Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10](B(O)O)=[CH:9][CH:8]=1)=[O:6])#[N:2].[Br:16][C:17]1[C:18](I)=[N:19][C:20]([I:23])=[N:21][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[Br:16][C:17]1[C:18]([C:10]2[CH:11]=[CH:12][C:7]([C:5]([NH:4][CH2:3][C:1]#[N:2])=[O:6])=[CH:8][CH:9]=2)=[N:19][C:20]([I:23])=[N:21][CH:22]=1
Reactant: N#CCNC(=O)c1ccc(B(O)O)cc1
Reactant: Brc1cnc(I)nc1I
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: N#CCNC(=O)c1ccc(-c2nc(I)ncc2Br)cc1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 50.2 %

Procedure:
To a mixture of 4-(cyanomethylcarbamoyl)phenylboronic acid (see example 3) (185 mg, 0.9 mmol) and 5-bromo-2,4-diiodopyrimidine (410 mg, 1.0 mmol) in 1,4-dioxane (10 mL), was added 2M aqueous potassium carbonate (100 μL). The resulting mixture was stirred under nitrogen for 5 minutes then tetrakis(triphenylphosphine)palladium(0) (52 mg, 0.045 mmol) was added under a nitrogen atmosphere. The mixture was heated at 80° C. overnight. The cooled reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with water then brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product as a brown solid. The crude material was purified by flash chromatography, eluting with 50% ethyl acetate/petroleum spirit to give 4-(5-bromo-2-iodopyrimidine-4-yl)-N-(cyanomethyl)benzamide (200 mg, 35% over 2 steps). LC-ESI-MS (method B): rt 6.2 min.; m/z 443.0/445.0 [M+H]+.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]1[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[N:10]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([N:9]1[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[N:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccn(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.9 %

Procedure:
To a solution of benzyl bromide (0.29 g) in N,N-dimethylformamide (9 ml) was added 1H-pyrazole-3-carboxaldehyde (0.15 g) and potassium carbonate (0.24 g). The mixture was stirred at room temperature for 24 hours, silica gel was added, the solvent removed by evaporation and the crude material purified by chromatography (isohexane:ether, 2:1) to give the product as an oil (0.18 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.[I:19]N1C(=O)CCC1=O.S(=O)(=O)(O)O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([I:19])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ccc(-c2cccc(C(F)(F)F)c2)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Oc1cc(Cl)c(-c2cccc(C(F)(F)F)c2)cc1I
Temperature: 0 °C
Reaction time: 18 h
Yield: 50.9 %

Procedure:
2-Chloro-3′-(trifluoromethyl)biphenyl-4-ol (Preparation 50, 310 mg, 1.14 mmol) was dissolved in acetic acid (2 mL), and cooled to 0° C. N-iodosuccinimide (256 mg, 1.14 mmol) was added followed by concentrated sulphuric acid (0.067 μL). The reaction was stirred at room temperature for 18 hours. A second portion of N-iodosuccinimide (25 mg, 0.11 mmol) was added and the reaction stirred at room temperature for a further 1 hour. The reaction mixture was partitioned between ethyl acetate (70 mL) and water (50 mL). The ethyl acetate was separated, dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica eluting with a gradient of heptane:ethyl acetate 100:0 to 80:20 to give the title compound (230 mg, 0.58 mmol, 51%) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]([CH3:12])[CH3:11])[N:4]=1.C[O:14][C:15](=[O:27])[CH2:16][CH:17]1[C:21]2[CH:22]=[CH:23][C:24]([OH:26])=[CH:25][C:20]=2[O:19][CH2:18]1>>[CH:10]([S:9][C:5]1[N:4]=[C:3]([CH2:2][O:26][C:24]2[CH:23]=[CH:22][C:21]3[CH:17]([CH2:16][C:15]([OH:27])=[O:14])[CH2:18][O:19][C:20]=3[CH:25]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:12])[CH3:11]
Reactant: COC(=O)CC1COc2cc(O)ccc21
Reactant: CC(C)Sc1cccc(CCl)n1
Product: CC(C)Sc1cccc(COc2ccc3c(c2)OCC3CC(=O)O)n1
Yield: 83.5 %

