Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=2[N:10]([CH2:21][CH3:22])[C:9]1=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:24]N1C(=O)CCC1=O>C(O)(=O)C.C(Cl)(Cl)Cl>[Br:24][C:16]1[C:17]([O:19][CH3:20])=[CH:18][C:11]2[N:10]([CH2:21][CH3:22])[C:9](=[O:23])[CH:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:14][CH2:13][C:12]=2[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCN1C(=O)C(C(=O)OC(C)(C)C)CCc2ccc(OC)cc21
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCN1C(=O)C(C(=O)OC(C)(C)C)CCc2cc(Br)c(OC)cc21
Yield: 77.1 %

Procedure:
A solution of 3(R,S)-tert-butoxycarbonyl-1-ethyl-8-methoxy-2,3,4,5-tetrahydro-1H-1-benzazepine-2-one (3.38 g, 10.58 mmol) and N-bromosuccinimide (2.072 g, 11.64 mmol) in acetic acid (2.5 mL) and chloroform (25 mL) was heated at reflux for 2 hrs. The reaction mixture was diluted with chloroform (25 mL), washed with saturated aqueous solution of NaHCO3 and water, dried over Na2SO4, filtered and evaporated to dryness. Purification of the crude product by flash chromatography on silica gel column eluted with EtOAc/hexane (3:7) provided the desired compound (3.25 g, 77%) as white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:7]1)=[O:5])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Cc2ccccc2)CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of 4-oxopiperidine-1,3-dicarboxylic acid 1-tert-butyl 3-ethyl ester (6.0 g) in DMF (45 ml), sodium hydride (60% in oil, 0.85 g) was added, and then the reaction mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled to 0° C., and then benzyl bromide (2.64 ml) was added thereto, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate, and then sequentially washed with an aqueous 10% citric acid solution, water and saturated brine. The organic layer was dried, and then the solvent was evaporated under reduced pressure to obtain 3-benzyl-4-oxopiperidine-1,3-dicarboxylic acid 1-tert-butyl 3-ethyl ester as colorless crystals (7.19 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12]([C:14]2[N:19]=[C:18]3[N:20]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:21]([N:23]=[CH:24][N:25]([CH3:27])[CH3:26])=[N:22][C:17]3=[CH:16][CH:15]=2)=[C:11]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:10]=1.IC.[C:40]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[N:13]([CH3:40])[C:12]([C:14]2[N:19]=[C:18]3[N:20]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:21]([N:23]=[CH:24][N:25]([CH3:27])[CH3:26])=[N:22][C:17]3=[CH:16][CH:15]=2)=[C:11]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:10]=1
Reactant: CC(C)Cn1c(N=CN(C)C)nc2ccc(-c3[nH]c(-c4c(Cl)cccc4Cl)nc3-c3ccccc3)nc21
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)Cn1c(N=CN(C)C)nc2ccc(-c3c(-c4ccccc4)nc(-c4c(Cl)cccc4Cl)n3C)nc21

