Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C@@:9]3([CH2:15][N:14]4[CH2:16][CH2:17][CH:11]3[CH2:12][CH2:13]4)[O:8][C:5]2=[N:6][CH:7]=1.O.[CH:19]([C:21]1[O:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCO>[O:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:24]3[O:25][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=3)[CH:3]=[C:4]2[CH2:10][C@:9]21[CH2:15][N:14]1[CH2:16][CH2:17][CH:11]2[CH2:12][CH2:13]1
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: Brc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: O=Cc1ccc(-c2cnc3c(c2)C[C@@]2(CN4CCC2CC4)O3)o1
Temperature: 65 °C
Yield: 91.9 %

Procedure:
To a solution of (2R)-5′-bromo-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridine] (6 g, 20.3 mmol) in 400 mL of a DME:H2O:EtOH mixture (7:3:2) was added 5-formyl-2-furanboronic acid (5.67 g, 40.5 mmol). The reaction mixture was purged with N2 (directly into the solvent) and stirred for ten minutes until homogeneous. Solid Na2CO3 (8.6 g, 81.0 mmol) was added to the reaction mixture followed by Pd(PPh3)2Cl2 (711 mg, 1.0 mmol). The reaction mixture was again purged with N2 for 10 min, then heated at 65° C. for 6 h. The reaction mixture was stirred at rt overnight, then concentrated via rotary evaporator. The resulting residue was diluted with CHCl3 and filtered through diatomaceous earth. The CHCl3 filtrate was concentrated and the resulting residue was diluted with 1N HCl and extracted with EtOAc (3×150 mL). The acidic aqueous layer was made basic with the addition of 2N aqueous NaOH (to pH˜12) and the basic aqueous solution was extracted with CHCl3 (3×150 mL). The combined CHCl3 layer was washed with brine, dried (Na2SO4), filtered and concentrated to a solid (5.79 g, 92% yield). This material was used without further purification. 1H NMR (500 MHz, CDCl3) δ 1.46-1.53 (m, 1H), 1.68-1.71 (m, 2H), 2.03-2.04 (m, 1H), 2.22-2.26 (m, 1H), 2.78-2.94 (m, 3H), 2.97 (d, J=14.7 Hz, 1H), 3.00-3.04 (m, 1H), 3.07 (d, J=16.5 Hz, 1H), 3.40 (d, J=14.7 Hz, 1H), 3.47 (d, J=16.5 Hz, 1H), 6.74 (d, J=3.7 Hz, 1H), 7.30 (d, J=3.7 Hz, 1H), 7.89 (s, 1H), 8.48 (s, 1H), 9.62 (s, 1H) MS ES+, m/z=311 (M+H+).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@@H:8]([CH:12]([CH2:17][CH2:18][CH3:19])[C:13]([O:15]C)=[O:14])[C@@H:7]1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1.[Li+].[OH-].O1CCOCC1.Cl>C1COCC1.O>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:30][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@@H:8]([CH:12]([CH2:17][CH2:18][CH3:19])[C:13]([OH:15])=[O:14])[C@@H:7]1[C:20]1[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=1
Reactant: CCCC(C(=O)OC)[C@@H]1CCCN(Cc2cc(C(F)(F)F)ccc2C(F)(F)F)[C@H]1c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: O
Product: CCCC(C(=O)O)[C@@H]1CCCN(Cc2cc(C(F)(F)F)ccc2C(F)(F)F)[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Yield: 74.1 %

