Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:34](=[O:35])[N:4]2[C:5]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[S:19])=[C:6]([C:9]3[S:10][C:11]4[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)[CH2:7][S:8][C@H:3]12.[C:36]([NH:55][C:56]1[S:57][CH:58]=[C:59](/[C:61](=[N:65]/[O:66][CH2:67][C:68]([O:70][CH:71]([C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)[C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)=[O:69])/[C:62](O)=[O:63])[N:60]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>C(Cl)Cl>[C:36]([NH:55][C:56]1[S:57][CH:58]=[C:59](/[C:61](=[N:65]/[O:66][CH2:67][C:68]([O:70][CH:71]([C:78]2[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=2)[C:72]2[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=2)=[O:69])/[C:62]([NH:1][CH:2]2[C:34](=[O:35])[N:4]3[C:5]([C:18]([O:20][CH:21]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[S:19])=[C:6]([C:9]4[S:10][C:11]5[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=5[N:13]=4)[CH2:7][S:8][C@H:3]23)=[O:63])[N:60]=1)([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(c3nc4ccccc4s3)CS[C@H]12
Reactant: O=C(CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)OC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(c3nc4ccccc4s3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)OC(c1ccccc1)c1ccccc1
Yield: 70.6 %

Procedure:
165 mg of diphenylmethyl 7-amino-3-(benzothiazol-2-yl)thio-3-cephem-4-carboxylate as synthesized in the same manner as in Example 1 (b) above were dissolved in 4 ml of methylene chloride, and to the resulting solution were added 243 mg of (Z)-2-(2-tritylaminothiazol-4-yl)-2-diphenylmethoxycarbonylmethoxyiminoacetic acid, 0.10 of pyridine and 35 μl of phosphorus oxychloride. Next, the acylation reaction and the post-treatment of the reaction solution were carried out in the same manner as in Example 1 (b), and the resultant residue was then purified through a column chromatography on 30 g of silica gel (as developed with mixed solvents of toluene and ethyl acetate, 10:1) to afford 260 mg of the titled compound (yield, 73%).
Reaction SMILES: Cl.[CH3:2][C@@:3]([S:31]([CH3:34])(=[O:33])=[O:32])([CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][C:17]1=[O:30])[C:4]([NH:6][O:7]C1CCCCO1)=[O:5]>ClCCl.CO>[OH:7][NH:6][C:4](=[O:5])[C@:3]([CH3:2])([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:14][CH2:15][N:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:18][C:17]1=[O:30]
Reactant: C[C@@](CCn1ccc(CCc2ccccc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: C[C@@](CCn1ccc(CCc2ccccc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Reaction time: 2 h
Yield: 70.3 %

Procedure:
A solution of hydrochloric acid (1.0 mL, 4.0 M in 1,4-dioxane) was added to a solution of (2R)-2-methyl-2-(methylsulfonyl)-4-[2-oxo-4-(2-phenylethyl)pyridin-1(2H)-yl]-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (14 mg, 0.029 mmol) in 5:1 dichloromethane-methanol (1.2 mL) at 0° C. After 2 h, the reaction was concentrated under reduced pressure. The resulting residue was triturated with 1:1 pentane-dichloromethane, filtered, washed with pentane, and dried under reduced pressure to provide a light pink solid (8 mg, 70%). MS (APCI) m/z 393.3 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51 (s, 3H) 2.00-2.14 (m, 1H) 2.24-2.36 (m, 1H) 2.63-2.74 (m, 2H) 2.78-2.88 (m, 2H) 3.06 (s, 3H) 3.58-3.73 (m, 1H) 3.94-4.08 (m, 1H) 6.16-6.26 (m, 2H) 7.11-7.32 (m, 5H) 7.55 (d, J=7.41 Hz, 1H) 11.14 (br s, 1H).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([CH2:16][CH2:17][CH3:18])[CH:11]=[C:12]([C:13]([OH:15])=O)[C:7]=2[CH:6]=[N:5]1)[CH3:3].[NH2:19][CH2:20][C:21]1[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=1[CH3:27].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[CH3:27][C:26]1[CH:25]=[C:24]([CH3:28])[NH:23][C:22](=[O:29])[C:21]=1[CH2:20][NH:19][C:13]([C:12]1[C:7]2[CH:6]=[N:5][N:4]([CH:2]([CH3:1])[CH3:3])[C:8]=2[N:9]=[C:10]([CH2:16][CH2:17][CH3:18])[CH:11]=1)=[O:15]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CCCc1cc(C(=O)O)c2cnn(C(C)C)c2n1
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CS(C)=O
Product: CCCc1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C(C)C)c2n1

