Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:10]3[O:11][CH2:12][CH2:13][NH:14][C:9]=3[CH:8]=2)[CH2:3][CH2:2]1.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Cl:28])[CH:26]=2)[N:21]=[C:20]([CH3:29])[C:19]=1[CH3:30]>>[Cl:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([CH3:29])[C:19]([CH3:30])=[C:18]2[N:14]1[C:9]2[CH:8]=[C:7]([N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:16]=[CH:15][C:10]=2[O:11][CH2:12][CH2:13]1
Reactant: Cc1nc2ccc(Cl)cc2c(Cl)c1C
Reactant: c1cc2c(cc1N1CCOCC1)NCCO2
Product: Cc1nc2ccc(Cl)cc2c(N2CCOc3ccc(N4CCOCC4)cc32)c1C

Procedure:
Prepared according to procedure T using 6-morpholino-3,4-dihydro-2H-benzo-[b][1,4]oxazine (0.1 g, 0.454 mmol) and 4,6-dichloro-2,3-dimethylquinoline (0.2053 g, 0.908 mmol) to give 4-(6-chloro-2,3-dimethyl-4-quinolinyl)-6-(4-morpholinyl)-3,4-dihydro-2H-1,4-benzoxazine as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ ppm 8.01 (1H, d, J=9.5 Hz), 7.64-7.73 (2H, m), 6.77 (1H, d, J=8.6 Hz), 6.22 (1H, dd, J=8.7, 2.6 Hz), 5.41 (1H, d, J=2.7 Hz), 4.26-4.47 (2H, m), 3.57-3.67 (2H, m), 3.47-3.55 (4H, m), 2.69 (3H, s), 2.60-2.66 (4H, m), 2.22 (3H, s); Mass Spectrum (ESI) m/e=410.2 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:12])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C>[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][O:6][C:5](=[O:7])[C:4]1[CH:3]=[C:2]([I:1])[C:10]([O:11][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Br:13])[CH:15]=2)=[C:9]([I:12])[CH:8]=1
Reactant: O=C(O)c1cc(I)c(O)c(I)c1
Reactant: BrCc1cccc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(OCc1cccc(Br)c1)c1cc(I)c(OCc2cccc(Br)c2)c(I)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 83.8 %

Procedure:
A suspension of 3,5-diiodo-4-hydroxybenzoic acid (0.39 g, 1.0 mmol), 3-bromobenzyl bromide (0.62 g, 2.5 mmol), and cesium carbonate (0.98 g, 3.0 mmol) in 10 mL DMF was stirred for 15 hours at room temperature. The mixture was then poured into 1 M HCl (100 mL) and a white precipitate formed. The precipitate was isolated by filtration and was recrystallized from hot isopropanol/chloroform, yielding the title compound as bright white crystals (610 mg, 84%). 1H NMR (400 MHz, CDCl3): δ 8.51 (s, 2H), 7.88 (d, J=7.6 Hz, 1H), 7.62 (d, J=8 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.47-7.34 (m, 3H), 7.26-7.21 (m, 2H), 5.44 (s, 2H), 5.15 (s, 2H). TLC (9:1 Hex:EtOAc), Rf 0.49.
