Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13](=[O:29])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:38][C:39]1[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=1B(O)O.[F-].[Cs+]>>[F:38][C:39]1[C:44]([F:45])=[CH:43][CH:42]=[CH:41][C:40]=1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[C:13]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:15]=1)=[O:29]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: OB(O)c1cccc(F)c1F
Agent: [Cs+]
Agent: [F-]
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3cccc(F)c3F)ccc2c1
Temperature: 85 °C
Yield: 70.1 %

Procedure:
Charge a flask with trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (2.0 g, 3.7 mmol), 2,3 difluorophenyl boronic acid (1.17 g, 7.4 mmol) palladium dichloride bis(triphenylphosphine) (518 mg, 0.74 mmol) and cesium fluoride (5.06 g, 33.3 mmol) and add 250 mL degassed acetonitrile. Heat the mixture at 85° C. for two hours, cool the reaction and filter off any solids. Purify on an SCX column eluting with 2N ammonia/methanol. Purify further on a silica gel column eluting with a 0-10% methanol/methylene chloride gradient to give 1.3 g (70%) of the title compound: 1H-NMR (CD3OD, 400 MHz) δ7.92 (d, J=8.8 Hz, 1H); 7.54 (dd, J=8.4, 4.0 Hz, 3H); 7.43 (dd, J=8.4, 1.6 Hz, 1H); 7.31 (d, J=2.8 Hz, 1H); 7.09 (dd, J=9.2, 2.4 Hz, 1H); 7.05-6.92 (m, 3H); 6.79 (d, J=8.8 Hz, 2H); 4.10 (t, J=5.6 Hz, 2H); 3.93 (s, 3H); 2.73 (t, J=5.2 Hz, 2H); 2.50-2.50 (m, 4H); 1.62-1.57 (m, 4H); 1.48-1.43 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[C:20]1(OB(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[N+:17]([C:3]1[CH:4]=[C:5](/[CH:8]=[CH:9]/[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:6]=[CH:7][C:2]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(Br)c([N+](=O)[O-])c1
Reactant: OB(O)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)/C=C/c1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 93.2 %

Procedure:
tert-Butyl trans-3-(4-bromo-3-nitrophenyl)acrylate (7.07 g, 21.5 mmol) was dissolved in 1,4-dioxane (200 mL) and thereto were added phenyl boric acid (5.25 g, 42.1 mmol), cesium carbonate (56.1 g, 172.2 mmol), 1,1-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (0.88 g, 1.1 mmol), and purified water (50 mL). The mixture was stirred under a nitrogen flow at 80° C. for 4 hours. The reaction solution was filtered through celite, alumina, and Florisil, and, thereafter, extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography to obtain tert-butyl trans-3-(3-nitro-4-phenylphenyl)acrylate (6.52 g).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#N.CC(C[AlH]CC(C)C)C.Cl.[OH-:28].[Na+]>C1COCC1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][N:6]2[CH2:7][CH2:8][CH:3]([CH:1]=[O:28])[CH2:4][CH2:5]2)=[CH:12][CH:13]=1
Reactant: [OH-]
Reactant: N#CC1CCN(CCc2ccc(F)cc2)CC1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: O=CC1CCN(CCc2ccc(F)cc2)CC1
Reaction time: 3 h

