Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([N:10]([CH3:12])[CH3:11])[CH:4]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][O:25][CH3:26].[Li]CCCC>C1COCC1.CCCCC>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][O:25][CH3:26])[N:6]=[C:5]([N:10]([CH3:12])[CH3:11])[CH:4]=1
Reactant: COc1cc(C)nc(N(C)C)c1
Reactant: COCOCCCCCCCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: COCOCCCCCCCCCCc1cc(OC)cc(N(C)C)n1
Temperature: 23 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution containing 156 mg (0.94 mmol) of 4-methoxy-N,N,6-trimethylpyridin-2-amine in 5 mL of anhydrous THF were added 252 mg (0.94 mmol) of 1-bromo-9-(methoxymethoxy)nonane followed by 650 μL (1.04 mmol) of 1.6M n-BuLi in pentane. The reaction mixture was stirred at 23° C. for 15 min. The reaction was quenched with satd. aq. ammonium chloride and poured into 50 mL of water. The mixture was extracted with two 50-mL portions of ethyl acetate. The combined organic solution was washed with a 50-mL portion of brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column (3×10 cm). Elution with 1:1 hexanes-ethyl acetate afforded the expected product as yellowish oil: yield 235 mg (70%); silica gel TLC Rf 0.47 (1:1 hexanes-ethyl acetate); 1H NMR (CDCl3) δ 1.24 (br m, 12H), 1.55 (quint, 2H, J=6.4 Hz), 1.68 (quint, 2H, J=7.6 Hz), 2.55 (dd, 2H, J=7.6, 7.6 Hz), 3.03 (s, 6H), 3.46 (s, 3H), 3.49 (t, 2H, J=6.8 Hz), 3.76 (s, 3H), 4.59 (s, 2H), 5.77 (s, 1H) and 6.01 (s, 1H); 13C NMR (CDCl3) δ 26.17, 29.25, 29.39, 29.48, 29.50, 29.55, 29.60, 29.62, 29.72, 37.96, 37.96, 54.63, 55.01, 67.85, 87.44, 96.36, 97.86, 160.77, 162.05 and 167.41; mass spectrum (APCI), m/z (M+H)+353.2808 (C20H37N2O3 requires 353.2804).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:17])[CH:9]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][C:29]([NH2:32])=[N:30][CH:31]=2)O1>O.C1(C)C=CC=CC=1.C(O)C.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>[NH2:32][C:29]1[N:30]=[CH:31][C:26]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:17])[CH:9]=2)=[CH:27][N:28]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
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: Cc1ccccc1
Solvent: O
Product: Nc1ncc(-c2ccc(C(=O)O)c(F)c2)cn1
Temperature: 120 °C

Procedure:
A solution of sodium carbonate (1.4 g, 0.014 mol) in water (8 mL) was added to a mixture of 4-bromo-2-fluorobenzoic acid (1.0 g, 0.0046 mol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (1.5 g, 6.8 mmol), and tetrakis(triphenylphosphine)palladium (0.3 g, 0.2 mmol) in toluene (16 mL) and ethanol (8 mL). The resulting mixture was heated at 120° C. for 15 min. The reaction mixture was washed with ether (3×10 mL) to remove impurity. The aqueous layer was adjusted with 1N HCl to pH 7.0, and purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=234.1.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[N:13]=[CH:14]2)=[CH:9][CH:8]=1)(=O)=O.[OH:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[OH:23][C:24]1[CH:29]=[CH:28][C:27]([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[N:13]=[CH:14]3)=[CH:9][CH:8]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)c1cc2ccc(OS(=O)(=O)C(F)(F)F)cc2cn1
Reactant: OB(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cc2ccc(-c3ccc(O)cc3)cc2cn1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 45.9 %