Procedure:
2-Chloromethyl-6-isopropylsulfanyl-pyridine (20 mg, 0.10 mmol) obtained in Step C of Preparation Example 16 and (6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (20 mg, 0.10 mmol) obtained in Preparation Example 52 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (30 mg, 84%).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5]I)[CH2:3][CH2:2]1.C([Li])(C)(C)C.[Cl:12][C:13]1[CH:22]=[CH:21][C:20]2[N:19]=[C:18]3[C:23](=[O:27])[NH:24][CH:25]=[N:26][C:17]3=[C:16]([C:28]([F:31])([F:30])[F:29])[C:15]=2[CH:14]=1>CCOCC.C1COCC1>[Cl:12][C:13]1[CH:22]=[CH:21][C:20]2[NH:19][C:18]3[C:23](=[O:27])[NH:24][CH:25]=[N:26][C:17]=3[C:16]([CH2:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)([C:28]([F:30])([F:29])[F:31])[C:15]=2[CH:14]=1
Reactant: O=c1[nH]cnc2c(C(F)(F)F)c3cc(Cl)ccc3nc12
Reactant: ICCC1CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=c1[nH]cnc2c1Nc1ccc(Cl)cc1C2(CCC1CC1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.83 h
Yield: 61.7 %

Procedure:
To a stirred solution of 1-cyclopropyl-2-iodoethane (12.5g, 63.9 mmol, 5 equiv) in anhydrous Et2O (128 mL) at −78° C. was added tert-butyl lithium (1.7M in pentane, 75 mL, 128 mmol, 10 equiv). The resulting white suspension was stirred at −78° C. for 50 min and added via cannula to a suspension of 7 (3.83 g, 12.8 mmol) in THF (64 mL) at −78° C. The resulting dark yellow mixture was stirred at −78° C. for 30 min and then allowed to warm to 0° C. over 5 h. The reaction was quenched with satd. NH4Cl (100 mL) and H2O (100 mL). The reaction mixture was extracted with EtOAc (3×100 mL) and the combined organic layers washed with brine and dried (MgSO4). Chromatography (SiO2, 40 to 50% EtOAc-hexane) provided the desired product as a yellow solid (2.92 g, 62%). ESI HRMS m/z 370.1735 (M++H, C17H16ClF3N3O requires 370.0934).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:8](=[O:10])[CH3:9])[C:5](=[O:7])[CH3:6].[OH:11][CH2:12][C:13]([CH3:17])([CH2:15]O)[CH3:14].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[CH3:1][O:2]/[N:3]=[C:4](/[C:8]1([CH3:9])[O:11][CH2:12][C:13]([CH3:17])([CH3:15])[CH2:14][O:10]1)\[C:5](=[O:7])[CH3:6]
Reactant: CON=C(C(C)=O)C(C)=O
Reactant: CC(C)(CO)CO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CO/N=C(\C(C)=O)C1(C)OCC(C)(C)CO1
Reaction time: 2 h
Yield: 79 %

Procedure:
20 g (0.14 mol) of pentane-2,3,4-trione 3-(O-methyloxime), 43.4 g (0.42 mol) of neopentyl glycol and 0.1 g of conc. sulfuric acid in 80 ml of toluene were heated at the boil on a water separator at a pressure of 800 mbar for 2 hours. The mixture was extracted with water and toluene and then worked up as in Example 4b). This gave 30 g of an oil of a purity of 84% (yield 79%).
Reaction SMILES: C1(C)C=CC=CC=1.S(=O)(=O)(O)O.[F:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[CH2:22][OH:23])=[CH:16][CH:15]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([CH3:41])([CH2:39][CH3:40])[CH2:37]O)=[CH:32][CH:31]=1>O>[F:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([CH3:41])([CH2:39][CH3:40])[CH2:37][O:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[C:19]([O:18][C:17]3[CH:27]=[CH:28][C:14]([F:13])=[CH:15][CH:16]=3)[CH:20]=2)=[CH:32][CH:31]=1
Reactant: OCc1cccc(Oc2ccc(F)cc2)c1
Reactant: CCC(C)(CO)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(C)(COCc1cccc(Oc2ccc(F)cc2)c1)c1ccc(F)cc1
Temperature: 25 °C
Yield: 46 %

