Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:8])/[CH:3]=[CH:4]/[C:5]([OH:7])=[O:6].[CH2:9]=[CH:10][CH:11]=[CH:12][CH3:13].CC(C)C=CC(O)=O.S(=O)(=O)(O)O>CCOCC>[CH:2]([CH:3]1[CH:4]([C:5]([OH:7])=[O:6])[CH:12]([CH3:13])[CH:11]=[CH:10][CH2:9]1)([CH3:8])[CH3:1]
Reactant: CC(C)/C=C/C(=O)O
Reactant: C=CC=CC
Agent: CC(C)C=CC(=O)O
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CC(C)C1CC=CC(C)C1C(=O)O
Temperature: 200 °C
Yield: 65.7 %

Procedure:
A mixture of 70 g (0.61 mol) of trans-4-methyl-2-pentenoic acid and 49 g (0.72 mol) of 1,3-pentadiene was heated for 12 hours at approx. 200° C. in an autoclave. After the reaction mixture had cooled, it was checked by means of GLC for the presence of 4-methyl-2-pentenoic acid. A further 25 g (0.36 mol) of 1,3-pentadiene were added, after which the mixture was again heated for 12 hours at 200° C. This procedure was repeated until no further decrease in the content of 4-methyl-2-pentenoic acid was any longer observed. The reaction mixture obtained was dissolved in 300 ml of ether and extracted with 300 ml of 10% NaOH solution. The alkaline solution thus obtained was acidified with 40 g of concentrated sulphuric acid and then extracted three times with ether. The ether extract was washed with water, dried on MgSO4, evaporated down and distilled. 73 g of 6-isopropyl-2-methyl-3-cyclohexene-1-carboxylic acid were obtained, b.p.: 95°-100° C./70 Pa.
Reaction SMILES: N[C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[C:3]([OH:5])=O.[CH:14]1([NH:22][C:23]([NH2:25])=[S:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([NH:22][C:23]2[S:24][CH:2]([CH2:6][C:7]3[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=3)[C:3](=[O:5])[N:25]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: NC(=S)NC1CCCCCCC1
Product: O=C1N=C(NC2CCCCCCC2)SC1Cc1ccc(O)cc1

Procedure:
Synthesis was performed from (2S)-2-amino-3-(4-hydroxyphenyl)propanoic acid and N-cyclooctylthiourea according to Method E and C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([N+:10]([O-:12])=[O:11])=[CH:5][C:6]=1[N+:7]([O-:9])=[O:8].[N:13](OS(=O)(=O)O)=O.[CH2:20]([N:22]([CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([F:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:21].CO>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O.C(O)(=O)CC>[N+:7]([C:6]1[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[S:3][C:2]=1[N:1]=[N:13][C:26]1[CH:25]=[CH:24][C:23]([N:22]([CH2:20][CH3:21])[CH2:29][CH2:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([S:38]([F:41])(=[O:39])=[O:40])=[CH:36][CH:37]=2)=[CH:28][CH:27]=1)([O-:9])=[O:8]
Reactant: O=NOS(=O)(=O)O
Reactant: Nc1sc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CCN(CCCc1ccc(S(=O)(=O)F)cc1)c1ccccc1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: CCC(=O)O
Solvent: CO
Product: CCN(CCCc1ccc(S(=O)(=O)F)cc1)c1ccc(N=Nc2sc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
2-Amino-3,5-dinitrothiophene (0.01 mol) was dispersed in a mixture of acetic:propionic acid (86:14; 25 cm3), cooled to 0°-5° C. and nitrosyl sulphuric acid (0.01 mol) added portionwise at 0°-5° C. The reaction mixture was stirred for 10 minutes at 0°-5° C. then added dropwise to a mixture of the N-ethyl-N-(4-fluorosulphonylphenylpropyl)aniline (0.01 mol), methanol (50 cm3) and ice (50 g). The resultant precipitate was filtered washed with water and then methanol and oven dried at 50° C. The dry dye has a λmax of 617 nm and gives good fastness to washing, light and heat.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:22])[CH2:9][N:10](CC2C=CC=CC=2)[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[C:23]([F:26])([F:25])[F:24].[H][H]>CO.Cl.[Pd]>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:22])[CH2:9][NH:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[CH:4][C:3]=1[C:23]([F:24])([F:25])[F:26]
Reactant: CC(C)(C)N(Cc1ccccc1)CC(O)c1ccc(N)c(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)NCC(O)c1ccc(N)c(C(F)(F)F)c1