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=2)[CH:13]=[C:12]([N:21]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[CH3:22])[N:11]=1.C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>ClCCl>[Cl:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=2)[CH:13]=[C:12]([N:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:25][CH:24]=2)[CH3:22])[N:11]=1
Reactant: CN(c1ccc(O)cc1)c1cc2ccc(F)cc2c(Cl)n1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccc(F)cc3c(Cl)n2)cc1
Yield: 88.4 %

Procedure:
A mixture of ethyl 2-bromopropionate (1.12 g), 4-[N-(1-chloro-7-fluoroisoquinolin-3-yl)-N-methylamino]phenol (1.70 g), anhydrous potassium carbonate (0.86 g) and methyl ethyl ketone (20 ml) was heated under reflux for a period of 3 hours. The mixture was cooled, diluted with dichloromethane, washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to give an oil which was purified by column chromatography over silica gel (eluant dichloromethane) to give ethyl 2-{4-[N-(1-chloro-7-fluoroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (2.00 g) as a yellow oil. The assigned structure was confirmed by proton magnetic spectroscopy and mass spectrometry. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 1.29 (3H, t); 1.65 (3H, d); 3.47 (3H, s); 4.27 (2H, q); 4.75 (1H, q); 6.47 (1H, s) 6.85-7.20 (6H, m); 7.30 (1H, d).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[CH2:12][NH:11][CH2:10][CH:9]3[F:16])[CH2:3][CH2:2]1.C(OC(=O)[NH:23][C@H:24]([C:26]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=1)[CH3:25])(C)(C)C.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[CH2:12][N:11]([CH2:32][C:29]2[CH:30]=[CH:31][C:26]([C@@H:24]([NH2:23])[CH3:25])=[CH:27][CH:28]=2)[CH2:10][CH:9]3[F:16])[CH2:2][CH2:3]1
Reactant: FC1CNCc2ccc(OCC3CC3)cc21
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@H](N)c1ccc(CN2Cc3ccc(OCC4CC4)cc3C(F)C2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 170 mg (0.660 mmol) 6-cyclopropylmethoxy-4-fluoro-1,2,3,4-tetrahydro-isoquinoline (example XLVII.5) and 164 mg (0.660 mmol) [(S)-1-(4-formyl-phenyl)-ethyl]-carbamic acid tert-butyl ester (example II) in 2 mL THF are added 113 μL (1.98 mmol) AcOH and the mixture is stirred at r.t. for 10 min. The resulting mixture is cooled to 0° C., 210 mg (0.989 mmol) sodium triacetoxyborohydride are added and the reaction mixture is stirred at r.t. for 2 h. The reaction is quenched by the addition of 200 μL water and purified by HPLC (ACN/H2O/NH3).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][C@@H:10](O)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1C=CC(P([N:60]=[N+:61]=[N-:62])(C2C=CC=CC=2)=O)=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:14])[NH:7][C@H:8]1[CH2:12][CH2:11][C@H:10]([N:60]=[N+:61]=[N-:62])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N=[N+]=[N-])C1
Reaction time: 0.08 h
Yield: 99.5 %

Procedure:
To a stirring solution of cis-(3-hydroxy-cyclopentyl)-carbamic acid tert-butyl ester (850 mg, 4.22 mmol) and triphenylphosphine (1.53 g, 5.83 mmol) in THF (25 mL) cooled to 2° C. was added DEAD reagent (0.92 mL, 5.84 mol) over 5 minutes. The mixture was stirred for 5 minutes and DPPA (1.26 mL, 5.84 mmol) was added over 5 minutes. Stirring was continued for 17 hours at room temperature. The mixture was evaporated to dryness. The residue was stirred in ethyl ether briefly and the white solid triphenylphosphine oxide was removed by filtration (1 g). The filtrate was again reduced in volume and purified by silica gel chromatography eluting with ethyl acetate and hexanes to afford trans-(3-azido-cyclopentyl)-carbamic acid tert-butyl ester (950 mg).
