Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:19][C@H:18]([OH:20])[CH2:17][C@H:13]2[C:14](O)=[O:15])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C@@H:13]3[CH2:17][C@@H:18]([OH:20])[CH2:19][N:12]3[C:10]2=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)Nc1cc(Cl)cc(Cl)c1
Agent: Cl
Product: O=C1[C@@H]2C[C@@H](O)CN2C(=O)N1c1cc(Cl)cc(Cl)c1
Yield: 50.6 %

Procedure:
(4R)-1-{[(3,5-dichlorophenyl)amino]carbonyl}-4-hydroxy-L-proline (6.8 g) (0.021 mol) (Preparation 5) was combined with 35 mL of 1N HCl and refluxed for 11 hrs. The organic oil was separated from the reaction mixture and dissolved in EtOAc. The organic layer was washed with water, dried over MgSO4, and evaporated under reduced pressure. The resulting residue was purified on a SiO2 column (eluent: DCM/acetone-90/10) to afford the titled compound as a white solid (3.2 g). 1H NMR (CDCl3): 7.4 (2H,d), 7.35 (1H,m), 4.8 (1H,m), 4.60 (1H,dd), 3.98 (1H,dd), 3.35 (1H,d), 2.39 (1H,dd), 2.05 (1H,d,OH), 1.80–1.95 (1H,m).
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH3:16])[CH:10]=2)[C:5]2[C:17]([CH2:23][CH3:24])=[CH:18][C:19]([CH2:21][CH3:22])=[CH:20][C:4]=2[N:3]=1.[C:25](OCC)(=[O:28])[C:26]#[CH:27]>C(O)C>[CH2:23]([C:17]1[C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH3:16])[CH:10]=3)=[N:7][CH2:8][C:2]3[N:3]([CH:27]=[CH:26][C:25](=[O:28])[N:1]=3)[C:4]=2[CH:20]=[C:19]([CH2:21][CH3:22])[CH:18]=1)[CH3:24]
Reactant: C#CC(=O)OCC
Reactant: CCc1cccc(C2=NCC(N)=Nc3cc(CC)cc(CC)c32)c1
Solvent: CCO
Product: CCc1cccc(C2=NCc3nc(=O)ccn3-c3cc(CC)cc(CC)c32)c1

Procedure:
In the manner given in Example 1, 2-amino-6,8-diethyl-5-(m-ethylphenyl)-3H-1,4-benzodiazepine, ethyl propiolate and ethanol were refluxed. The mixture was chromatographed to give 8,10-diethyl-7-(m-ethylphenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([N+:10]([O-])=O)[CH:4]=1.[ClH:13]>[Pd].C(OCC)(=O)C>[NH2:10][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[OH:9].[ClH:13].[NH2:10][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[OH:9]
Reactant: COc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(O)c(N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A 1 L round bottom 3-neck flask equipped with a magnetic stir bar was charged with 4-methoxy-2-nitrophenol (10.0 g, 59.0 mmol) and 10% Pd/C (1 g, 10% by weight) under argon. Ethyl acetate (200 mL) was then added very slowly to the mixture under argon. The mixture was stirred vigorously at room temperature for several minutes before 1.8 mL of concentrated hydrochoric acid was added. The argon was evacuated from the flask under reduced pressure and the flask was then charged with 1 atm of hydrogen gas and stirred for 18 hours at room temperature before its progress was checked by HPLC (Eclipse XDB-C18, 4.6×250 mm, 5 micron, 1-99% CH3CN/H2O with 0.1% trifluoroacetic acid). The chromatogram indicated that all of the starting material (Rt=5.9 min) was consumed and a new single peak had formed (Rt=2.3 min). The reaction was filtered through 10 g plug of Celite. The organic filtrate was then concentrated by rotary evaporation to give 2-amino-4-(methyloxy)phenol as the HCl salt (6.62 g, 38 mmol, 64%) in the form of a brown amorphous solid. MS (ES) m/e 140 [M+H]+.
Reaction SMILES: [O:1]([C:8]1[CH:28]=[CH:27][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][CH:20]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.CN1C[CH2:39][CH2:38][C:37]1=[O:41]>ClCCl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:37](=[O:41])[CH2:38][CH3:39])=[CH:21][CH:20]=2)=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCCC1=O
Reactant: NCc1ccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)NCc1ccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)cc1
Yield: 43 %