Procedure:
A solution of the ester from Step 1 (0.098 g, 0.17 mmol) and LiOH (0.082 g, 3.4 mmol) in THF (3 ml) and water (3 ml) was heated at 60° C. for 16 hrs. Then dioxane (3 ml) was added and the reaction was heated at 100° C. for 16 hrs. The reaction mixture was acidified to pH6 with 2N HCl and extracted with EtOAc. The combined extracts were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (silica, 1-2% MeOH/DCM) to give the acid (0.070 g, 74%). 1H NMR (400 MHz, CD3OD): δ 0.84 (3H, t, J 7.2), 0.86-0.97 (1H, m), 1.21-1.47 (3H, m), 1.61-1.83 (5H, m), 2.17 (1H, dt, J 3.0, 11.7), 2.28-2.34 (1H, m), 2.83 (1H, d, J 11.6), 3.37-3.57 (3H, m), 7.65 (5H, m), 7.75 (1H, d, J 8.2), 8.19 (1H, s).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:7][O:8][P:9](=[O:12])([OH:11])[OH:10].[OH-].[Na+].C(=O)(O)[O-].[Na+].O=C1CCC(=O)N1[O:42][C:43](=O)[CH:44]([NH:58][C:59]([O:61][CH3:62])=[O:60])[CH:45]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CC(C)=O>[CH3:62][O:61][C:59](=[O:60])[NH:58][CH:44]([C:43](=[O:42])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([N:13]([S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:7][O:8][P:9]([OH:10])([OH:11])=[O:12])[CH:45]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: COC(=O)NC(C(=O)ON1C(=O)CCC1=O)C(c1ccccc1)c1ccccc1
Reactant: CC(C)CN(C(CCCCN)COP(=O)(O)O)S(=O)(=O)c1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COC(=O)NC(C(=O)NCCCCC(COP(=O)(O)O)N(CC(C)C)S(=O)(=O)c1ccc(N)cc1)C(c1ccccc1)c1ccccc1
Reaction time: 12 h
Yield: 66 %

Procedure:
57 mL (or approximately 26 mmol) of the aqueous solution of phosphoric acid mono-{6-amino-2-[(4-amino-benzenesulfonyl)-isobutyl-amino]-hexyl}ester (XIX) was neutralized with 40 mL of 1N sodium hydroxide. The pH of the solution (pH-4-5) was then adjusted to pH=8 by adding 150 mL solution of saturated of sodium bicarbonate. To this well stirred solution was added a freshly prepared solution, in 130 mL of acetone, of methoxycarbonylamino-3,3-diphenyl-propionic acid 2,5-dioxo-pyrrolidin-1-yl ester (13.34 g, 34 mmol) prepared according to Anderson et al J. Am. Chem. Soc. 1964, 1839. The resulting clear solution was stirred for 12 h. The reaction mixture was concentrated and the remaining aqueous phase extracted twice with ethyl acetate. The aqueous phase was then acidified with 1N hydrochloric acid and the resulting suspension extracted with ethyl acetate. The organic phase was washed with water then dried over sodium sulfate, filtered and concentrated on a rotary evaporator. The solid residue was again suspended in ethyl acetate and acidified with HCl (g). The resulting beige precipitate was collected by filtration to give 12.5 g (66%) of the title product. Purity was determined by LC_MS and is greater than 97%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](C)[CH:14]=2)[CH2:10][CH2:11][CH3:12])[CH:5]=[N:4][CH:3]=1.[CH3:20]C1(C)C(C)(C)OB(C2C=CC(O)=CC=2)O1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(O)CC.C1(C)C=CC=CC=1.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>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]([C:13]2[CH:14]=[CH:15][C:16]([CH3:20])=[CH:17][CH:18]=2)[CH2:10][CH2:11][CH3:12])[CH:5]=[N:4][CH:3]=1
Reactant: CCCC(Nc1cncc(Cl)n1)c1cccc(C)c1
Reactant: CC1(C)OB(c2ccc(O)cc2)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: Cc1ccccc1
Solvent: CCCO
Solvent: CCOC(C)=O
Product: CCCC(Nc1cncc(Cl)n1)c1ccc(C)cc1

Procedure:
Under a nitrogen atmosphere a mixture of 6-chloro-N-[1-(3-methylphenyl)butyl]pyrazin-2-amine (0.21 g, 0.76 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.23 g, 91 mmol), tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.08 mmol) in toluene-n-propanol (4 mL, 3:1) was treated with 2M aqueous sodium carbonate solution (0.4 mL, 0.84 mmol). The resulting mixture was stirred vigorously whilst being heated under reflux for 22 hours. Once cool ethyl acetate was added and the mixture dried (MgSO4) and filtered. Removal of solvent in vacuo then yielded crude product, which was purified by column chromatography using dichloromethane:diethyl ether (90:10) as eluent to furnish (0.165 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[OH:19].C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].O>CN(C)C=O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)CCCCCBr
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCOc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Reaction time: 0.5 h