Procedure:
A suspension of 38 g (113 mmol) of methyl 7-{[(trifluoromethyl)sulfonyl]oxy}-3-isoquinolinecarboxylate, 23.4 g (170 mmol) of (4-hydroxyphenyl)boronic acid, 6.54 g (5.67 mmol) of tetrakistriphenylphosphine palladium(0) and 200 mL of 2.0 M Na2CO3 (aq) in 700 mL of 1,2-dimethoxyethane was stirred at 50° C. for 90 min. The suspension was filtered through a pad of Celite® and the filter cake was washed with EtOAc. The combined organics were washed with water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine before being dried with Na2SO4, filtered and concentrated. Ethyl acetate was added and the mixture was stirred and heated. The mixture was filtered and the concentrated filtrate was purified by silica gel chromatography (eluting with 0-20% acetone in CH2Cl2). Fractions containing the product were combined and concentrated and combined with the solid which had been collected by filtration to give 14.50 g (46%) of methyl 7-(4-hydroxyphenyl)-3-isoquinolinecarboxylate. 1H NMR (400 MHz, DMSO-d6): δ 9.75 (s, 1H), 9.38 (s, 1H), 8.42 (s, 1H), 8.23 (s, 1H), 8.21 (d, J=8 Hz, 1H), 8.15 (d, J=8 Hz, 1H), 7.72 (d, J=9 Hz, 2H), 6.91 (d, J=9 Hz, 2H), 3.91 (s, 3H). ESI-LCMS m/z 280 (M+H)+.
Reaction SMILES: O.[CH2:2]=[CH:3][CH3:4].CCC.[CH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([CH:3]([CH3:4])[CH3:2])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=CC
Reactant: c1ccccc1
Solvent: CCC
Solvent: O
Product: CC(C)c1ccccc1

Procedure:
The first alkylation reactor effluent stream enters a heat exchanger 22, where the first alkylation reactor effluent stream is cooled by exchanging heat indirectly with another stream in the process or with boiler feed water to produce low pressure steam. The cooled first alkylation reactor effluent stream passes through a line 24 and is admixed with another stream containing propylene and propane that enters the process in a line 28. This produces a second alkylation reactor feed stream carried by a line 26. The second alkylation reactor feed stream may be heated in a heat exchanger or a heater, which is not shown, and enters a second alkylation reactor 30. The second alkylation reactor feed stream contacts a beta zeolite catalyst maintained at alkylation conditions to alkylate benzene with propylene to produce cumene. The second alkylation reactor effluent stream, which contains benzene, cumene, DIPB, heavier alkylated hydrocarbons, and water, exits the second alkylation reactor 30 in a line 32. The second alkylation reactor effluent stream may be depressured by passing through a pressure control valve which is not shown, may be heated in a heater or heat exchanger which is also not shown, or both. The second alkylation reactor effluent stream then enters a stripping column 40 at a feed point above the top tray of the stripping column 40.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]2[CH2:25][O:24]2)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:27]>C(O)C>[CH2:1]([O:8][C:9](=[O:26])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]([OH:24])[CH2:25][NH2:27])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: O=C(NCCCCc1ccc(OCC2CO2)cc1)OCc1ccccc1
Solvent: CCO
Product: NCC(O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
An ethanol solution of 39 (0.86 g, 2.42 mmol) was saturated with ammonia and stirred overnight at room temperature. The solvent was evaporated and the residue was purified by Flash™ (BIOTAGE, Inc) (90 g silica gel cartridge 40M, 6:1:0.1 chloroform/ethanol/concentrated ammonium hydroxide) to provide 40 (0.75 g, 87%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.40 (m, 2H), 1.51 (m, 2H), 2.50 (m, 2H), 2.58 (m, 1H), 2.68 (m, 1H), 3.00 (m, 2H), 3.69 (m, 1H), 3.80 (m, 1H), 3.90 (m, 1H), 5.08 (s, 2H), 6.82 (d, 2H), 7.06 (d, 2H), 7.35 (br s, 5H).
Reaction SMILES: [Br:1]C1C=C(C2C(C(Cl)=O)=CC=CC=2)[ClH]C=1.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[CH:20]=[CH:19][C:18]=1[C:24]1[C:29]([C:30]2[NH:31][CH:32]=[CH:33][N:34]=2)=[CH:28][N:27]=[C:26]([NH:35][CH2:36][CH2:37][NH:38][C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][N:40]=2)[N:25]=1>>[Br:1][C:21]1[CH:20]=[CH:19][C:18]([C:24]2[C:29]([C:30]3[NH:31][CH:32]=[CH:33][N:34]=3)=[CH:28][N:27]=[C:26]([NH:35][CH2:36][CH2:37][NH:38][C:39]3[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][N:40]=3)[N:25]=2)=[C:17]([Cl:16])[CH:22]=1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Product: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Br)cc3Cl)n2)nc1