Procedure:
To a stirred solution of 4-cyano-1-[2-(4-fluorophenyl)ethyl]piperidine (1.00 g, 4.3 mmol) in THF (20 mL) under argon at 0° C. was added DIBAL-H (4.6 mL of a 1.0M solution in THF, 4.6 mmol) via syringe. After stirring overnight at room temperature 10% aqueous HCl (25 mL) was added and the solution was stirred for 3 hours. The entire mixture was then poured into 10% aqueous NaOH (50 mL), then extracted 2x with ether. The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated to afford a pale yellow oil. The oil was chromatographed on silica gel a eluting with EtOAc. The appropriate fractions were combined and evaporated to afford an oil. This oil was distilled (b.p. 166° C., 0.05 mm Hg) to afford 1-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxaldehyde, obtained as a colorless oil. Anal. Calcd for C14H18FNO: C, 71.46; H, 7.71; N, 5.95. Found: C, 71.08, H, 7.81; N, 5.86.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)O1.C([O-])(=O)C.[K+].Cl[C:32]1[CH:37]=[CH:36][N:35]=[C:34]([NH2:38])[N:33]=1.C(#N)C>C(Cl)Cl.O>[N+:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:32]2[CH:37]=[CH:36][N:35]=[C:34]([NH2:38])[N:33]=2)=[CH:21][CH:20]=1)([O-:24])=[O:23]
Reactant: Nc1nccc(Cl)n1
Reactant: CC1(C)OB(c2ccccc2Oc2ccc([N+](=O)[O-])cc2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: Nc1nccc(-c2ccccc2Oc2ccc([N+](=O)[O-])cc2)n1
Temperature: 85 °C

Procedure:
The compound of step 1 (0.034 g, 0.054 mmol), potassium acetate (0.26 g, 2.7 mmol), 4,4,5,5-tetramethyl-2-(2-(4-nitrophenoxy)phenyl)-1,3,2-dioxaborolane (0.460 g, 1.3 mmol), and 4-chloropyrimidin-2-amine (0.17 g, 1.3 mmol) were combined in a sealed tube under nitrogen, to which 7 mL ACN and water (0.73 ml, 40 mmol) were added. The reaction was sealed and heated to 85° C. overnight. The reaction was diluted with DCM and water, and extracted 2× with DCM. The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting material was purified by silica gel chromatography (MeOH/DCM) to give 4-(2-(4-nitrophenoxy)phenyl)pyrimidin-2-amine as a white solid MS m/z=309 [M+H]+. Calc'd for C16H12N4O3: 308.3.
Reaction SMILES: C(N1C2C=CC(C)=CC=2C2CN(C)CCC1=2)#C.Br[C:19]1[CH:28]=[CH:27][C:22]([C:23]([NH:25][CH3:26])=[O:24])=[C:21]([F:29])[CH:20]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[F:29][C:21]1[CH:20]=[CH:19][CH:28]=[CH:27][C:22]=1[C:23]([NH:25][CH3:26])=[O:24]
Reactant: CNC(=O)c1ccc(Br)cc1F
Agent: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: CNC(=O)c1ccccc1F
Temperature: 80 °C

Procedure:
A mixture of 5-ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (268 mg, 1.2 mmol), 4-bromo-2-fluoro-N-methyl-benzamide (230 mg, 1.0 mmol), dichlorobistriphenyl phosphinepalladium (II) (21 mg, 0.03 mmol) and TBAF.3H2O (945 mg, 3.0 mmol) were added to a reaction vessel and the contents heated at 80° C. for 5 min in microwave. After completion of reaction (as monitored by TLC & LCMS), the reaction mixture was poured into water (25 mL) and the compound extracted with EtOAc (3×60 mL). The combined organic layers were dried over sodium sulfate, concentrated under vacuum and purified by reverse phase chromatography to obtain 22 mg of 4-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-5-yl)-2-fluoro-vinyl]-2-fluoro-N-methyl-benzamide and 63 mg of product. 1H NMR (CD3OD, oxalate salt) δ (ppm): 8.30 (m, 1H), 8.80 (t, 1H), 7.50 (t, 1H), 7.38-7.24 (m, 3H), 7.10 (d, 1H), 6.80 (m, 2H), 3.60 (m, 2H), 3.25 (m, 2H), 3.04 (s, 3H), 2.96 (d, 3H), 2.82 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)C(C)=C)[CH2:2][CH2:3]C.Br[C:18]1[CH:25]=[C:22]([CH:23]=[O:24])[C:21]([O:26][CH3:27])=[CH:20][CH:19]=1.CCOCC.[F-].[K+]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:2]([C:20]1[CH:19]=[CH:18][CH:25]=[C:22]([CH:23]=[O:24])[C:21]=1[O:26][CH3:27])([CH3:3])=[CH2:1]
Reactant: COc1ccc(Br)cc1C=O
Reactant: C=C(C)[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=C(C)c1cccc(C=O)c1OC
Reaction time: 3 h
Yield: 50.6 %