Reaction SMILES: [OH:1][C:2]1([C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][N:4]([C:6]([O:8]CC2C=CC=CC=2)=O)[CH2:3]1.CCN(C(C)C)C(C)C.[F:38][C:39]1[C:40]([NH:49][C:50]2[CH:55]=[CH:54][C:53]([I:56])=[CH:52][C:51]=2[F:57])=[C:41]([CH:45]=[CH:46][C:47]=1[F:48])C(F)=O>[Pd].CO>[F:38][C:39]1[C:40]([NH:49][C:50]2[CH:55]=[CH:54][C:53]([I:56])=[CH:52][C:51]=2[F:57])=[C:41]([C:6]([N:4]2[CH2:5][C:2]([C@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])([OH:1])[CH2:3]2)=[O:8])[CH:45]=[CH:46][C:47]=1[F:48]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C1(O)CN(C(=O)OCc2ccccc2)C1
Reactant: O=C(F)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
1,1-Dimethylethyl (2R)-2-(3-hydroxy-1-{[(phenylmethyl)oxy]carbonyl}azetidin-3-yl)piperidine-1-carboxylate (60.8 mg, 0.16 mmol) and 10% Pd/C (30 mg) were taken into methanol (2 mL) and the mixture hydrogenated at ambient pressure for one hour. The suspension was then filtered through a celite pad and concentrated then dried in vacuo to a colorless solid. The solid amine was taken into THF (1 mL) followed by addition of DIPEA (42 μL, 0.24 mmol) and 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride (63 mg, 0.16 mmol), prepared using procedures similar to those described in Reference 1, and the mixture stirred at room temperature for 30 minutes. The reaction mixture was partitioned with ethyl acetate and 1 N aqueous hydrochloric acid and the organic layer washed with brine, dried over anhydrous magnesium sulfate then filtered and concentrated. Purification of the residue by silica gel flash chromatography using hexanes:ethyl acetate 3:2 as eluent afforded 1,1-dimethylethyl (2R)-2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (74.9 mg, 74% yield) as an amorphous solid. 1,1-Dimethylethyl (2R)-2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate 1H NMR (400 MHz, CDCl3): 8.53 (br s, 0.5H), 8.40 (br s, 0.5H), 7.41-7.38 (dd, 1H), 7.34-7.31 (dt, 1H), 7.17-7.14 (m, 1H), 6.86-6.79 (m, 1H), 6.63-6.587 (m, 1H), 4.24-3.90 (m, 4H), 3.37-3.23 (m, 1H), 2.90-2.80 (m, 1H), 1.85-1.54 (m, 7H), 1.43 (s, 9H); MS (EI) for C26H29F3IN3O4: 576 (M-C4H9+).
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([C:24](=[O:34])[N:25]([CH2:31][CH:32]=[CH2:33])[CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[CH2:31]([N:25]([CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:24](=[O:34])[C:19]1[CH:18]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:22]=[C:21]([Cl:23])[CH:20]=1)[CH:32]=[CH2:33]
Reactant: C=CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)C1CCCC1
Reaction time: 2 h

Procedure:
A solution of {2-[3-(allyl-cyclopentyl-carbamoyl)-5-chloro-phenoxy]-ethyl}-pyridin-4-yl-carbamic acid tert-butyl ester (0.030 g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 2 h and then concentrated under reduced pressure The residue was subjected to preparative hplc and the title compound (0.026 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:12][C:3]1[C:2]([CH3:1])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: Cc1c([N+](=O)[O-])ccc2cccnc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1c(N)ccc2cccnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
To a solution of 1.45 g of 8-methyl-7-nitroquinoline in 20 mL of ethanol are added 1.45 g of ammonium formate and a catalytic amount of palladium-on-carbon. The resulting suspension is stirred at room temperature for 3 hours. The reaction mixture is filtered on Celite and the filtrate is rotary evaporated. The residue is purified by flash column chromatography on silica gel, eluting with 50% ethyl acetate/hexanes followed by recrystallization from hexanes/methylene chloride to provide 1.10 g of 7-amino-8-methylquinoline as a pale yellow solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[P:17](Cl)([Cl:20])([Cl:19])=[O:18]>CCOCC>[P:17]([Cl:20])([Cl:19])(=[O:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1
