Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Se](=O)=[O:2].[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)(=[O:6])[CH3:5]>>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]([CH:5]=[O:2])=[O:6]
Reactant: CC(=O)c1ccccn1
Reactant: O=[Se]=O
Product: O=CC(=O)c1ccccn1
Yield: 72.2 %

Procedure:
2-Pyridylglyoxal (8.0 g, crude) was prepared from selenium dioxide (15 g, 135 mmol) and 2-acetyl pyridine (10 g, 82 mmol) according to the typical procedure used for Preparation 1.
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11](Cl)[S:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:14]>>[CH2:1]([C:8]1[N:12]=[C:11]([NH2:14])[S:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: Clc1nc(Cc2ccccc2)ns1
Product: Nc1nc(Cc2ccccc2)ns1
Temperature: 50 °C

Procedure:
A mixture of 3-benzyl-5-chloro-[1,2,4]thiadiazole (105 mg, 0.5 mmol) in ammonia (2 N in MeOH, 2 ml) was heated in a pressure tube at 50° C. for 5 h. The solvents were evaporated, the residue diluted with dichloromethane, the white solid (ammonium chloride) was filtered off, the filtrate was concentrated and then purified by silica gel chromatography using dichloromethane/methanol as eluent. The title compound was obtained as a light yellow liquid (40 mg, 41%). MS ISP (m/e): 192.1 (100) [(M+H)+].
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[NH2:9][CH2:10][CH:11]([OH:23])[CH2:12][N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1>CC(O)C>[Cl:8][C:4]1[N:3]=[C:2]([NH:9][CH2:10][CH:11]([OH:23])[CH2:12][N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)[CH:7]=[N:6][CH:5]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: Clc1cncc(Cl)n1
Solvent: CC(C)O
Product: OC(CNc1cncc(Cl)n1)CN1CCc2ccccc2C1
Temperature: 130 °C

Procedure:
To a solution of 2,6-dichloropyrazine (150 mg, 1 mmol) in 5 mL i-PrOH was added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (206 mg, 1 mmol), the solution sealed and the mixture heated at 130° C. for 2 h. After cooling, the solvent was evaporated and the residue used directly in the next step without purification. LCMS (m/z): 319 (M+1).
Reaction SMILES: [I:1]I.[CH2:3]([C:5]1[NH:6][C:7]([CH2:12][CH3:13])=[CH:8][C:9](=[O:11])[CH:10]=1)[CH3:4].[OH-].[Na+]>O>[CH2:3]([C:5]1[NH:6][C:7]([CH2:12][CH3:13])=[CH:8][C:9](=[O:11])[C:10]=1[I:1])[CH3:4]
Reactant: II
Reactant: CCc1cc(=O)cc(CC)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1cc(=O)c(I)c(CC)[nH]1
Reaction time: 1 h
Yield: 36.9 %

Procedure:
Iodine (720 mg) was added to a solution of compound F (430 mg) and sodium hydroxide (120 mg) in water (15 ml) and the mixture was stirred for 1 hour. The precipitated solid was collected by filtration and purified by flash chromatography, eluting with methanol/dichloromethane (1:19 v/v), to give 2,6-diethyl-3-iodo-4(1H)pyridone (G) (290 mg), m.p. 225°-227° C.; NMR (d6 -DMSO): 1.15(t, 6H), 2.5(q, 2H), 2.8(q, 2H), 5.9(s, 1H), 11.4(br s, 1H).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:26]([OH:28])=[O:27])[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H][H].C(N(CC)CC)C.O>Cl.[Pd]>[NH2:1][C@H:2]([C:26]([OH:28])=[O:27])[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(C[C@H](NC(=O)OCc1ccccc1)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O

