Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:20]2[CH2:25][CH2:24][N:23]([C:26]3[N:31]=[CH:30][N:29]=[C:28]([NH2:32])[C:27]=3Br)[CH2:22][CH2:21]2)[CH2:4][CH2:3][CH2:2]1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36](B(O)O)[CH:35]=1>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH3:19])[CH:13]=3)[N:9]=[C:8]2[CH:20]2[CH2:25][CH2:24][N:23]([C:26]3[N:31]=[CH:30][N:29]=[C:28]([NH2:32])[C:27]=3[C:36]3[CH:35]=[N:34][CH:39]=[CH:38][CH:37]=3)[CH2:22][CH2:21]2)[CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1cccnc1
Reactant: Cc1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4Br)CC3)n2)ccc1F
Product: Cc1cc(-c2cn(CCN3CCC3)c(C3CCN(c4ncnc(N)c4-c4cccnc4)CC3)n2)ccc1F

Procedure:
The title compound was prepared according to the procedure described for the preparation of compound “8” by using 6-{4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-5-bromo-pyrimidin-4-ylamine and pyridin-3-ylboronic acid as the starting materials. LC-MS (M+H=513, obsd=513).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[CH:6][CH2:7][N:8]1[C:13]([C:14](=[O:24])[C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([C:22]#[N:23])[CH:16]=2)=[C:12]([CH:25]([CH3:27])[CH3:26])[C:11](=[O:28])[NH:10][C:9]1=[O:29])C.[NH4+:31].[OH-]>CO>[C:22]([C:17]1[CH:16]=[C:15]([CH:20]=[C:19]([CH3:21])[CH:18]=1)[C:14]([C:13]1[N:8]([CH2:7][CH:6]=[CH:5][C:4]([NH2:31])=[O:3])[C:9](=[O:29])[NH:10][C:11](=[O:28])[C:12]=1[CH:25]([CH3:26])[CH3:27])=[O:24])#[N:23]
Reactant: [NH4+]
Reactant: CCOC(=O)C=CCn1c(C(=O)c2cc(C)cc(C#N)c2)c(C(C)C)c(=O)[nH]c1=O
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C#N)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2CC=CC(N)=O)c1
Temperature: 120 °C
Yield: 6.6 %

Procedure:
In a 5 mL microwave reaction tube, 4-[6-(3-cyano-5-methyl-benzoyl)-5-isopropyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl]-but-2-enoic acid ethyl ester (69 mg, 0.168 mmol) and 0.5 mL MeOH was added, followed by 0.7 mL NH4OH (30% in water, excess). The reaction mixture was heated in the microwave at 120° C. for 30 minutes. The reaction mixture concentrated down and purified by reverse phase prep HPLC (MeCN/water) to give a white powder (4.2 mg, 6.6%). 1H NMR (300 MHz, CD3OD): δ 8.8 (d, 1H), 7.64 (m, 2H), 7.4-7.28 (m, 2H), 3.19 (dd, 1H), 2.52 (m, 1H), 0.95 (d, 3H), 0.65 (dd, 3H). LC-MS shows 381.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:11]2[CH2:12][CH2:13][N:14]=[C:10]2[C:9]2[CH:8]=[CH:7][C:6]([O:15][CH2:16][CH2:17][CH2:18][S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[C:5]([O:25][CH3:26])[C:4]=2[N:3]=1.[NH2:27][C:28]1[N:33]=[CH:32][C:31]([C:34](O)=[O:35])=[CH:30][N:29]=1>>[NH2:27][C:28]1[N:33]=[CH:32][C:31]([C:34]([NH:1][C:2]2[N:11]3[CH2:12][CH2:13][N:14]=[C:10]3[C:9]3[CH:8]=[CH:7][C:6]([O:15][CH2:16][CH2:17][CH2:18][S:19]([N:22]([CH3:24])[CH3:23])(=[O:20])=[O:21])=[C:5]([O:25][CH3:26])[C:4]=3[N:3]=2)=[O:35])=[CH:30][N:29]=1
Reactant: COc1c(OCCCS(=O)(=O)N(C)C)ccc2c1N=C(N)N1CCN=C21
Reactant: Nc1ncc(C(=O)O)cn1
Product: COc1c(OCCCS(=O)(=O)N(C)C)ccc2c1N=C(NC(=O)c1cnc(N)nc1)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 16, Step 2 was used to prepare the title compound from 3-[(5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl)oxy]-N,N-dimethylpropane-1-sulfonamide (Step 1) and 2-aminopyrimidine-5-carboxylic acid. High vacuum drying gave the title compound (261 mg, 79%): HPLC MS RT=2.09 min, MH+=503.2; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.20-2.25 (2H, m), 2.78 (6H, s), 3.20-3.25 (2H, m), 3.99 (3H, s), 4.18-4.25 (2H, m), 4.37 (2H, t), 4.48-4.55 (2H, m), 7.44 (1H, d), 8.02 (1H, d), 9.07 (2H, s).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][CH:26]1[OH:30]>>[OH:30][CH:26]1[CH2:27][CH2:28][CH2:29][CH:25]1[NH:24][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: NC1CCCC1O
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCC2O)cn1
Yield: 31 %

