Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:18]=2)=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH3:13])=[O:10])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[Li+].CCC[CH2-].[B:35](OC)([O:38]C)[O:36]C.Cl>C1COCC1.O>[CH2:12]([NH:11][C:9](=[O:10])[NH:8][C:5]1[N:6]=[CH:7][C:2]([B:35]([OH:38])[OH:36])=[C:3]([C:14]2[S:15][CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:18]=2)[CH:4]=1)[CH3:13]
Reactant: COB(OC)OC
Reactant: CCNC(=O)Nc1cc(-c2nc(-c3ccccc3)cs2)c(Br)cn1
Agent: CC(C)[Mg]Cl
Agent: Cl
Agent: [CH2-]CCC
Solvent: O
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(-c2nc(-c3ccccc3)cs2)c(B(O)O)cn1
Temperature: -15 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A solution of 1-(5-bromo-4-(4-phenylthiazol-2-yl)pyridin-2-yl)-3-ethylurea (2.97 g, 7.36 mmol, Intermediate 15) in THF (25 mL) was cooled to −78° C. Isopropylmagnesium chloride (2.0M in THF; 8.84 mL, 17.67 mmol, Aldrich) was added slowly and the reaction was slowly warmed to −15° C. before being cooled back down to −78° C. N-Butyllithium (2.5M in hexanes; 14.73 mL, 36.82 mmol, Aldrich) was then added and the reaction was stirred at −78° C. for 1 hour. Trimethyl borate (8.21 mL, 73.64 mmol, Aldrich) was added all at once and an exotherm was observed. Following the exotherm, the reaction mixture was allowed to warm to room temperature and stir for 3 h. The reaction mixture was then cooled to 0° C. and 20 mL of water was added slowly followed by 10 mL of 6N HCl. The reaction mixture was allowed to warm to room temperature and stir for 30 min The reaction mixture was concentrated under reduced pressure to remove THF. The aqueous portion was diluted with 1N NaOH and diethylether. The impurities went into the ether layer (yellow) and the remaining white solid was filtered, washed with water and dried. The solid was then triturate with dilute acid (pH 4.5) to remove salts. The solid was dried overnight to yield product as a white solid (1.60 g).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].Cl[CH2:33][CH2:34][CH2:35][CH:36]([C:44]1[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=1)[C:37]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(=O)CC>[F:43][C:40]1[CH:39]=[CH:38][C:37]([CH:36]([C:44]2[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=2)[CH2:35][CH2:34][CH2:33][N:9]2[CH2:10][CH2:11][C:6]3([N:5]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:4][N:3]([CH2:18][C:19]4[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=4)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:2]3=[O:1])[CH2:7][CH2:8]2)=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCC(c4ccc(F)cc4)c4ccc(F)cc4)CC3)C2=O)c1
Temperature: 81 °C
Reaction time: 16 h
Yield: 79.1 %

Procedure:
A mixture of tert-butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (400 mg, 0.949 mmol, 1 equiv), 4,4′-(4-chlorobutane-1,1-diyl)bis(fluorobenzene) (222.06 μl, 0.949 mmol, 1 equiv), potassium carbonate (393.5 mg, 2.847 mmol, 3 equiv), and sodium iodide (42.7 mg, 0.285 mmol, 0.3 equiv) in 2-butanone was stirred at 81° C. for 16 h. After cooling, the reaction mixture was filtered, filtrate concentrated, and the crude residue was purified using the Biotage flash chromatography system (SNAP 50 g cartridge, Rf=0.5, gradient—1%-10% methanol in dichloromethane) to afford the title compound as a white crystalline solid (500 mg, 80.8%); 1H NMR (400 MHz, DMSO-d6): δ 1.35 (bs, 2H); 1.51 (s, 9H); 1.59 (d, 2H, J=13.2 Hz); 2.02-2.04 (m, 2H); 2.36 (bs, 2H); 2.52-2.53 (m, 2H); 2.64-2.67 (m, 4H); 4.11 (s, 1H); 4.57 (s, 2H); 4.60 (s, 2H); 6.75 (bs, 1H); 6.81 (d, 2H, J=8.4 Hz); 7.08-7.12 (m, 4H); 7.16-7.20 (m, 2H); 7.32-7.36 (m, 4H); 7.49-7.53 (m, 2H); 7.78 (bs, 1H); 7.82-7.84 (m, 1H); MS for C4iH45F2N3O3 m/z 666.18 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH:8]([CH3:10])[CH3:9].[CH2:12]([O:14][C:15]([C:17]1[S:21][C:20]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([C:29]#[N:30])[CH:23]=2)=[N:19][C:18]=1[CH3:31])=[O:16])[CH3:13].O>CN(C)C=O>[CH2:12]([O:14][C:15]([C:17]1[S:21][C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:7][CH:8]([CH3:10])[CH3:9])=[C:24]([C:29]#[N:30])[CH:23]=2)=[N:19][C:18]=1[CH3:31])=[O:16])[CH3:13]
Reactant: CC(C)CBr
Reactant: CCOC(=O)c1sc(-c2ccc(O)c(C#N)c2)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1sc(-c2ccc(OCC(C)C)c(C#N)c2)nc1C
Temperature: 75 °C
Reaction time: 1 h