Procedure:
0.45 gm of 1-(4'-amino-3'-trifluoromethyl-phenyl)-2-(N-benzyl-N-tert.butylamino)-ethanol were dissolved in 10 ml of methanol and 1.4 ml of 1N hydrochloric acid, and the solution was hydrogenated in a hydrogenation vessel in the presence of 50 mgm of palladium/coal-catalyst (10%) until 1 mol of hydrogen had been absorbed. The catalyst was removed by filtration, the filtrate was evaporated in vacuo, and the residue was distributed between ethyl acetate and 2N ammonia. The organic layer was washed with water, dried and again evaporated in vacuo. The residue was crystallized from ethanol/water. M.p. 145°-147° C.
Reaction SMILES: [CH3:1][N:2]([C:4](=[O:36])[C:5]([NH:7][C:8]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][N:10]1[C:17](=[O:35])[C:18]([O:26]C(C3C=CC=CC=3)=O)=[C:19]([C:21]([O:23]CC)=O)[N:20]=[C:9]21)=[O:6])[CH3:3].CNC.Cl.[CH:41]1([C:44]2[CH:45]=[C:46]([CH2:51][NH2:52])[CH:47]=[CH:48][C:49]=2[F:50])[CH2:43][CH2:42]1.C(N(CC)CC)C>C(O)C>[CH:41]1([C:44]2[CH:45]=[C:46]([CH:47]=[CH:48][C:49]=2[F:50])[CH2:51][NH:52][C:21]([C:19]2[N:20]=[C:9]3[C:8]4([NH:7][C:5](=[O:6])[C:4]([N:2]([CH3:1])[CH3:3])=[O:36])[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16]4)[CH2:11][N:10]3[C:17](=[O:35])[C:18]=2[OH:26])=[O:23])[CH2:42][CH2:43]1
Reactant: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC1CCC2(NC(=O)C(=O)N(C)C)CC1
Reactant: NCc1ccc(F)c(C2CC2)c1
Agent: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(C)C(=O)C(=O)NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)c(C3CC3)c2)c(O)c1=O
Temperature: 50 °C
Reaction time: 1 h
Yield: 23.5 %

Procedure:
A suspension of ethyl 10-(((dimethylamino)(oxo)acetyl)amino)-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate (0.025 g, 0.050 mmol) and dimethylamine (0.050 mL, 0.101 mmol) (2 M in methanol) in ethanol (1 mL) was stirred at 50° C. for 1 h. Added to the mixture were (3-cyclopropyl-4-fluorophenyl)methanamine hydrochloride salt (0.025 g, 0.126 mmol) and triethylamine (0.070 mL, 0.504 mmol) and the mixture stirred at 90° C. for 5 h. The mixture was cooled to room temperature and concentrated. The brown residue was purified by preparative HPLC: Solvent A=10% ACN/90% H2O/0.1% trifluoroacetic acid; Solvent B=90% ACN/10% H2O/0.1% trifluoroacetic acid; Start % B=0; Final % B=100; Gradient time=20 min; Stop time=23 min; Column=Sunfire 19×100 mm, C18, 5 μm. The resulting purple solid was triturated with hot methanol to give the title compound as a white solid (6.0 mg, 21% yield). 1H NMR (500 MHz, CDCl3) δ: 12.03 (1 H, s), 8.56 (1 H, t, J=5.49 Hz), 8.15 (1 H, s), 7.11-7.20 (1 H, m), 6.85-7.01 (2 H, m),4.49 (2 H, d, J=6.10 Hz), 4.16 (2 H, d, J=3.97 Hz), 3.28 (3 H, s), 2.91 (3 H, s), 2.42-2.65 (3 H, m), 2.01-2.18 (3 H, m), 1.86-2.00 (2 H, m), 1.71 (2 H, ddd, J=13.28, 6.56, 6.41 Hz), 0.90-1.02 (2 H, m), 0.67-0.80 (2 H, m). LCMS (M+H) calcd for C26H31FN5O5: 512.23; found: 512.24.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:4]=1[O:13][CH3:14].C([Li])CCC.[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>O1CCCC1.CCCCCC>[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:8]1[CH:7]=[CH:6][C:5]([C:9]([CH3:11])([CH3:10])[CH3:12])=[C:4]([O:13][CH3:14])[C:3]=1[O:2][CH3:1]
Reactant: BrCCCCCCBr
Reactant: COc1cccc(C(C)(C)C)c1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1c(CCCCCCBr)ccc(C(C)(C)C)c1OC
Reaction time: 3 h
Yield: 15 %