Procedure:
As described for example 191, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using 2-amino cyclopentanol instead of 2-aminoethyl isopropylether, to the title compound (80 mg, 31%) which was obtained as a white solid. MS: m/e=494.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([N:12]=[C:13]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:5]=[C:6]([S:8]C(=N)N)[N:7]=1.[OH-].[K+].Cl>>[NH2:1][C:2]1[C:3]2[N:4]([N:12]=[C:13]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[N:14]=2)[CH:5]=[C:6]([SH:8])[N:7]=1
Reactant: N=C(N)Sc1cn2nc(-c3ccco3)nc2c(N)n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Nc1nc(S)cn2nc(-c3ccco3)nc12

Procedure:
A solution containing the crude 2-(8-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-isothiourea and aqueous KOH (1 M, 4 ml) was refluxed for 1 hour. The reaction was neutralized with conc. HCl and the water was removed in vacuo to afford the crude product 8-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazine-6-thiol, which was used in the next step without purification.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=[O:12].OS(O)(=O)=O.[CH3:19]O>>[CH3:19][O:12][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[N:1]=1)=[O:13]
Reactant: O=C(O)c1ccc2cnccc2n1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2cnccc2n1
Temperature: 25 °C

Procedure:
To a mixture of 1,6-naphthyridine-2-carboxylic acid (1 g, 5.7 mmol) and 100 mL of methanol was added carefully ˜0.5 mL of conc. H2SO4. The mixture was kept under reflux overnight. The mixture was cooled to room temperature and solvent was evaporated. To the residue was added carefully (carbon dioxide evolution) half saturated sodium bicarbonate solution to neutralize the acid. The mixture was extracted from ethyl acetate (3 times) and the combined organic was washed with brine. After drying over anhydrous MgSO4, solvent was evaporated. The product, 1,6-naphthyridine-2-carboxylic acid methyl ester, (IIIe) was isolated as a solid (932 mg, 87% yield), which was used for the next step without further purification. A mixture of ester (IIIe) (322 mg, 1.71 mmol) and methylacetate (dry, 10 mL) was treated with NaH (60% dispersion in mineral oil, 100 mg, 2.5 mmol) and the resulting mixture was kept under reflux for 2 h, during which a cake formation was noticed. The reaction mixture was cooled to room temperature and solvent was evaporated. The residue was treated ˜20 mL of water. The mixture was neutralized with conc. HCl. A solid was obtained which was filtered, washed (water followed by hexane) and dried. Yield: 158 mg (40%). The product, ethyl 3-oxo-3-pyridino[3,4-e]pyridin-2-yl-propanoate, (Vf) was used for the next step without further purification.
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][NH:17][CH2:16]3)[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(CC)CC.[Br:27][CH2:28][C:29](Br)=[O:30]>C1COCC1>[Br:27][CH2:28][C:29]([N:17]1[CH2:18][CH2:19][CH:15]([N:12]2[CH2:11][CH2:10][CH:9]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:14][CH2:13]2)[CH2:16]1)=[O:30]
Reactant: O=C(Br)CBr