Procedure:
Potassium carbonate (300 g, 2.17 mol) and isobutyl bromide (142.7 g, 1.041 mol) were added to a solution of ethyl-2-(3-cyano-4-hydroxyphenyl)-4-methyl-5-thiazole carboxylate (100 g, 0.347 mol) in dimethylformamide (300 mL), and the reaction mixture was heated at a temperature of about 75° C. for about 8 hours. After completion of reaction, the reaction mixture was cooled to about 40° C. and water was added. The reaction mixture was further cooled to about 0° C. and stirred for about 1 hour. The solid thus obtained was filtered, washed with water and dried to give title compound. (Yield: 111g, 92.9%)
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:88]=[CH:89][CH:90]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:76][CH2:75][CH:74]([OH:77])[CH2:73][CH2:72]5)=[N:69][CH:70]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:88]=[CH:89][CH:90]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([N:71]5[CH2:76][CH2:75][CH:74]([OH:77])[CH2:73][CH2:72]5)=[N:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCC(O)CC5)nc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: OC1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Yield: 32.4 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 1-(5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)pyridin-2-yl)piperidin-4-ol (160 mg, 0.25 mmol) was hydrolyzed with lithium hydroxide (33 mg, 0.77 mmol) in THF/methanol/water (3/3/1 mL) to yield 38 mg (25.4%) of desired product. 1H NMR (CD3OD, 300 MHz): δ 8.49-8.41 (m, 3H), 8.21 (s, 2H), 7.98 (s, 1H), 7.70 (s, 1H), 7.55-7.51 (s, 1H), 7.42-7.33 (m, 1H), 7.11-6.97 (m, 3H), 5.43 (s, 2H), 4.06-3.98 (m, 3H), 3.65-3.57 (m, 2H), 2.09-2.03 (m, 2H), 1.80-1.65 (m, 2H). MS: m/z=469.2 (M+1), HPLC: 93.72% in method A.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[N:13][CH:12]=[CH:11][N:10]=2)O1.Br[C:17]1[CH:18]=[C:19]2[C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:24][N:23](C3CCCCO3)[C:20]2=[CH:21][N:22]=1>>[C:26]1([C:25]2[C:19]3[C:20](=[CH:21][N:22]=[C:17]([C:9]4[CH:14]=[N:13][CH:12]=[CH:11][N:10]=4)[CH:18]=3)[NH:23][N:24]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Brc1cc2c(-c3ccccc3)nn(C3CCCCO3)c2cn1
Reactant: CC1(C)OB(c2cnccn2)OC1(C)C
Product: c1ccc(-c2n[nH]c3cnc(-c4cnccn4)cc23)cc1
Yield: 28 %

Procedure:
Following the procedures in Example 204, 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine and 5-bromo-3-phenyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine were reacted and the product was deprotected to give 214 as a yellow solid (22 mg, 28%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.61 (s, 1H), 9.26 (s, 1H), 8.97 (s, 1H), 8.76 (s, 1H), 8.67 (d, 1H), 8.05 (t, 2H), 7.61 (t, 2H), 7.48 (t, 1H). ESI MS m/z=274 (M+1)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].C1(C)C=CC(S(O[CH2:22][C@@H:23]2[O:25][CH2:24]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:25]1[CH2:24][C@@H:23]1[CH2:22][O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(O)c(C=O)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(OC[C@H]2CO2)c(C=O)c1
Temperature: 60 °C
Yield: 79.7 %