Procedure:
The title compound was prepared in the same manner as described in example 109 using 1-(1-methylethyl)-6-propyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (70 mg, 0.283 mmol), DMSO (3 mL), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (80 mg, 0.425 mmol), N-methylmorpholine (0.124 mL, 1.132 mmol), 1-hydroxy-7-azabenzotriazole (77 mg, 0.566 mmol), and EDC (109 mg, 0.566 mmol). The collected solid was washed with water and methanol and dried under high vacuum to give 73 mg (68%) of product. LCMS E-S (M+H)=382.3 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82-1.10 (m, 3H), 1.48 (d, J=6.8 Hz, 6H), 1.77 (m, 2H), 2.13 (s, 3H), 2.21 (s, 3H), 2.85 (t, J=7.6 Hz, 2H), 4.36 (d, J=4.8 Hz, 2H), 5.20 (m, 1H), 5.90 (s, 1H), 7.38-7.58 (m, 1H), 8.26 (s, 1H), 8.73 (t, J=4.7 Hz, 1H), 11.57 (br. s., 1H).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](=O)[CH2:8][Br:9])=[CH:5][CH:4]=1)#[N:2].[BrH:13].[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28]([NH2:30])=[S:29])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(OCC)C>CO>[BrH:9].[BrH:13].[CH2:14]([N:21]1[CH2:22][CH2:23][CH:24]([NH:27][C:28]2[S:29][CH:8]=[C:7]([C:6]3[CH:11]=[CH:12][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[N:30]=2)[CH2:25][CH2:26]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: NC(=S)NC1CCN(Cc2ccccc2)CC1
Agent: Br
Solvent: CO
Solvent: CCOCC
Product: N#Cc1ccc(-c2csc(NC3CCN(Cc4ccccc4)CC3)n2)cc1
Temperature: 25 °C
Yield: 86 %

Procedure:
12.46 g of 4-cyanophenacyl bromide are added to 18.38 g of N-(1-benzylpiperid-4-yl)thiourea hydrobromide in 200 ml of methanol, and then the reaction mixture is heated under reflux for 4 hours. The mixture is cooled to room temperature and then, successively, 200 ml of diethyl ether are added and the precipitate is filtered and washed with diethyl ether in order to obtain white crystals which melt at 280° C.; yield: 86%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[N:2]=1.[C:16]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:17]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:16]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:23][CH2:24][N:25]([C:8]([NH:7][C:3]3[N:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:15])[CH2:26][CH2:27]2)[CH:17]=1
Reactant: c1ccc(-c2cccc(N3CCNCC3)c2)cc1
Reactant: O=C(Nc1cccnn1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(Nc1cccnn1)N1CCN(c2cccc(-c3ccccc3)c2)CC1
Yield: 20 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl pyridazin-3-ylcarbamate (250 mg, 0.923 mmol), 1-biphenyl-3-ylpiperazine (200 mg, 0.839 mmol) and diisopropylethylamine (0.292 ml, 1.68 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 12 hours. Water was poured into the reaction solution, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the titled compound 60.3 mg (20.0%) as solid product.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH2:26].O1CCOCC1>CC(O)C.Cl.O1CCOCC1>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[C:3]3[C:10]4[CH2:11][CH2:12][NH:13][CH2:14][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Reactant: Nc1ccc(F)c(Cl)c1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Fc1ccc(Nc2ncnc3sc4c(c23)CCNC4)cc1Cl
Temperature: 80 °C
Yield: 94.8 %

Procedure:
tert-Butyl 4-chloro-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7(6H)-carboxylate from Example 11A (407.5 g, 1.251 mol) was dissolved in 2-propanol (5.7 L). 3-Chloro-4-fluoroaniline (191.2 g, 1.313 mol) and a 4 M solution of gaseous hydrogen chloride in dioxane (17.4 mL, 63 mmol) were added. The mixture was heated to 80° C. for 3 days. The thick suspension was then diluted with additional 2-propanol (1 L), and further 4 M hydrogen chloride in dioxane (695 mL, 2.5 mol) was added. The mixture was again heated to 80° C. for 3 h. The solvent was then removed in vacuo, and the residue was treated with 1 M aqueous sodium hydroxide solution (12 L). The precipitate was collected by suction filtration and washed with water. The product was dried for 2 days at 50° C., then triturated with tert-butyl methyl ether and collected by suction filtration to yield 397 g (95%) of the title compound.
Reaction SMILES: Br[C:2]1[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:17])=[C:7]([Cl:16])[CH:8]=2)[N:3]=1.[SH:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1>>[Cl:16][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:17])[N:3]=[C:2]([S:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1)[C:11]([C:12]([F:15])([F:14])[F:13])=[N:10]2
Reactant: Sc1nccs1
Reactant: FC(F)(F)c1nc2cc(Cl)c(Cl)cc2nc1Br
Product: FC(F)(F)c1nc2cc(Cl)c(Cl)cc2nc1Sc1nccs1