Procedure:
N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)propionamide was prepared from (4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine and pyridine instead of N, N-diethylethanamine, 1-methylpyrrolidin-2-one, dichloromethane using Method G (43% yield). HPLC: 99%, RT=4.032 min. MS: m/z=425 [M+H]+, RT=3.22 min.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.Cl[C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].C(O)C>Cl.O>[Br:12][C:10]1[CH:11]=[C:2]2[C:3]([C:4](=[O:6])[N:22]3[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([OH:18])=[O:17])[C:14]3=[N:1]2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(Br)cc1N
Reactant: O=C(O)c1cccnc1Cl
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccn2c(=O)c3ccc(Br)cc3nc12
Temperature: 0 °C

Procedure:
A solution of methyl 2-amino-4-bromo-benzoate (460 mg; 2 mmol), 2-chloronicotinic acid (315 mg; 2 mmol), concentrated hydrochloric acid (5 drops), ethanol (5 ml) and water (25 ml) was heated at reflux for 18 hours, cooled to 0° C. and filtered. The solid filter cake obtained was dried in vacuo and used directly in the next example.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([C:18]#[C:19][CH2:20][CH2:21]O)=[CH:17][C:12]=3[S:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:25][O:26][CH2:27][CH2:28][NH:29][CH3:30]>>[CH3:25][O:26][CH2:27][CH2:28][N:29]([CH3:30])[CH2:21][CH2:20][C:19]#[C:18][C:16]1[CH:15]=[CH:14][C:13]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:24])([F:23])[F:1])=[CH:4][CH:5]=3)=[N:10][S:11][C:12]=2[CH:17]=1
Reactant: CNCCOC
Reactant: OCCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1
Product: COCCN(C)CCC#Cc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
In analogy to example 19.1, 4-[3-(4-Trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol and 2-Methoxyethylmethylamine were converted to yield (2-Methoxy-ethyl)-methyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yl]-but-3-ynyl}-amine as light brown oil, MS: 419 (MH+).
Reaction SMILES: [I-].[CH3:2][S+](C)C.[H-].[Na+].[CH2:8]([O:10][C:11](=[O:20])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[CH3:9]>CS(C)=O>[N:17]1[CH:18]=[CH:19][C:14]([C@@H:13]2[CH2:2][C@H:12]2[C:11]([O:10][CH2:8][CH3:9])=[O:20])=[CH:15][CH:16]=1
Reactant: CCOC(=O)C=Cc1ccncc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccncc1
Reaction time: 0.67 h
Yield: 18.7 %

Procedure:
Trimethylsulfonium iodide (1.50 g, 7.34 mmol) and sodium hydride (0.293 g, 7.34 mmol) were placed into a dry round bottom under nitrogen. DMSO (25 mL) was added and the mixture was stirred for 40 min. The solution turned cloudy. 3-Pyridin-4-yl-acrylic acid ethyl ester (7A, 1.0 g, 5.6 mmol) in DMSO (40 ml) was added dropwise at room temperature. The mixture was left to stir overnight and product was observed the next day by analytical HPLC. The reaction was quenched with 10 mL of water and the mixture was partitioned between ethyl acetate and water. The separated organic layer was dried over Mg2SO4, filtered, and concentrated under reduced pressure. The crude mixture was chromatographed on silica using 10-20% methanol/CH2Cl2 gradient, to give trans-ethyl 2-(pyridin-4-yl)cyclopropanecarboxylate (7B, 0.20 g, 18%) as a cream solid. 1H NMR (METHANOL-d4) δ: 8.39 (d, J=6.1 Hz, 2H), 7.21 (d, J=6.1 Hz, 2H), 4.17 (q, J=7.1 Hz, 2H), 2.42-2.55 (m, 1H), 2.02-2.13 (m, 1H), 1.59-1.69 (m, 1H), 1.42-1.51 (m, 1H), 1.27 (t, 3H). ESI-MS: m/z 192.0 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[C:12]1[CH:13]=[C:14]([C:17]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:18])[S:15][CH:16]=1.[NH4+].[Cl-]>C1COCC1.[Cu]I>[CH:1]1([CH2:7][O:8][C:12]2[CH:13]=[C:14]([C:17]([O:19][CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:18])[S:15][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(OCC1CCCCC1)c1cc(Br)cs1
Reactant: OCC1CCCCC1
Agent: [Cu]I
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: O=C(OCC1CCCCC1)c1cc(OCC2CCCCC2)cs1
Temperature: 25 °C
Reaction time: 288 h