Procedure:
A mixture of 2-hydroxy-5-methoxybenzaldehyde (6.65 g), (R)-glycidyl 4-toluenesulphonate (10.0 g) and potassium carbonate (6.1 g) in dry dimethylformamide (100 ml) was stirred and heated at 60° C. for five hours. The solvent was removed in vacuo, water was added to the residue and the mixture extracted with ether (2×200 ml). The combined extracts were washed with water and dried over magnesium sulphate. The solvent was evaporated and the residue purified by flash chromatography over silica eluting with a 2:1 mixture of ether and petroleum ether (b.p. 40-60° C.). Appropriate fractions were combined and the solvent evaporated to give (R)-2-(2,3-epoxypropoxy)-5-methoxybenzaldehyde (7.25 g) as a clear oil.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17]Cl)[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:20]([CH:22]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:23][OH:24])[CH3:21].[I-].[K+]>O1CCCC1>[N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17][O:24][CH2:23][CH:22]([CH2:20][CH3:21])[CH2:25][CH2:26][CH2:27][CH3:28])[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Cc1cc(CCl)c(O)c(-n2nc3ccccc3n2)c1
Reactant: CCCCC(CC)CO
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCC(CC)COCc1cc(C)cc(-n2nc3ccccc3n2)c1O
Temperature: 70 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
) 2-(2H-Benzotriazol-2-yl)-6-chloromethyl-4-methyl-phenol (1.0 g, 3.7 mmol) is partly solved in tetrahydrofurane (20 mL) at 70° C. 2-Ethyl-hexan-1-ol (9.6 g, 73 mmol), potassium tert.butylate (1.0 g, 7.3 mmol), and a catalytic amount of potassium iodide are added subsequently. The orange reaction mixture is stirred at 70° C. for one hour and evaporated to dryness. The residue is dissolved in ethyl acetate and extracted with water. The organic layer is dried over sodium sulphate, filtered and evaporated to dryness. Excess alcohol is removed and recovered by distillation. The crude product is purified by column chromatography (ethyl acetate/heptane 1:12) to yield 1.2 g of 2-(2H-Benzotriazol-2-yl)-6-(2-ethylhexyloxymethyl)-4-methyl-phenol. b.) 2-(2H-benzotriazol-2-yl)-6-chloromethyl-4-methyl-phenol (0.5 g, 1.9 mmol) is suspended in 2-ethylhexan-1-ol (5.0 g, 38 mmol) at 60° C. 1.1 equivalent K2HPO4 is added and the mixture is stirred for 12 hours at 60° C. resulting in 63.3% of 2-(2H-Benzotriazol-2-yl)-6-(2-ethylhexyloxymethyl)-4-methyl-phenol (determined by means of HPLC analysis). c.) 2-(2H-Benzotriazol-2-yl)-6-chloromethyl-4-methylphenol (1.0 g, 3.7 mmol) is suspended in 2-ethylhexan-1-ol (4.0 g, 31 mmol) at 80° C. 1.1 equivalent of the respective base as given in table 1 is added and the mixture is stirred for 15 minutes at 80° C. The turnover and impurity profile is determined by means of HPLC analysis.
Reaction SMILES: C(=[N:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[CH:14]([CH3:16])[CH3:15])C1C=CC=CC=1.[ClH:17]>>[ClH:17].[NH2:8][N:9]1[CH:13]=[CH:12][N:11]=[C:10]1[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)c1nccn1N=Cc1ccccc1
Agent: Cl
Product: CC(C)c1nccn1N