Procedure:
6,7-Dichloro-2-cyclopentyl-2,3-dihydro-5-hydroxy-2-methyl-1H-inden-1-one (12 g., 0.04 mole) is dissolved in dimethylformamide (50 ml.), treated with potassium carbonate (5.5 g., 0.04 mole) and heated and stirred on a steam bath for 30 minutes. Ethyl 6-bromohexanoate (8.9 g., 0.04 mole) is added dropwise with good stirring over 15 minutes, then the mixture is heated and stirred in a steam bath for two hours. The reaction mixture is poured into water (400 ml.) and extracted with ether (2×150 ml.). The either extract is dried over sodium sulfate, filtered and the ether removed at reduced pressure. The residue, which crystallizes upon standing, is recrystallized from a mixture of ether and petroleum ether to give ethyl 6-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]hexanoate, 16 g., m.p. 69°-72° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](=O)[CH3:11])[CH:6]=[CH:7][CH:8]=1.P(Cl)(Cl)(Cl)=O.[N:18]#[C:19][NH2:20].O>C1(C)C=CC=CC=1.CCOCC.[Ti](Cl)(Cl)(Cl)Cl>[NH2:20][C:19]1[C:6]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH:9]=[C:10]([CH3:11])[N:18]=1
Reactant: N#CN
Reactant: COc1cccc(CC(C)=O)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc2c(N)nc(C)cc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 17.3 %

Procedure:
A solution of 2.12 g of 3-methoxyphenylacetone and 1.26 mL of phosphoryl chloride in 45 mL of anhydrous toluene was heated under reflux. After 30 minutes the mixture was cooled to 0° C. and a solution of 0.57 g of cyanamide in 23 mL of anhydrous ether was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred at this temperature for one hour. Then the stirred mixture was cooled to 0° C. and 1.5 mL of titanium tetrachloride was added dropwise. The reaction mixture was heated under reflux for 2.5 hours, cooled, 34 mL of water added, the mixture filtered and the sediment was washed with ethyl acetate. The filtrate was made basic using 2N aqueous sodium hydroxide and acted with ethyl acetate. The organic extracts were washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by silica chromatography (dichloromethane/methanol=95/5) yielding 0.42 g of the title compound. 1H-NMR 400 MHz (CDCl3) δ: 2.45 (3H, s), 3.91 (3H, s), 5.0 (2H, br. s), 6.81 (1H, s), 6.90 (1H, d, J=3 Hz), 7.02 (1H, dd, J=3 Hz and J=9 Hz), 7.65 (1H, d, J=9 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:15][CH2:16][CH:17]1[O:21][C:20](=[O:22])[N:19]([CH3:23])[CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH:17]3[O:21][C:20](=[O:22])[N:19]([CH3:23])[CH2:18]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN1CC(CCCl)OC1=O
Reactant: Fc1cccc(N2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: CN1CC(CCN2CCN(c3cccc(F)c3)CC2)OC1=O

Procedure:
A mixture of 8.0 g (0.044 mol) of 1-(3-fluorophenyl)piperazine, 8.0 g (0.049 mol) of 5-(2-chloroethyl)-3-methyl-2-oxazolidinone, 18.7 g (0.176 mol) of anhydrous sodium carbonate, and 0.3 g (0.002 mol) of potassium iodide in 250 mL of 1-butanol was heated at reflux for 16 h. The mixture was concentrated under reduced pressure and the residue partitioned between 300 mL of benzene and 300 mL of water. The benzene layer was washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to give a light-yellow solid. The solid was recrystallized from benzene-petroleum ether (30°-60° C.) to yield 9.5 g (70%) of white soldi, mp 92°-93° C.
Reaction SMILES: [I-:1].[Na+].Br[C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:20])=[N:9][N:10]2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)=[CH:6][CH:5]=1.O1CCOCC1.CNCCNC>[Cu]I.CN(C=O)C>[I:1][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH3:20])=[N:9][N:10]2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=2)=[CH:6][CH:5]=1
Reactant: Cc1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Cc1nn(-c2ccnc(N)n2)c2cc(I)ccc12
Temperature: 115 °C
Reaction time: 8 h

