Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([C:14]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:22](=[O:30])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH3:31])[N:15]=1)[CH2:12][CH3:13])C1C=CC=CC=1>C(O)C.[Pd]>[NH2:10][CH:11]([C:14]1[N:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:22](=[O:30])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[CH3:31])[N:15]=1)[CH2:12][CH3:13]
Reactant: CCC(NC(=O)OCc1ccccc1)c1nc2cccc(C)c2c(=O)n1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCC(N)c1nc2cccc(C)c2c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A catalytic amount of 10% Pd/C was added to a solution of compound 16 (691 mg, 1.62 mmol) in ethanol (8 mL). The resulting mixture was placed under a hydrogen atmosphere (balloon pressure) and allowed to stir at ambient temperature overnight. The reaction was filtered, and the filtrate concentrated in vacuo. The resulting crude residue was purified by flash chromatography to afford the free amine, compound 17, as a pale yellow oil. (ES): m/z 294 (M+H), 237. 1H NMR (300 MHz, DMSO-d6) δ 7.68 (t, 1H, J=7.7 Hz), 7.49-7.63 (m, 3H), 7.43-7.49 (m, 1H), 7.36-7.43 (m, 1H), 7.19-7.34 (m, 2H), 4.03-4.19 (m, 1H), 2.72 (s, 3H), 2.04 (br. s, 2H), 1.63-1.79 (m, 1H), 1.29-1.44 (m, 1H), 0.68 (t, 3H, J=7.3 Hz). The reaction described above and compound 17 are shown below.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[C:12]([CH3:20])[CH:11]=2)[CH:2]=1.[CH2:21]([N:23]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:28]=1[C:34]([F:37])([F:36])[F:35])[CH2:24][CH3:25])[CH3:22]>C(Cl)Cl.CO>[CH2:21]([N:23]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:17](=[O:19])[CH2:16][C:13]2[CH:14]=[CH:15][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:11][C:12]=2[CH3:20])=[CH:29][C:28]=1[C:34]([F:35])([F:36])[F:37])[CH2:24][CH3:25])[CH3:22]
Reactant: CCN(CC)Cc1ccc(N)cc1C(F)(F)F
Reactant: Cc1cc(-n2cnc3cccnc32)ccc1CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)Cc1ccc(NC(=O)Cc2ccc(-n3cnc4cccnc43)cc2C)cc1C(F)(F)F

Procedure:
The title compound is prepared as described in Example 7 but using (4-imidazo[4,5-b]pyridin-3-yl-2-methyl-phenyl)-acetic acid and 4-diethylaminomethyl-3-trifluoromethyl-phenylamine (disclosed in WO2005/051366). Title compound: ES-MS: 496.0 [M+H]+; tR=3.31 min (System 1); Rf=0.43 (CH2Cl2/MeOH, 95:5+0.1% NH3aq).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]2[CH:35]=[CH:34][C:17]([C:18]([NH:20][C@@H:21]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([Cl:33])[CH:27]=3)[CH2:22][N:23]=[N+]=[N-])=[O:19])=[C:16]([F:36])[CH:15]=2)=[N:4][C:5]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][N:7]=1.[NH4+].[OH-].CP(C)C.CCO>N1C=CC=CC=1>[NH2:23][CH2:22][C@@H:21]([NH:20][C:18](=[O:19])[C:17]1[CH:34]=[CH:35][C:14]([C:3]2[C:2]([NH2:1])=[N:7][CH:6]=[C:5]([CH:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[N:4]=2)=[CH:15][C:16]=1[F:36])[C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([Cl:33])[CH:27]=1
Reactant: [N-]=[N+]=NC[C@@H](NC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F)c1cc(F)cc(Cl)c1
Agent: CP(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccncc1
Product: NC[C@@H](NC(=O)c1ccc(-c2nc(C3CCOCC3)cnc2N)cc1F)c1cc(F)cc(Cl)c1
Reaction time: 2 h
Yield: 79.8 %