Procedure:
The title compound was prepared from 2-bromo-6,7-dichloro-3-trifluoromethylquinoxaline and 2-mercaptothiazole in analogy with the method outlined in example 1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][NH:6][N:5]=1)[CH3:2].Cl[CH2:17][C:18]1[CH:37]=[CH:36][CH:35]=[CH:34][C:19]=1[O:20][CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27].CN(C)C=O.[H-].[Na+]>O>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][N:6]([CH2:17][C:18]2[CH:37]=[CH:36][CH:35]=[CH:34][C:19]=2[O:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccccc2OCc2nc(-c3ccccc3)oc2C)nc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
To a mixture of ethyl 3-(3-ethoxy-1H-pyrazol-4-yl]propionate (509 mg), 4-(2-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (753 mg), and N,N-dimethylformamide (10 ml), sodium hydride (60%, oily, 96.0 mg) was added at 0° C., and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-ethoxy-1-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (1.09 g, yield: 93%) was obtained as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:11]([O:17][CH2:18]Cl)(=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].O>CC(C)=O.C(N(CC)CC)C>[Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:18][O:17][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: CC(C)(C)C(=O)OCCl
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OCOC(=O)c1cccnc1Cl
Reaction time: 0.5 h

Procedure:
Into a suspension of 2-chloro-3-pyridinecarboxylic acid (23.7 g) in 500 ml of acetone, triethylamine (30.7 ml) is added. After 30 minutes of stirring, pivaloyloxymethyl chloride (22.5 ml) is poured into the reaction mixture, and the resulting mixture heated to reflux for 2 hours. The mixture is then cooled to a temperature of 15°-20° C., and then poured into 1000 ml of cooled water. The resulting mixture is then extracted with methylene chloride (2×100 ml), and the water layer discarded. To the remaining organic extract, 10 g of anhydrous magnesium sulfate is added and then separated by filtration. The organic extract is distilled at normal pressures to separate methylene chloride. When all methylene chloride is distilled off, the distillation is continued under vacuum (0.17 mm Hg) to separate the desired product compound. The distilled product fraction separates at 131°-133° C., and is pivaloyloxymethyl 2-chloro-3-pyridine-carboxylate. Yield: 21.8 g (53.5% of theory).
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([O:15]C)[C:7]=1[CH:8]=[O:9].CO.O>ClCCl>[F:5][C:6]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([OH:15])[C:7]=1[CH:8]=[O:9]
Reactant: COc1ccc(F)c(F)c1C=O
Agent: BrB(Br)Br
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: O=Cc1c(O)ccc(F)c1F
Temperature: 25 °C

Procedure:
A solution of boron tribromide in dichloromethane (1.0 M; 197.4 ml) was added to a solution of 2,3-difluoro-6-methoxybenzaldehyde (10.4 g; prepared in a similar manner to that described above) in dichloromethane (100 ml) under nitrogen stirring below -20° C. The resulting solution was allowed to warm to ambient temperature overnight, then methanol (200 ml) followed by water (100 ml) were added, and the mixture heated at 40° C. for 2 hours. The aqueous layer was separated and extracted with dichloromethane (2×300 ml). The combined organic solutions were extracted with aqueous sodium hydroxide solution (1 M; 3×400 ml) and the combined extracts acidified with concentrated hydrochloric acid, then extracted with ethyl acetate (3×300 ml). These combined extracts were dried over magnesium sulphate and the solvent removed in vacuo to give 2,3-difluoro-6-hydroxybenzaldehyde (8.12 g) as a solid.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[CH2:7][N:8]([CH3:14])[C:9](=[O:13])[C:10]=3[CH:11]=[CH:12][C:4]=2[CH:3]=1.C([Li])CCC.[CH3:22][CH:23]([CH3:50])[C:24]([C:26]1[N:27]=[CH:28][N:29]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=1)=[O:25].[Cl-].[NH4+]>C1COCC1.CCCCCC>[OH:25][C:24]([C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[CH2:7][N:8]([CH3:14])[C:9](=[O:13])[C:10]=3[CH:11]=[CH:12][C:4]=2[CH:3]=1)([C:26]1[N:27]=[CH:28][N:29]([C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=1)[CH:23]([CH3:50])[CH3:22]
Reactant: CN1Cc2c(ccc3cc(Br)ccc23)C1=O
Reactant: CC(C)C(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)C(O)(c1ccc2c3c(ccc2c1)C(=O)N(C)C3)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: -70 °C
Reaction time: 1 h
Yield: 53.5 %