Procedure:
Tri-n-butyl-isopropenyltin (12.1 g, 36.6 mmol) dissolved in toluene (10 ml) was added to a mixture of 5-bromo-o-anisaldehyde (6.00 g, 27.9 mmol), tetrakis(triphenylphosphine)-palladium (1.21 g, 1.05 mmol), and 2,6-t-butyl-4-methylphenol (10 mg) in toluene (50 ml) under nitrogen at room temperature. This mixture was heated at reflux for 7 h. Ether and aq. KF solution (80 ml) were added to the reaction mixture, and the resulting solution was stirred for 3 h. Insoluble materials were removed by filtration through Celite. The filtrate was extracted with ether, and the organic phase was washed with 1N-NaHSO4, aq. NaHCO3 and brine. The extracts were dried over Na2SO4, and concentrated by evaporation. The residual oil was purified by chromatography (SiO2, 140 g, 5% EtOAc-hexane) to afford -isopropenyl-o-anisaldehyde as a yellow oil (2.49 g, 51%). 1H NMR δ: 10.47 (s, 1H), 7.93 (d, J=2.6 Hz, 1H), 7.69 (dd, J=8.8, 2.6 Hz, 1H), 6.96 (d, J=8.8 Hz, 1H), 5.35 (br. s, 1H), 5.07 (m, 1H), 3.94 (s, 3H), 2.15 (m, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:23]([F:26])([F:25])[F:24])=[C:13]([C:17]3[CH2:18][CH2:19][O:20][CH2:21][CH:22]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:23]([F:25])([F:26])[F:24])=[C:13]([CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(C3=CCOCC3)c(C(F)(F)F)cc2C1
Agent: O=C[O-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)N1Cc2cc(C3CCOCC3)c(C(F)(F)F)cc2C1

Procedure:
Prepared in analogy to Example A49(b) from 5-(3,6-dihydro-2H-pyran-4-yl)-6-trifluoromethyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and ammonium formate. Off-white solid. MS (m/e): 316.1 ([M+H-Me2C═CH2]+, 100%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][NH:5][CH2:4]1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:14]1([S:20]([N:5]2[CH2:6][CH:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:3]([CH2:2][O:1][S:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:22])=[O:21])[CH2:4]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCC1CNCC1c1ccccc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=S(=O)(OCC1CN(S(=O)(=O)c2ccccc2)CC1c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
A solution of 196 mg (1.1 mmol) of 3-(SR)-hydroxymethyl-4-(SR)-phenylpyrrolidine (from Example 1, Step C) and 27 mg (0.2 mmol) of 4-(N,N-dimethylamino)pyridine in 5 mL of pyridine at 0 ° C. was treated with 488 mg (2.8 mmol) of benzenesulfonyl chloride. The cooling bath was removed and the resulting mixture was stirred at rt for 1 h. The reaction mixture was treated with an additional 290 mg of benzenesulfonyl chloride and the resulting mixture was stirred at rt for 1 h. The reaction mixture was partitioned between 50 mL of ether and 20 mL of sat'd CuSO4 and the layers were separated. The organic layer was washed with 30 mL of H2O, 30 mL of sat'd NaCl, dried over MgSO4 and concentrated in vacuo. Flash chromatography on 30 g of silica gel using3:2 v/v hexanes/ether afforded 340 mg (67%) of the title compound as a solid. 1H NMR (500 MHz, CDCl3): δ2.65-2.72 (m, 1H), 3.21 (dd, J=7.8, 10.3, 1H), 3.44-3.67 (6H), 6.94-7.90 (15H). Mass Spectrum (NH3-CI): m/z 458 (M+1).
Reaction SMILES: [CH:1]1([N:4]2[C:8](=[O:9])[N:7]([CH2:10][C:11]3[C:12]([Cl:21])=[C:13]([CH:17]=[CH:18][C:19]=3[Cl:20])[C:14](O)=[O:15])[N:6]=[N:5]2)[CH2:3][CH2:2]1.S(Cl)([Cl:24])=O>CN(C=O)C.ClCCCl>[CH:1]1([N:4]2[C:8](=[O:9])[N:7]([CH2:10][C:11]3[C:12]([Cl:21])=[C:13]([CH:17]=[CH:18][C:19]=3[Cl:20])[C:14]([Cl:24])=[O:15])[N:6]=[N:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(Cl)c(Cn2nnn(C3CC3)c2=O)c1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Cl)c1ccc(Cl)c(Cn2nnn(C3CC3)c2=O)c1Cl
Yield: 102.4 %

