Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:31]=[CH:30][C:7]2[N:8]([CH2:12][CH2:13][O:14][C:15]3[CH:29]=[CH:28][C:18]([O:19][C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=3)[C:9](=[O:11])[S:10][C:6]=2[CH:5]=1)(=O)[CH3:2].[CH3:32][O:33][NH2:34]>>[CH3:32][O:33][N:34]=[C:1]([C:4]1[CH:31]=[CH:30][C:7]2[N:8]([CH2:12][CH2:13][O:14][C:15]3[CH:29]=[CH:28][C:18]([O:19][C:20]([CH3:27])([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=3)[C:9](=[O:11])[S:10][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCn2c(=O)sc3cc(C(C)=O)ccc32)cc1
Reactant: CON
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCn2c(=O)sc3cc(C(C)=NOC)ccc32)cc1

Procedure:
Starting from the compound obtained in Step A, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-methylhydroxylamine. The two (Z) and (E) compounds are not separated.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Cl[CH2:16][CH:17]([CH3:20])[C:18]#[N:19].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[CH3:16][CH:17]([CH2:20][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[C:18]#[N:19]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C#N)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C#N)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.050 g, 0.26 mmol), 3-chloro-2-methylpropanenitrile (27 uL, 0.28 mmol, Aldrich, Cat. No. 150428), and cesium carbonate (250 mg, 0.77 mmol) in acetonitrile (1 mL) in a sealed reaction vial was stirred at 90° C. overnight. After cooling it was diluted with ethyl acetate. Then the organic solution was washed with water, brine; dried over Na2SO4. After filtration the filtrate was concentrated to yield 41 mg product. It was directly used in the next step reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]2=[N:17][CH:18]=[N:19][C:20]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[C:15]2[CH:14]=[N:13]1.C(N(CC)CC)C.[CH2:35]([O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1)[CH3:36]>C1COCC1>[CH2:35]([O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42]([N:25]2[CH2:24][CH2:23][CH:22]([O:21][C:20]3[N:19]=[CH:18][N:17]=[C:16]4[N:12]([C:3]5[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:7][C:2]=5[F:1])[N:13]=[CH:14][C:15]=34)[CH2:27][CH2:26]2)=[O:43])=[CH:40][CH:39]=1)[CH3:36]
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(OC4CCNCC4)ncnc32)c(F)c1
Reactant: CCOc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOc1ccc(C(=O)N2CCC(Oc3ncnc4c3cnn4-c3ccc(S(C)(=O)=O)cc3F)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a 50 mL round-bottomed flask fitted with N2 inlet was placed 1-(2-fluoro-4-methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine (50 mg, 0.117 mmol) and triethylamine (65 μl) and THF (0.8 mL). The reaction flask was immersed in an ice-bath. 4-Ethoxy-benzoyl chloride (24 mg, 0.129 mmol) was added to the solution and the mixture was stirred 2 h under N2 at 0° C. After all of the starting amine was completely converted as indicated by LCMS, the reaction was stopped by quenching with water. The reaction mixture was then concentrated under vacuum and purified by column chromatography using EtOAc as eluent to give Compound A184. 1H NMR (CDCl3, 400 MHz) δ 1.43 (t, 3H), 1.96 (m, 2H), 2.17 (m, 2H), 3.13 (s, 3H), 3.55 (m, 2H), 4.06 (m, 2H), 4.12 (m, 2H), 5.71 (m, 1H), 6.92 (d, 2H), 7.43 (d, 2H), 7.92 (m, 3H), 8.33 (s, 1H), 8.62 (s, 1H). Exact mass calculated for C26H26FN5O5S 539.16, found 540.2 (MH+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[O:12].[CH3:13][C:14]1C=CC(S(O)(=O)=O)=CC=1.[CH2:24]([OH:26])[CH3:25]>>[CH2:13]([O:12][CH:11]([O:26][CH2:24][CH3:25])[C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)[CH3:14]
Reactant: CCO
Reactant: O=Cc1ccc2ccccc2n1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(OCC)c1ccc2ccccc2n1