Reactant: COc1ccc(O)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1ccc(OP(=O)(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
Dry triethylamine (4.2 ml, 30 mmol) and p-methoxyphenol (3.72 g, 30 mmol) in 100 ml dry ether were added dropwise to a stirred solution of dry ether (50 ml) containing phosphorus oxychloride (2.80 ml, 30 mmol), at −78° C. under nitrogen. Following the addition, the reaction mixture was slowly allowed to warm at room temperature and stirred for one hour. The solvent was removed under reduced pressure to give the crude product (6.6 g, 92%) as an oil, which was used in the following step without any further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:20][C:21]1[S:25][CH:24]=[C:23]([N:26]2[C:30]([C:31]([OH:33])=O)=[CH:29][C:28]([C:34]([F:37])([F:36])[F:35])=[N:27]2)[CH:22]=1)[CH2:9][CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:38][O:39][C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH2:42][NH2:43]>>[C:16]([O:15][C:13]([N:11]([CH3:12])[CH2:10][CH2:9][N:8]([CH2:20][C:21]1[S:25][CH:24]=[C:23]([N:26]2[C:30]([C:31](=[O:33])[NH:43][CH2:42][C:41]3[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=3[O:39][CH3:38])=[CH:29][C:28]([C:34]([F:35])([F:36])[F:37])=[N:27]2)[CH:22]=1)[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:14])([CH3:18])([CH3:19])[CH3:17]
Reactant: CN(CCN(Cc1cc(-n2nc(C(F)(F)F)cc2C(=O)O)cs1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1csc(CN(CCN(C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1

Procedure:
The titled compound 214 (140 mg, 38%) was obtained as a white crusty solid after following the method described to obtain compound 15a (scheme 2, example 1c, step 8) by using 212 (0.300 g, 0.547 mmol) and 2-methoxybenzylamine (75 mg, 0.547 mmol). LRMS(ESI): (calc.) 667.2 (found) 690.4 (MNa)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH2:20]([O:23][CH:24]([C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1)[CH3:25])[CH2:21][CH3:22]>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:30](=[O:31])[C:29]1[CH:33]=[CH:34][C:26]([CH:24]([O:23][CH2:20][CH2:21][CH3:22])[CH3:25])=[CH:27][CH:28]=1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: CCCOC(C)c1ccc(C(=O)O)cc1
Product: CCCOC(C)c1ccc(C(=O)Nc2ccc(N3CCC(N4CCCC4C)C3)cc2C)cc1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 4-(1-propoxy-ethyl)-benzoic acid. MS: 463.3 (M+H).
Reaction SMILES: [CH2:1]([C:3]1([CH3:14])[CH:8]([CH3:9])[CH:7]([OH:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2].[H-].[Na+].[C:17]([O:22][CH3:23])(=[O:21])[C:18]#[C:19][CH3:20]>C1C=CC=CC=1>[CH2:1]([C:3]1([CH3:14])[CH:8]([CH3:9])[CH:7]([O:10]/[C:19](/[CH3:20])=[CH:18]\[C:17]([O:22][CH3:23])=[O:21])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2]
Reactant: CC#CC(=O)OC
Reactant: CCC1(C)CC(O)C(C)C(C)(CC)N1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCC1(C)CC(O/C(C)=C\C(=O)OC)C(C)C(C)(CC)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a solution of 3.0 g of 2,6-diethyl-2,3,6-trimethyl-4-piperidinol (Compound 1) in 30 ml of benzene was added, in small portions at room temperature, 0.72 g of 50% sodium hydride. The mixture was then stirred for 30 minutes at room temperature. A solution of 2.2 g of methyl tetrolate in 10 ml of benzene was then added dropwise, with ice-cooling, to the mixture and the whole mixture was stirred at room temperature for 64 hours. The mixture was then poured into ice water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulphate. After removing the solvent, the residue was distilled under reduced pressure, giving 3.4 g of Compound 97 as a pale yellow oil (bp 109°-111° C./0.15 mmHg).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C@H:7]([C:12]([OH:14])=O)[CH2:6][CH2:5]2.Cl.Cl.[NH2:17][CH2:18][C@@H:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[OH:20]>>[OH:20][C@H:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:18][NH:17][C:12]([C@@H:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[O:8]1)=[O:14]