Procedure:
To a solution of (S)-4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-N-(2-azido-1-(3-chloro-5-fluorophenyl)ethyl)-2-fluorobenzamide (118 mg, 0.230 mmol) in pyridine (2 mL) was added NH4OH (200 μl) and trimethylphosphine (344 μl, 0.344 mmol) sequentially at room temperature. The reaction mixture was stirred for 2 h. After EtOH (1 mL) was added, the reaction mixture was concentrated in vacuo. The crude product was purified by flash chromatography (20% MeOH in DCM containing 0.5% NH3/DCM) to provide 89.6 mg of (S)—N-(2-amino-1-(3-chloro-5-fluorophenyl)ethyl)-4-(3-amino-6-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yl)-2-fluorobenzamide (79%). LCMS (m/z): 488.2 (MH+), 0.66 min. 1H NMR (500 MHz, METHANOL-d4) δ ppm 7.98-7.89 (m, 1H), 7.89-7.79 (m, 1H), 7.74 (td, J=1.4, 8.0 Hz, 1H), 7.69-7.61 (m, 1H), 7.41-7.28 (m, 1H), 7.27-7.08 (m, 2H), 5.27-5.12 (m, 1H), 4.07 (dd, J=3.8, 11.0 Hz, 2H), 3.69-3.52 (m, 2H), 3.14-3.03 (m, 2H), 2.96 (tt, J=3.9, 11.7 Hz, 1H), 2.02-1.77 (m, 4H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5]Cl.[Cl:7][SiH:8]([Cl:10])[Cl:9]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[Cl:7][Si:8]([Cl:10])([Cl:9])[CH2:2][CH2:3][CH2:4][CH2:5][Si:8]([Cl:10])([Cl:9])[Cl:7]
Reactant: ClCCCCCl
Reactant: Cl[SiH](Cl)Cl
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: Cl[Si](Cl)(Cl)CCCC[Si](Cl)(Cl)Cl
Yield: 82.9 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.44 g (1.50 mmol) of tetrabutylphosphonium chloride, 0.95 g (7.5 mmol) of 1,4-dichlorobutane, and 10.16 g (75.0 mmol) of trichlorosilane were reacted at 150° C. for 20 hrs. The resulting mixture was distilled to give 2.02 g of 1,4-bis(trichlorosilyl)butane (yield; 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:28]=[CH:29][C:30]=2[CH3:31])[CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]([NH:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:32][C:33](=[O:37])[CH:34]([CH3:36])[CH3:35])[CH:28]=[CH:29][C:30]=4[CH3:31])[CH2:21][CH2:20]3)=[O:14])[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C2(c3ccc(Cl)cc3)CCC2)CC1

Procedure:
Example 86 was prepared from 1-(4-chlorophenyl)cyclobutanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.46 (d, 1H, J=1.6 Hz), 7.34 (s, 4H), 7.28–7.23 (m, 2H), 7.10 (d, 1H, J=8.4 Hz), 6.45 (br s, 1H), 3.31 (dd, 2H, J=5.6, 11.6 Hz), 2.95 (d, 2H, J=11.6 Hz), 2.88–2.81 (m, 2H), 2.68 (m, 1H), 2.54–2.44 (m, 3H), 2.33 (t, 2H, J=6.4 Hz), 2.29 (s, 3H), 2.11–1.90 (m, 4H), 1.76–1.63 (m, 6H), 1.26 (d, 6H, J=7.2 Hz) ESMS m/e: 510.3 (M+H)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Cl:34])[C:12]=1[NH:13][C:14]1[C:23]2[C:18](=[C:19]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[O:17][C:16](=[O:33])[CH:15]=1.[P:35](OC)([O:39]C)([O:37]C)=[O:36]>O>[P:35]([OH:39])([OH:37])([O:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][O:26][C:19]1[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[C:23]2[C:18]=1[O:17][C:16](=[O:33])[CH:15]=[C:14]2[NH:13][C:12]1[C:11]([Cl:34])=[CH:10][N:9]=[CH:8][C:7]=1[Cl:6])=[O:36]
Reactant: COP(=O)(OC)OC
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCO
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCOP(=O)(O)O
Reaction time: 1 h