Procedure:
A mixture of 2-quinolinecarboxaldehyde (0.08 mol) and 4-methylbenzenesulfonic acid (0.25 g) in ethanol (100 ml) was stirred and refluxed for 48 hours and brought to room temperature. The reaction was carried out again using the same quantities. The mixtures were combined. The solvent was evaporated. The residue was taken up in CH2Cl2. The organic solution was washed with K2CO3 10% and with H2O, then dried (MgSO4), filtered and the solvent was evaporated. The product was used without further purification, yielding 32.5 g of 2-(diethoxymethyl)quinoline (interm. 30).
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[O:9]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10]1>>[OH:9][CH2:13][CH2:12][N:11]([CH2:10][P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4])[CH2:14][CH2:15][OH:16]
Reactant: CCOP([O-])OCC
Reactant: OCCN1CCOC1
Product: CCOP(=O)(CN(CCO)CCO)OCC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Diethyl phosphite (2.5 mol, 352/3 g) was added slowly to a mixture of the product from stage (1.1) and Amberlight™ IR120 resin—acid form (available from Aldrich, 100 g) to form a reaction mixture. On completion of the addition, the reaction mixture was stirred at 60° C. for 2 hours and then allowed to cool to a temperature of 25° C. The product was extracted with a 2:1 mixture of diethyl ether and ethyl acetate (5×300 ml), the combined extracts were dried over magnesium sulphate and evaporated to give 354 g of diethyl [bis(2-hydroxyethyl)amino]methylphosphonate in the form of a pale yellow liquid. The product was stored over 4A molecular sieves. This was designated Monomer (1).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C:11]([O:15][C:16](=[O:31])[NH:17][C@@H:18]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:19](=[O:26])[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([CH3:14])([CH3:13])[CH3:12].C(O)(C)C>CCOC(C)=O>[C:11]([O:15][C:16](=[O:31])[NH:17][C@@H:18]([CH2:27][CH:28]([CH3:29])[CH3:30])[C:19]([N:20]1[CH2:21][CH2:22][N:23]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH2:24][CH2:25]1)=[O:26])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCNCC1
Reactant: Fc1ccc2nccn2n1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(c2ccc3nccn3n2)CC1
Yield: 78 %

Procedure:
To 305 mg (2.23 mmol) of 6-fluoroimidazo[1,2-b]pyridazine, was added 1.00 g (3.34 mmol) of (S)-tert-butyl(4-methyl-1-oxo-1-(piperazin-1-yl)pentan-2-yl)carbamate, 10 mL of isopropyl alcohol, and 0.93 mL (6.68 mmol) of TEA. This was microwaved at 150° C. for 0.5 hr. It was diluted with EtOAc, washed with brine, and the organic layer was dried over MgSO4, and then concentrated. It was purified on the ISCO with a 40 gram column eluting with 0-10% MeOH/DCM to obtain the desired product in 78% yield.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[NH2:7])([CH3:3])[CH3:2].O[CH2:14][CH:15]([CH2:17]O)O.OS(O)(=O)=O.C([O-])(O)=O.[Na+]>O.C(OCC)(=O)C>[CH:1]([C:4]1[CH:5]=[C:6]2[C:8]([CH:14]=[CH:15][CH:17]=[N:7]2)=[CH:9][C:10]=1[O:11][CH3:12])([CH3:3])[CH3:2]
Reactant: COc1ccc(N)cc1C(C)C
Reactant: OCC(O)CO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2cccnc2cc1C(C)C
Temperature: 100 °C
Yield: 54.3 %