Procedure:
Stir N′-{5-[2-(2,6-dichlorophenyl)-5-phenyl-3H-imidazol-4-yl]-3-isobutyl-3H-imidazo[4,5-b]pyridin-2-yl}-N,N-dimethylformamidine prepared essentially as described in EXAMPLE 63 (0.10 g, 0.188 mmol), iodomethane (0.040 g, 0.282 mmol), and Cs2CO3 (0.09 g, 0.28 mmol) in DMF (1.5 mL) at RT for about 24 h. Extract with EtOAc and wash with water (3×), saturated aqueous NaCl, then dry over Na2SO4. Filter and concentrate to give a mixture of methyl isomers. Purify (silica gel chromatography) eluting with 1:1:0.4 CH2Cl2:acetonitrile:hexanes to give the title compound (0.02 g).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]2=[O:21])[S:4][C:3]=1[C:22](O)=[O:23].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.[NH2:56][CH2:57][C:58]1[CH:59]=[N:60][CH:61]=[CH:62][CH:63]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][O:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:8]2=[O:21])[S:4][C:3]=1[C:22]([NH:56][CH2:57][C:58]1[CH:59]=[N:60][CH:61]=[CH:62][CH:63]=1)=[O:23]
Reactant: NCc1cccnc1
Reactant: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
To a 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid (0.08 g, 0.23 mmol), 1-hydroxybenzotriazole (0.05 g, 0.35 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.07 g, 0.35 mmol) in N,N-dimethylformamide (2 mL) was added N,N-diisopropylethylamine (0.12 mL, 0.70 mmol), followed by the addition of 3-(aminomethyl)pyridine (0.02 mL, 0.24 mmol). The resulting reaction mixture was stirred at ambient temperature for 18 h, and then diluted with ethyl acetate (75 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (3×35 mL) and water (35 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with ethyl acetate in hexanes to afford the title compound as a colorless solid in 79% yield (0.08 g): mp 78-80° C.; 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.52 (s, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.32-7.23 (m, 3H), 6.96 (t, J=7.6 Hz, 1H), 6.88 (d, J=7.6 Hz, 2H), 6.15 (t, J=5.7 Hz, 1H), 6.08 (s, 1H), 4.57 (d, J=5.7 Hz, 2H), 4.15 (t, J=4.9 Hz, 2H), 3.80 (br s, 4H), 3.69 (t, J=4.9 Hz, 2H), 2.48 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.5, 158.2, 156.0, 149.2, 148.8, 142.5, 141.7, 135.5, 129.6, 123.6, 121.2, 118.9, 114.3, 112.4, 66.9, 43.8, 43.0, 41.2, 16.1; MS (ES+) m/z 437.4 (M+1).
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:11])=[N:6][CH:7]=[CH:8][C:9]=1[OH:10])([O-:3])=[O:2].[H-].[Na+].[CH2:14](I)[CH3:15]>CN(C=O)C>[CH2:14]([N:6]1[CH:7]=[CH:8][C:9]([OH:10])=[C:4]([N+:1]([O-:3])=[O:2])[C:5]1=[O:11])[CH3:15]
Reactant: CCI
Reactant: O=[N+]([O-])c1c(O)ccnc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc(O)c([N+](=O)[O-])c1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 53.4 %

Procedure:
To a solution of 3-nitro-pyridine-2,4-diol (1.0 g, 6.41 mmol) in DMF (10 mL) at 0° C., was added NaH (0.51 g, 12.82 mmol 60% in mineral oil). After stirring at 0° C. for 15 min, ethyl iodide (1.10 g, 7.05 mmol) was added and the reaction was stirred at 55° C. for 17 h. After cooling to room temperature, the mixture was poured into ice water, and then filtered to remove insoluble material. The filtrate was acidified with 1 N HCl, extracted with CH2Cl2, dried with MgSO4, and concentrated. The product was rinsed with EtOH to give 1-ethyl-4-hydroxy-3-nitro-1H-pyridin-2-one (0.63 g, 53% yield). 1H-NMR (DMSO): δ, 7.79 (d, 1H, J=7.6 Hz), 6.09 (d, 1H, J=7.6 Hz), 3.90 (q, 2H, J=7.2 Hz), 1.19 (t, 3H, J=7.2 Hz).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH3:11])([CH3:10])[C:5](=O)[CH2:6][C:7]#[N:8].C(C1C=C(N)[O:17][N:16]=1)(C)C>>[CH3:1][O:2][CH2:3][C:4]([C:5]1[CH:6]=[C:7]([NH2:8])[O:17][N:16]=1)([CH3:11])[CH3:10]
Reactant: CC(C)c1cc(N)on1
Reactant: COCC(C)(C)C(=O)CC#N
Product: COCC(C)(C)c1cc(N)on1
Yield: 69 %