Reactant: c1ccc(C2CCN(C3CCNC3)CC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CBr)N1CCC(N2CCC(c3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-phenyl-1-pyrrolidin-3-yl-piperidine dihydrochloride (prepared using general procedures E, F, 0.051 g, 0.17 mmol) and Et3N (0.05 mL, 0.34 mmol) in THF (1.7 mL) was added bromoacetylbromide (0.015 mL, 0.17 mmol). The reaction mixture was stirred at ambient temperature for about 12 h then concentrated in vacuo to give 2-bromo-1-[3-(4-phenyl-piperidin-1-yl)-pyrrolidin-1-yl]-ethanone that was used without further purification.
Reaction SMILES: [N:1]1([C:6]([CH2:8][N:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH2:20][C:21]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])[C:12](=[O:28])[CH:11]([NH:29][C:30]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][O:40][C:41](=[O:50])[NH:42][CH2:43][CH2:44][CH2:45][C:46]([O:48]C)=[O:47])[CH:34]=3)=[O:31])[C:10]2=[O:51])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+]>CO.O>[N:23]1([C:21]([CH2:20][N:13]2[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:9]([CH2:8][C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[C:10](=[O:51])[CH:11]([NH:29][C:30]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][O:40][C:41](=[O:50])[NH:42][CH2:43][CH2:44][CH2:45][C:46]([OH:48])=[O:47])[CH:34]=3)=[O:31])[C:12]2=[O:28])=[O:22])[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COC(=O)CCCNC(=O)OCc1cccc(NC(=O)NC2C(=O)N(CC(=O)N3CCCC3)c3ccccc3N(CC(=O)N3CCCC3)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCNC(=O)OCc1cccc(NC(=O)NC2C(=O)N(CC(=O)N3CCCC3)c3ccccc3N(CC(=O)N3CCCC3)C2=O)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 94.1 %

Procedure:
To a solution of Compound 9a (243 mg, 0.344 mmol) in methanol (3.5 ml) is added a solution of lithium hydroxide monohydrate (35 mg, 0.834 mmol) in water (0.6 ml) and the mixture is stirred at room temperature for 7 hr. After the addition of water, the mixture is washed with chloroform. After acidifying with 10% HCl, the mixture is extracted with chloroform containing 10% methanol. The extract is washed with water, dried over sodium sulfate, and distilled under reduced pressure to remove the solvent to obtain Compound 11a (224 mg, 94.1%).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH:18]([C:20]2[CH:25]=[CH:24][C:23]([C@@H:26]([NH:28][C:29]3[N:34]=[C:33]([C:35]4[N:39]5[CH:40]=[CH:41][CH:42]=[C:43]([CH3:44])[C:38]5=[N:37][CH:36]=4)[C:32]([C:45]#[N:46])=[CH:31][N:30]=3)[CH3:27])=[CH:22][CH:21]=2)[OH:19])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>O1CCCC1.CO.[OH-].[Pd+2].[OH-]>[OH:19][CH:18]([C:20]1[CH:21]=[CH:22][C:23]([C@@H:26]([NH:28][C:29]2[N:34]=[C:33]([C:35]3[N:39]4[CH:40]=[CH:41][CH:42]=[C:43]([CH3:44])[C:38]4=[N:37][CH:36]=3)[C:32]([C:45]#[N:46])=[CH:31][N:30]=2)[CH3:27])=[CH:24][CH:25]=1)[CH2:17][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1
Reactant: Cc1cccn2c(-c3nc(N[C@@H](C)c4ccc(C(O)CC5CCN(C(=O)OCc6ccccc6)CC5)cc4)ncc3C#N)cnc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccn2c(-c3nc(N[C@@H](C)c4ccc(C(O)CC5CCNCC5)cc4)ncc3C#N)cnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.5 %