Procedure:
To 20 ml of toluene were added 2 ml of concentrated sulfuric acid, 2.7 g of 3-(4-fluorophenoxy)benzyl alcohol and 2.3 g of 2-(4-fluorophenyl)-2-methylbutyl alcohol, and the mixture was refluxed for 6 hours (water formed by reaction was removed). The mixture was cooled to room temperature, and water was added to the mixture and the toluene layer was separated, washed with water, dried, and evaporated under reduced pressure, and the obtained crude ether was purified by column chromatography on 100 g of silica gel (1:1 mixed solvent of toluene and n-hexane was used as eluent) to give 2.2 g of the desired ether (the yield was 46% of the theoretical yield).
Reaction SMILES: F[C@H]1CN(C2C=CC(CC3C=CC=CC=3C)=CC=2)[C@H]([CH2:21][C:22]([O:24][CH3:25])=[O:23])C1.[C:26]([Cl:29])(=O)C.[ClH:30].C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl>[ClH:29].[CH3:22][OH:23].[CH2:26]([Cl:29])[Cl:30].[CH3:25][O:24][C:22]([CH3:21])=[O:23]
Reactant: CC(=O)Cl
Reactant: COC(=O)C[C@@H]1C[C@@H](F)CN1c1ccc(Cc2ccccc2C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
methyl 2-((2R,4R)-4-fluoro-1-(4-(2-methylbenzyl)phenyl)pyrrolidin-2-yl)acetate: A ˜3 M solution of HCl/MeOH/CH2Cl2/MeOAc was prepared by addition of acetyl chloride (0.64 mL) to a 1:1 solution of MeOH/CH2Cl2 (2.4 mL) at 0° C. The resulting solution of HCl was added to 37C (0.0051 g, 0.017 mmol). After stirring at rt for 2 h, the reaction was basified with sat. Na2CO3 (aq) and the desired product was extracted with CH2Cl2. The combined organic layers were washed with brine, dried (MgSO4), and concentrated. The crude product was purified by silica gel chromatography to provide 37D (yellow oil, 0.0021 g, 6.2 mmol, 37% yield). LC-MS Anal. Calc'd for C21H24FNO2 341.42. found [M+H] 342.0. 1H NMR (400 MHz, chloroform-d) δ ppm 7.14 (3 H, q, J=4.77 Hz), 7.07-7.11 (1 H, m), 7.01 (2 H, d, J=8.25 Hz), 6.56 (2 H, d, J=8.25 Hz), 5.30 (1 H, d, J=53.34 Hz), 4.29-4.38 (1 H, m), 3.89 (2 H, s), 3.67-3.69 (1 H, m), 3.63-3.75 (3 H, m), 3.50-3.61 (1 H, m), 2.99 (1 H, dd, J=15.40, 2.75 Hz), 2.54-2.68 (1 H, m), 2.25 (3 H, s), 2.17 (2 H, dd, J=15.40, 9.90 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[NH:4][CH:5]([CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[C:6](=[O:34])[N:7]1[CH:12]([C:13]2[NH:14][C:15]([C:18]3[CH:23]=[CH:22][C:21](B4OC(C)(C)C(C)(C)O4)=[CH:20][CH:19]=3)=[CH:16][N:17]=2)[CH:11]2[CH2:33][CH:8]1[CH2:9][CH2:10]2.[C:42]([O:46][C:47]([N:49]1[CH2:53][CH2:52][CH2:51][CH:50]1[C:54]1[NH:55][C:56]([C:59]2[CH:68]=[CH:67][C:66]3[C:61](=[CH:62][CH:63]=[C:64](Br)[CH:65]=3)[CH:60]=2)=[CH:57][N:58]=1)=[O:48])([CH3:45])([CH3:44])[CH3:43].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:42]([O:46][C:47]([N:49]1[CH2:53][CH2:52][CH2:51][CH:50]1[C:54]1[NH:55][C:56]([C:59]2[CH:68]=[CH:67][C:66]3[C:61](=[CH:62][CH:63]=[C:64]([C:21]4[CH:22]=[CH:23][C:18]([C:15]5[NH:14][C:13]([CH:12]6[CH:11]7[CH2:33][CH:8]([CH2:9][CH2:10]7)[N:7]6[C:6](=[O:34])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:41])[CH:35]6[CH2:36][CH2:37][O:38][CH2:39][CH2:40]6)=[N:17][CH:16]=5)=[CH:19][CH:20]=4)[CH:65]=3)[CH:60]=2)=[CH:57][N:58]=1)=[O:48])([CH3:45])([CH3:44])[CH3:43]
Reactant: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)C1CCOCC1
Temperature: 80 °C
Yield: 77.4 %