Procedure:
3-[(4-Cyclopropyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)methyl]-2,4-dichlorobenzoic acid (5.05 g) and thionyl chloride (5.48 g) were added to 1,2-dichloroethane (60 ml) and the mixture, after adding several drops of DMF, was refluxed upon heating. After cooling, the solvent was distilled off to obtain crude 3-[(4-cyclopropyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)methyl]-2,4-dichlorobenzoyl chloride (5.46 g).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:2][C:3]([O:5]N1C(=O)CCC1=O)=O.[CH3:20][O:21][C:22](=[O:44])[C@H:23]([CH2:25][C:26]1[CH:33]=[C:31]([I:32])[C:30]([O:34][C:35]2[CH:42]=[C:40]([I:41])[C:39]([OH:43])=[C:37]([I:38])[CH:36]=2)=[C:28]([I:29])[CH:27]=1)[NH2:24]>O>[CH3:20][O:21][C:22](=[O:44])[C@H:23]([CH2:25][C:26]1[CH:27]=[C:28]([I:29])[C:30]([O:34][C:35]2[CH:36]=[C:37]([I:38])[C:39]([OH:43])=[C:40]([I:41])[CH:42]=2)=[C:31]([I:32])[CH:33]=1)[NH:24][C:3](=[O:5])[CH2:2][NH:1][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14]
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reactant: COC(=O)[C@@H](N)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Solvent: O
Product: COC(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)CNC(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 82.5 %

Procedure:
To the Boc-Gly-OSu solution was added under ice-cooling the thyroxine methyl ester solution. The resulting mixture was allowed to stand to reach room temperature, and then stirred for 1.5 hrs. The reaction liquid was allowed to stand overnight, and to this were added 25 ml. of distilled water and 50 ml. of ethyl acetate for extraction with the ethyl acetate. The extraction with 25 ml. of ethyl acetate was repeated three times. The ethyl acetate extracts were combined and dried over anhydrous magnesium sulfate. The dry extract was concentrated in a rotary evaporator and subjected to gel chromatography using a column filled with Sephadex LH-20 (tradename of Pharmacia Corp.). In this procedure, a mixture of acetone and methanol in a volume ratio of 4:1 was employed as the developing solvent. Under confirmation by TLC, the fractions containing the desired product were collected and concentrated under reduced pressure to obtain a crystalline product. There was obtained 950 mg. (yield 82.5%) of the desired product.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[NH2:8][C:9]1[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=1[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>C(O)=O>[CH:5]([NH:8][C:9]1[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=1[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[O:7]
Reactant: Nc1ccccc1CCc1ccccn1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNc1ccccc1CCc1ccccn1
Temperature: 25 °C
Yield: 83 %

Procedure:
An aceticformic anhydride mixture is prepared by mixing acetic anhydride (140 ml.) and formic acid (70 ml.). To this mixture, 2-(o-aminophenethyl)pyridine (59 g., 0.3 mole) is added in one portion with vigorous stirring at 25° C. After 15 minutes the solution is diluted with 450 ml. of water and concentrated in vacuo. The resulting residue is taken up in 1 liter of water and made basic with 50% sodium hydroxide. The basified solution is extracted with chloroform, the chloroform extract washed with water, dried over magnesium sulfate and the chloroform solvent evaporated. Crystallization of the residue from isopropyl acetate provides 57 g. (83% yield) of 2-(o-formamidophenethyl)pyridine melting at 78°-81° C. (uncorrected). An analytical sample (from isopropyl acetate) has a melting point of 83°-83.5° C. (corr.).
Reaction SMILES: O1CCCC1.C([O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][O:19]2)=[CH:12][C:11]=1CC)C.[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(OCC)(=O)C>[O:19]1[CH2:20][CH2:21][CH2:22][CH:18]1[CH2:17][CH2:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][OH:8])=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1ccc(CCC2CCCO2)cc1CC
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1ccc(CCC2CCCO2)cc1
Reaction time: 0.5 h
Yield: 31 %