Procedure:
21 mg of the compound [17-1] was dissolved in a mixed solvent of 3 mL of tetrahydrofuran and 3 mL of methanol, then 20 mg of a carbon catalyst of 20% palladium hydroxide was added thereto, and the mixture was stirred for 2 hours at room temperature under hydrogen atmosphere. The catalyst was filtered through celite, and the filtrate was concentrated under reduced pressure. Diethylether was added to the resulting residue, and thus produced solid was taken by filtration to obtain 6 mg of 2-({(1S)-1-[4-(1-hydroxy-2-piperidin-4-ylethyl)phenyl]ethyl}amino)-4-(8-methylimidazo[1,2-a]pyridin-3-yl)pyrimidine-5-carbonitrile [17-2] (hereinafter, referred to as the compound [17-2]).
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20](OC(C)(C)C)=[O:21])[CH2:16][CH2:15]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+].[F:47][C:48]([F:65])([F:64])[C:49]1[CH:54]=[CH:53][C:52]([CH:55]2[CH2:60][CH2:59][N:58](C(Cl)=O)[CH2:57][CH2:56]2)=[CH:51][CH:50]=1>CN(C=O)C.O.C(Cl)Cl>[CH3:1][C@@:2]1([CH2:13][N:14]2[CH2:15][CH2:16][N:17]([C:20]([N:58]3[CH2:59][CH2:60][CH:55]([C:52]4[CH:53]=[CH:54][C:49]([C:48]([F:47])([F:64])[F:65])=[CH:50][CH:51]=4)[CH2:56][CH2:57]3)=[O:21])[CH2:18][CH2:19]2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Reactant: O=C(Cl)N1CCC(c2ccc(C(F)(F)F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Product: C[C@]1(CN2CCN(C(=O)N3CCC(c4ccc(C(F)(F)F)cc4)CC3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.1 %

Procedure:
A mixture of tert-butyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-piperazine-1-carboxylate prepared in Example 393 (1.17 g, 3.32 mmol), trifluoroacetic acid (5 ml) and methylene chloride (10 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride (10 ml). To the resulting solution, triethylamine (5 ml, 35.87 mmol) was added followed by stirring at room temperature for 10 minutes. The solution was concentrated under reduced pressure, the residue was dissolved in DMF (15 ml). To the mixture, potassium carbonate (920 mg, 6.64 mmol) and a solution of 4-(4-trifluoromethylphenyl)-piperidine-1-carbonylchloride (1.07 g, 3.65 mmol) in DMF (10 ml) was added slowly with cooling on ice-bath followed by stirring at room temperature overnight. To the reaction mixture, water was added followed by extraction with ethyl acetate. The extract was washed with water three times and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=30/1) to afford (S)-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]-[4-(4-trifluoromethylphenyl)piperidin-1-yl]methanone (575 mg, yield 33%) as a white powder.
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[C:9]([O-:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].C1C=[N+:18]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)[CH:17]=C(C(N)=O)C=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.CN.Cl.[OH-].[Na+]>>[CH3:17][NH:18][C@H:8]([C:9]([OH:11])=[O:10])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Reactant: O=C([O-])C(=O)Cc1ccccc1
Agent: CN
Agent: Cl
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: CN[C@@H](Cc1ccccc1)C(=O)O
Temperature: 30 °C
Yield: 75 %

Procedure:
To the resting cells obtained, a reaction solution containing sodium phenylpyruvate in a final concentration of 100 mM, NADP in a final concentration of 0.2 mM, glucose in a final concentration of 100 mM, and methylamine-hydrochloric acid (pH 9) in a final concentration of 700 mM was added to achieve cell turbidity of 20 (absorbance at 660 nm). The reaction was conducted while stirring at 30° C. and adjusting pH to 8 to 9 with 10 N aqueous sodium hydroxide solution. The amount of N-methylphenylalanine produced after 24 hours of reaction was 13.4 g/L (reaction yield=75%).
Reaction SMILES: [CH3:1][C:2]([OH:9])([C:5]([CH3:8])([CH3:7])[CH3:6])[C:3]#[CH:4].Br[C:11]1[CH:12]=[C:13]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH:14]=[CH:15][CH:16]=1.CN(C=O)C>C(N(CC)CC)C>[F:23][C:22]([F:24])([F:25])[C:21]([NH:20][CH2:19][CH2:18][CH2:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:4]#[C:3][C:2]([OH:9])([CH3:1])[C:5]([CH3:8])([CH3:7])[CH3:6])[CH:12]=1)=[O:26]
Reactant: O=C(NCCCc1cccc(Br)c1)C(F)(F)F
Reactant: C#CC(C)(O)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)C(C)(O)C#Cc1cccc(CCCNC(=O)C(F)(F)F)c1