Procedure:
To a solution of [2-Oxo-1-(tetrahydro-pyran-4-yl)-2-(3-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-2-azabicyclo[2.2.1]hept-2-yl)-ethyl]-carbamic acid methyl ester (0.24 g, 0.42 mmol) in DME (2.5 mL) was added 2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.19 g, 0.43 mmol), Tetrakis(triphenylphosphine)Palladium (0.03 g, 0.02 mmol) and aqueous potassium phosphate (2 M, 0.65 mL, 1.3 mmol). The solution was degassed with argon for 15 min and heated to 80° C. for 18 h with stirring. The solution was cooled and concentrated. The crude oil was purified by column chromatography (SiO2, 30-100% EtOAc (10% MeOH) in Hexanes to 50% MeOH in EtOAc) to provide 2-(5-{6-[4-(2-{2-[2-Methoxycarbonylamino-2-(tetrahydro-pyran-4-yl)-acetyl]-2-azabicyclo[2.2.1]hept-3-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.26 g, 76%). LCMS-ESI+: calc'd for C46H53N7O6: 799.41 (M+); Found: 800.4 (M+H+).
Reaction SMILES: [C:1]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].C(N(CC)CC)C.[Br-].[C:22]([O:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][N+:33]([CH2:36][C:37]([C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[C:41]([O:48][CH3:49])[CH:40]=2)=[O:38])=[CH:32][CH:31]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CN(C)C=O.[O-2].[Mn+2]>[C:22]([O:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][N:33]2[C:32]([CH:31]=1)=[C:2]([C:1]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])[C:3]([CH3:4])=[C:36]2[C:37](=[O:38])[C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[C:41]([O:48][CH3:49])[CH:40]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: C/C=C/C(=O)OCc1ccccc1
Reactant: COc1cc(C(=O)C[n+]2ccc(NC(=O)OC(C)(C)C)cc2)ccc1[N+](=O)[O-]
Agent: [Mn+2]
Agent: [Br-]
Agent: [O-2]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)c2c(C)c(C(=O)OCc3ccccc3)c3cc(NC(=O)OC(C)(C)C)ccn23)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 43.5 %

Procedure:
9.4 g (53.38 mmol) of benzyl crotonate, 1.8 mL (12.8 mmol) of triethylamine and 3.7 g (42.68 mmol) of manganese oxide are successively added to a solution of 5.0 g (10.67 mmol) of 4-[N-(tert-butoxycarbonyl)amino]-1-[2-(3-methoxy-4-nitrophenyl)-2-oxoethyl]pyridinium bromide in 40 mL of dimethylformamide. The reaction mixture is then heated at 90° C. for 4 hours and then filtered on a silica bed, eluting with ethyl acetate. The filtrate is poured over water and extracted with ethyl acetate. After decantation, the organic phase is washed with a saturated sodium chloride solution, dried over sodium sulfate and then concentrated under reduced pressure. The product is purified by chromatography on silica gel, eluting with a toluene/ethyl acetate (95/5 to 70/30) mixture. 2.6 g of an orange-coloured powder are obtained.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:30])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[CH3:29])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].Cl.[NH2:34][CH2:35][C:36]1[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=1.C(N(CC)CC)C>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:34][CH2:35][C:36]4[CH:37]=[CH:38][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:44][CH:45]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:30])=[C:23]([CH3:29])[CH:24]=1
Reactant: Cc1cc(Cl)ccc1OCC(=O)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)COc2ccc(Cl)cc2C)C3)cc1