Procedure:
Prepared from 5-methoxy-4,4-dimethyl-3-oxopentanenitrile (500 mg, 3.22 mmol) according to the method described for 3-isopropylisoxazol-5-amine in Example 122A Step 2, to afford 3-(1-methoxy-2-methylpropan-2-yl)isoxazol-5-amine as a orange oil (380 mg, 69%) which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 5.08 (s, 1H), 4.41 (brs, 2H), 3.39 (s, 2H), 3.35 (s, 3H), 1.28 (s, 6H).
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:48])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:47])[CH2:12][CH2:13][C@@:14]3([CH:31]4[O:35][C:34](=[O:36])[N:33]([C:37]5([C:40]6[N:45]=[CH:44][C:43]([Cl:46])=[CH:42][N:41]=6)[CH2:39][CH2:38]5)[CH2:32]4)[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:30])[CH3:29])=[C:15]32)[C:6]1([CH3:50])[CH3:49])(=O)C.Cl>O1CCOCC1.CO>[Cl:46][C:43]1[CH:42]=[N:41][C:40]([C:37]2([N:33]3[CH2:32][CH:31]([C@:14]45[CH2:26][C:25](=[O:27])[C:24]([CH:28]([CH3:29])[CH3:30])=[C:15]4[C@@H:16]4[C@@:11]([CH3:47])([CH2:12][CH2:13]5)[C@@:10]5([CH3:48])[C@@H:19]([C@:20]6([CH3:23])[C@@H:7]([CH2:8][CH2:9]5)[C:6]([CH3:49])([CH3:50])[C@@H:5]([OH:4])[CH2:22][CH2:21]6)[CH2:18][CH2:17]4)[O:35][C:34]3=[O:36])[CH2:39][CH2:38]2)=[N:45][CH:44]=1
Reactant: CC(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@@H]4C5=C(C(C)C)C(=O)C[C@]5(C5CN(C6(c7ncc(Cl)cn7)CC6)C(=O)O5)CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(C2CN(C3(c4ncc(Cl)cn4)CC3)C(=O)O2)CC1=O
Temperature: 40 °C
Reaction time: 8 h
Yield: 17.5 %

Procedure:
To a solution of (3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-(3-(1-(5-chloropyrimidin-2-yl)cyclopropyl)-2-oxooxazolidin-5-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl acetate (107) (350 mg, 0.496 mmol) in 1,4-dioxane (10 mL) and methanol (5 mL) was added hydrochloric acid (5 mL, 165 mmol). The reaction mixture was stirred at 40° C. overnight. The solvents were removed under reduced pressure and taken up in DCM (100 ml), washed with sat. NaHCO3 (20 ml), water (20 ml) and brine (20 ml), dried over sodium sulfate, filtered and concentrated to give residue, which was subjected to a silica gel column eluting with petroleum ether/EtOAc (6:1 to 3:1) to give 3-(1-(5-chloropyrimidin-2-yl)cyclopropyl)-5-((3aR,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)oxazolidin-2-one (130 mg, 0.087 mmol, 17%) as a white solid. LC/MS: m/z calculated 663.4. found 664.3 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:12])[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:22]=1[C:23](Cl)=O>O1CCCC1>[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:22]=1[C:23]1[O:11][CH2:10][CH2:9][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:12]=1
Reactant: NC(CCO)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Fc1cccc(F)c1C1=NC(c2ccc(Cl)cc2)CCO1
Temperature: 25 °C
Reaction time: 5 h
Yield: 35.9 %