Procedure:
Coupling of 3,4,4-trimethylpent-1-yn-3-ol with bromide 10 in a 1:1 mixture of DMF and triethylamine gave 2,2,2-trifluoro-N-(3-(3-(3-hydroxy-3,4,4-trimethylpent-1-ynyl)phenyl)propyl)acetamide as an orange oil. Yield (0.84 g, 73%): 1H NMR (400 MHz, CD3OD) δ 7.15-7.25 (m, 4H), 3.29 (t, J=7.2 Hz, 2H), 2.61 (t, J=8.0 Hz, 2H), 1.86 (quint, J=7.6 Hz, 2H), 1.49 (s, 3H), 1.09 (br s, 9H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.Cl.[I-:19].[Na+].C(#N)C>C1COCC1.CCOCC>[I:19][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: [I-]
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCOCC
Product: Ic1nc(-c2ccccc2)nc2ccccc12

Procedure:
To the 4-chloro-2-phenylquinazoline (4.15 mmol) in dry THF (10 ml) was added a solution of 2 M HCl in ether (4 ml). After 5 min the solvents were removed by vacuum. Dry sodium iodide (41.5 mmol) and acetonitrile (30 ml) were added to the hydrochloride salt and refluxed for 4 hrs. The reaction was quenched by the addition of an aqueous solution of 10% K2CO3 and 5% NaHSO3 (15 ml). Extraction with dichloromethane and drying of the combined organic layers was followed by evaporation of solvents under reduced pressure. The resulting crude product was purified by alumina chromatography with (1:10)
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6]O.[BrH:11]>O>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[CH2:5][CH2:6][Br:11]
Reactant: Br
Reactant: OCCc1cccc(I)c1
Solvent: O
Product: BrCCc1cccc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of 3-iodophenethyl alcohol (see Preparation 26) (1.2 g) and 48% aqueous hydrobromic acid (20 ml) was stirred at room temperature for 8 hours, poured into water and extracted into methylene chloride. The organic extracts were washed with saturated aqueous sodium hydrogen carbonate solution and water, dried over sodium sulphate and evaporated to give the title compound as a pale brown oil (1.1 g, 73%), which was characterised by its 1H-n.m.r. spectrum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][C:7]([C:14]#[N:15])=[C:6]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1.[CH:28]([O:31][CH2:32][CH:33]1[O:35][CH2:34]1)([CH3:30])[CH3:29]>CC(O)C>[OH:35][CH:33]([CH2:32][O:31][CH:28]([CH3:30])[CH3:29])[CH2:34][N:8]1[C:7]([C:14]#[N:15])=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13]
Reactant: COc1ccc2c(=O)[nH]c(C#N)c(-c3ccccc3)c2c1
Reactant: CC(C)OCC1CO1
Solvent: CC(C)O
Solvent: c1ccncc1
Product: COc1ccc2c(=O)n(CC(O)COC(C)C)c(C#N)c(-c3ccccc3)c2c1
Temperature: 25 °C