Procedure:
The title compound was synthesized from 2,2,2-trichloro-1-{10-[(4-chloro-2-methylphenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 75 (0.3 mmol), methyl 4-(aminomethyl)benzoate hydrochloride (2.2 eq.) and triethylamine (2.4 eq.) in the manner of Example 68, m.p.165-167° C. MS [(+)ESI, m/z]: 558 [M+H]+ Anal. Calcd for C31H28CIN3O5: C, 66.72; H, 5.06; N, 7.53. Found: C, 66.46; H, 5.26; N, 7.24.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[CH:6]([C:9]1[O:13][N:12]=[C:11]([CH3:14])[CH:10]=1)[O:7][CH3:8].CN(C)C=O.[CH3:24][CH:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H-].[Na+]>CCOCC>[CH3:8][O:7][CH:6]([C:9]1[O:13][N:12]=[C:11]([CH3:14])[CH:10]=1)[C:5]1[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=1[CH:3]=[N:2][O:1][CH:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:24]
Reactant: CC(Br)c1ccccc1
Reactant: COC(c1cc(C)no1)c1ccccc1C=NO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(c1cc(C)no1)c1ccccc1C=NOC(C)c1ccccc1
Reaction time: 3 h
Yield: 91.3 %

Procedure:
To a mixture of 0.25 g (1 mmol) of 5-(2-hydroxyiminomethyl-α-methoxybenzyl)-3-methylisoxazole, 3 ml of N,N-dimethylformamide and 0.24 g (1.3 mmol) of α-methylbenzyl bromide was added 0.05 g (1.3 mmol) of 60% sodium hydride under ice-cooling and stirred at the same temperature for 3 hours. After completion of the reaction, 100 ml of ether was added and washed twice with 80 ml of brine. The ether layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 5-[α-methoxy-2-(4-phenyl-2-aza-3-oxa-1-pentenyl)benzyl]-3-methylisoxazole (0.32 g, 91.3%) as colorless oil.
Reaction SMILES: N[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[N:8]2[C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])=[C:4]([Cl:26])[N:3]=1.N(OCCC(C)C)=O.[I:35]CI>O1CCCC1>[Cl:26][C:4]1[N:3]=[C:2]([I:35])[N:10]=[C:9]2[C:5]=1[N:6]=[C:7]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1)[N:8]2[C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15]
Reactant: ICI
Reactant: N#Cc1cccc(-n2c(-c3cccc(F)c3)nc3c(Cl)nc(N)nc32)c1
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: N#Cc1cccc(-n2c(-c3cccc(F)c3)nc3c(Cl)nc(I)nc32)c1
Temperature: 25 °C
Yield: 50 %

Procedure:
3-[2-Amino-6-chloro-8-(3-fluorophenyl)-9H-9-purinyl]-benzonitrile (2.6 g) was dissolved in 105 ml of tetrahydrofuran, then 2.9 ml of isoamyl nitrite, 5.8 ml of diiodomethane and 1.37 g of cuprous iodide were added thereto and the mixture was heated under reflux for 1 hour. After the resulting mixture was cooled to room temperature, it was filtered to remove unnecessary substances and washed with 100 ml of ethyl acetate. The filtrate was concentrated to dryness and purified by a silica gel column (50 g of silica gel). It was eluted with ethyl acetate and hexane (1:1). The fractions containing the aimed product were collected, concentrated and suspended in 100 ml of a mixed solvent of ethyl acetate and hexane (1:4), and the resulting precipitates were collected by filtration to give 1.7 g of 3-[6-chloro-8-(3-fluorophenyl)-2-iodo-9H-9-purinyl]benzonitrile. The yield was 50%.
Reaction SMILES: ON=CC1C=CC([NH:10][C:11]([NH:13][CH2:14][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:16])=[O:12])=CC=1.C[O-].[Na+].C(Br)C=C>O>[O:17]([C:15]([CH2:14][NH:13][C:11](=[O:12])[NH2:10])=[O:16])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(NCC(=O)Oc1ccccc1)Nc1ccc(C=NO)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C=CCBr
Product: NC(=O)NCC(=O)Oc1ccccc1