Procedure:
[4-(4-bromo-2-chlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine was prepared from 4-bromo-2-chlorolbenzoyl chloride using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:8][CH:7]=1>C1COCC1.[Cl-].[Cl-].[Zn+2]>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([OH:13])[CH2:1][CH3:2])=[CH:10][CH:11]=1
Reactant: CC[Mg]Cl
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCC(O)(c1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of ethylmagnesium chloride (153.1 mg, 1.723 mmol) in THF (10.0 mL, 123 mmol) was added zinc dichloride (47.0 mg, 0.345 mmol) at rt. The resulting mixture was stirred at rt for 1 h. Then to this mixture, (4-bromophenyl)phenyl methanone (300.00 mg, 1.1489 mmol) in THF (5 mL) was added at 0° C. The mixture was then stirred at 0° C. for 2 h. The solvent was then removed under reduced pressure and the resulting residue was purified by a flash chromatography(2% EtOAc in hexane).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10](=[CH:11][O:12]C)[CH2:9][CH2:8][N:7]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:6]1)=[O:4].[OH-].[Na+]>C1COCC1.Cl>[CH3:1][O:2][C:3]([C:5]1([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:10]([CH:11]=[O:12])[CH2:9][CH2:8][N:7]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:6]1)=[O:4]
Reactant: COC=C1CCN(Cc2ccccc2)CC1(Cc1ccccc1)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2ccccc2)CN(Cc2ccccc2)CCC1C=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of the compound of Example 200, Step B (3.02 g, 8.26 mmol) in THF (40 mL) and 10% aqueous HCl solution (40 mL) was allowed to stir at room temperature for 14 h. The solution was adjusted to pH 9 with 5N NaOH and extracted twice with CH2Cl2. The combined organic layers were washed with a saturated aqueous brine solution, dried over Na2SO4, filtered and concentrated under vacuum. Purification by silica gel chromatography employing 3-5% EtOAc/CH2Cl2 as the eluant afforded the compound of Example 200, Step C as a mixture of isomers (1.89 g): +APcI MS (M+1)+ 352; 1H NMR (400 MHz, CDCl3) δ: 9.82 and 9.81 (s, 1H), 7.02-7.45 (arom, series of m, 10H), 3.64 and 3.60 (s, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:17][C:18](O)=[O:19])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1>>[Br:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:18](=[O:19])[CH2:17][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)=[CH:8][CH:9]=2)=[CH:24][C:23]=1[N:29]1[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]1
Reactant: O=C(O)Cc1ccc(-c2ccncc2)c2ccccc12
Reactant: CN1CCN(c2cc(N)ccc2Br)CC1
Product: CN1CCN(c2cc(NC(=O)Cc3ccc(-c4ccncc4)c4ccccc34)ccc2Br)CC1

