Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)=[O:10])(C)(C)C.[ClH:27].O1CCOCC1>>[ClH:27].[NH2:7][C@@H:8]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)[C:9]([N:11]1[CH2:12][CH2:13][CH:14]([OH:17])[CH2:15][CH2:16]1)=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N1CCC(O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-[1-(4-Hydroxy-benzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (450 mg, 1.2 mmol) was dissolved in 4M HCl-dioxane (2 mL) at 0° C. The mixture was stirred at 25° C. for 1 hour, concentrated and the residue triturated with ether. Yield, 400 mg, 107%; MS 265 (MH+, 100%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Br)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cccc(Br)n1
Reaction time: 1 h
Yield: 96.6 %

Procedure:
A solution of 6-bromopyridine-2-carbaldehyde (10.00 g, 53.76 mmol) in MeOH (120 mL) was treated with sodium borohydride (2.04 g, 53.76 mmol), stirred for 1 h and partitioned between EtOAc and water. The organic phase was separated and the aqueous re-extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give the title compound (9.76 g, 97%) as a pale-yellow liquid; LC-MS retention time 1.52 min, (M+H)+ 188 and 190.
Reaction SMILES: [C:1]([N:8]([CH3:14])[C@H:9]([C:11](O)=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Cl)CCl.C1C=[N:23]C2N(O)N=NC=2C=1.C(=O)([O-])O.[NH4+]>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[N:8]([C@H:9]([C:11](=[O:12])[NH2:23])[CH3:10])[CH3:14])([CH3:7])([CH3:6])[CH3:5]
Reactant: On1nnc2cccnc21
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: C[C@@H](C(N)=O)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
Boc-N-methyl-L-alanine (3.12 g, 15.3 mmol), EDC (2.94 g, 15.3 mmol), HOAt (2.09 g, 15.3 mmol) and ammonium hydrogencarbonate (3.63 g, 45.9 mmol) were added to DMF (20 mL) and stirred at ambient temperature overnight. The mixture was partitioned between EtOAc and water. The EtOAc layer was washed with aqueous potassium hydrogen sulfate solution (×2), dilute aqueous sodium carbonate solution and brine. The EtOAc was evaporated to give the title compound as a white solid (1 g). 1H NMR (400 MHz, DMSO-d6): 7.19 (1H, br), 6.95 (1H, br), 4.60-4.20 (1H, m), 2.73 (3H, s), 1.39 (9H, s), 1.24 (3H, d).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][C:6]=1[F:15])([CH3:4])([CH3:3])[CH3:2].[F:16][CH2:17][C:18]1[CH:22]=[C:21]([NH2:23])[N:20]([C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[CH:27][CH:28]=[N:29]3)[N:19]=1.[OH-].[Li+].[OH-].[Na+].Cl>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:23][C:21]2[N:20]([C:24]3[CH:33]=[CH:32][CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[N:29]4)[N:19]=[C:18]([CH2:17][F:16])[CH:22]=2)(=[O:13])=[O:12])=[CH:7][C:6]=1[F:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cc(CF)nn1-c1cccc2ncccc12
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1F
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [Li+]
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(CF)nn2-c2cccc3ncccc23)cc1F
Temperature: 85 °C
Yield: 7 %

Procedure:
To a mixture of 4-t-butyl-3-fluorobenzene-1-sulfonyl chloride (prepared from Example 27 step c, 0.050 g, 0.20 mmol), 3-(fluoromethyl)-1-(quinolin-5-yl)-1H-pyrazol-5-amine (0.025 g, 0.10 mmol), and DMAP (0.012 g, 0.095 mmol) in pyridine (3 mL) was heated at 85° C. for 2 h with stirring. After cooling to room temperature, 1 M aqueous lithium hydroxide (1 mL) and 1 M aqueous sodium hydroxide (1 mL) were added to the reaction mixture and heated at 75° C. for 1 h. After cooling to room temperature, the reaction mixture was neutralized with 1 N aqueous hydrochloric acid. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with aqueous saturated sodium bicarbonate, dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.003 g, 0.007 mmol, 7%). 1H NMR (400 MHz, CD3OD) 8.83 (dd, J=4.4, 11.6 Hz, 1H), 8.10 (dd, J=1.2, 8.8 Hz, 1H), 7.83 (ddd, J=1.6, 7.6, 8.8 Hz, 1H), 7.63 (dd, J=0.8, 8.8 Hz, 1H), 7.53 (dd, J=0.8, 7.6 Hz, 1H), 7.41 (dd, J=1.6, 8.4 Hz, 1H), 7.38-7.31 (m, 2H), 7.24 (dd, J=1.6, 12.4 Hz, 1H), 6.05 (d, J=1.6 Hz, 1H), 5.28 (s, 1H), 5.16 (s, 1H), 1.40 (d, J=0.8 Hz, 9H); MS: (ES) m/z calculated for C23H26N5O2S [M+H]+ 457.2. found 457.