Procedure:
To a solution of 0.9 g of 3-(4-chlorophenyl)-3-amino-1-propanol, 0.5 g of triethylamine in 10 ml of tetrahydrofuran at 0° C., was added dropwise 0.8 g of 2,6-difluorobenzoyl chloride. The reaction mixture was stirred at room temperature for 5 hours. The precipitated solid was filtered off and the filtrate was concentrated under reduced pressure. To the residue, there was added 20 ml of tetrahydrofuran and 2.4 g of triphenylphosphine and further added 2.0 g of diisopropyl azodicarboxylate. The reaction mixture was stirred at room temperature for 12 hours and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to afford 0.5 g of 2-(2,6-difluorophenyl)-4-(4-chlorophenyl)-5,6-dihydro-4H-1,3-oxazine. ND23.2 1.5532
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=[O:4])=[O:3].[O:10]1[CH:14]=[CH:13][C:12]([CH:15](O)[CH3:16])=[N:11]1.C(N(CC)CC)C.C(OCC)(=O)C>C1COCC1>[CH3:1][S:2]([O:5][CH:15]([C:12]1[CH:13]=[CH:14][O:10][N:11]=1)[CH3:16])(=[O:4])=[O:3]
Reactant: CC(O)c1ccon1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)c1ccon1
Reaction time: 18 h

Procedure:
Methanesulfonic anhydride (825 mg, 4.74 mmol) was added to a solution of 1-isoxazol-3-ylethanol (C6 from the previous step, 536 mg) and triethylamine (0.90 mL, 6.5 mmol) in THF (10 mL), and the reaction mixture was stirred for 18 hours. After addition of ethyl acetate, the mixture was washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The reaction was judged to be incomplete by proton NMR spectroscopy, so this material was resubjected to the reaction conditions, using two equivalents of methanesulfonic anhydride, and worked up in the same manner. The crude material was purified by silica gel chromatography (Eluants: 25% ethyl acetate in heptane followed by 50% ethyl acetate in heptane) to provide the product as a colorless oil. Yield: 276 mg, 1.44 mmol, 14% over 2 steps. 1H NMR (400 MHz, CDCl3) δ 1.81 (d, J=6.6 Hz, 3H), 3.01 (s, 3H), 5.93 (q, J=6.6 Hz, 1H), 6.50 (d, J=1.8 Hz, 1H), 8.45 (d, J=1.7 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH2:22])=[CH:16][CH:15]=2)[N:3]=1.[C:23]1([CH3:35])[CH:28]=[CH:27][C:26]([S:29]([N:32]=[C:33]=[O:34])(=[O:31])=[O:30])=[CH:25][CH:24]=1>ClCCl>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:33]([NH:32][S:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:35])=[CH:24][CH:25]=3)(=[O:31])=[O:30])=[O:34])=[CH:18][CH:19]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCN)cc2)c(C)c1-c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3nc(C)c(-c4ccccc4)c3C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
To a solution of 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylamine (step 3, 166 mg, 0.57 mmol) in dichloromethane (10 ml) was added p-toluenesulfonyl isocyanate (135 mg, 0.68 mmol). The resulting mixture was stirred at room temperature for 30 min. The reaction mixture washed with water and the organic phase was dried (Na2SO4). After removal of the solvent, the crude product was purified by TLC with dichloromethane/methanol (10:1) to afford 110 mg (39%) of the title compound as yellow solids: MS (ESI) m/z 489 [M+H]+, 487 [M−H]−, 1H-NMR (CDCl3) δ 7.77 (2H, d, J=8.0 Hz), 7.45-7.16 (11H, m), 6.54 (1H, br.s), 3.36 (2H, br.s), 2.73 (2H, br.s), 2.31 (3H, s), 2.28 (3H, s), 2.20 (3H, s).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1.[CH2:14]([O:16][C:17]([CH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)=[O:18])[CH3:15].O>C(OCC)C>[CH2:14]([O:16][C:17]([CH:19]1[CH2:24][CH2:23][C:22]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=2)([OH:25])[CH2:21][CH2:20]1)=[O:18])[CH3:15]
Reactant: Clc1ccc(Br)nc1
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C1CCC(O)(c2ccc(Cl)cn2)CC1
Reaction time: 0.5 h