Procedure:
A pressure tube containing copper (1) iodide (37.57 mg, 0.20 mmol), sodium iodide (591.42 mg, 3.95 mmol) and 4-(6-bromo-3-methyl-1H-indazol-1-yl)pyrimidin-2-amine (600 mg, 1.97 mmol) was flushed with nitrogen before the addition of 1,4-dioxane, DMF (3 ml each) and N,N′-dimethylethane-1,2-diamine (0.021 ml, 0.20 mmol). The vessel was sealed and stirred at 115° C. overnight. Reaction was cooled and added to ice water (15 ml) before extracting into DCM (2×20 mL). Combined organics were dried (Na2SO4), filtered and concentrated in vacuo. Crude material purified by column chromatography (Elution with 2% MeOH-DCM to 12% MeOH-DCM) to give the title compound: 1H NMR (500 MHz, DMSO) delta 7.02 (3H, dd, J=5.5, 3.1 Hz), 7.73-7.53 (2H, m), 8.25 (1H, d, J=5.5 Hz), 9.25 (1H, s); LC-MS: m/z=+351.90 (M+H)+. This compound of 79% purity LC-MS was used for the next step without further purification
Reaction SMILES: [S:1]([Cl:4])(Cl)=[O:2].[Br:5][C:6]1[CH:11]=[CH:10][C:9](S(O)=O)=[CH:8][CH:7]=1>ClCCl>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([S:1]([Cl:4])=[O:2])=[CH:8][CH:7]=1
Reactant: O=S(O)c1ccc(Br)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=S(Cl)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (0.53 mL) is added to an ice-cooled solution of 4-bromobenzenesulfinic acid (400 mg) in dichloromethane (15 mL) under an argon atmosphere. The reaction mixture is stirred for 2 h at 0° C., warmed to room temperature, and stirred for an additional 30 min. The mixture is concentrated and the residue is co-evaporated twice with toluene to give crude 4-bromobenzenesulfinic chloride, which is dissolved in tetrahydrofuran (3 mL) and cooled to −78° C. n-Butyllithium (1.6 M in hexane; 2.26 mL) is added to 2,2,2-trifluoroacetamide (205 mg) in tetrahydrofuran (3 mL) at −78° C. and the reaction mixture is stirred for 10 min. The mixture is added to the 4-bromobenzenesulfinic chloride solution at −78° C. and the reaction mixture is stirred for 1 h. The cooling bath is removed and the reaction is quenched by addition of water and brine. The aqueous layer is extracted with ethyl acetate and the combined extracts are washed with brine and concentrated in vacuo to give the title compound which is used for the next step without further purification. LC (method 1): tR=0.92 min; Mass spectrum (ESI+): m/z=314 [M−H]−.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)[CH2:6][CH3:7])C.[OH-].[Na+]>C(O)C.C1COCC1>[CH3:23][C:22]1[O:21][C:20]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[N:19][C:18]=1[CH2:17][CH2:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH:5]([CH2:6][CH3:7])[C:4]([OH:30])=[O:3])=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(CC)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC(Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O
Temperature: 55 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
Under N2, a solution of 2-{4-[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]phenoxy}butyric acid ethyl ester (216 mg, 0.53 mmol) in ethanol (2.5 mL) and THF (2.5 mL) was treated with 2.0 N NaOH (2.0 mL). The reaction mixture was stirred at 55° C. for 1 h and concentrated in vacuo. The resulting slurry was suspended in ethyl acetate, acidified to pH 1 with 1N HCl, and partitioned. The organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo to give a white solid (155 mg, 77%): 1H NMR (400 MHz, CDCl3) δ 1.05 (t, 3H, J=7.57 Hz), 1.92-1.96 (m, 2H), 2.35 (s, 3H), 2.94 (t, 2H, J=6.35 Hz), 4.16 (t, 21H, J=6.60 Hz), 4.41 (t, 1H, J=6.11 Hz), 6.76-6.83 (m, 4H), 7.39-7.41 (m, 3H), 7.97-7.99 (m, 2H); MS (ES) m/e 382.0 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:30])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)(O)[CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][CH3:15])=[CH:8][CH:7]=1.C(O)C.[ClH:34]>C(Cl)(Cl)Cl.CO>[ClH:34].[CH3:30][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9](/[C:12](/[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=2)=[C:13](\[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)/[CH2:14][CH3:15])=[CH:10][CH:11]=1
Reactant: CCC(c1ccccc1)C(O)(c1ccc(OCCN(C)C)cc1)c1cccc(O)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCO
Product: CC/C(=C(/c1ccc(OCCN(C)C)cc1)c1cccc(O)c1)c1ccccc1