Procedure:
To an anhydrous tetrahydrofuran (20 mL) solution of ethyl 4-(2-(tetrahydrofuran-2-yl)-ethyl)-benzoic acid ethyl ester (2.2 g, 9.39 mmol) described in Manufacturing Example 82-1-1 was added diisobutyl aluminum hydride (0.97 M toluene solution, 24.2 mL, 23.5 mmol) on a dry ice-ethanol bath (−78° C.) under nitrogen atmosphere. After stirring for 30 minutes, 15% aqueous potassium sodium tartrate solution (100 mL) was added to the reaction liquid, and stirred for 30 minutes at room temperature. After addition of ethyl acetate (200 mL), the organic layer and water layer were separated. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:9 then 2:8) to obtain the title compound (600 mg, 31%).
Reaction SMILES: [Li+].[OH-].O.C([O:6][C:7](=[O:19])[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[C:11]([NH2:16])=[C:10]([CH3:17])[C:9]=1[OH:18])C>C(O)C.O>[NH2:16][C:11]1[C:12]([C:14]#[N:15])=[CH:13][C:8]([C:7]([OH:19])=[O:6])=[C:9]([OH:18])[C:10]=1[CH3:17]
Reactant: CCOC(=O)c1cc(C#N)c(N)c(C)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(N)c(C#N)cc(C(=O)O)c1O
Temperature: 80 °C
Yield: 98.9 %