Procedure:
Cyclohexylmethanol (0.50 mL, 4.06 mmol) was added to a suspension of NaH (0.080 g, 3.33 mmol) in anhydrous THF (5 mL). Then cyclohexylmethyl 4-bromothiophene-2-carboxylate (0.56 g, 1.847 mmol) was added to the reaction mixture followed by CuI (0.34 g, 1.79 mmol). The reaction mixture was stirred at room temperature for 12 days then aqueous NH4Cl (25%) was added. Aqueous layer was extracted with EtOAc and combined organic layers were washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. Flash chromatography purification (2%-10% EtOAc—hexanes gradient) gave cyclohexylmethyl 4-(cyclohexylmethoxy)thiophene-2-carboxylate as a colorless oil. Yield (0.17 g, 27%); 1H NMR (400 MHz, CD3OD) δ 7.35 (d, J=1.7 Hz, 1H), 6.75 (d, J=1.7 Hz, 1H), 4.07 (d, J=6.3 Hz, 2H), 3.78 (d, J=6.3 Hz, 2H), 1.65-1.90 (m, 12H), 1.15-1.38 (m, 6H), 1.00-1.15 (m, 4H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13](Br)[N:12]=2)([F:10])[CH3:9])[CH:5]=[CH:4][CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[F-].[K+]>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:18]1([C:2]2[N:7]=[C:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:12]=3)([F:10])[CH3:9])[CH:5]=[CH:4][CH:3]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(F)(c1cccc(Br)n1)c1cccc(Br)n1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1CCOC1
Product: CC(F)(c1cccc(-c2ccccc2)n1)c1cccc(-c2ccccc2)n1
Yield: 88 %

Procedure:
600 μl (2.6 mmol) of tri-tert-butylphosphine and 449 mg (2.0 mmol) of palladium(II) acetate were added to a degassed suspension of 18.0 g (50 mmol) of 1,1-bis(6-bromo-2-pyridyl)-1-fluoroethane, 24.4 g (200 mmol) of benzeneboronic acid and 19.2 g (330 mmol) of potassium fluoride in 350 ml of THF, and the mixture was heated under reflux for 3 h with stirring. After cooling, the THF was removed under reduced pressure, and the residue was taken up in 500 ml of dichloromethane and washed three times with 300 ml of water. After drying over magnesium sulfate, filtration through silica gel and stripping-off of the solvent, the yellow oil remaining was recrystallised three times from ethanol, giving 15.7 g (44 mmol) of the product, corresponding to a yield of 88.6%, in the form of colourless crystal needles—purity according to 1H-NMR>99%.
Reaction SMILES: [CH2:1]1[O:36][C:18]2([CH2:23][CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:21][CH:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:19]2)[O:17][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CC1(C)O[O:39]1>C(O)C>[CH2:1]1[O:36][C:18]2([CH2:23][CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:21]([OH:39])[CH:20]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:19]2)[O:17][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCC1COC2(CC(c3ccccc3)NC(c3ccccc3)C2)O1
Reactant: CC1(C)OO1
Solvent: CCO
Product: CCCCCCCCCCCCCCC1COC2(CC(c3ccccc3)N(O)C(c3ccccc3)C2)O1
Yield: 64.8 %