Procedure:
To 27.0 g (0.139 mole) of 1,2-dimethoxy-3-(1,1-dimethylethyl)benzene in 350 mL of anhydrous tetrahydrofuran cooled in an ice-brine bath at -5° was added. 87 mL (0.139 mole) of 1.6M butyl lithium in hexane over 30 minutes. The reaction mixture was stirred at -5° for 3 hours and then at reflux for 1 hour. After cooling in an ice bath, 21.5 mL (0.139 mole) of 1,6-dibromohexane in 75 mL of tetrahydrofuran was added dropwise. The reaction mixture was then stirred at reflux for 17 hours. The solvent was removed under reduced pressure, 50 mL of 3N hydrochloric acid was added and the product was extracted with ether. The extract was washed with sodium bicarbonate solution, dried and concentrated at reduced pressure to an oil. Purification by HPLC using 20% toluene-hexane gave 7.6 g ((15% yield) of 1-(6-bromohexyl)-2,3-dimethoxy-4-(1,1-dimethylethyl)benzene.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][NH:9][CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=[C:4]([OH:19])[C:3]=1[OH:20].[CH2:21]1[O:23][CH2:22]1.Cl>CC(C)=O.C(OCC)(=O)C.C(O)C>[ClH:1].[Cl:1][C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH2:21][CH2:22][OH:23])[CH2:8][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=[C:4]([OH:19])[C:3]=1[OH:20]
Reactant: Oc1cc2c(c(Cl)c1O)CCNCC2c1ccccc1
Reactant: C1CO1
Agent: Cl
Solvent: CCO
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: OCCN1CCc2c(cc(O)c(O)c2Cl)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A 3.9 g sample of 6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine is slurried in 25 ml of acetone and 0.7 g (0.016 mol, 10% excess) of ethylene oxide is added. The mixture is placed in a pressure bottle and stirred at ambient temperature for about 40 hours. The reaction mixture is then heated to 60°-80° for 30 minutes, cooled and filtered. Concentration of the filtrate gives a solid which is taken up in ethyl acetate and reprecipitated with ether. The solid thus obtained is dissolved in ethanol and treated with ethereal hydrogen chloride to give 6-chloro-7,8-dihydroxy-3-(2-hydroxyethyl)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride.
Reaction SMILES: [Br:1][C:2]1[C:8]([Br:9])=[C:7]([O:10][CH3:11])[C:6]([Br:12])=[CH:5][C:3]=1[NH2:4].[CH2:13]([O:15][C:16]([N:18]=[C:19]=[S:20])=[O:17])[CH3:14]>CC(C)=O>[Br:1][C:2]1[C:8]([Br:9])=[C:7]([O:10][CH3:11])[C:6]([Br:12])=[CH:5][C:3]=1[NH:4][C:19]([NH:18][C:16](=[O:17])[O:15][CH2:13][CH3:14])=[S:20]
Reactant: COc1c(Br)cc(N)c(Br)c1Br
Reactant: CCOC(=O)N=C=S
Solvent: CC(C)=O
Product: CCOC(=O)NC(=S)Nc1cc(Br)c(OC)c(Br)c1Br
Temperature: 40 °C
Reaction time: 8 h

Procedure:
2,3,5-Tribromo-4-methoxy-aniline (4.72 g, 13.1 mmol) was dissolved in acetone (150 mL) and ethoxycarbonyl isothiocyanate (1.63 mL, 14.4 mmol) was added. The solution was heated to 40° C. After 20 minutes a pale yellow precipitate had formed. The viscous mixture was cooled to rt and stirred at rt overnight. The solvent was removed under reduced pressure. Cyclohexane (˜150 mL) was added to the residue and the suspension sonicated. The solid was collected by filtration through a PTFE filter to give an off-white fluffy solid which was dried in the vacuum oven (40° C.) to afford the desired compound as an off-white solid, 6.00 g (93%). m/z: 488.78/490.80/492.75/494.80 [M+H]+.
Reaction SMILES: C[CH2:2][N:3]([CH:7]([CH3:9])C)[CH:4](C)C.C1C=CC2N(O)N=[N:16][C:14]=2[CH:15]=1.[CH3:20][N:21](C=O)[CH3:22]>>[CH3:15][CH2:14][N:16]=[C:20]=[N:21][CH2:22][CH2:9][CH2:7][N:3]([CH3:2])[CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CN(C)C=O
Reactant: CCN(C(C)C)C(C)C
Product: CCN=C=NCCCN(C)C