Procedure:
Butyllithium (15% in hexane; 15 ml) was added dropwise to a solution of 2-bromo-5-chloropyridine (3.8 g) in diethyl ether (80 ml) at −78° C. and, after one hour, a solution of 4-oxocyclohexanecarboxylic acid ethyl ester (3.7 g) in diethyl ether (10 ml) was added dropwise. After 30 minutes, water was cautiously added and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 283.76 (C14H18ClNO3); MS (ESI): 284 (M+H+) was obtained in this way.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[C:6](=[N:8]NC(OC)=O)[CH3:7])[CH3:2].[S-:23][C:24]#N.[K+]>Cl>[F:21][C:18]1[CH:17]=[CH:16][C:15]([N:14]2[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:22])=[C:6]([CH3:7])[N:8]=[C:24]2[SH:23])=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(Nc1ccc(F)cc1)C(C)=NNC(=O)OC
Reactant: N#C[S-]
Agent: Cl
Agent: [K+]
Product: CCOC(=O)c1c(C)nc(S)n1-c1ccc(F)cc1
Temperature: 70 °C

Procedure:
To a suspension of methyl 2-(4-ethoxy-3-((4-fluorophenyl)amino)-4-oxobutan-2-ylidene)hydrazinecarboxylate (3.1 g, 10 mmol) (this material was synthesized according to the protocol described in J. Org. Chem. Soc. 1978, 43, 3392) in 4N HCl (100 mL) was added potassium thiocyanate (1.5 g, 15 mmol) and the mixture was heated to 70° C. for 2 hours. After cooling to room temperature, the solid was filtered and dried to afford ethyl 1-(4-fluorophenyl)-2-mercapto-4-methyl-1H-imidazole-5-carboxylate (57).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=O)[CH:12]([CH3:15])[CH2:13][Br:14])=[CH:10][C:5]=2[O:4][C:3]1=[O:17].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH:12]([CH3:15])[CH2:13][Br:14])=[CH:10][C:5]=2[O:4][C:3]1=[O:17]
Reactant: CC(CBr)C(=O)c1ccc2c(c1)oc(=O)n2C
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(CBr)Cc1ccc2c(c1)oc(=O)n2C
Reaction time: 24 h

Procedure:
0.03 mole of 3-methyl-6-(3-bromo-2-methylpropionyl)benzoxazolinone is dissolved in 0.3 mole of trifluoroacetic acid in a 150-cm3 flask. 0.066 mole of triethylsilane is added dropwise and with cooling. Stirring is continued for 24 hours at room temperature. The reaction mixture is poured into 5 volumes of ice-cold water. The precipitate obtained is drained, washed with water until the washing liquors are neutral, dried and recrystallized in cyclohexane.
Reaction SMILES: C([SiH](CC)CC)C.[I:8][C:9]1[C:18]([O:19][CH2:20][CH2:21][C:22]2[N:23](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:24]=[CH:25][N:26]=2)=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:10]=1.FC(F)(F)C(O)=O>>[NH:23]1[CH:24]=[CH:25][N:26]=[C:22]1[CH2:21][CH2:20][O:19][C:18]1[C:9]([I:8])=[N:10][CH:11]=[C:12]([CH:17]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cnc(I)c(OCCc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cnc(I)c(OCCc2ncc[nH]2)c1
Reaction time: 4 h
Yield: 62.5 %

Procedure:
Triethylsilane (0.160 mL, 1.00 mmol) was added to a solution of 1.45 g (2.36 mmol) of methyl 6-iodo-5-(2-(1-trityl-1H-imidazol-2-yl)ethoxy)nicotinate in trifluoroacetic acid (30.0 mL, 389 mmol). The mixture was stirred for 4 hours, concentrated in vacuum and triturated with 50 ml of anhydrous ethyl ether. The solid material was collected, washed with several portions of ether and partitioned between 1 M of aqueous sodium carbonate and ethyl acetate. The organic extracts were washed with water, brine, dried over magnesium sulfate and concentrated in vacuum to give a residue (0.55 g, 62%) of methyl 5-(2-(1H-imidazol-2-yl)ethoxy)-6-iodonicotinate. MS (ESI+): 374.0
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.F[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[O:22]([C:14]1[CH:13]=[C:12]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: COC(=O)c1ccc(F)cc1Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1Oc1ccccc1