Procedure:
The general procedure of Example 2 is repeated using 10.9 g (22.2 mmol) of 2,6-diphenyl-4-piperidone 1,2-hexadecylene ketal and 376 mL (22.2 mmol) of dimethyldioxirane (0.059M in acetone). 7.3 g (65% yield) of the title compound is isolated as a white solid by recrystallization from ethanol: mp 98°-100° C.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].[OH:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[C:10]([O:12]CC)=[O:11].C(=O)([O-])[O-].[K+].[K+].C(OC1C=C(C=CC=1)C(O)=O)CC>>[CH2:1]([O:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: CCCCBr
Agent: CCCOc1cccc(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCOc1cccc(C(=O)O)c1

Procedure:
The reaction of butyl bromide and ethyl 3-hydroxybenzoate in the presence of potassium carbonate was performed as described for Compound 24 to give 3-butoxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.93 (s, COOH); 7.48 (m, 1 arom. H); 7.40 (m, 2 arom. H); 7.12 (m, 1 arom. H); 3.97 (t, CH3CH2CH2CH2O); 1.69 (m, CH3CH2CH2CH2O); 1.42 (m, CH3CH2CH2CH2O); 0.91 (t, CH3CH2CH2CH2O). 13C-NMR (100 MHz, d6-DMSO): 167.12 (—C═O); 158.63; 132.13; 129.67; 121.40; 119.31; 114.41; 67.30; 30.64; 18.68; 13.65.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](I)[C:3]=1[C:4]#[N:5].[S:11]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12]1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:13]2[CH:14]=[CH:15][S:11][CH:12]=2)[C:3]=1[C:4]#[N:5]
Reactant: OB(O)c1ccsc1
Reactant: N#Cc1c(F)cccc1I
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: O
Solvent: COCCOC
Product: N#Cc1c(F)cccc1-c1ccsc1
Temperature: 25 °C
Yield: 36.5 %

Procedure:
In a dry round bottom flask were added 2-fluoro-6-iodobenzonitrile (500 mg; 2.02 mmol), 3-thiophene boronic acid (311 mg; 2.43 mmol), sodium carbonate (2.32 g; 21.86 mmol), tetrakis(triphenylphosphine)palladium(0) (77 mg; 0.07 mmol), DME (20 mL) and water (20 mL) and heated to reflux for 5 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (3×), washed with brine (1×) and water (1×). Organic layers were combined and dried over sodium sulfate and then filtered and solvent removed to yield crude material which was purified by column chromatography (4% ethyl acetate/hexane) to obtain 150 milligrams of 2-fluoro-6-thiophen-3-yl-benzonitrile.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH2:20](I)[CH3:21]>CN(C=O)C>[CH2:20]([O:12][C:11](=[O:13])[CH2:10][C:5]1[CH:6]=[CH:7][C:8]([F:9])=[C:3]([C:1]#[N:2])[CH:4]=1)[CH3:21]
Reactant: N#Cc1cc(CC(=O)O)ccc1F
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(F)c(C#N)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
To a suspension of (3-cyano-4-fluoro-phenyl)-acetic acid (500 mg, 2.79 mmol) (Preparation 126) and potassium carbonate (770 mg, 5.58 mmol) in DMF (5 mL) was added ethyl iodide (0.89 mL, 11.16 mmol) and the reaction mixture stirred at room temperature for 4 hours. The crude reaction mixture was poured onto water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with water (5×10 mL), brine (10 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure to afford the title compound as an off-white solid in 87% yield, 500 mg.
Reaction SMILES: C([O:3][C:4]([CH:6]=[C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:10][CH2:9][CH2:8]1)=[O:5])C.[OH-].[Na+]>CO>[C:4]([CH2:6][C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)(=[O:19])=[O:20])[CH2:10][CH2:9][CH:8]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)C=C1CCCN(S(=O)(=O)c2ccc(C)cc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2CCC=C(CC(=O)O)c3ccccc32)cc1
Yield: 99.2 %