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[N:8][O:9][CH2:10][CH2:11][OH:12])=[CH:3][CH:2]=1.O[C:14]1[CH:46]=[CH:45][C:17]([CH2:18][CH:19]2[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]2=[O:44])=[CH:16][CH:15]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCNCC1)=O)=NC(N1CCNCC1)=O>>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[N:8][O:9][CH2:10][CH2:11][O:12][C:14]2[CH:46]=[CH:45][C:17]([CH2:18][CH:19]3[S:23][C:22](=[O:24])[N:21]([C:25]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]3=[O:44])=[CH:16][CH:15]=2)=[CH:3][CH:2]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCON=Cc1ccncc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCNCC1)N1CCNCC1
Product: O=C1SC(Cc2ccc(OCCON=Cc3ccncc3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 41.7 %

Procedure:
Following a procedure similar to that described in Example 3(a), but using 0.88 g of 2-(4-pyridylmethyleneaminooxy)ethanol (prepared as described in Preparation 6), 2.00 g of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 1.32 ml of tributylphosphine and 1.23 g of 1,1'-(azodicarbonyl)dipiperazine, 1.10 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=3)[CH2:12][CH2:11]2)=[N:2]1.[CH3:25][C:26]([CH3:31])=[CH:27][C:28](Cl)=[O:29]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]3[CH:19]=[C:20]([NH:24][C:28](=[O:29])[CH:27]=[C:26]([CH3:31])[CH3:25])[CH:21]=[CH:22][CH:23]=3)[CH2:14][CH2:15]2)=[N:2]1
Reactant: Nc1cccc(CCN2CCN(c3nsc4ccccc34)CC2)c1
Reactant: CC(C)=CC(=O)Cl
Product: CC(C)=CC(=O)Nc1cccc(CCN2CCN(c3nsc4ccccc34)CC2)c1
Yield: 96.5 %

Procedure:
Starting from {3-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-amine (338 mg, 1 mmol) and 3,3 dimethyl acryloyl chloride (116 μL, 1.05 mmol) and following the procedure as outlined in Example 1, 406 mg of 3-methyl-but-2-enoic acid {3-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-amide was isolated as a light yellow solid in 100% purity @ 254 nm; LCMS (APCI): 421 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([NH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:12].[F:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[N:25][CH:26]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].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.CN(C=O)C>[F:20][C:21]1[CH:22]=[C:23]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[C:5]3[C:11]([NH:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:12])[CH:24]=[N:25][CH:26]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: O=C(Nc1cccnc1)c1n[nH]c2ccc(Br)cc12
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: CN(C)C=O
Solvent: O
Product: O=C(Nc1cccnc1)c1n[nH]c2ccc(-c3cncc(F)c3)cc12
Temperature: 180 °C
Yield: 1.6 %

Procedure:
To a microwave vial was added 5-bromo-N-(pyridin-3-yl)-1H-indazole-3-carboxamide (CXXXV) (0.200 g, 0.63 mmol), 5-fluoropyridine-3-boronic acid (CXXIX) (0.098 g, 0.694 mmol), tetrakis(triphenylphosphine)palladium(0) (0.036 g, 0.032 mmol), potassium phosphate (0.201 g, 0.947 mmol), water (1 mL), and DMF (5 mL) The reaction vial was capped, purged with argon and heated under microwave irradiation for 1 h at 180° C. The solution was filtered through a pad of Celite and concentrated under vacuum. The crude product was purified by column chromatography (100% CHCl3→2:98 MeOH[7N NH3]:CHCl3) to afford 5-(5-fluoropyridin-3-yl)-N-(pyridin-3-yl)-1H-indazole-3-carboxamide (13) (4 mg, 0.01 mmol, 2% yield) as a white solid. 1H NMR (DMSO-d6) δ ppm 14.02 (br s, 1H), 10.70 (s, 1H), 9.08 (d, J=2.5 Hz, 1H), 8.83 (t, J=1.8 Hz, 1H), 8.60 (d, J=2.7 Hz, 1H), 8.53-8.52 (m, 1H), 8.34-8.29 (m, 2H), 8.14-8.09 (m, 1H), 7.89-7.81 (m, 2H), 7.42-7.38 (m, 1H). ESIMS found for C18H12FN5O m/z 334.0 (M+H).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][C:13](=[O:16])[CH:14]=[CH2:15].[O-]CC.[Na+]>C(OCC)(=O)C.C(O)C>[O:16]=[C:13]([CH3:12])[CH2:14][CH2:15][N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6]