Procedure:
General procedure using: the racemic Boc-protected peptidomimetic (400 mg, 1.2 mmol); (2S,3S)-epoxysuccinic acid monoester (160 mg, 1.0 mmol), DIPEA (0.43 mL, 2.5 mmol) and HOBT (76 mg, 0.56 mmol) in DMF (5 ml); EDCI (210 mg, 1.1 mmol) in DMF (0.5 mL) gave the title compound (217 mg, 45.8%) as a racemic mixture in the form of a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 12.50 (bs, 1H); 11.90 (bs, 1H); 8.85-8.76 (dd, 1H, J=7.14 Hz); 7.95-7.91 (q, 2H); 7.64-7.58 (m, 2H); 7.28-7.24 (t, 2H); 6.84 (bs, 1H): 4.79-4.75 (q, 1H); 4.22-4.18 (q, 2H); 3.74-3.73 (dd, 1H, J=1.80 Hz); 3.63-3.62 (dd, 1H; J=1.80 Hz); 3.17-3.08 (m, 2H); 1.25-1.21 (t, 3H). 13C NMR (DMSO-d6, 100 MHz): 169.53, 168.87, 168.81, 165.98, 165.83, 162.89, 160.47, 157.65, 147.82, 134.58, 132.10, 127.64, 127.56, 116.40, 115.60, 115.40, 108.04, 52.98, 52.75, 51.90, 28.55, 28.42.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.[CH:15]1([CH2:27][CH2:28][N:29]=[C:30]=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[K+].[Br-]>C(Cl)(Cl)Cl>[CH:15]1([CH2:27][CH2:28][NH:29][C:30]([C:1]2[C:6](=[O:7])[O:5][CH2:4][C:2]=2[OH:3])=[O:31])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C=NCCC1CCCCCCCCCCC1
Reactant: O=C1COC(=O)C1
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(NCCC1CCCCCCCCCCC1)C1=C(O)COC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a dry flask containing 40 mL of chloroform was added 1.87 g (18.7 mmol) of tetronic acid, 2.29 g (18.7 mmol) of 4-N,N-dimethylaminopyridine, 2.6 mL (18.7 mmol) of triethylamine followed by 4.4 g (18.7 mmol) of 2-cyclododecylethyl isocyanate. The reaction mixture was allowed to stir overnight at room temperature, after which time a small amount of starting materials was still evident by TLC. The reaction mixture was quenched with 1N HCl, the layers separated, the organic fraction dried over MgSO4, filtered, and stripped of solvent. The residue was flash chromatographed using acidic silica gel eluting with 25% EtOAc/hexane to give a yellow solid. M.P. 135°-137° C. Spectral data follow: 1H NMR (DMSO-d6) δ8.05 (bs, 1H), 4.6 (s, 2H), 4.2 (bs, 10 H), 3.25 (t, 2H), 2.5 (s, 3H), 1.2-1.4 (bm, >20 H); IR (KBr) 3340, 2920, 2850 (C--H), 1750, 1650 cm-1 (C=O);
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2].[Cl-].[NH4+].O.O1CCCC1>C(O)C.[Fe]>[C:1]([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[CH:8][N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc(Sc2ccc([N+](=O)[O-])cc2)s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ncc(Sc2ccc(N)cc2)s1
Yield: 79.5 %

Procedure:
To a mixture of 2-acetylamino-5-(4-nitrophenylthio)thiazole (2.8 g) and ammonium chloride (0.3 g) in a mixture of ethanol (60 ml), water (30 ml) and tetrahydrofuran (20 ml) was portionwise added the iron powder (3 g) at 80° C. with stirring. The mixture was refluxed for 2.5 hours with stirring. The reaction mixture was filtered by suction and the filtrate was concentrated under reduced pressure. The residue was triturated with water, the precipitates were collected by filtration, washed with water and dried in vacuo to give 2-acetylamino-5-(4-aminophenylthio)thiazole (2.0 g, yield: 79.5%). mp: 255°-257° C. (dec.)
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].CC1C=CC(S(O[CH2:22][CH2:23][C:24]([OH:27])([CH3:26])[CH3:25])(=O)=O)=CC=1>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:22][CH2:23][C:24]([CH3:26])([OH:27])[CH3:25])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Product: Cc1cc(OCCC(C)(C)O)cc(C)c1Br
Yield: 101.9 %