Procedure:
A mixture of 5-ethoxycarbonylmethylidene-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (18.6 g), methanol (130 ml) and a 4N sodium hydroxide solution in methanol (9.7 ml) is refluxed for three hours. To the mixture is added a 4N sodium hydroxide solution in methanol (12 ml), and the mixture is refluxed for 4.5 hours. Further, to the mixture is added a 5N aqueous sodium hydroxide solution (9.7 ml), and the mixture is refluxed for one hour and concentrated. To residue are added water and ethyl acetate, and the mixture is acidified with conc. hydrochloric acid. The mixture is extracted with ethyl acetate. The organic layer is washed with water, and dried over magnesium sulfate, and concentrated. The residue is crystallized from diethyl ether--n-hexane, and recrystallized from methanol--water to give 5-carboxymethyl-2,3-dihydro-1-(p-toluenesulfonyl)-1H-benzazepine (17.1 g).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])[CH:15]=2)[C:12](=[O:29])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:30])[N:5]=1)[CH3:3].Cl[C:32]1[C:33]2[CH:40]=[CH:39][NH:38][C:34]=2[N:35]=[CH:36][N:37]=1.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[N:35]1[C:34]2[NH:38][CH:39]=[CH:40][C:33]=2[C:32]([NH:1][C@H:2]([C:4]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([F:28])([F:27])[C:23]([F:24])([F:25])[F:26])[CH:15]=3)[C:12](=[O:29])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[F:30])[N:5]=2)[CH3:3])=[N:37][CH:36]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: C[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)C(F)(F)F)c1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]ccc12)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 36 h
Yield: 10.9 %

Procedure:
Under nitrogen, to (S)-2-(1-aminoethyl)-5-fluoro-3-(3-(2,2,3,3,3-pentafluoropropoxy)phenyl)quinazolin-4(3H)-one (86 mg, 0.20 mmol, 1.0 equiv) in t-BuOH (0.2 mL) at 23° C. was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (34 mg, 0.22 mmol, 1.1 equiv) and diisopropylethylamine (70 μL, 0.40 mmol, 2.0 equiv). After stirring for 36 hr at 120° C. in a sealed tube, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with CH2Cl2/MeOH to afford 12 mg of the title compound (11% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([S:9][CH3:10])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:17]([O:21][CH3:22])(=[O:20])[CH:18]=[CH2:19].N#N>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH3:22][O:21][C:17](=[O:20])[CH:18]=[CH:19][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[S:9][CH3:10]
Reactant: CSc1cc(F)ccc1I
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc(F)cc1SC
Yield: 83.8 %