Procedure:
Phosphoryl trichloride (69.4 mg, 0.46 mmol) was added to a solution of 4-(3,5-dichloropyridin-4-ylamino)-8-(5-hydroxypentyloxy)-7-methoxy-2H-chromen-2-one (100 mg, 0.22 mmol, Example 72) and trimethyl phosphate (2 mL). After 1 h at rt, water (0.5 mL) was added, and the reaction was stirred for an additional 2 h. The solution was directly purified by reverse-phase HPLC to give 5-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)pentyl dihydrogen phosphate: 1H NMR (400 MHz, DMSO-d6): δ 10.88 (br, 2H), 9.52 (s, 1H), 8.81 (s, 2H), 7.94 (d, 1H), 7.20 (d, 1H), 4.64 (s, 1H), 3.98 (t, 2H), 3.92 (s, 3H), 3.82 (m, 2H), 1.70 (m, 2H), 1.62 (m, 2H), 1.51 (m, 2H); MS (ESI): 518.9.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([NH:13][CH2:14][CH3:15])[CH3:12])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C:38](Cl)=[O:39])[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([N:13]([C:38]([CH:35]2[CH2:36][CH2:37][N:32]([C:30]([O:29][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:31])[CH2:33][CH2:34]2)=[O:39])[CH2:14][CH3:15])[CH3:12])=[CH:6][CH:5]=1
Reactant: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCNC(C)Cc1ccc(OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCN(C(=O)C1CCN(C(=O)OCc2ccccc2)CC1)C(C)Cc1ccc(OC)cc1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
To a mixture of N-[2-(4-methoxyphenyl)-1-methylethyl]ethylamine hydrochloride (2.0 grams, 8.71 mole) and sodium carbonate (3.2 grams, 30 mole) in toluene (75 ml) and water (50 ml) was added dropwise to a solution of 1-benzyloxycarbonylpiperidine-4-carbonyl chloride (2.67 grams, 9.5 mmole) in toluene (25 ml). The reaction mixture was stirred at 22° C. for 16 hours.The mixture was diluted with ethyl acetate (100 ml), the organic phase was dried (anhydrous magnesium sulfate) and concentrated under reduced pressure. The residue was subjected to flash column chromatography over silica gel eluting with 30% ethyl acetate in hexane. The N-[2-(4-methoxyphenyl)-1-methylethyl]-N-ethyl-[1-(benzyloxycarbonyl)piperidin-4-ylcarbonyl]amine was obtained as an oil, (3.5 grams, 95%), M+H 439.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C.ClCCl>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][C:6]([N+:10]([O-:12])=[O:11])=[CH:7][C:2]=1[CH3:1]
Reactant: COc1ccccc1C
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Methylanisole (2.5 ml) in acetic acid (140 ml) and dichloromethane (150 m) was cooled to 15° C. Concentrated nitric acid (20 ml) was added slowly keeping the temperature of the reaction below 40° C. The reaction was stirred at ambient temperature for 30 minutes and cooled to 0° C. before adding fuming nitric acid (50 ml) dropwise. The reaction mixture was allowed to warm to ambient temperature slowly and stirred for a further 4 days. The reaction mixture was poured onto ice water (600 ml) and the organic layer was washed with water (2×40 ml) and saturated sodium hydrogencarbonate (2×40 ml), dried over magnesium sulfate and concentrated. The residual deep red solid was subjected to flash silica chromatography on silica eluting with isohexane/ethyl acetate (9:1) to (7:3) to yield 1-methoxy-2-methyl-4-nitrobenzene (2.70 g) as an off white solid. LC-MS (Method J): RT=3.74 minutes, 168.27 (M+H)+. (b) 5,6-Dinitro-benzo[1,3]dioxole
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[CH2:10][CH2:11][C:12]([C:14]1[S:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:17][CH:18]=1)=[O:13].I[CH2:30][CH2:31][CH2:32][C:33]([CH3:39])([CH3:38])[C:34]([O:36][CH3:37])=[O:35]>>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([CH2:10][CH2:11][C:12](=[O:13])[C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:21][CH:20]=3)=[CH:17][CH:18]=2)[CH:4]=[CH:5][C:6]=1[O:9][CH2:30][CH2:31][CH2:32][C:33]([CH3:39])([CH3:38])[C:34]([O:36][CH3:37])=[O:35]
Reactant: COC(=O)C(C)(C)CCCI
Reactant: O=C(CCc1ccc(O)c(Cl)c1Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Product: COC(=O)C(C)(C)CCCOc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl

Procedure:
Methyl 5-(2,3-dichloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2,2-dimethylpentanoate is prepared from 3-(2,3-dichloro-4-hydroxyphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propan-1-one and methyl 5-iodo-2,2-dimethylpentanoate according to general procedure D.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:22]3[N:23]=[C:24]([Cl:27])[S:25][CH:26]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([O:3]C)=[O:2].[OH-].[Na+].Cl.C(Cl)Cl>CO>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:22]3[N:23]=[C:24]([Cl:27])[S:25][CH:26]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([OH:3])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)N2CCOC(c3csc(Cl)n3)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC(Cc1ccc(OCC(=O)O)cc1)N1CCOC(c2csc(Cl)n2)C1

Procedure:
0.55 g (0.0013 mol) of N-[2-(4-carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-chloro-thiazol-4-yl)-morpholine are stirred in 4 ml of methanol and 4 ml of 1N sodium hydroxide solution at room temperature for 10 minutes. The mixture is then neutralised with 4 ml of 1N hydrochloric acid, and the product is obtained by extraction with methylene chloride.
Reaction SMILES: C[O:2][C:3](=[O:21])[C@@H:4]([O:19][CH3:20])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]([C:16]([OH:18])=O)([CH3:15])[CH3:14])[CH:7]=1.[C:22]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH2:29])[CH:23]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[C:22]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:29][C:16]([C:13]([CH3:14])([O:12][C:8]2[CH:7]=[C:6]([CH2:5][C@H:4]([O:19][CH3:20])[C:3]([OH:2])=[O:21])[CH:11]=[CH:10][CH:9]=2)[CH3:15])=[O:18])[CH:23]=1
Reactant: COC(=O)[C@H](Cc1cccc(OC(C)(C)C(=O)O)c1)OC
Reactant: NCc1cccc(-c2ccccc2)c1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1cccc(OC(C)(C)C(=O)NCc2cccc(-c3ccccc3)c2)c1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-2-methoxy-propionic acid methyl ester (EXAMPLE 56, step 2) and C-biphenyl-3-yl-methylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C27H28NO5 [M−H]−: 446.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:10])[C:5]([F:9])=[C:6]([OH:8])[CH:7]=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.[C:33]([O:37][CH2:38][CH3:39])(=[O:36])[CH:34]=[CH2:35].C(N(C(C)C)CC)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2].C(#N)CC>[F:10][C:4]1[CH:3]=[C:2](/[CH:35]=[CH:34]/[C:33]([O:37][CH2:38][CH3:39])=[O:36])[CH:7]=[C:6]([OH:8])[C:5]=1[F:9]
Reactant: Oc1cc(Br)cc(F)c1F
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CCOC(=O)/C=C/c1cc(O)c(F)c(F)c1
Temperature: 25 °C

Procedure:
A second 1 L round-bottomed flask was charged with a stir bar, 5-bromo-2,3-difluorophenol (50.2 g, 240 mmol) and propionitrile (460 mL). The solution was deoxygenated by bubbling nitrogen for 15 minutes. To this solution was added Pd(OAc)2 (5.42 g, 24.1 mmol), P(O-tol)3 (29.3 g, 96.1 mmol), ethyl acrylate (52 mL, 480 mmol) and diisopropylethylamine (167 mL, 959 mmol) sequentially. The flask was immersed into a preheated (120° C.) oil bath. The reaction was heated at this temperature for 22 h. Upon cooling to room temperature, the reaction mixture was filtered through a Celite-plugged filter frit, washed with CH2Cl2, and concentrated.
Reaction SMILES: [C:1]1([C:7]([OH:11])([CH3:10])[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOC(C)=O>C(Cl)Cl>[OH:11][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:10])[CH:8]=[O:9]
Reactant: CC(O)(CO)c1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(O)(C=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.6 %