Procedure:
To a suspension of 97 (52 mg, 0.19 mmol) in iPrOH (3 mL) were added pyridine (0.03 mL, 0.38 mmol) and glycidyl isopropyl ether (0.047 mL, 0.38 mmol). The resulting mixture was heated to reflux overnight then cooled to room temperature. It was partitioned between EtOAc and NaHCO3. The organic phase was washed with brine, dried (Na2SO4) and concentrated. The product 98 was purified by automated flash chromatography (20-50% EA/Hex).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:14]=[CH:13][N:12]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH:34]=[CH:33][N:32]=[CH:31]3)=[CH:26][CH:25]=2)[C:11]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH2:1]([O:8][CH2:9][C@@H:10]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:13][N:12]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH:34]=[CH:33][N:32]=[CH:31]3)=[CH:26][CH:25]=2)[C:11]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C=CN(Cc2ccc(-n3ccnc3)cc2)C(=O)[C@@H]1COCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-n3ccnc3)cc2)C(=O)[C@@H]1COCc1ccccc1
Reaction time: 9 h
Yield: 89.9 %

Procedure:
In ethanol (80 ml) was dissolved (S)-3-benzyloxymethyl-4-(tert-butoxycarbonyl)-1-[4-(1H-imidazol-1-yl)benzyl]-2-oxo-1,2,3,4-tetrahydropyrazine (1.13 g), and to the solution was added 10% palladium on carbon (1 g). The mixture was subjected to catalytic reduction for 9 hours with medium pressure reduction apparatus, and the catalyst was removed. The solvent was evaporated under reduced pressure to give colorless amorphous of the title compound (1.02 g).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:7]=1.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(#N)C>[C:8]1([C:5]2[N:4]=[N:3][C:2]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:7][CH:6]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Clc1ccc(-c2ccccc2)nn1
Reactant: C1CNCCN1
Solvent: CC#N
Product: c1ccc(-c2ccc(N3CCNCC3)nn2)cc1
Yield: 99 %

Procedure:
To a solution of 3-chloro-6-phenylpyridazine (0.960 g, 5.000 mmol) in acetonitrile (25 mL) was added piperazine (2.580 g, 30.00 mmol) and the mixture was stirred at reflux for 16 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane. The resulting solution was washed with water, dried over MgSO4 and concentrated. The title compound was obtained in 99% yield (1.200 g).
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[CH:9]=[C:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1.[C:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(=[O:18])[CH2:16][CH3:17]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:14][C:10]1[CH:11]=[CH:12][CH:13]=[CH:8][C:9]=1[CH:16]([CH3:17])[C:15]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]
Reactant: Cc1cccc(Br)c1
Reactant: CCC(=O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Product: Cc1ccccc1C(C)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 45.9 %

Procedure:
An oven dried Schlenk tube equipped with a rubber septum was cooled under an argon purge. The septum was removed and the tube was charged with palladium acetate (2.3 mg, 0.01 mmol) and sodium t-butoxide (125 mg, 1.3 mmol). The tube was capped with the septum, purged with argon. Toluene (2 mL) was added and the mixture stirred for 1 min at room temperature. 3-Bromotoluene (0.120 mL, 1.0 mmol) and propiophenone (0.16 mL, 1.2 mmol) were added to the tube. The mixture was heated to 80° C. and stirred until the starting halide had been completely consumed, as judged by GC analysis. The mixture was cooled to room temperature, quenched with saturated aqueous ammonium chloride (10 mL) and diluted with ether (20 mL). The mixture was poured into a separatory funnel and the layers were separated. The aqueous layer was extracted with ether (20 mL), the combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 103 mg (46%) of α-(2-Methylphenyl)propiophenone. 1H NMR (CDCl3, 300 MHz) 7.81-7.84 (m, 2H), 7.47-6.99 (m, 71), 4.75 (q, 3=6.9 Hz, 1H), 2.49 (s, 3H), 1.46 (d, J=6.9 Hz, 3H) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Br)[CH:30]=1.CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([Br:28])[CH:30]=2)[C:19]2[N:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][N:24]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Reactant: BrCc1cccc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2cccc(Br)c2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
2-[(4-{2-[(5-Ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (5.5 g) synthesized in Example 265-1 and 1-bromo-3-(bromomethyl)benzene (4.04 g) were dissolved in N,N-dimethylformamide (55 mL), potassium tert-butoxide (1.82 g) was added thereto, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=4:1) to give the title compound (6.3 g) as a colorless oil.