Procedure:
4-fluoro-1-iodo-2-methylsulfanyl-benzene (6.8 g 25.3 mmol), K2CO3 (9.9 g, 63.4 mmol), methyl acrylate (5.7 ml, 63.4 mmol), Tetra-n-butylammonium chloride (7.0 g, 25.3 mmol) and Pd(OAc)2 (1.1 g, 5.07 mmol) were mixed in DMF (150 ml). The mixture was heated at 50° C. under the atmosphere of N2 overnight, after which water was added and then extracted with ethyl acetate. The extracts were combined, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography to give the desired product (4.8 g, yield 89%).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][C:6](=[O:9])[NH:5][CH2:4][CH2:3][C:2]1=[O:10].[H-].[Na+].Br[CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CN(C=O)C>[C:18]([O:17][C:15]([CH2:14][N:1]1[C:2](=[O:10])[CH2:3][CH2:4][N:5]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6](=[O:9])[CH2:7][CH2:8]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C1CCNC(=O)CCN1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCC(=O)N(CC(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3.3 g of perhydro-1,5-diazocine-2,6-dione are suspended in 30 ml of absolute DMF, and 732 mg of sodium hydride (80%) are then added. The mixture is stirred at RT for 15 min and then cooled to 0° C., and 3.76 ml of tert-butyl bromoacetate are then added. The mixture is stirred at 0° C. for 15 min and at RT for 30 min and then once more cooled to 0° C., and another 732 mg of sodium hydride (80%) are added. After 15 min, a further 3.76 ml of tert-butyl bromoacetate are added using a pipette, and after 15 min, the ice bath is removed and the mixture is stirred at RT overnight. The mixture is diluted with dichloromethane, water is added, the phases are separated and the organic phase is washed twice with water. The organic phase is dried over MgSO4 and concentrated, and the residue is dried under high vacuum and recrystallized from n-hexane. This gives 2.5 g of the title compound of melting point 180° C.; the mass spectrum shows the molecular peaks MH+ and MNH4+ at 371 and 388 Da, respectively.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([CH:7]([C:10]1[CH:14]=[CH:13][NH:12][N:11]=1)[CH2:8][CH3:9])[CH3:6].C(N(CC)C(C)C)(C)C.O[CH:25]1[O:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)[C:26]1=[O:40].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:5]([CH:7]([C:10]1[CH:14]=[CH:13][N:12]([CH:25]2[O:29][CH2:28][N:27]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:37])[F:39])[CH:31]=3)[C:26]2=[O:40])[N:11]=1)[CH2:8][CH3:9])[CH3:6]
Reactant: CCC(CC)c1cc[nH]n1
Reactant: O=C1C(O)OCN1c1cccc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CCC(CC)c1ccn(C2OCN(c3cccc(C(F)(F)F)c3)C2=O)n1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of thionyl chloride (5 mL, 68.55 mmol) in methylene chloride (100 mL) at ˜10° C. was slowly added 3-(1-ethylpropyl)-1H-pyrazole (11.74 g, 84.94 mmol). The resulting solution was stirred for ˜20 minutes and was then cooled to ˜0° C. To this solution was added N,N-diisopropylethylamine (24.7 mL, 141.8 mmol) dropwise and then 5-hydroxy-3-[3-(trifluoromethyl)phenyl]-4-oxazolidinone (14 g, 56.64 mmol), portionwise at temperatures between 0° C. and 15° C. After the addition, the reaction mixture was allowed to warm to room temperature, and then stirred at room temperature for 2 days. To the reaction mixture was then added concentrated aqueous sodium bicarbonate solution (100 mL). The methylene chloride layer was separated, and the aqueous layer was extracted twice with methylene chloride (˜100 mL each). The methylene chloride layers were combined, dried over MgSO4 and then concentrated. The residue was loaded on silica gel in a column and eluted with methylene chloride to give a crude product. The crude product was further purified by trituration in hexanes followed by filtration to give the title compound, a compound of this invention, as a white solid (10.67 g) melting at 83–85° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11](I)=[CH:10][N:9]2[CH:15]=1)=[O:4].C([Mg]Cl)(C)C.CN([CH:26]=[O:27])C.[NH4+].[Cl-]>C1COCC1>[F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([CH:26]=[O:27])=[CH:10][N:9]2[CH:15]=1)=[O:4]
Reactant: CN(C)C=O
Reactant: O=C(Nc1cn2cc(I)ccc2n1)C(F)(F)F
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1ccc2nc(NC(=O)C(F)(F)F)cn2c1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
2,2,2-Trifluoro-N-(6-iodo-imidazo[1,2-a]pyridin-2-yl)-acetamide (Stage 153.2, 1 g, 2.82 mmol) was dissolved in THF (15 mL) and cooled down to −40° C. under nitrogen atm. iPrMgCl in THF (2 M, 2.8 mL) was added dropwise. After 1 h stirring, cold DMF (0.65 mL, 8.46 mmol) in THF (1 mL) was added and the RM warmed up to −10° C. in 4 h. NH4Cl solution was added and the mixture was extracted 3 times with EtOAc. Combined organic layers were washed with brine and dried on Na2SO4. After evaporation of the solvent the crude was purified by preparative HPLC with acetonitrile/water (with 0.1% TFA) to afford the title compound (tR 0.88 min (conditions 2), (MH+=258).