Procedure:
The title compound was prepared from 4-(pyridin-4-yl)naphth-1-ylacetic acid (D2) and 4-bromo-3-(4-methylpiperazin-1-yl)aniline (Intermediate 44, EP 0533268A1) using a similar procedure to Example 20 (73%).
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[CH2:3][CH2:4][N:5]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([NH:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:8]=1>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([N:5]([CH2:27][CH2:28][CH:29]([CH3:30])[CH3:31])[CH2:4][CH2:3][CH:2]([CH3:1])[CH3:32])=[O:26])=[CH:8][C:9]=1[NH:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(NCCCN2CCCCC2)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccc(N)c(NCCCN2CCCCC2)c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
N,N-bis(3-methylbutyl)-4-nitro-3-[(3-piperidin-1-ylpropyl)amino]benzamide (1 g) in solution in a mixture of ethyl acetate/ethanol 2:1 (100 ml) and 10% palladium on carbon (100 mg) are introduced into an autoclave. After stirring for 3 hours under a hydrogen atmosphere (3 bars) at a temperature of approximately 20° C., the catalyst is eliminated by filtration on celite and the filtrate is concentrated under reduced pressure at 40° C. in order to produce the expected compound in the form of an oil (910 mg, 97% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]([F:16])([F:15])[F:14])[N:5]=[C:4]([NH:17][CH3:18])[N:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[F:30])#[N:20].C([O-])(O)=O.[Na+]>O1CCOCC1.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>[F:30][C:22]1[CH:23]=[C:24]([C:2]2[CH:7]=[C:6]([N:8]3[CH2:12][CH2:11][CH2:10][C@H:9]3[C:13]([F:16])([F:15])[F:14])[N:5]=[C:4]([NH:17][CH3:18])[N:3]=2)[CH:25]=[CH:26][C:21]=1[C:19]#[N:20]
Reactant: CNc1nc(Cl)cc(N2CCC[C@H]2C(F)(F)F)n1
Reactant: N#Cc1ccc(B(O)O)cc1F
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: C1COCCO1
Product: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2CCC[C@H]2C(F)(F)F)n1
Temperature: 100 °C

Procedure:
4-Chloro-N-methyl-6-[(2S)-2-(trifluoromethyl)-1-pyrrolidinyl]-2-pyrimidinamine (110 mg, 0.392 mmol) and (4-cyano-3-fluorophenyl)boronic acid (97 mg, 0.588 mmol) were dissolved in 1,4-dioxane (4 mL) in a 20 mL sealable vial. Saturated NaHCO3 solution (5 mL) was added, and N2 gas was bubbled through the mixture for 10 minutes. Then Pd(Ph3P)4 (371 mg, 0.321 mmol) was added, and N2 gas was bubbled through the mixture for an additional 5 minutes. The reaction vial was then capped and heated at 100° C. overnight. The reaction was diluted with water (10 mL) and then extracted with EtOAc (3×10 mL). Organic was then combined, dried over MgSO4, filtered and concentrated. The yellow oil was then purified on Biotage SNAP 10 g column with a gradient of 0 to 35% EtOAc in Hexane for 30 minutes to afford the title compouns (167 mg). LC-MS (ES) m/z=366 [M+H]+.
Reaction SMILES: Cl[CH2:2][O:3][CH3:4].C(N(C(C)C)CC)(C)C.[OH:14][CH2:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1>ClCCl>[CH3:4][O:3][CH2:2][O:14][CH2:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: COCCl
Reactant: COC(=O)c1ccc(-c2cccc(CO)c2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOCc1cccc(-c2ccc(C(=O)OC)cc2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Chloromethylmethyl ether (0.24 ml) and diisopropylethylamine (0.74 ml) was added to a solution of methyl 3′-hydroxymethylbiphenyl-4-carboxylate (504 mg), which is the product of Reference example 15(a), in anhydrous dichloromethane (10 ml) at 0° C. The mixture was stirred at 0° C. for 1 hour and then allowed to stand at ambient temperature for 14 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the layers were separated. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified via chromatography on a silica gel column using hexane/ethyl acetate=2/1 as the eluant to afford the desired compound (467 mg) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[C:7]([CH2:9][OH:10])[NH:6][N:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:17][C:18]1([CH3:21])[CH2:20][O:19]1>>[OH:10][CH2:9][C:7]1[N:6]([CH2:17][C:18]([CH3:21])([OH:19])[CH3:20])[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=1
Reactant: CC1(C)CO1
Reactant: O=[N+]([O-])c1cc(CO)[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(C)(O)Cn1nc([N+](=O)[O-])cc1CO
Temperature: 70 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
A sealed tube was charged with 330d (2.145 g, 15 mmol), Cs2CO3 (978 mg, 3.0 mmol), and 2,2-dimethyloxirane (15 mL). The mixture was stirred at 70° C. for 3 h. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (5:1 to 1:1) to afford 330e (1.2 g, 38%) as a white solid. MS-ESI: [M+H]+ 216.2
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[C:6](OCC)=[O:7])[CH3:2].O.[NH2:16][NH2:17]>C(O)C>[CH2:1]([O:3][C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([NH:16][NH2:17])=[O:7])[CH3:2]
Reactant: CCOC(=O)c1ccccc1OCC
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCOc1ccccc1C(=O)NN
Temperature: 25 °C