Reactant: C=CC(C)=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a well-stirred milky suspension of phthalimide (60.0 g, 408.0 mmol, 1.00 eq.) and 3-buten-2-one (33.2 mL, 408.0 mmol, 1.00 eq.) in anhydrous ethyl acetate (400 mL) under N2, a freshly prepared yellow homogeneous solution of sodium ethoxide (1.4 g, 20.4 mmol, 0.05 eq.) in anhydrous ethanol (100 mL) was added dropwise (over 35 min.). After completion of the addition, the resulting slightly yellow heterogeneous mixture was further stirred at r.t. for 2 hours. The beige heterogeneous mixture was then refluxed (oil bath temperature=90° C.) for 2 hours. The resulting orange homogeneous solution was then allowed to slowly cool down to r.t. The resulting heterogeneous mixture was concentrated to dryness in vacuo to afford a beige solid which was recrystallized from EtOH to afford the title compound as a beige solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.C1(C)C=CC(S([Cl:29])(=O)=O)=CC=1.O>O1CCCC1>[Cl:29][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=1
Reactant: CC1(C)COC(c2cccc(F)c2)=N1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)COC(c2cccc(F)c2Cl)=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a stirred solution of 2-(3-fluorophenyl)-4,4-dimethyloxazoline (36.7 g) in dry tetrahydrofuran (500 ml.) at -65° C. was added dropwise n-butyl-lithium (119 ml. of 1.6M solution in hexane). The solution was stirred at the same temperature for 1 hour and then a solution of 4-toluenesulphonic chloride (36.2 g.) in dry tetrahydrofuran (250 ml.) was added over 45 minutes, maintaining the temperature below -50° C. The mixture was stirred at -50° C. for 1 hour and then allowed to warm up to room temperature and stirred for a further 2 hours. An excess of water was added and the mixture was evaporated to a low volume and extracted several times with diethyl ether. The combined extracts were washed with diluted sodium hydroxide solution, water and then dried over sodium sulphate. Evaporation of the solvent gave an oil which was distilled to give 2-(2-chloro-3-fluorophenyl)-4,4-dimethyloxazoline (29.0 g.), b.p. 138°-140° C. at 15 m.m. Found: C, 57.93; H, 4.77; N, 6.20. C11H11ClFNO requires: C, 58.03; H, 4.87; N, 6.15%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[C:17]3[CH:18]=[C:19]([C:22](O)=[O:23])[CH:20]=[CH:21][C:16]=3[O:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[NH2:25][C:26]1[S:27][CH:28]=[C:29]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:30]=1>>[CH2:35]([O:34][C:32](=[O:33])[CH2:31][C:29]1[N:30]=[C:26]([NH:25][C:22]([C:19]2[CH:20]=[CH:21][C:16]3[O:15][CH2:14][CH2:13][N:12]([S:9]([C:4]4[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=4)(=[O:10])=[O:11])[C:17]=3[CH:18]=2)=[O:23])[S:27][CH:28]=1)[CH3:36]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: Cc1cc(C)cc(S(=O)(=O)N2CCOc3ccc(C(=O)O)cc32)c1
Product: CCOC(=O)Cc1csc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(C)cc(C)c2)CCO3)n1

Procedure:
The title compound, MS (ISP)=486.3 (M−H)−, was produced as described in example 1, steps 1-6. Step 3 was performed using 3,5-dimethylbenzenesulfonyl chloride, furnishing 4-(3,5-Dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester, which was hydrolyzed in step 4, leading to 4-(3,5-dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid. This was reacted with ethyl 2-amino-4-thiazoleacetate in step 5 and yielded (2-{[4-(3,5-dimethyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-acetic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH2:9][CH3:10])=[CH:6][CH:7]=1.[S-:11][C:12]#[N:13].[K+].C(Cl)(=O)C1C=CC=CC=1>CC(C)=O>[CH2:9]([O:8][C:5]1[N:4]=[CH:3][C:2]([NH:1][C:12]([NH2:13])=[S:11])=[CH:7][CH:6]=1)[CH3:10]
Reactant: CCOc1ccc(N)cn1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O=C(Cl)c1ccccc1