Procedure:
A mixture of 3-isopropyl-4-methoxyaniline (4.22 g, 23.6 mmol), 5.87 g (63.7 mmole) of glycerol and 3.25 g (14 mmol) of As2O5 was heated to 100° C. with stirring At 100° C., 4.0 mL of concentrated H2SO4 was added dropwise. The mixture was heated at 150-160° C. for six hours, then cooled to 80° C., and 20 mL water was added, followed by aqueous saturated NaHCO3 until the mixture reached pH7-8. The mixture was diluted with 100 mL of water and 300 mL of ethyl acetate and the solution mixture was decanted from insolubles. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography with silica eluting with 20% ethyl acetate in hexanes to give 2.58 g of 7-isopropyl-6-methoxyquinoline, together with 0.65 g of 6-hydroxy-7-isopropylquinoline as a minority product.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH2:5]([C:8]12[CH2:15][O:14][C:11]([CH:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]3)([O:12][CH2:13]1)[O:10][CH2:9]2)[CH2:6][CH3:7].N1C=CC=CC=1>ClCCl>[C:1]([N:18]1[CH2:19][CH2:20][CH2:21][CH:16]([C:11]23[O:10][CH2:9][C:8]([CH2:5][CH2:6][CH3:7])([CH2:13][O:12]2)[CH2:15][O:14]3)[CH2:17]1)(=[O:3])[CH3:2]
Reactant: CCCC12COC(C3CCCNC3)(OC1)OC2
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC12COC(C3CCCN(C(C)=O)C3)(OC1)OC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Acetyl chloride (81 μl) was added to a stirred solution of 3-(4-n-propyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)piperidine (0.25 g.) and pyridine (92 μl) in dichloromethane (15 ml) at 0°. The mixture was stirred at room temperature for 3 hours. The mixture was washed with water, saturated aqueous sodium hydrogen carbonate solution and finally brine. The dichloromethane extracts were dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by chromatography on alumina (Alumina Woelm TSC) eluting with 1:3 dichlormethane:hexane, saturated with ammonia. N-Acetyl- 3-(4-n-propyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)piperidine (0.15 g.) was obtained as a colourless oil.
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)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH3:32][C:33]1[NH:34][C:35](NC)=[N:36][N:37]=1.[CH3:40][N:41]1C(=O)CCC1>>[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:41][CH2:40][C:35]3[NH:34][C:33]([CH3:32])=[N:37][N:36]=3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CN1CCCC1=O
Reactant: CNc1nnc(C)[nH]1
Product: Cc1nnc(CNc2nc(-c3ccc(F)cc3C)c3ccc(=O)n(-c4c(F)cccc4F)c3n2)[nH]1
Yield: 14 %

Procedure:
A solution of the product of Example 48 (150 mg, 0.34 mmol) and (5-methyl-4H-[1,2,4]triazol-3-yl)-methylamine (190 mg, 1.7 mmol) in NMP (2 mL) was stirred at 100° for 16 h to give the crude material. Preparative HPLC, eluting with acetonitrile/H2O (10/90, v/v to 90/10, v/v, over 10 min), gave the desired product 23 mg (14%). LC-MS: 478.2 (MH+, m/z), 1.70 (Rt, min).
Reaction SMILES: C[O:2][C:3](=[O:30])[C@H:4]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[NH:5][C:6]([C:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[CH3:31][C:32]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:33]=1[C:34](O)=[O:35]>>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:8]2([C:6]([NH:5][C@H:4]([C:3]([OH:2])=[O:30])[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:34]([C:33]4[CH:37]=[C:38]([N+:41]([O-:43])=[O:42])[CH:39]=[CH:40][C:32]=4[CH3:31])=[O:35])=[CH:25][CH:24]=3)=[O:7])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:15][CH:16]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)O
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)C1(Cc2ccc(OC)cc2)CCCC1
Product: COc1ccc(CC2(C(=O)N[C@@H](Cc3ccc(NC(=O)c4cc([N+](=O)[O-])ccc4C)cc3)C(=O)O)CCCC2)cc1
Yield: 72.1 %