Procedure:
7-Bromo-2-methyl-1,2-dihydro-3H-benzo[e]isoindol-3-one (0.14 g) was suspended in THF (6 mL) and dissolved by heating. This solution was cooled to −70° C. and a solution (1.6 M: 0.75 mL) of n-butyllithium in hexane was slowly added dropwise. After stirring for 1 hr., a solution (1 mL) of 2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanone (0.16 g) in THF was added dropwise. After stirring at −70° C. for 30 min., 20% aqueous ammonium chloride was added to stop the reaction. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography (carrier: silica gel, developing solvent: hexane-ethyl acetate, 1:1—ethyl acetate) to give the title compound (0.13 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:14][CH:15]4[CH2:19][NH:18][CH2:17][CH:16]4[CH:20]=3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22].[O:25]1[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[N:26]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([CH:13]3[CH2:14][CH:15]4[CH2:19][N:18]([C:30]([C:27]5[CH:28]=[CH:29][O:25][N:26]=5)=[O:31])[CH2:17][CH:16]4[CH2:20]3)=[CH:10][CH:11]=2)[N:6]([CH3:21])[C:5]1=[O:22]
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CNCC4C3)nc21
Reactant: O=C(O)c1ccon1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3CC4CN(C(=O)c5ccon5)CC4C3)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(2,2-Dimethylpropyl)-5-(1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (11-1, 50 mg, 0.15 mmol, 1.0 equiv), isoxazole-3-carboxylic acid (2-6, 25.8 mg, 0.22 mmol, 1.5 equiv), DIPEA (0.080 mL, 0.45 mmol, 3.0 equiv) and HATU (87 mg, 0.22 mmol, 1.5 equiv) were added to anhydrous acetonitrile (2 mL). After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (20-100% CH3CN:0.1% TFA in H2O) provided 11-2 as a white solid. MS m/z (M+H): calculated=424.2345; observed=424.2353.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C@@H:13]1[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH2:16][N:15]([C@@H:25]([CH:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[O:27])[CH2:14]1.C(N(CC)CC)C>C(Cl)Cl>[CH:12]([C@@H:13]1[C@@H:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH2:16][N:15]([C@@H:25]([CH:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)=[O:27])[CH2:14]1)=[O:11]
Reactant: CCC(CC)[C@@H](C(=O)OCc1ccc(OC)cc1)N1C[C@H](CO)[C@@H](c2cccc(F)c2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCC(CC)[C@@H](C(=O)OCc1ccc(OC)cc1)N1C[C@H](c2cccc(F)c2)[C@@H](C=O)C1
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To a solution of 0.1 mL (1.15 mmol) of oxalyl chloride in 2 mL of CH2Cl2 cooled in a −78° C. bath, 0.1 mL (1.41 mmol) of dry DMSO was added. After 0.5 hr, a solution of 0.26 g (0.59 mmol) of 2(S)-(3-(R)-hydroxymethyl-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-3-ethylvaleric acid, 4-methoxybenzyl ester (step D) in 2.5 mL of CH2Cl2 was added. After 0.5 hr, 0.5 mL (3.57 mmol) of triethylamine was added to the reaction and the cold bath was removed. After stirring for 2 hr, the reaction was partitioned between water and CH2Cl2. The organic layer was washed with brine, dried and concentrated. The residue was purified on a flash column using a gradient of 20-30% EtOAc in hexane to isolate 0.23 g of the title compound. 1H NMR (CDCl3) 0.86 (m, 6H), 1.2-1.8 (m, 5H), 2.82 (m, 2H), 3.05 (t, 1H), 3.18 (m, 2H), 3.32 (d, 1H), 3.52 (m, 1H), 3.83 (s, 3H), 5.13 (s, 2H), 6.9-7.4 (m, 8H), 9.64 (d, 1H).
Reaction SMILES: [CH3:1][C:2]([OH:6])([CH:4]=[CH2:5])[CH3:3].[CH3:7][Si:8]([SiH:11]([Si:16]([CH3:19])([CH3:18])[CH3:17])[Si:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:9]>N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>[CH3:1][C:2]([OH:6])([CH2:4][CH2:5][Si:11]([Si:12]([CH3:15])([CH3:14])[CH3:13])([Si:16]([CH3:19])([CH3:18])[CH3:17])[Si:8]([CH3:7])([CH3:9])[CH3:10])[CH3:3]
Reactant: C=CC(C)(C)O
Reactant: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Product: CC(C)(O)CC[Si]([Si](C)(C)C)([Si](C)(C)C)[Si](C)(C)C
Temperature: 110 °C
Yield: 75 %