Procedure:
40.5 G. (0.1 mole) of the diastereomeric mixture of 1-[4'-(2-dimethylaminoethoxy)phenyl]-1-(3'-hydroxyphenyl)2-phenyl-n-butan-1-ol in 500 ml. ethanol are added to 25 ml. concentrated hydrochloric acid and refluxed for 2 hours. Then the solvent is removed in vacuo and the residue is crystallized from methanol/ ether (1/1). Obtained are colorless crystals having a melting point of 221° C. (dec.); Rf 0.25 [CHCl3 /CH3OH (7/3)]; yield 20.3 g. (48%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[H-].[Na+].[CH2:20]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[CH2:20])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(Oc2ccc(C=O)cc2)cc1Cl
Reactant: C1CCOC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Product: C=Cc1ccc(Oc2ccc(C)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.3 %

Procedure:
To a stirred suspension of 4-[(3-chloro-4-methylphenyl)oxy]benzaldehyde (5.5 g, 22.30 mmol) and methyl(triphenyl)phosphonium bromide (7.96 g, 22.30 mmol) in THF (50 mL) was added NaH (3.12 g, 78 mmol) under nitrogen at 0° C. After the mixture was stirred at room temperature for 3 h, the organic layer was washed three times with brine, dried over Na2SO4, filtered, and concentrated. Purification via flash chromatography afforded the title compound (2.8 g, 51.3% yield). LCMS: rt=4.37 min, [M+H+]=323
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:9]=[C:8]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])OC3C=CC=CC=3)=[CH:20][CH:19]=2)[N:7]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:41][NH:42][CH2:43][CH2:44][OH:45]>CN1C(=O)CCC1>[OH:45][CH2:44][CH2:43][N:42]([CH3:41])[C:25]([NH:24][C:21]1[CH:20]=[CH:19][C:18]([C:8]2[N:7]=[C:6]([CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:9]=2)=[CH:23][CH:22]=1)=[O:33]
Reactant: CNCCO
Reactant: CS(=O)(=O)Cc1cc(N2CCOCC2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CN(CCO)C(=O)Nc1ccc(-c2nc(CS(C)(=O)=O)cc(N3CCOCC3)n2)cc1
Temperature: 70 °C

Procedure:
A solution of phenyl N-[4-[4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]phenyl]carbamate (94 mg, 2 mmol) and triethylamine (0.09 mL, 9.2 mmol) in NMP (1 mL) was added to 2-methylaminoethanol (10 mmol). The mixture was heated at 70° C. for 2 hours and the reaction purified by prep HPLC, to give the desired compound.
Reaction SMILES: [C:1]([N:14](OCC)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].B.C1C[O:28][CH2:27][CH2:26]1>C(N(CC)CC)C>[CH2:1]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([O:28][CH2:27][CH3:26])=[CH:19][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: C1CCOC1
Reactant: CCCCCCCCCCCC(=O)N(OCC)c1ccccc1
Agent: B
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCNc1ccc(OCC)cc1
Reaction time: 20 h
Yield: 75 %