Procedure:
4-Amino-N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-L-phenylalanine methyl ester (23.4 mg, 0.057 mmol) and 2-methyl-5-nitrobenzoic acid 13 mg, 0.07 mmol) were reacted as described in example 40 to give 23 mg (69%) of N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-4-[[(2-methyl-5-nitrophenyl)carbonyl]amino]-L-phenylalanine, HR—FAB—MS: obs. mass 560.2413. Calcd. mass 560.2397 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]1)[C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([OH:19])[CH:13]=[CH:12]3)=[CH:5][CH:4]=1.[H-].[Na+].[CH2:32](I)[CH:33]=[CH2:34]>CN(C=O)C.CCOC(C)=O>[CH2:34]([O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:6]1[N:7]=[N:8][C:3]([N:2]([CH3:1])[CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[NH:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)=[CH:4][CH:5]=1)[CH:18]=[CH:17]2)[CH:33]=[CH2:32]
Reactant: CN(c1ccc(-c2ccc3cc(O)ccc3c2)nn1)C1CC(C)(C)NC(C)(C)C1
Reactant: C=CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCOc1ccc2cc(-c3ccc(N(C)C4CC(C)(C)NC(C)(C)C4)nn3)ccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 37.2 %

Procedure:
To a solution of 6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol (208 mg, 0.53 mmol) in DMF (5.3 mL) was added 60% wt NaH (47 mg, 1.17 mmol) followed by allyl iodide (54 μL, 0.59 mmol). The reaction was stirred at RT for 10 min. The crude reaction mixture was diluted with EtOAc. The organic layer was washed with water (5×) and brine, then dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified via HPLC to give 6-(6-(allyloxy)naphthalen-2-yl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (85 mg). LCMS Rt=1.46 min (condition B); MS (M+1)=431.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.37 (d, J=1.5 Hz, 1H), 8.20 (dd, J=8.6, 1.8 Hz, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.83 (d, J=8.6 Hz, 1H), 7.79 (d, J=9.9 Hz, 1H), 7.20-7.25 (m, 1H), 7.19 (d, J=2.3 Hz, 1H), 6.92 (d, J=9.6 Hz, 1H), 6.09-6.23 (m, 1H), 5.51 (dd, J=17.2, 1.5 Hz, 1H), 5.36 (dd, J=10.5, 1.4 Hz, 1H), 5.16-5.31 (m, 1H), 4.66-4.74 (m, 2H), 3.03 (s, 3H), 1.76 (dd, J=12.5, 3.4 Hz, 2H), 1.45-1.53 (m, 2H), 1.41 (s, 6H), 1.24 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][C:5]2[C:7]3[CH2:8][C:9]([CH3:19])([CH3:18])[O:10][C:11]=3[C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:4]=2[N:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[Cl:42][C:43]1[CH:51]=[CH:50][CH:49]=[C:48]([F:52])[C:44]=1[C:45](O)=[O:46]>C1COCC1>[Cl:42][C:43]1[CH:51]=[CH:50][CH:49]=[C:48]([F:52])[C:44]=1[C:45]([NH:1][C:2]1[NH:6][C:5]2[C:7]3[CH2:8][C:9]([CH3:19])([CH3:18])[O:10][C:11]=3[C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][C:4]=2[N:3]=1)=[O:46]
Reactant: COC(=O)c1cc2nc(N)[nH]c2c2c1OC(C)(C)C2
Reactant: O=C(O)c1c(F)cccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COC(=O)c1cc2nc(NC(=O)c3c(F)cccc3Cl)[nH]c2c2c1OC(C)(C)C2
Reaction time: 18 h
Yield: 44 %