Procedure:
According to the method of (Example 10) <Step 2>, from 4-bromo-3,5-dimethylphenol (3.60 g) and 3-hydroxy-3-methylbutyl 4-methylbenzene sulfonate (5.09 g), the subject compound (5.24 g) was obtained as a colorless oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:28]2[NH:33][C:32](=[O:34])[CH:31]=[C:30]([CH3:35])[N:29]=2)[NH:17]C(OCC2C=CC=CC=2)=O)=[CH:11][C:10]=1[C:36]([CH3:39])([CH3:38])[CH3:37])C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:17][CH:16]([C:28]1[NH:33][C:32](=[O:34])[CH:31]=[C:30]([CH3:35])[N:29]=1)[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([C:36]([CH3:37])([CH3:38])[CH3:39])[CH:11]=1
Reactant: [H][H]
Reactant: Cc1cc(=O)[nH]c(C(Cc2ccc(OCc3ccccc3)c(C(C)(C)C)c2)NC(=O)OCc2ccccc2)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(=O)[nH]c(C(N)Cc2ccc(O)c(C(C)(C)C)c2)n1
Yield: 81.6 %

Procedure:
A suspension of 2-[2-(4-benzyloxy-3-tert-butylphenyl)-1-benzyloxycarbonylaminoethyl]-6-methyl-4-pyrimidinone (1.76 g, 3.35 mmol) and 20% palladium hydroxide/carbon (0.15 g) in methanol (30 ml) was stirred in a hydrogen atmosphere for 16 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: methylene chloride:methanol=10:1), giving the titled compound (824 mg, 82%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39].[CH3:40][N:41]([CH3:45])[CH2:42][CH2:43][NH2:44]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:44][CH2:43][CH2:42][N:41]([CH3:45])[CH3:40])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39]
Reactant: CN(C)CCN
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(NCCN(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 71.2 %

Procedure:
To a solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (15 mg, 0.027 mmol) in DCM (5 mL) was added N,N-dimethyl-1,2-ethanediamine (0.009 mL, 0.083 mmol). The resultant mixture was stirred at room temperature overnight. The mixture was concentrated under vacuo. Flash chromatography (90% CH2Cl2/7% MeOH/3% NH4OH) then provide the title compound (11 mg, 72%). LC-MS (ES) m/z 573 (M+H)+; 1H-NMR(CDCl3) δ 2.21 (s, 6H), 2.30 (s, 3H), 2.40 (br, 1H), 2.43 (m, 2H), 3.17 (m, 2H), 3.55 (br, 1H), 6.23 (d, 1H), 6.89 (m, 1H), 7.04 (m, 3H), 7.29 (m, 1H), 7.36 (m, 1H), 7.47 (d, 1H), 7.61 (m, 2H), 7.84 (s, 1H), 8.05 (d, 1H).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([CH3:21])([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.C([Mg]Cl)(C)C.[CH2:27]([Sn:31](Cl)([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH3:30]>O1CCCC1>[CH3:12][C:11]([C:9]1[CH:8]=[CH:7][N:6]2[C:2]([Sn:31]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:27][CH2:28][CH2:29][CH3:30])=[CH:3][N:4]=[C:5]2[N:10]=1)([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:21]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(Br)cnc2n1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(C)(C)O[Si](CC)(CC)CC)ccn12
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a cooled (−78° C.) solution of 3-bromo-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (440 mg, 1.20 mmol) in tetrahydrofuran (4 ml) was added isopropylmagnesium chloride (0.63 ml of a 2M solution in tetrahydrofuran, 1.26 mmol). After stirring at −78° C. for 5 min tributyltin chloride (0.36 ml, 1.32 mmol) was added, the reaction stirred for 10 min at −78° C., then allowed to warm to ambient temperature, to give a solution of 7-(1-methyl-1-triethylsilanyloxyethyl)-3-tributylstannanylimidazo[1,2-α]pyrimidine: m/z (ES+) 581 (M++H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N+:3]=1[O-].Cl.[NH2:12][C@H:13]1[CH2:17][CH2:16][N:15]([C:18](=[O:31])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)[CH2:14]1.NN1CCCC1.[CH3:38][CH:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.C(N(CC)C(C)C)(C)C>C(O)CCC>[CH3:38][CH:39]1[CH2:44][CH2:43][N:42]([C:6]2[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([NH:12][C@H:13]3[CH2:17][CH2:16][N:15]([C:18](=[O:31])[CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][C:27]([F:28])([F:29])[F:30])=[CH:24][CH:25]=4)[CH2:14]3)[CH:7]=2)[CH2:41][CH2:40]1
Reactant: N[C@H]1CCN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C1
Reactant: CC1CCNCC1
Reactant: Cc1cc(Cl)cc(Cl)[n+]1[O-]
Agent: Cl
Agent: NN1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(N2CCC(C)CC2)cc(N[C@H]2CCN(C(=O)Cc3ccc(OC(F)(F)F)cc3)C2)n1
Temperature: 110 °C
Yield: 3 %