Procedure:
N-dodecanoyl-p-ethoxyaminobenzene (6g, 0.019 mole) was placed in a 250 ml round-bottom flask with Borane/THF complex (50 ml, 1M solution in tetrahydrofuran, stabilized with 5 mole percent sodium borohydride). The flask was flushed with nitrogen, stoppered with a drierite tube and allowed to stand at room temperature for 20 hours. Water was then added slowly to react with excess diborane. Formation of the amine salt was avoided by refluxing the reaction mixture with triethylamine (5 ml) for one hour. The mixture was cooled and the layers separated. The upper layer was washed with water (3 × 20 ml). A fourth wash emulsified the mixture. It was broken by addition of salt. The upper layer was dried with anh. sodium sulphate and evaporated to dryness yielding 5.56g (97%) of white plates of crude product. Crystallization from methanol afforded 4.3g (75%) of N-dodecyl-p-ethoxy-aminobenzene in the form of white plates, m.p. 38°-39° C.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH:11]([C@:14]1([C:20]([N:22]2[CH2:27][C:26]3[CH:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[CH:30]=[CH:31][C:25]=3[O:24][CH2:23]2)=[O:21])[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15]1)([CH3:13])[CH3:12].C(N(CC)CC)C.Cl>C(Cl)Cl>[CH:11]([C@:14]1([C:20]([N:22]2[CH2:27][C:26]3[CH:28]=[C:29]([C:32]([F:34])([F:35])[F:33])[CH:30]=[CH:31][C:25]=3[O:24][CH2:23]2)=[O:21])[CH2:18][CH2:17][C:16](=[O:19])[CH2:15]1)([CH3:13])[CH3:12]
Reactant: CC(C)[C@]1(C(=O)N2COc3ccc(C(F)(F)F)cc3C2)CCC(O)C1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)[C@]1(C(=O)N2COc3ccc(C(F)(F)F)cc3C2)CCC(=O)C1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A solution of DMSO (0.656 mL, 9.24 mmol) in 7 mL of DCM was added dropwise to a cooled (−78° C.) solution of oxalyl chloride (0.403 mL, 4.62 mmol) in 30 mL of DCM. After 5 min, a solution of (3S)-3-isopropyl-3-{[6-(trifluoromethyl)-2H-1,3-benzoxazin-3(4H)-yl]carbonyl}cyclopentanol (826 mg, 2.31 mmol) in 8 mL of DCM was added dropwise. The reaction mixture was stirred at −78° C. for 25 min, then was treated dropwise with neat triethylamine (2.58 mL, 18.5 mmol). After stirring at −78° C. for an additional 10 min, the reaction mixture was allowed to warm to rt and stir for 1.5 h. The mixture was then poured into 1N HCl solution and extracted with DCM. The organic layer was washed with more 1N HCl solution, then with saturated NaHCO3 solution and brine. The organic layer was then dried over anhydrous MgSO4, filtered, and concentrated. The crude product was purified by MPLC (silica, 75% ethyl acetate/hexanes) to provide (3S)-3-isopropyl-3-{[6-(trifluoromethyl)-2H-1,3-benzoxazin-3(4H)-yl]carbonyl}cyclopentanone.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[N:19]=1.O>CS(C)=O>[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[N:19]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCNCC1
Reactant: COc1cccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cccc(N2CCC(NC(C)=O)CC2)n1
Temperature: 130 °C
Reaction time: 50 h
Yield: 43 %

Procedure:
A mixture of 0.088 mole of 4-acetamidopiperidine, 15 g of potassium carbonate, 0.088 mole of 2-chloro-6-methoxypyridine in 100 ml of dimethylsulfoxide is heated with stirring to 130° C. for 50 hours, then it is cooled, the mixture is poured into water and the suspension thus obtained is extracted with diethyl ether. The aqueous phase is extracted with methylene chloride, the organic phase is washed with water, it is dried on anhydrous sodium sulfate and evaporated to dryness. 4-acetamido-1-(6-methoxy-2-pyridyl)piperidine is thus obtained which, after crystallisation in 95% ethanol, melts at 125° to 127° C.