Procedure:
To a solution of methyl 2-amino-7,7-dimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (1.00 g, 3.81 mmol) in THF (25 mL) was added EDCI.HCl (1.4 g, 7.62 mmol), HOBT (1.00 g, 7.62 mmol), 2-chloro-6-fluorobenzoic acid (1.32 g 7.62 mmol) and TEA (3 mL). The reaction mass was stirred for 18 h. The reaction mass was quenched in water extracted with 10% DCM: methanol. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained crude was purified by column chromatography on basic alumina eluting with 0.7% DCM: MeOH to afford 0.700 g of the desired product. 1HNMR (DMSO-d6): δ 1.43 (s, 6H), 3.02 (s, 2H), 3.58 (s, 3H), 6.08 (bs, 1H), 7.59-7.69 (m, 2H), 7.83 (q, J=6.6 Hz, 1H), 8.14 (bs, 2H); MS [M+H]+: 418.05.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][C:10]=1[CH2:18][CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[BrH:32].BrBr>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH2:16][Br:32])=[CH:11][C:10]=1[CH2:18][CH2:19][O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Br
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(CCOCc2ccccc2)c1
Agent: BrBr
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc(OCc2ccccc2)c(CCOCc2ccccc2)c1
Temperature: 25 °C

Procedure:
4'-Benzyloxy-3'-(2-benzyloxyethyl)acetophenone (8.0 g) and 0.4 ml of 30% hydrogen bromide acetic acid solution were dissolved in 80 ml of chloroform, and a solution of 1.1 ml of bromine in 30 ml of chloroform was added to the solution dropwise during 2 hours with stirring at room temperature. The reaction solution was concentrated under reduced pressure and the resulting residue was purified by silica gel medium pressure liquid column chromatography (eluent: hexane/diethyl ether=2/1) to give 3.9 g of 4'-benzyloxy-3'-(2-benzyloxyethyl)-2-bromoacetophenone having a melting point of 53 to 56° C.
Reaction SMILES: II.[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11](=[O:18])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1.Br[CH:20]([C:22]1[N:27]=[CH:26][N:25]=[C:24]([Cl:28])[C:23]=1[F:29])[CH3:21]>O1CCCC1.[Zn]>[Cl:28][C:24]1[C:23]([F:29])=[C:22]([CH:20]([CH3:21])[C:11]([C:5]2[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:4]=2[F:3])([OH:18])[CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[N:27]=[CH:26][N:25]=1
Reactant: CC(Br)c1ncnc(Cl)c1F
Reactant: O=C(Cn1cncn1)c1ccc(F)cc1F
Agent: II
Agent: [Zn]
Solvent: C1CCOC1
Product: CC(c1ncnc(Cl)c1F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
A solution of iodine (2.25 g) in tetrahydrofuran (6 ml) was added dropwise to a stirred slurry of zinc (Britannia Alloys) (3.00 g) and lead (0.15 g) in tetrahydrofuran (19 ml) under a nitrogen atmosphere at 25° C. The reaction temperature was allowed to rise during the addition. The mixture was then cooled to 2° C. A solution of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (2.00 g), 6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine (see Preparation 1) (2.84 g) and iodine (0.02 g) in tetrahydrofuran (16 ml) was added dropwise over 10 minutes. The reaction temperature was limited to a maximum of 16° C. during the addition by cooling. Further cooling was then applied to obtain a temperature below +5° C. The reaction was stirred below +5° C. for 30 minutes. A sample of the reaction mixture was taken and subjected to HPLC analysis according to the conditions set out in Example 1. The analysis showed a 10.3:1 molar ratio of the 2R,3S/2S,3R to the 2R,3R/2S,3S enantiomeric pair of the title compound. The yield of the 2R,3S/2S,3R enantiomeric pair was calculated to be 90% using an internal standard.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:17][NH2:18].[CH3:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1>>[ClH:1].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:17][NH:18][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:25]2[C:24]([CH3:23])=[CH:28][C:27]([CH3:29])=[N:26]2)[N:11]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: NCc1ccc(F)c(F)c1
Product: Cc1cc(C)n(-c2nc(NCc3ccc(F)c(F)c3)c3ccccc3n2)n1
Product: Cl

