([CH3:10])[CH3:9])[S:12][CH:13]=3)=[O:17])[CH2:23]2)[CH2:28][CH2:27]1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: O=Cc1cccc(CCO)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCO)c4Cl)CC3)C2)cs1
Reaction time: 0.08 h

Procedure:
A solution of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (0.325 g) in NMP (3 mL) was treated with acetic acid (0.067 mL) and stirred for 5 minutes. A solution of 2-chloro-3-(2-hydroxyethyl)benzaldehyde (example 80, step d) (0.217 g) in NMP (4 mL) was then added, the resulting solution was stirred for 1 hour and then treated with sodium triacetoxyborohydride (1.025 g). The mixture was stirred overnight at room temperature, then poured into saturated sodium bicarbonate and extracted twice with ethyl acetate. The combined extracts were washed three times with water, once with brine, then dried over anhydrous magnesium sulphate and purified by flash chromatography on silica eluted with 1:2:97 triethylamine:methanol:dichloromethane to afford the subtitled compound as a colourless gum. Yield 0.411 g.