Procedure:
To a solution of LiOH×H2O (8.4 g, 0.2 mol) in ethanol/water (1:1, 300 mL) was added compound 74 (22 g, 0.1 mol) at RT and the reaction mixture was refluxed at 80° C. for 4 h. The reaction mixture was concentrated under vacuum, the obtained residue was diluted with water (100 mL), washed with pet. ether/ethyl acetate (1:1, 2×200 mL). The aqueous layer was separated, acidified to pH=5 using 1.5N HCl and the obtained solid product was filtered off. The aqueous layer was further extracted with ethyl acetate (2×300 mL), dried and concentrated to give more product. The combined products was washed with 5% ethyl acetate in pet. ether to give the pure title compound (19 g, >95%).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28](N(CC)C(C)C)(C)[CH3:29].BrCC>C1COCC1>[CH2:28]([N:13]1[CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])=[CH:17][CH:16]=2)[CH2:9][C@@H:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:29]
Reactant: Clc1ccccc1-c1ccc(CN2CCN[C@@H](Cc3ccccc3)C2)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCBr
Product: CCN1CCN(Cc2ccc(-c3ccccc3Cl)cc2)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound was made in the following manner: 100 mg of 3-(S)-benzyl-1-(2′-chloro-biphenyl-4-ylmethyl)-piperazine was dissolved in THF, 3 equiv. of N,N-diisopropylethylamine were added followed by 2 equiv. of bromoethane. The reaction was be shaken at room temperature overnight. The reaction was concentrated in vacuo. The residue was diluted with DCM and washed with 1N aqueous NaOH solution. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to afford the title compound as free base. Treatment with 1 equiv. 2M HCl in dioxane and concentration in vacuo gave 16 mg of its hydrochloride salt. Yield 27%, ES MS (+) m/z 405
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([NH:18][S:19](=[O:33])(=[O:32])[NH:20][CH:21]([O:24]CC3C=CC=CC=3)[CH2:22][CH3:23])[C:13]=2[C:34]2[CH:39]=[CH:38][C:37]([Br:40])=[CH:36][CH:35]=2)=[N:6][CH:7]=1.B(Br)(Br)Br.CO>C(Cl)Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([NH:18][S:19](=[O:32])(=[O:33])[NH:20][CH:21]([OH:24])[CH2:22][CH3:23])[C:13]=2[C:34]2[CH:35]=[CH:36][C:37]([Br:40])=[CH:38][CH:39]=2)=[N:4][CH:3]=1
Reactant: CCC(NS(=O)(=O)Nc1ncnc(OCCOc2ncc(Br)cn2)c1-c1ccc(Br)cc1)OCc1ccccc1
Agent: BrB(Br)Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CO
Product: CCC(O)NS(=O)(=O)Nc1ncnc(OCCOc2ncc(Br)cn2)c1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
A solution of 1-benzyloxypropanesulfamic acid[6-(2-(5-bromopyrimid-2-yloxy)-ethoxy)-5-(4-bromophenyl)-pyrimidin-4-yl]-amide (283 mg, 0.408 mmol) in DCM (15 mL) is cooled to −78° C. an then slowly treated with BBr3 (0.816 mL of a 1 M solution in DCM). The reaction mixture is allowed to warm to rt and stirring is continued for 1 h. Methanol (approx. 10 mL) is added to the suspension and stirring is continued for another 10 min before the mixture is diluted with 10% aq. citric acid solution (75 mL) and extracted with DCM (2×75 mL). The organic extracts are washed with water (50 mL), dried over MgSO4, filtered and concentrated. The crude product is purified on prep. tlc plates (silica gel, DCM with 10% methanol) to afford 1-hydroxypropanesulfamic acid[6-(2-(5-bromopyrimid-2-yloxy)-ethoxy)-5-(4-bromophenyl)-pyrimidin-4-yl]-amide (223 mg) as a pale grey foam. LC-MS: tR=0.92 min, [M+H]+=602.87; 1H NMR (CDCl3): δ 8.48 (s, 2H), 8.44 (s, 1H), 7.58-7.54 (m, 2H), 7.18-7.13 (m, 2H), 6.91 (s, 1H), 5.93 (t, J=6.4 Hz, 2H), 4.75-4.70 (m, 2H), 4.65-4.60 (m, 2H), 3.75 (t, J=5.2 Hz, 2H), 3.17 (q, J=6.4 Hz, 2H), 1.85-1.76 (m, 3H).
Reaction SMILES: O.NN.[CH3:4][C:5]1([CH3:20])[CH2:11][CH2:10][C:9](=[O:12])[NH:8][C:7]2[CH:13]=[CH:14][C:15]([N+:17]([O-])=O)=[CH:16][C:6]1=2>[Pd].C(O)C>[NH2:17][C:15]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][CH2:11][C:5]([CH3:20])([CH3:4])[C:6]=2[CH:16]=1
Reactant: CC1(C)CCC(=O)Nc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: CC1(C)CCC(=O)Nc2ccc(N)cc21

Procedure:
Added 13 mL of ethanol, 10% Palladium on activated carbon (62 mg), and hydrazine monohydrate (171 ul) to 5,5-Dimethyl-7-nitro-1,3,4,5-tetrahydrobenzo[b]azepin-2-one (206 mg, 0.8793 mmol). Heated reaction to 60° C. overnight. Filtered reaction through Celite, and purified by normal phase silica gel chromatography eluting with 90/10/1 CH2Cl2/MeOH/NH4OH to obtain an off-white solid to yield 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one. mp 168° C.; LCMS: m/z=205.12 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.35 (br s, 1H), 6.78 (d, 1H, J=8.3 Hz), 6.72 (s, 1H), 6.54 (d, 1H, J=8.3 Hz), 3.76 (br s, 2H), 2.32 (m, 2H), 2.06 (m, 2H), 1.35 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19].O>C(Cl)Cl>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(F)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-fluoroaniline (50.0 g) and triethylamine (157 ml) in CH2Cl2 (700 ml) were added 2,2-dimethyl-propionyl chloride (58.0 ml) over a 30 minutes period. The resulting solution was stirred at r.t. for 2 hour, then water was added and the mixture extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 86.0 g of the title compound. M.p. 124-125° C.; Retention Time HPLC 2.57 min; MS (ES+) 196 (M+H+).