Procedure:
Ethyl 2-ethoxybenzoate (100 g, 128.7 mmol) and hydrazine hydrate (100%, 25 ml, 128.7 mmol) are dissolved in 200 ml of ethanol and heated under reflux for 5 hours. A further 12.5 ml (64.3 mmol) of hydrazine hydrate are added and the reaction mixture is heated under reflux for a further 7 hours. For working up, the reaction mixture is extensively concentrated and then stirred with 300 ml of cyclohexane at room temperature. After cooling to 0° C., the crystals are filtered off with suction, washed twice with 50 ml of cold cyclohexane each time and finally dried in a vacuum oven at 35° C. and 300 mbar overnight.
Reaction SMILES: [CH:1]1([NH:5][CH:6]([CH3:46])[CH2:7][CH2:8][N:9]([C@@H:24]([C:26]2[N:27]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH3:45])=[CH:39][CH:38]=3)[C:28](=[O:36])[C:29]3[CH:35]=[CH:34][CH:33]=[N:32][C:30]=3[N:31]=2)[CH3:25])[C:10](=[O:23])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)[CH2:4][CH2:3][CH2:2]1.C=O.[C:49](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.ClCCl>[CH:1]1([N:5]([CH3:49])[CH:6]([CH3:46])[CH2:7][CH2:8][N:9]([C@@H:24]([C:26]2[N:27]([C:37]3[CH:38]=[CH:39][C:40]([O:43][CH2:44][CH3:45])=[CH:41][CH:42]=3)[C:28](=[O:36])[C:29]3[CH:35]=[CH:34][CH:33]=[N:32][C:30]=3[N:31]=2)[CH3:25])[C:10](=[O:23])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]([F:21])([F:20])[F:22])[CH:13]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CCOc1ccc(-n2c([C@@H](C)N(CCC(C)NC3CCC3)C(=O)Cc3ccc(F)c(C(F)(F)F)c3)nc3ncccc3c2=O)cc1
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCOc1ccc(-n2c([C@@H](C)N(CCC(C)N(C)C3CCC3)C(=O)Cc3ccc(F)c(C(F)(F)F)c3)nc3ncccc3c2=O)cc1