Reactant: NC[C@H](O)c1cccnc1
Reactant: O=C(O)[C@@H]1CCc2cc(I)ccc2O1
Agent: Cl
Product: O=C(NC[C@H](O)c1cccnc1)[C@@H]1CCc2cc(I)ccc2O1
Yield: 87 %

Procedure:
Using the same procedure described in Method A, using (2S)-6-iodo-3,4-dihydro-2H-chromene-2-carboxylic acid (Example 7, Method B) and (1R)-2-amino-1-(3-pyridinyl)ethanol dihydrochloride (U.S. Pat. No. 6,051,586), the title compound was obtained as a white solid in 87% yield. 1H NMR (DMSO-d6) δ 8.47 (d, J=2.2 Hz, 1 H), 8.43 (dd, J=6.6, 1.8 Hz, 1 H), 7.90 (t, J=7.1 Hz, 1 H), 7.69-7.60 (m, 1 H), 7.40-7.37 (m, 2 H), 7.30-7.26 (m, 1 H), 6.66 (d, J=9.1 Hz, 1 H), 5.66 (d, J=4.6 Hz, 1 H), 4.72 (q, J=5.0 Hz, 1 H), 4.52 (dd, J=8.3, 3.3 Hz, 1 H), 4.12 (dd, J=6.1, 1.8 Hz, 1 H), 3.36-3.32 (m, 1 H), 2.77-2.65 (m, 1 H), 2.58-2.52 (m, 1 H), 2.08-2.00 (m, 1 H), 1.85-1.73 (m, 1 H). LC-MS m/z 425.1 (MH+), RT=2.07 minutes.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]([OH:25])=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.[NH2:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:20]=[CH:19][C:18]([NH:21][CH2:22][C:23]([NH:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[O:25])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)CNc1ccc(-c2ccc(F)cc2)nc1
Reactant: Nc1nccs1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1ccc(-c2ccc(F)cc2)nc1)Nc1nccs1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 98 mg (0.27 mmol) of [6-(4-fluoro-phenyl)-pyridin-3-ylamino]-acetic acid trifluoroacetic acid salt and 54.5 mg (0.54 mmol) 2-aminothiazole. Yield: 2.3 mg.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[O:10])=[C:4]([Cl:11])[N:3]=1.[CH3:12][Mg+].[Br-]>C1COCC1>[NH2:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]([CH:9]([OH:10])[CH3:12])=[C:6]([Cl:8])[N:7]=1
Reactant: C[Mg+]
Reactant: Nc1nc(Cl)c(C=O)c(Cl)n1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(O)c1c(Cl)nc(N)nc1Cl
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A fine suspension of 2-amino-4,6-dichloro-pyrimidine-5-carbaldehyde (3.0 g, 15 mmol); (Seela, F.; Stecker, H. Helv. Chim. Acta 1986, 69, 1602) in THF was cooled to −78° C. A 3M solution of MeMgBr in THF (25 mL, 75 mmol, 5 equiv.) was added over 3 h, keeping the internal temperature at −78° C. The mixture was stirred for a further 0.5 h, quenched with 100 ml H2O, and neutralized with aw. HCl. Extraction (EtOAc) gave 1-(2-amino-4,6-dichloro-pyrimidin-5-yl)-ethanol as a pale yellow solid (2.5 g, 76%) which was used without further purification.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH2:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1)=[O:13].[N:24]#[C:25]Br.C([O-])([O-])=O.[K+].[K+]>CC#N.CCOC(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:11][C:12]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1)=[O:13])[C:25]#[N:24]
Reactant: N#CBr
Reactant: O=C(CNc1nc2ccccc2s1)N1CCCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#CN(CC(=O)N1CCCc2ccccc21)c1nc2ccccc2s1
Reaction time: 12 h
Yield: 21.9 %

Procedure:
To a suspension of compound 83 (340 g, 1.05 mmol) in dry CH3CN (10 mL) were added cyanogen bromide (5M in CH3CN) (0.42 mL, 2.1 mmol) and K2CO3 (580 g, 4.2 mmol). The reaction was heated to reflux for 4 h under N2. 0.84 mL (4.2 mmol) of cyanogen bromide was added and the reflux was continued for 12 h. The reaction mixture was diluted with EtOAc (50 mL). The solids were filtered off, filtrate was concentrated, and the yellow residue was purified by column chromatography (20% EtOAc in hexanes) to afford 84 as an off-white solid (80 mg, 28%). MS m/z: 349 (M+H)+. Anal. Calcd. For, C19H16N4OS.0.6 H2O: C, 63.53; H, 4.83; N, 15.60; S, 8.92. Found: C, 63.24; H, 4.67; N, 15.25; S, 8.76.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([P:14]([CH2:17][C:18]([C:20]([O:22]C)=[O:21])=[CH2:19])(=[O:16])[OH:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[CH2:1]([O:8][C:9]([NH:11][CH:12]([P:14]([CH2:17][C:18]([C:20]([OH:22])=[O:21])=[CH2:19])(=[O:15])[OH:16])[CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(CP(=O)(O)C(C)NC(=O)OCc1ccccc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=C(CP(=O)(O)C(C)NC(=O)OCc1ccccc1)C(=O)O
Yield: 100.8 %

Procedure:
To a solution of 341 mg (1 mmol) of [1-(benzyloxycarbonylamino)-ethyl](2-methoxycarbonyl-2-propenyl)phosphinic acid in methanol (20 ml) and H2O (8 ml), was 1N NaOH (2.2 ml, 2.2. mmol) and the mixture was refluxed for 3 hours. After evaporation of methanol, the aqueous layer was washed with chloroform twice and then acidified with 2N HCl. The aqueous solution was extracted with chloroform four times and the combined organic layer was dried over anhydrous magnesium sulfate. Filtration followed by evaporation gave 330 mg (yield 100%) of [1-(benzyloxycarbonylamino)ethyl](2-carboxy-2-propenyl)phosphinic acid. The obtained above phosphinic acid (163 mg, 0.5 mmol) and sodium iodide (300 mg, 2 mmol) were dissolved in acetonitrile (3 ml). Then trimethylsilyl chloride (0.25 ml) was added and the mixture was stirred at room temperature for 6 hours. H2O was added and the mixture was washed with chloroform eight times and adjusted at pH 4 by the addition of saturated sodium carbonate solution. After evaporation to dryness, ethyl acetate (10 ml) was added and the precipitate was filtered. It was dissolved in methanol (10 ml) and the insoluble material was filtered off. Methanol was evaporated and the residue was purified by reversed-phase column chromatography (C-18, eluted with H2O) to give 60 mg (yield 62%) of (1-aminoethyl)(2-carboxy-2-propenyl)phosphinic acid.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([C:17](O)=[O:18])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.Cl.[CH2:34]([C@@H:36]1[CH2:41][CH2:40][CH2:39][CH2:38][NH:37]1)[CH3:35]>C1(C)C=CC=CC=1>[CH2:34]([C@@H:36]1[CH2:41][CH2:40][CH2:39][CH2:38][N:37]1[C:17]([C:9]1[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:18])[CH3:35]
Reactant: CC[C@@H]1CCCCN1
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2)n1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC[C@@H]1CCCCN1C(=O)c1cc2ccccc2c(-c2ccccc2)n1
Yield: 57.9 %

Procedure:
Operations are carried out as for Example 7, starting from 2.5 g of 1-phenyl isoquinoline 3-carboxylic acid, 2.86 g of triethylamine, 1.24 g of ethyl chloroformate and 1.93 g of 2(R)-ethyl piperidine hydrochloride in 100 ml of toluene. After chromatography, 2 g of 2(R)-ethyl 1-[(1-phenyl 3-isoquinolyl) carbonyl]piperidine in the form of oil are obtained. αD26 =+1.4° (2% in ethanol).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH:13]1[CH2:16][CH2:15][CH2:14]1.C([BH3-])#N.[Na+]>C(O)C.C(OCC)(=O)C>[N:13]1([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: C1CNC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(CN2CCC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6.2 g (41 mmol) of 4-nitrobenzaldehyde and 3.8 g (40.6 mmol) of azetidine-hydrochloride are dissolved in 120 ml of ethanol. 2.6 g (41 mmol) of sodium cyanoborohydride are added at 0° C. The mixture is slowly heated to ambient temperature and then stirred for 18 hours. Then the solvent is eliminated in vacuo, the residue is taken up in ethyl acetate and washed with water. The solvent is eliminated in vacuo and after chromatography of the residue on silica gel (ethyl acetate/methanol/NH4OH=95:5:0.5) a light brown oil is obtained.