Procedure:
Was prepared according to Method A from 2,4-dichloroquinazoline, 3,4-difluorobenzylamine and 3,5-dimethylpyrazole. Mp. 165° C.
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][N:10]2[CH2:15][C:14]3[CH:16]=[C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=O)[CH:18]=[N:19][C:13]=3[NH:12][C:11]2=[O:25])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1.[CH2:45]1[C:55]2=[C:56]3[C:51](=[CH:52][CH:53]=[CH:54]2)[C:50]([CH2:57][NH:58][CH3:59])=[CH:49][CH:48]=[C:47]3[CH2:46]1.CNCC1C=CC2C(=CC=CC=2)C=1CCC>>[ClH:1].[CH2:45]1[C:55]2=[C:56]3[C:51](=[CH:52][CH:53]=[CH:54]2)[C:50]([CH2:57][N:58]([CH3:59])[C:22](=[O:24])/[CH:21]=[CH:20]/[C:17]2[CH:18]=[N:19][C:13]4[NH:12][C:11](=[O:25])[N:10]([CH2:9][CH2:8][N:2]5[CH2:7][CH2:6][O:5][CH2:4][CH2:3]5)[CH2:15][C:14]=4[CH:16]=2)=[CH:49][CH:48]=[C:47]3[CH2:46]1
Reactant: CNCc1ccc2c3c(cccc13)CC2
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: CN(Cc1ccc2c3c(cccc13)CC2)C(=O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)C(=O)N2
Yield: 43 %

Procedure:
According to the procedure of Example 1, except substituting (E)-3-[3-(2-morpholin-4-yl-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, and substituting acenaphthen-5-ylmethyl-methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, the title compound (175 mg, 43%) was prepared as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 10.15-10.11 (m, 2H), 8.41-8.33 (m, 1H), 7.98-7.96 (m, 1H), 7.88-7.74 (m, 1H), 7.60-7.44 (m, 2H), 7.38-7.12 (m, 4H), 5.23-5.01 (m, 2H), 4.55-4.46 (m, 2H), 4.00-3.96 (m, 2H), 3.86-3.36 (m, 10H), 3.12-2.89 (m, 7H); MS (ESI) m/e 512 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[C:5]([CH3:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:6]2[C:5]([CH3:9])=[CH:4][N:3]=[C:2]([F:1])[CH:7]=2)=[CH:13][CH:12]=1
Reactant: Cc1cnc(F)cc1I
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1cnc(F)cc1-c1ccc(Cl)cc1

Procedure:
A mixture of 2-fluoro-4-iodo-5-methylpyridine (1.9 g), 4-chlorophenylboronic acid (1.504 g), tetrakis(triphenylphosphine)palladium(0) (0.463 g), and sodium carbonate (2.55 g) in ethanol (20 mL), water (10 mL) and toluene (10 mL) was heated under reflux for 6 hours. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layers were extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified with flash column chromatography on silica gel using 5% ethyl acetate in hexanes to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15](SC)=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.O[O:23][S:24]([O-:26])=O.[K+].[CH3:28]O>>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:24]([CH3:28])(=[O:26])=[O:23])=[CH:14][CH:13]=2)=[CH:8][CH:9]=1
Reactant: CO
Reactant: O=S([O-])OO
Reactant: COC(=O)c1ccc(C(=O)Cc2ccc(SC)cc2)cc1
Agent: [K+]
Product: COC(=O)c1ccc(C(=O)Cc2ccc(S(C)(=O)=O)cc2)cc1

Procedure:
To 7.10 g of 4-(2-(4-methylthiophenyl)-1-oxo-ethyl)benzoic acid methyl ester in MeOH (100 mL) was added oxone (21.0 g) in H20 (20.0 mL) at 0° C. After a few hours at r.t., the reaction mixture was extracted with EtOAc and H2O to afford after flash chromatography (50 to 100% EtOAc in hexane), the title product as a white solid (3.20 g). 1H NMR (CD3COCD3) d 3.10 (3H, s), 3.95 (3H, s), 4.65 (2H, s), 7.60 (2H, d), 7.96 (2H, d), 8.20 (4H, q).