Procedure:
A dried reaction flask equipped for magnetic stirring and fitted with a reflux condenser was flushed with nitrogen and charged with toluene (500 mL). Oxygen was purged from the system by passing a stream of nitrogen through the solvent, 2-methyl-3-buten-2-ol (43.1 g, 500 mmol), tris(trimethylsilyl)silane (25.0 g, 100 mmol), and 1,1′-azobis(cyclohexanecarbonitrile) (1.22 g, 5 mmol) were added to the flask, and the reaction mixture was heated for 20 hours at 110° C. with stirring. The resulting solution was concentrated under reduced pressure, and distillation under vacuum (bp 90-104° C. at 0.10 mm) afforded the title compound (25.1 g, 74%) as a colorless solid. The distilled product was characterized by the following NMR data: 1H NMR (CDCl3) δ 0.14 (s, 27 H), 0.70-0.80 (m, 2 H), 1.17 (s, 6 H), 1.30 (br s, 1 H), 1.45-1.55 (m, 2 H); 13C NMR (CDCl3) δ 1.06 (9 C), 1.24 (1 C), 28.35 (2 C), 42.99 (1 C), 71.64 (1 C); 29Si NMR (CDCl3) δ −80.90 (1 Si), −12.83 (3 Si).
Reaction SMILES: [H-].[Na+].[CH:3]1([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:10]=3[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.[CH3:19][O:20][C:21]([C:23]1[CH:28]=[N:27][C:26](Cl)=[CH:25][N:24]=1)=[O:22]>CN(C)C=O.ClCCl>[CH3:19][O:20][C:21]([C:23]1[CH:28]=[N:27][C:26]([O:18][C:15]2[CH:16]=[CH:17][C:10]3[CH2:9][CH2:8][N:7]([CH:3]4[CH2:6][CH2:5][CH2:4]4)[CH2:13][CH2:12][C:11]=3[CH:14]=2)=[CH:25][N:24]=1)=[O:22]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% disp. in mineral oil, 332 mg, 8.3 mmol) was added to a stirred solution of 3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ol (E3) (1.64 g, 7.5 mmol) in dimethyl formamide (4 ml). After 0.5 hours, a solution of 5-chloro-pyrazine-2-carboxylic acid methyl ester (1.95 g, 11.3 mmol) in dimethyl formamide (8 ml) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane and the organic layer was washed with water, brine and dried over magnesium sulfate. The organic layer was filtered, concentrated in vacuo and the resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title compound (E122). MS (ES+) m/e 354 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)#[N:2].[NH2:9][C:10]1[S:11][C:12]([Cl:20])=[CH:13][C:14]=1[C:15](OCC)=O.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:15]1[C:14]2[CH:13]=[C:12]([Cl:20])[S:11][C:10]=2[N:9]=[C:1]([C:3]2[CH:8]=[N:7][CH:6]=[CH:5][N:4]=2)[N:2]=1
Reactant: CCOC(=O)c1cc(Cl)sc1N
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cnccn1
Product: Clc1cc2c(Cl)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 477, the reaction of 2-cyanopyrazine and 2-amino-5-chloro-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(pyrazin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine
Reaction SMILES: C(O[K])(C)(C)C.[Br:7][C:8]([F:15])([F:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10].C(O)[C:17]1[CH:22]=[CH:21]C=[CH:19][CH:18]=1>CCCCCC>[Br:7][C:8]([F:15])([F:14])[C:9]([O:11][CH2:12][C:13]1[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=1)=[O:10]
Reactant: OCc1ccccc1
Reactant: CCOC(=O)C(F)(F)Br
Agent: CC(C)(C)O[K]
Solvent: CCCCCC
Product: O=C(OCc1ccccc1)C(F)(F)Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
1.60 g (14 mmol) of t-butoxypotassium was added to a solution prepared by dissolving 20.30 g (0.1 mol) of ethyl 2-bromo-2,2-difluoroacetate in 140 ml of benzyl alcohol and 1200 ml of hexane at 0° C. in a nitrogen atmosphere. The mixture was stirred at 0° C. for 1 hour. After confirming disappearance of the raw materials by thin-layer chromatography (TLC), the reaction was terminated by adding 120 ml of concentrated hydrochloric acid. The mixture was washed twice with water, washed twice with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the product was purified by column chromatography to obtain 15.37 g of benzyl 2-bromo-2,2-difluoroacetate shown by the following formula (yield: 58%).