Procedure:
To a solution of 2-phenylpropane-1,2-diol (3 g, 19.7 mmol) in DCM (60 mL) was added Dess-Martin periodinane (8.36 g, 19.7 mmol) at 0° C. The reaction mixture was stirred for 2 hours at ambient temperature. After completion of the reaction (monitored by TLC (TLC eluent: 30% EtOAc in petroleum ether)), the reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layers were combined and washed with water, washed with saturated NaCl solution, and dried on anhydrous Na2SO4. The organic layer was then filtered and concentrated under vacuum to yield intermediate 2-hydroxy-2-phenylpropanal (2 g unpurified) as a colorless liquid. The intermediate thus obtained was used in the next step without any further purification. 1H NMR (400 MHz, CDCl3): δ 9.50 (s, 1H). The 1H NMR spectrum was not completely clean, but since the aldehyde peak at 9.50 ppm was observed, this intermediate was used in the next step without purification.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([CH:14]([OH:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)=O.Cl.[NH2:24][C:25]([NH2:27])=[NH:26].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:26][C:25]1[N:27]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[C:9]([CH:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[OH:21])[CH:8]=2)[CH:4]=[CH:3][N:24]=1
Reactant: N=C(N)N
Reactant: CN(C)/C=C/C(=O)c1ccc(F)c(C(O)c2ccccc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Nc1nccc(-c2ccc(F)c(C(O)c3ccccc3)c2)n1
Temperature: 150 °C

Procedure:
A 5 mL microwave tube was charged with (2E)-3-(dimethylamino)-1-{4-fluoro-3-[hydroxy(phenyl)methyl]phenyl}-2-propen-1-one (0.2 mmol), guanidine hydrochloride (0.4 mmol), potassium carbonate (0.6 mmol) and ethanol (3.5 mL). The reaction was heated to 150° C. for 600 s using microwave irradiation. The reaction was concentrated to dryness and the residue was taken up in water and extracted with ethyl acetate. The organics were dried over magnesium sulfate, filtered and concentrated to dryness. Reconcentration from diethyl ether provided [5-(2-amino-4-pyrimidinyl)-2-fluorophenyl]-(phenyl)methanol as a white foam. H1 NMR (d6-dmso): 8.34 (dd, 1H), 8.26 (d, 1H), 7.93 (m, 1H), 7.31 (m, 4H), 7.21 (m, 2H), 7.05 (d, 1H), 6.67 (br s, 2H), 6.10 (d, 1H), 5.94 (d, 1H). Mass (ES+)=296.1 (100%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[C:7]([NH:9][C:10]1[S:11][CH:12]=[CH:13][C:14]=1[C:15]([NH2:17])=[O:16])=O)[CH2:2][CH3:3].[OH-].[Na+].Cl>N1C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=1[C:7]1[NH:17][C:15](=[O:16])[C:14]2[CH:13]=[CH:12][S:11][C:10]=2[N:9]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccccc1C(=O)Nc1sccc1C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCCOc1ccccc1-c1nc2sccc2c(=O)[nH]1

Procedure:
A stirred mixture of 2-(2-propoxybenzamido)thiophene-3-carboxamide (0.90 g) and pyridine (1 ml) in 2 Normal sodium hydroxide (25 ml) was heated under reflux for hours. The cooled reaction mixture was neutralised with concentrated hydrochloric acid to afford a precipitate and the resulting mixture was extracted with chloroform (3×25 ml). The combined extracts were washed with water (20 ml) and brine (20 ml), dried magnesium sulphate) and evaporated under reduced pressure to afford a crude product which was recrystallised from ethanol-water to afford the title compound, 0.41 g, m.p. 115-117° C.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:22][CH2:23][CH:24]1[O:28][C:27](=[O:29])[N:26]([CH3:30])[CH2:25]1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33]>>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:8])[CH:9]2[CH2:14][CH2:13][N:12]([CH2:22][CH2:23][CH:24]3[O:28][C:27](=[O:29])[N:26]([CH3:30])[CH2:25]3)[CH2:11][CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1CC(CCCl)OC1=O
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Agent: O=C(O)C(=O)O
Product: CN1CC(CCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)OC1=O

Procedure:
Following the procedure of Example 1, α,α-diphenyl-4-piperidinemethanol and 5-(2-chloroethyl)-3-methyl-2-oxazolidinone are reacted and the product thereof is reacted with oxalic acid to give the title compound.
Reaction SMILES: N1CCC[C@H:2]1[CH2:3][OH:4].[C:8]([O:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@@H:16]1[CH:20]=O)=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH2:20][CH2:2][CH:3]=[O:4])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: OC[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CCC=O