Procedure:
A mixture of 1 g of 1-benzylideneamino-2-isopropylimidazole and 50 ml of 1N hydrochloric acid is subjected to a steam distillation until benzaldehyde no longer passes over. The residual solution is evaporated in a vacuum. Methanol and benzene are added to the residue. The mixture is evaporated, methanol and benzene are again added and the mixture is again evaporated. Crude 1-amino-2-isopropylimidazole hydrochloride is obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH3:24][N:25]([C:33]1[N:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=1)C(=O)OC(C)(C)C>>[CH3:24][NH:25][C:33]1[N:38]=[CH:37][C:36]([C:2]2[N:3]=[C:4]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13]4)[S:8][C:6]=3[N:7]=2)=[CH:35][N:34]=1
Reactant: OC1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)C1
Reactant: CN(C(=O)OC(C)(C)C)c1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CNc1ncc(-c2nc(N3CCOCC3)c3cc(CN4CCC(O)C4)sc3n2)cn1
Yield: 29 %

Procedure:
1-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)pyrrolidin-3-ol (235 mg, 0.67 mmol) was utilized in a Suzuki coupling with tert-butyl methyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)carbamate (311 mg, 0.93 mmol) according to General Procedure Suzuki to provide 380 (83 mg) after reverse phase HPLC purification. MS (Q1) 428 (M)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[C:12]([CH:16]=[O:17])[CH:11]=[C:10]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:22](Cl)(=[O:24])[CH3:23]>>[C:22]([NH:21][S:18]([C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=2)[C:13]([O:14][CH3:15])=[C:12]([CH:16]=[O:17])[CH:11]=1)(=[O:19])=[O:20])(=[O:24])[CH3:23]
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc(N)c1
Reactant: CC(=O)Cl
Product: COc1c(C=O)cc(S(=O)(=O)NC(C)=O)cc1-c1cccc(N)c1

Procedure:
Proceeding as in Reference 21, but substituting 3′-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide and acetyl chloride, gave N-acetyl-3′-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3[N:7]=[C:8]([C:14]#[N:15])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.C[O-].[Na+].CO[CH:23](OC)[CH2:24][NH2:25].C(O)(=O)C.Cl>CO.O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[NH:25][CH:24]=[CH:23][N:15]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: N#Cc1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: COC(CN)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: Brc1ccc2c(c1)OCCc1sc(-c3ncc[nH]3)nc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbonitrile (0.100 g, 0.326 mmol) in 1.0 ml of Methanol was added 25% Sodium methoxide (0.020 mL, 0.087 mmol) in Methanol. The reaction was stirred 1 h rt. Aminoacetaldehyde dimethyl acetal (0.0390 mL, 0.358 mmol) was added to the reaction mixture followed by Acetic acid (0.0370 mL, 0.651 mmol). The reaction was heated at 50° C. for 1 h and then cooled to rt. Methanol (0.650 mL, 16.0 mmol) and 6.00 M of Hydrogen chloride in Water (0.163 mL) were added, the reaction was heated 100 for 12 h. The reaction mixture was concentrated then added EtOAc and water. The combined organic layers was concentrated to give 8-Bromo-2-(1H-imidazol-2-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene. MS: (ESI+)=349.1
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[N:9]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:8]=1[CH2:26]Br)=[O:6].[C:28]([CH2:30][NH:31][S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])#[N:29].Cl>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Br:16])[CH:14]=2)[N:9]([S:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)(=[O:18])=[O:19])[C:8]=1[CH2:26][N:31]([CH2:30][C:28]#[N:29])[S:32]([C:35]1[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=1)(=[O:34])=[O:33])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)NCC#N)cc1
Reactant: COC(=O)c1c(CBr)n(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(CN(CC#N)S(=O)(=O)c2ccc(C)cc2)n(S(=O)(=O)c2ccccc2)c2ncc(Br)cc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.8 %