Procedure:
1,4-dioxa-8-azaspiro[4.5]decane (1.18 g), methyl 4-fluoro-2-phenoxybenzoate (1.85 g), and K2CO3 (1.14 g) was stirred at 125° C. in dimethylsulfoxide (25 mL) for 24 hours. The mixture was cooled, poured into 300 mL water, extracted three times with ether, and the ether extracts were combined, rinsed three times with water, and brine, and concentrated. The residue was chromatographed on silica gel using 10-30% ethyl acetate in hexanes as eluent to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]3[C:31]([NH:43][CH:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[C:32]4[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]4=[N:34][C:35]=3[CH2:36][CH3:37])=[O:27])[CH:21]=2)=[O:19])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)[CH:7]=1.[N:50]1(C(OC(C)(C)C)=O)[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[F:81][C:82]([F:87])([F:86])[C:83]([OH:85])=[O:84]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]3[C:31]([NH:43][CH:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[C:32]4[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]4=[N:34][C:35]=3[CH2:36][CH3:37])=[O:27])[CH:21]=2)=[O:19])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:50]3[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]3)[CH:9]=2)[CH:7]=1.[C:83]([OH:85])([C:82]([F:87])([F:86])[F:81])=[O:84]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(Cl)cc(-c3cccc(C=O)c3)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(Cl)cc(-c3cccc(CN4CCCNCC4)c3)c2)c1
Reaction time: 0.5 h

Procedure:
N-[(5-Chloro-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (40 mg, 0.059 mmol) and 1,1-dimethylethyl hexahydro-1H-1,4-diazepine-1-carboxylate (23.59 mg, 0.118 mmol) were dissolved in 1,2-dichloroethane (DCE) (1 mL) in a 1 dram vial and acetic acid (3.71 μL, 0.065 mmol) was added. The mixture was stirred for 30 min and then MP-Triacetoxyborohydride (126 mg, 0.294 mmol) was added. The mixture was stirred overnight. The mixture was filtered through glass fibre filter paper and washed 2× with 0.3 mL of DCE. Trifluoroacetic acid (0.18 mL, 2.336 mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was concentrated and taken up in 1.3 mL of DMSO and purified on a Gilson HPLC eluting at 20 mL/min with a linear gradient running from 10% CH3CN/H2O (0.1% TFA) to 90% CH3CN/H2O (0.1% TFA). The desired fractions were concentrated to give the desired product as a TFA salt. This was converted to the free base by taking up the residue in EtOAc (30 mL) and 2.5 N NaOH (5 mL). The organic phase was washed with 2.5 N NaOH (3×5 mL) and then with brine (2×5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated to give N-{[5-chloro-3′-(hexahydro-1H-1,4-diazepin-1-ylmethyl)-3-biphenylyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (28.2 mg, 62.3%) as a white solid. LC-MS m/z 763 M+; mp 121-124° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Li:10]CCCC>CCCCCCC>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Li:10]
Reactant: [Li]CCCC
Reactant: COc1ccccc1Br
Solvent: CCCCCCC
Product: [Li]c1ccccc1OC
Reaction time: 0.5 h

Procedure:
To a solution of 2-bromoanisole (11.2 g, 60.08 mmol) in heptane (150 mL) was slowly added n-BuLi (1.6 M in hexenes, 36.7 mL). White precipitate formed. The slurry was stirred for 0.5 hrs and was filtered. The solid was washed with pentane and was dried under vacuum. The yield was 6.5 g (94%).