Procedure:
Prepared from L-prolinol using the procedure described for Intermediate 2.
Reaction SMILES: O.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[C@@H:17]([OH:18])[C:16](=[O:19])[N:15]([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[C:14]3[CH:25]=[CH:26][CH:27]=[C:28]([Cl:29])[C:13]=3[S:12]2)=[CH:7][CH:6]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(O)(=O)C>[OH2:4].[ClH:29].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[C@@H:17]([O:18][C:30](=[O:32])[CH3:31])[C:16](=[O:19])[N:15]([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[C:14]3[CH:25]=[CH:26][CH:27]=[C:28]([Cl:29])[C:13]=3[S:12]2)=[CH:7][CH:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc([C@@H]2Sc3c(Cl)cccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc([C@@H]2Sc3c(Cl)cccc3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1
Temperature: 110 °C
Reaction time: 6.5 h
Yield: 89.4 %

Procedure:
A mixture of 0.95 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(dimethylamino)ethyl]-9-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride hydrate, 10 ml of acetic anhydride and 10 ml of acetic acid is stirred at 110° C. for 6.5 hours. After the reaction is completed, the reaction mixture is evaporated under reduced pressure to remove solvent. Toluene is added to the residue, and the mixture is evaporated under reduced pressure to remove solvent. The residue is recrystallized from a mixture of methanol and ether. 0.93 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-9-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrochloride hydrate is obtained. Yield: 89.4%
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[CH:8]=[CH:7]2)([O-])=O.Cl.C([O:26][C:27](=[O:31])[CH2:28][CH2:29][NH2:30])C.[F:32][C:33]([F:46])([F:45])[O:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>>[F:46][C:33]([F:32])([F:45])[O:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH:1][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[N:9]([CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:30][CH2:29][CH2:28][C:27]([OH:26])=[O:31])=[O:20])=[CH:16][CH:15]=2)[CH:8]=[CH:7]3)(=[O:43])=[O:42])=[CH:37][CH:36]=1
Reactant: CCOC(=O)CCN
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1ccc(Cn2ccc3cc([N+](=O)[O-])ccc32)cc1
Agent: Cl
Product: O=C(O)CCNC(=O)c1ccc(Cn2ccc3cc(NS(=O)(=O)c4ccc(OC(F)(F)F)cc4)ccc32)cc1

Procedure:
The title compound was prepared from 4-[(5-nitro-1H-indol-1-yl)methyl]benzoic acid, β-alanine ethyl ester hydrochloride, and 4-trifluoromethoxyphenyl sulfonyl chloride following the procedure of Example 10: MS (ESI) m/z 562; MS (ESI) m/z 560.
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12](=O)[CH3:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4].N1C=CC=CC=1.Cl.[CH2:24]([O:26][NH2:27])[CH3:25].O>O1CCOCC1>[CH2:24]([O:26][N:27]=[C:12]([CH2:11][O:10][C:9]1[CH:15]=[CH:16][C:6]([O:5][CH:2]([CH3:1])[CH2:3][CH3:4])=[CH:7][CH:8]=1)[CH3:13])[CH3:25]
Reactant: CCC(C)Oc1ccc(OCC(C)=O)cc1
Reactant: CCON
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: C1COCCO1
Product: CCON=C(C)COc1ccc(OC(C)CC)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 4-(1-methylpropoxy)phenoxyacetone (0.70 g, 3.1 mmol) and pyridine (0.50 g, 6.3 mmol) in 10 ml of p-dioxane is added a solution of ethoxyamine hydrochloride (0.70 g, 7.2 mmol) in a minimum amount of water. The reaction mixture is stirred at RT for 16 hours, after which the dioxane is removed in vacuo. The residue is taken up in ether and the organic layer is washed with water. The aqueous phase is extracted with ether, and the combined organic phases are dried, the solvent is evaporated off and the product is purified by column chromatography to give 4-(1-methylpropoxy)phenoxyacetone O-ethyloxime, MS m/e 265 (M+).