Procedure:
Sodium hydride (11.7 g, 60% dispersion in mineral oil, 293 mmol) was added portionwise to a cooled (0° C.) solution of 1-benzenesulfonyl-5-bromo-2-bromomethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (130 g, 266 mmol) and N-cyanomethyl-4-methyl-benzenesulfonamide (61.5 g, 293 mmol) in DMF (1.25 L). The reaction mixture was stirred at 0° C. for 15 minutes, then allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture was poured into a cooled, stirred solution of 2M hydrochloric acid (1.25 L). The resultant precipitate was collected by filtration (slow) and the cake washed with water, followed by methanol and then diethyl ether. The resulting cake was dried to afford the title compound as a grey solid (154 g, 94%). LCMS (Method B): RT=4.28 min, M+H+=617/619. 1H NMR (400 MHz, CDCl3): 8.49 (d, J=2.3 Hz, 1H), 8.42 (d, J=2.3 Hz, 1H), 8.33-8.33 (m, 2H), 7.78-7.76 (m, 2H), 7.64-7.64 (m, 1H), 7.55-7.54 (m, 2H), 7.34 (d, J=8.1 Hz, 2H), 5.43 (s, 2H), 4.28 (s, 2H), 3.96 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: II.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[CH2:29]([C:36]1([C:51]([NH:53][NH:54][C:55]([C:57]2[CH:62]=[C:61]([O:63][CH3:64])[CH:60]=[C:59]([O:65][CH3:66])[CH:58]=2)=[O:56])=O)[C:40](=[O:41])[N:39]([C@@H:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH3:43])[C:38](=[O:50])[NH:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:29]([C@:36]1([C:51]2[O:56][C:55]([C:57]3[CH:62]=[C:61]([O:63][CH3:64])[CH:60]=[C:59]([O:65][CH3:66])[CH:58]=3)=[N:54][N:53]=2)[NH:37][C:38](=[O:50])[N:39]([C@@H:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH3:43])[C:40]1=[O:41])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COc1cc(OC)cc(C(=O)NNC(=O)C2(Cc3ccccc3)NC(=O)N([C@H](C)c3ccccc3)C2=O)c1
Agent: II
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)cc(-c2nnc([C@@]3(Cc4ccccc4)NC(=O)N([C@H](C)c4ccccc4)C3=O)o2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of iodine (354 mg, 1.394 mmol) in dichloromethane (8 mL) was added triphenylphosphine (375 mg, 1.429 mmol). After 5 min triethylamine (0.389 mL, 2.79 mmol) was added. After 5 min a solution of the product from Step A (180 mg, 0.348 mmol) in dichloromethane (3 mL) was added. After stirring at ambient temperature for 1 h, a 1:1 mixture of saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium thiosulfate (5 mL) was added. The biphasic mixture was stirred for 10 min, the layers were separated and the aqueous phase extracted with dichloromethane (3×5 mL). The combined organic phases were washed with saturated aqueous brine (1×5 mL), dried with anhydrous sodium sulfate, filtered and the solvent removed in vacuo. The residue was purified by column chromatography (silica gel 40 g column) eluting with ethyl acetate/hexane (gradient from 0% to 100%) to give a mixture of diastereomers as a colorless amorphous solid. The isomers were separated via chiral HPLC (ChiralPak AS-H; 40% 2:1 methanol:acetonitrile/carbon dioxide) to afford the first eluting isomer (5R)-5-Benzyl-5-[5-(3,5-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]imidazolidine-2,4-dione (2.25 minutes) and the second eluting isomer (5S)-5-Benzyl-5-[5-(3,5-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]-3-[(1R)-1-phenylethyl]imidazolidine-2,4-dione (3.45 minutes) as colorless amorphous solids. LC/MS 499.1 (M+1). IC50 value=C rating for the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[C:8]([NH:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13][SH:14])(=[O:10])[CH3:9].OO>O.CC(C)=O>[C:8]([NH:11][C@@H:12]([CH2:13][S:14][S:4][CH2:3][C@H:2]([NH2:1])[C:5]([OH:7])=[O:6])[C:15]([OH:17])=[O:16])(=[O:10])[CH3:9]
Reactant: CC(=O)N[C@@H](CS)C(=O)O
Reactant: N[C@@H](CS)C(=O)O
Agent: OO
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)N[C@@H](CSSC[C@H](N)C(=O)O)C(=O)O
Reaction time: 8 h
Yield: 10 %