Procedure:
In the same manner as in Example 13 (1), 1-((S)-3-(4-chloro-6-methyl-1-oxypyridin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.64 g) was obtained from 2,4-dichloro-6-methylpyridin-1-oxide (0.50 g) and 1-((S)-3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride (1.1 g). (2) A mixture of 1-((S)-3-(4-chloro-6-methyl-1-oxypyridin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (300 mg), 4-methylpiperidine (0.30 g), N,N-diisopropylethylamine (0.40 mL), and n-butanol (0.60 mL) was heated at 110° C. for 15 h. The mixture was cooled to room temperature, then the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate−ethyl acetate/methanol=10:1) to obtain the title compound (40 mg) and 1-((S)-3-(4,6′-dimethyl-1′-oxy-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (200 mg). (3) 1-((S)-3-(4,6′-Dimethyl-1′-oxy-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-2′-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (200 mg) was dissolved in methanol (6 mL), followed by addition of 10% Pd—C (200 mg), and the mixture stirred overnight at 40° C. under hydrogen atmosphere. The catalyst was removed by Celite filtration, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, chloroform/methanol=10:1) to obtain the title compound (64 mg).
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](Br)[C:8]=1[F:14].[B:15](OC)([O:18]C)[O:16]C.Cl>CCCCCC.C(OCC)C.O>[Br:6][C:7]1[C:8]([F:14])=[C:9]([B:15]([OH:18])[OH:16])[CH:10]=[CH:11][CH:12]=1
Reactant: Fc1c(Br)cccc1Br
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: OB(O)c1cccc(Br)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
290 ml of a 1.6 molar solution of butyllithium in hexane are added dropwise at −70° C. to a solution of 112 g of 2,6-dibromofluorobenzene [1435-54-7] in 1000 ml of diethyl ether. After the mixture has been kept at the same temperature for 2 hours, 60 ml of trimethyl borate are added, and the mixture is stirred at this temperature for 12 hours. After the mixture has been slowly warmed to room temperature, 300 ml of water are added, and the pH is adjusted to 1 by addition of hydrochloric acid. The organic phase is separated off, the aqueous phase is extracted twice with 100 ml of ether each time, and the combined organic phases are dried under reduced pressure, giving 91 g of 3-bromo-2-fluorophenylboronic acid (mixed with its cyclic anhydride) as a brown solid; 1H-NMR (DMSO-d6): 7.1-7.7 (m) ppm, 19F-NMR (DMSO-d6): −99 ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[F:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([OH:55])[C:50]=1[CH2:56][CH2:57][NH:58][C:59](=[O:61])[CH3:60]>>[C:59]([NH:58][CH2:57][CH2:56][C:50]1[C:49]([F:48])=[CH:54][CH:53]=[CH:52][C:51]=1[O:55][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19]1)(=[O:61])[CH3:60]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: CC(=O)NCCc1c(O)cccc1F
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2cccc(F)c2CCNC(C)=O)cc1

Procedure:
Analogously to Method G, 0.45 g of tert-butyl 4-{4-[3-(2-methoxybenyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.27 g of N-[2-(2-fluoro-6-hydroxyphenyl)ethyl]acetamide are reacted. The title compound is obtained as a yellow oil. Rf=0.58 (EtOAc); Rt=5.57.