Product: CCOc1ccc(NC(N)=S)cn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 12 g of 3-amino-6-ethoxypyridine in 30 ml of acetone was admixed with a solution of 7.6 g of potassium thiocyanate in 60 ml of acetone, and under stirring, 15.4 g of benzoyl chloride was added dropwise. The mixture was then boiled for 10 minutes. The reaction mixture was poured into ice-water and the resulting crystals (m.p. 130°-133° C.) were recovered by filtration and boiled with 50 ml of 10% sodium hydroxide for 15 minutes. After cooling, crystals (m.p. 142°-146° C.) of 6-ethoxy-3-pyridylthiourea were obtained. These crystals were dissolved in 150 ml of hot 10% potassium hydroxide, and after addition of 37 g of lead acetate, the mixture was stirred at 80° C. for 20 minutes. The precipitated lead sulfide was filtered off and the filtrate was neutralized to give 5 g of 6-ethoxy-3-pyridylcyanamide as colorless needles melting 102°-104° C.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([CH:10]([OH:12])[CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:18]([N:37]1[C:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[C:48]2[CH:55]=[CH:54][C:51]([CH2:52]Br)=[CH:50][CH:49]=2)=[N:40][N:39]=[N:38]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC(C)([O-])C.[K+]>>[CH2:1]([C:5]1[N:6]([CH2:52][C:51]2[CH:50]=[CH:49][C:48]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[C:41]3[N:37]([C:18]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:38]=[N:39][N:40]=3)=[CH:55][CH:54]=2)[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:8]([CH:10]([OH:12])[CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(C)O)c(C(=O)OCC)[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCCc1nc(C(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 78.8 %

Procedure:
Following a procedure similar to that described in Example 35(a), but using 400 mg of ethyl 2-butyl-4-(1-hydroxyethyl)imidazole-5-carboxylate [prepared as described in Preparation 24(iii)], 1.00 g of 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide and 197 mg of potassium t-butoxide, 0.94 g of the title compound was obtained as a viscous oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]3[CH2:26][C:25]4[C:20](=[CH:21][C:22]([O:29][CH2:30][CH2:31][N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)=[C:23]([O:27][CH3:28])[CH:24]=4)[C:17]=3[NH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:40][Si:41]([CH3:48])([CH3:47])[CH2:42][CH2:43][O:44][CH2:45]Cl>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16]3[CH2:26][C:25]4[C:20](=[CH:21][C:22]([O:29][CH2:30][CH2:31][N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)=[C:23]([O:27][CH3:28])[CH:24]=4)[C:17]=3[N:18]([CH2:45][O:44][CH2:43][CH2:42][Si:41]([CH3:48])([CH3:47])[CH3:40])[N:19]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(cc1OCCN1CCCCC1)-c1[nH]nc(-c3ccc(OCc4ccccc4)cc3)c1C2
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OCCN1CCCCC1)-c1c(c(-c3ccc(OCc4ccccc4)cc3)nn1COCC[Si](C)(C)C)C2
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To the solution of Example 301C (7.71 g, 15.56 mmol) in DMF (200 mL) was added 95% NaH (0.412 g, 16.34 mmol). After 0.5 hour, 2-(trimethylsilyl)ethoxymethyl chloride (2.89 mL, 16.34 mmol) was added dropwise. Then the reaction was run at room temperature for 2 hours. All the DMF was removed. The residue was purified by flash chromatography to give the desired product (5.50 g, 56%). MS (APCI) m/z 626 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>N1C=CC=CC=1.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH:17][C:23]([C:19]2[O:18][CH:22]=[CH:21][CH:20]=2)=[O:24])[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cccc(-c2cnc3ccccc3n2)c1)c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
A solution of (3-quinoxalin-2-ylphenyl)amine (2.21 g, 0.01 mol) in pyridine (10 mL) was cooled to 0° C. and 2-furoyl chloride (1 mL, 0.01 mol) was added dropwise over 10 min. The reaction mixture was stirred overnight at room temperature, diluted with water (50 mL), and stirred until precipitate formed. The solid was filtered, dried, and recrystallized from toluene to afford N-[3-(quinoxalin-2-yl)phenyl]furan-2-carboxamide (2.4 g, 76%). LCMS calculated for C19H13N3O2 (M+H): 316.10. found 316. 1H-NMR (DMSO-d6, 250 Mhz) δH: 10.45 (1H, s), 9.51 (1H, s), 8.68 (1H, s), 8.22-7.80 (7H, m), 7.61 (1H, m), 7.40 (1H, m), 6.81 (1H, m).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:10]#[N:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].O>CCCCCC.CS(C)=O>[C:4]1([CH:3]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:10]#[N:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCCCI
Reactant: N#CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCCCCC
Product: CCCCCC(C#N)c1ccccc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Sodium hydride (2.2 g of 50% w/w slurry in mineral oil, 47.0 mmol) was washed with hexane and dried under vacuum. Dimethylsulfoxide (40 mL) was added, and the mixture was stirred and cooled in an ice bath while a solution of benzyl cyanide (5.0 g, 42.7 mmol) in dimethyl-sulfoxide (10 mL) was added dropwise. The ice bath was removed, and the solution was allowed to stir for 4 hours. The deep red solution was then cooled again to 0° C., and a solution of 1-iodopentane (5.60 mL, 42.7 mmol) in dimethyl-sulfoxide (10 mL) was added dropwise. The mixture was stirred and allowed to come to ambient temperature over 12 hours. It was poured into water (200 mL), and extracted with ethyl acetate (2×200 mL). The extracts were washed in sequence with water (3×200 mL), then combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The oily residue was separated by column chromatography (3:97 ethyl acetate-hexane) to afford the product, 2-phenylheptanenitrile, as a clear oil (4.41 g, 23.5 mmol, 55%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]=[N:9][CH:8]=2)=[CH:3][CH:2]=1.Cl.Cl[CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.C(OCC)(=O)C.C(O)CCC>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:21][C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=4)=[CH:14][CH:13]=3)[CH:10]=[N:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: Oc1ccc(-n2cncc2-c2ccncc2)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: c1ccc2nc(COc3ccc(-n4cncc4-c4ccncc4)cc3)ccc2c1
Temperature: 23 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
A mixture of Preparation 84 (4-(5-(pyridin-4-yl)-1H-imidazol-1-yl)phenol, 95 mg, 0.4 mmol), 2-chloromethylquinoline hydrochloride (128 mg, 0.6 mmol), and cesium carbonate (391 mg, 1.2 mmol) in dimethylsulfoxide (2 mL) was stirred at 23° C. for 24 h. The mixture was diluted with ethyl acetate/n-butanol (100 mL/5 mL), was washed with water and then brine, and the organic layer was dried (MgSO4), was filtered, and was concentrated in vacuo. The residue was purified by silica gel chromatography using chloroform/methanol (50:1) to afford 150 mg (99% yield) of the title compound; diagnostic 13C NMR signals (100 MHz, CDCl3) δ 158.940, 157.116, 149.990, 147.836, 141.054, 137.405, 130.989, 130.204, 129.650, 129.239, 127.953, 127.871, 127.392, 127.011, 121.627, 119.324, 116.198, 71.990; MS (AP/CI) 379.4 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[N:10]([CH3:15])[C:9]2=[O:16])=[CH:4][CH:3]=1.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:15][N:10]1[C:11]([CH3:14])([CH3:13])[CH2:12][N:8]([C:5]2[CH:6]=[N:7][C:2]([C:24]#[C:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:3][CH:4]=2)[C:9]1=[O:16]
Reactant: CN1C(=O)N(c2ccc(Br)nc2)CC1(C)C
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1C(=O)N(c2ccc(C#Cc3ccccc3)nc2)CC1(C)C
Temperature: 90 °C
Reaction time: 4 h
Yield: 60.4 %

Procedure:
Bis-(triphenylphosphine)-palladium(II)dichloride (6 mg, 8.5 μmol, 0.03 equiv.) was dissolved in 1 ml DMF. (80 mg, 282 μmol) 1-(6-Bromo-pyridin-3-yl)-3,4,4-trimethyl-imidazolidin-2-one (E ample 3, step 2) and phenylacetylene (58 mg, 563 μmol, 2 equiv.) were added at room temperature. Triethylamine (118 μl 0.845 mmol, 3 equiv.), triphenylphosphine (4.4 mg, 16.9 μmol, 0.06 equiv.) and copper(I)iodide (1.6 mg, 8.45 μmol, 0.03 equiv.) were added and the mixture was stirred for 4 hours at 90° C. The reaction mixture was evaporated to dryness with Isolute® and the crude product was purified by flash chromatography by directly loading the solid onto a silica gel column and eluting with an ethyl acetate: heptane gradient 0:100 to 100:0. The desired 3,4,4-trimethyl-1-(6-phenylethynyl-pyridin-3-yl)-imidazolidin-2-one (52 mg, 61% yield) was obtained as a yellow solid, MS: m/e=306.2 (M+H+).