Procedure:
L-cysteine (2.42 g, 20 mmol) and N-acetyl-L-cysteine (3.26 g, 20 mmol) were dissolved in 25 mL of water. The pH of this solution was 2.6 according to lithmus paper. Aqueous hydrogen peroxide (30%, 2.3 mL, 21 mmol) was added, and the reaction mixture was allowed to stand at room temperature overnight. A white precipitate stand at room temperature overnight. A white precipitate was filtered off (1.26 g). This material was shown to be L-cystine by comparison of spectral data with an authentic sample. The yellowish filtrate, containing the desired compound and the two symmetrical compounds (R,R)-N,N'-diacetylcystine and (minor amounts of) cystine was separated on a preparative HPLC using a Dynamax C1 8-column (8 μm, 60 Å, 21.4×250 mm) with a Dynamax C1 8-guard column (8 μm, 21.4×50 mm) and with Gilson dual solvent delivery system (305 pump, pumphead 100 SC acting as a solvent delivery pump, pumphead 5 SC acting as a sample injector, 806 manometric module, 811B dynamic mixer, 115 UV detector, 201 fraction collector, 201-202 fraction controller). The solvents used were A=10 mM HOAc/H2O and B=MeOH, with a 95:5 ratio of A:B. The solvent flow was 10 mL/min and the separation was recorded at 230 nm. After detection of each fraction on TLC (Merck 16483, plastic sheets silica gel 60 WF 254s, eluent nBuOH/HOAc/H2O 1:1:1, I2 as visualization agent), the fractions with acceptable purity were pooled and evaporated to give an oily residue. This residue was dissolved in acetone (pa) and the solution was evaporated to give the title product as white crystals.
Reaction SMILES: [I:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:6]1[C:5]2[C:10](=[CH:11][C:2]([I:1])=[CH:3][CH:4]=2)[N:9]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1nc2cc(I)ccc2c(=O)[nH]1
Product: CCOC(=O)c1nc(Cl)c2ccc(I)cc2n1
Temperature: 110 °C
Yield: 48 %

Procedure:
A suspension of ethyl 7-iodo-4-oxo-3,4-dihydroquinazoline-2-carboxylate (1.0 g, 2.90 mmol) in phosphorus oxychloride (10 mL) was heated at 110° C. under argon for 12 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. The residue was purified by column chromatography using silica gel eluting with 30% EtOAc/hexanes to afford ethyl 4-chloro-7-iodoquinazoline-2-carboxylate as a white solid (0.510 g, 48%). 1H NMR (300 MHz, DMSO-d6) δ 1.32 (t, 3H), 4.48 (q, 2H), 7.88 (d, 1H), 7.92 (d, 1H), 8.25 (s, 1H); LC-MS (ESI) m/z 363 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1B(O)O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([C:22]3[S:21][CH:25]=[CH:24][CH:23]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:7]=1
Reactant: COc1ccc(Br)cc1NS(=O)(=O)c1ccc(I)cc1
Reactant: OB(O)c1cccs1
Product: COc1ccc(Br)cc1NS(=O)(=O)c1ccc(-c2cccs2)cc1

Procedure:
The title compound was prepared from the product of Step 1 and 2-thienylboronic acid using a similar method to that described for Examples 237-243 (E237-E243). MS (ES−) 422/424 [M−H]−.
Reaction SMILES: [CH:1](=O)[CH2:2][CH:3]([CH3:5])[CH3:4].[CH3:7][C:8]([CH3:10])=[O:9]>>[CH3:4][CH:3]([CH3:5])[CH2:2][CH:1]=[CH:7][C:8](=[O:9])[CH3:10]
Reactant: CC(C)CC=O
Reactant: CC(C)=O
Product: CC(=O)C=CCC(C)C
Yield: 35 %

Procedure:
In contrast, the processes comprising subjecting isovaleraldehyde and acetone to aldol condensation in the presence of an aqueous alkali have an advantage that the reaction can be carried out under mild conditions, using inexpensive materials. The process (iv), however, can give 6-methyl-3-hepten-2-one, the aldol condensate, only in a 35 to 40% yield at most. Also, the process (v) mainly forms 6-methyl-4-hydroxyheptan-2-one, and requires successive dehydration reaction in order to obtain the yield of the 6-methyl-3-hepten-2-one. In addition, the yield of the 6-methyl-3-hepten-2-one thus obtained is 51%, which is not satisfactory. Moreover, the process (v) must use acetone in excess, so it is not industrially advantageous in view of the necessity for recovering the excessive acetone and the volumetric efficiency of reaction.