Procedure:
A solution of N-[4-(hydroxyiminomethyl)phenyl]-N'-phenoxycarbonylmethylurea in 25% methanolic sodium methoxide (1.0 equivalent) is treated at room temperature with 1.1 equivalent of allyl bromide. The reaction mixture is stirred until the temperature falls to about 20° C. The reaction mixture is then poured into cold water and extracted with diethyl ether. The ether solution is dried over MgSO4 and filtered, and the solvent is removed by rotary evaporator to yield the corresponding N-[4-allyloxyiminomethyl)phenyl]-N'-phenoxycarbonylmethylurea.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH2:13][NH:12][CH2:11][CH2:10]2.[CH2:20]([O:22][CH2:23][CH2:24]Br)[CH3:21]>>[CH2:20]([O:22][CH2:23][CH2:24][N:12]1[CH2:11][CH2:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([O:6][CH2:5][C:4]3[CH:17]=[CH:18][CH:19]=[C:2]([F:1])[CH:3]=3)[CH:8]=2)[CH2:13]1)[CH3:21]
Reactant: Fc1cccc(COc2ccc3c(c2)CCNC3)c1
Reactant: CCOCCBr
Product: CCOCCN1CCc2cc(OCc3cccc(F)c3)ccc2C1

Procedure:
As described for example 44, 6-(3-fluoro-benzyloxy)-1,2,3,4-tetrahydro-isoquinoline (0.100 g, 0.39 mmol) was converted to the tide compound (0.075 g, 59%) using 2-bromoethyl ethyl ether (0.072,g, 0.47 mmol) instead of 2-bromopropionamide. MS: m/e=330.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH:17]([CH3:21])[C:18]([OH:20])=O)[N:9]=2)=[CH:4][CH:3]=1.[C:22]1([C@@H:32]([NH2:34])[CH3:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]3[CH2:14][CH2:15]3)[C:11](=[O:16])[N:10]([CH:17]([CH3:21])[C:18]([NH:34][C@H:32]([C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=[CH:24][CH:23]=3)[CH3:33])=[O:20])[N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)n1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Reactant: C[C@H](N)c1cccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C(=O)N[C@@H](C)c1cccc2ccccc12)n1nc(-c2ccc(Cl)cc2)n(C2CC2)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100.0 mg (0.325 mmol) of 2-[3-(4-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-propionic acid from Example 105A are placed in 2 ml of DMF and treated with 61.2 mg (0.357 mmol) of (1S)-1-(1-naphthyl)ethanamine, 52.7 mg (0.390 mmol) of HOBt and 81.0 mg (0.422 mmol) of EDC hydrochloride. The mixture is stirred overnight at room temperature, then partitioned between dichloromethane and water, and the organic is phase separated, dried over sodium sulphate and concentrated. The residue is purified by flash chromato-graphy on silica gel (eluent: first dichloromethane, then dichloromethane/methanol 100:1) and then further separated by preparative HPLC on chiral phase [Method 15]. 51 mg (34% of theory) of the diastereomerically pure target compound are thus obtained (see also Example 186).
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]3[C:24]([C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:23][N:22]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:19]3=[N:20][CH:21]=2)[CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:10]=1.Cl.C(OCC)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[OH:4][C:5]1[CH:6]=[C:7]([C:16]2[N:17]=[C:18]3[C:24]([C:25](=[O:30])[C:26]([CH3:29])([CH3:27])[CH3:28])=[CH:23][N:22]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:19]3=[N:20][CH:21]=2)[CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:10]=1
Reactant: COCOc1cc(-c2cnc3c(n2)c(C(=O)C(C)(C)C)cn3COCC[Si](C)(C)C)cc(N2CCCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cc(O)cc(N4CCCC4)c3)nc12
Reaction time: 2.5 h
Yield: 72.4 %

Procedure:
To a solution of 1-[2-(3-methoxymethoxy-5-pyrrolidin-1-yl-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (492 mg, 0.91 mmol) in CH2Cl2 (1.5 ml) was added a solution of 10% ethanolic hydrogen chloride (4 ml, dry). The flask was capped and stirred for 2.5 hours. The volatile material was stripped (rotovap). Ethyl acetate (25 ml) and aqueous 5% Na2CO3 (25 ml) was added and the 2 phase system vigorously stirred for 3 minutes. The material was partitioned and the organic phase collected and washed with brine (25 ml). The aqueous phases were back extracted with EtOAc (2×20 ml). The organics were combined, dried (MgSO4), filtered and stripped to provide a crude semi-solid. The material was purified by preparative TLC, eluting with 38% ethyl acetate in hexanes to afford 326 mg of 1-[2-(3-hydroxy-5-pyrrolidin-1-yl-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a yellow-brown solid.