Procedure:
E4 (31 mg, 0.048 mmol), formaldehyde (37% in water, 5.4 μL, 0.073 mmol), and sodium triacetoxyborohydride (31 mg, 0.15 mmol) was stirred in dichloroethane at room temperature for 45 min. The reaction mixture was diluted with dichloromethane, then washed with saturated aqueous sodium bicarbonate and brine. It was dried over magnesium sulfate, filtered, and concentrated in vacuo. 33 mg of E5 was recovered.
Reaction SMILES: F[C:2](F)(F)C([O-])=O.[C:8]([C:11]1[C:12]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:13][N:14]([C:16]2([CH2:20][C:21]#[N:22])[CH2:19][NH2+:18][CH2:17]2)[CH:15]=1)(=[O:10])[NH2:9].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.C([O-])(O)=O.[Na+]>ClCCCl>[C:21]([CH2:20][C:16]1([N:14]2[CH:15]=[C:11]([C:8]([NH2:9])=[O:10])[C:12]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:13]2)[CH2:17][N:18]([CH3:2])[CH2:19]1)#[N:22]
Reactant: O=C([O-])C(F)(F)F
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccccc3)n2)C[NH2+]C1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Solvent: ClCCCl
Product: CN1CC(CC#N)(n2cc(C(N)=O)c(Nc3ccccc3)n2)C1

Procedure:
To a suspension of 3-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-3-(cyanomethyl)azetidinium trifluoroacetate (Intermediate #38-2) (50 mg, 0.17 mmol) in DCE (2.0 mL) was added sodium triacetoxyborohydride (79 mg, 0.37 mmol), followed by formaldehyde (0.050 mL, 0.67 mmol, 37 wt % in water). The resulting mixture was allowed to stir for 1 hour before saturated aqueous NaHCO3 solution was added and the resulting mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-100%, EtOAc/hexanes) to afford the title compound, Example #20.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH3:17])=[C:5]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][N:10]2[CH2:11][CH2:12][CH:7]([O:6][C:5]3[CH:13]=[CH:14][C:15]([Cl:16])=[C:3]([Cl:2])[C:4]=3[CH3:17])[CH2:8][CH2:9]2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: Cc1c(OC2CCNCC2)ccc(Cl)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1c(OC2CCN(CC3CCN(C(=O)OC(C)(C)C)CC3)CC2)ccc(Cl)c1Cl
Temperature: 20 °C
Reaction time: 14 h
Yield: 79.9 %

Procedure:
Acetonitrile (144 mL) and water (336 mL) were added to a mixture of 4-(3,4-dichloro-2-methyl-phenoxy)-piperidine hydrochloride (60 g), 4-(toluene-4-sulfonyloxymethyl)-piperidine-1-carboxylic acid tert-butyl ester (74.7 g) and potassium carbonate (57.3 g) and the mixture was heated to reflux for 7 h, then cooled over 30 min to 75° C. and held at 75° C. for 14 h, then heated over 30 min to reflux. Acetonitrile (192 mL) was added and then the mixture was cooled to 20° C. over 2 h to give a suspension. The suspension was filtered under vacuum, the filter cake was washed with water (180 mL) and then with acetonitrile (180 mL) and dried under vacuum at 40° C. to give 4-[4-(3,4-dichloro-2-methyl-phenoxy)-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid (73.9 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][C:23]2([C:26]([O:28]C)=O)[CH2:25][CH2:24]2)=[O:21])=[CH:15][CH:14]=1.[H-].[Na+]>CN(C=O)C>[OH:28][C:26]1[C:23]2([CH2:25][CH2:24]2)[O:22][C:20](=[O:21])[C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)C1(OC(=O)Cc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1OC2(CC2)C(O)=C1c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.5 %

Procedure:
To a 0° C. solution of methyl 1-(2-(4-(quinolin-2-ylmethoxy)phenyl)acetoxy)cyclopropanecarboxylate (2.0 g, 6.825 mmol) in DMF (20 mL), NaH (49 mg, 20.477 mol) was added nd the mixture was stirred at RT for 12 h. After complete consumption of the starting material (monitored by TLC), the reaction mixture was quenched with ice water (3 mL) and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (30 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford crude 7-hydroxy-6-(4-(quinolin-2-ylmethoxy)phenyl)-4-oxaspiro[2.4]hept-6-en-5-one (2.0 g, 83%) as a light yellow solid.