Procedure:
A suspension of 10.2 g of Z-Asn(Trt)-OH (20 mmol) in 120 ml of one-normal aqueous hydrochloric acid is hydrogenated in the presence of 0.5 g of a 10% palladium on charcoal catalyst at room temperature and under atmospheric pressure. After uptake of hydrogen is complete, the catalyst is filtered off and thoroughly washed with methanol, and the filtrate is concentrated under reduced pressure to a weight of 100 g. Addition of 2.8 ml of triethylamine (20 mmol) is followed by further concentration to a weight of 50 g and the crystalline precipitate is filtered off and washed with a 1:1 mixture of methanol and water and then with water until free of chloride. The H-Asn(Trt)-OH contains 0.5 mole of water and slowly decomposes above 220°.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:22]2[N:23]=[CH:24][N:25]=[C:21]2[N:20]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([F:34])[CH:27]=2)[C:19](=[O:35])[C:18]=1[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[C:44]([C:49]#[N:50])=[CH:45][CH:46]=[CH:47][CH:48]=2)=[CH:39][CH:38]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:22]2[N:23]=[CH:24][N:25]=[C:21]2[N:20]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([F:34])[CH:27]=2)[C:19](=[O:35])[C:18]=1[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[C:49]2[NH:3][C:4](=[O:7])[O:5][N:50]=2)=[CH:41][CH:42]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(OC)c(F)c2)c2ncnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(-c2ccc(OC)c(F)c2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
A mixture of hydroxylammonium chloride (1.6 g), sodium hydrogen carbonate (2.6 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-({7-butyl-4-[3-fluoro-4-methoxyphenyl]-5-oxo-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.78 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.3 g) and then with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.46 g, 53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([S:12]([CH2:14][C:15]3[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=3)=[O:13])[NH:11][C:6]2=[CH:5][CH:4]=1.[C:25](=[O:37])([O:34][CH2:35][CH3:36])[O:26][CH2:27][CH2:28][N:29]([C:31](Cl)=[O:32])[CH3:30].C(N(CC)CC)C>O1CCCC1.CN(C)C1C=CN=CC=1>[C:25](=[O:37])([O:26][CH2:27][CH2:28][N:29]([C:31]([N:9]1[C:7]2=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=[C:6]2[N:11]=[C:10]1[S:12]([CH2:14][C:15]1[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=1)=[O:13])=[O:32])[CH3:30])[O:34][CH2:35][CH3:36]
Reactant: CCOC(=O)OCCN(C)C(=O)Cl
Reactant: COc1ccc2[nH]c(S(=O)Cc3ncc(C)c(OC)c3C)nc2n1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)OCCN(C)C(=O)n1c(S(=O)Cc2ncc(C)c(OC)c2C)nc2ccc(OC)nc21
Temperature: 50 °C
Reaction time: 18 h

Procedure:
5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-imidazo[4,5-b]pyridine synthesized according to the method described in JP-A-63-146882 was subjected to preparative HPLC for optical resolution to give a (−) enantiomeric form (0.10 g) thereof. To a solution (5 mL) of this form in tetrahydrofuran were added 2-[(chlorocarbonyl)(methyl)amino]ethyl ethyl carbonate (0.081 g) obtained in Reference Example 34, triethylamine (0.080 mL) and 4-dimethylaminopyridine (0.007 g) and the mixture was stirred at 50° C. for 18 hrs. After concentration under reduced pressure, water (30 mL) was added to the residue and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by basic silica gel column chromatography (eluted with ethyl acetate:hexane=2:1) to give the title compound (0.053 g) as a colorless oil.
Reaction SMILES: [C:1]([OH:11])(=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O1CCCC1.[N:29]1([CH2:34][CH2:35][CH2:36][NH2:37])[CH:33]=[CH:32][N:31]=[CH:30]1>O>[N:29]1([CH2:34][CH2:35][CH2:36][NH:37][C:1](=[O:11])[CH:2]=[CH:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: NCCCn1ccnc1
Reactant: O=C(O)/C=C/c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)NCCCn1ccnc1
Reaction time: 18 h

Procedure:
A mixture of 2.22 g. of trans-cinnamic acid, 2.43 g, of 1,1'-carbonyldiimidazole and 50 ml. of tetrahydrofuran was stirred for 2 hours, then 1.7 ml. of 1H-imidazole-1-propanamine was added. The reaction mixture was stirred for 18 hours, then 5 ml. of water was added, the mixture was heated for 30 minutes and then concentrated. Methylene chloride and 10 ml. of 1N sodium hydroxide were added and then layers were separated. The organic layer was washed with water, dried over magnesium sulfate and concentrated, giving the desired product as a viscous oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:8][CH2:9][CH2:10][CH2:11][C:12](Cl)=[O:13]>O1CCCC1>[Cl:8][CH2:9][CH2:10][CH2:11][C:12]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:13]
Reactant: Nc1ccccc1
Reactant: O=C(Cl)CCCCl
Solvent: C1CCOC1
Product: O=C(CCCCl)Nc1ccccc1
Yield: 97.5 %

Procedure:
A solution of 27.9 g (0.30 mole) of aniline in 100 ml of tetrahydrofuran was added dropwise to a solution of 21.2 g (0.15 mole) of 4-chlorobutyryl chloride in 100 ml of tetrahydrofuran. The reaction mixture was stirred mechanically and the temperature maintained between 5° C. and 15° C. throughout the addition. After the final addition, the solution was filtered to remove solid precipitates and the filtrate was concentrated under reduced pressure to yield 28.9 g (100%) of yellow solid. An analytical sample was prepared by recrystallizing the solid from benzene/petroleum ether (30°-60° C.) to give a white solid, mp 64°-66° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29](C(O)=O)=[C:28]([CH3:35])[CH:27]=1.[NH2:36][CH2:37][CH:38]([C:40]1[CH:41]=[C:42]([OH:46])[CH:43]=[CH:44][CH:45]=1)[OH:39]>>[OH:39][CH:38]([C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([OH:46])[CH:41]=1)[CH2:37][NH:36][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6]([C:29]1[CH:30]=[CH:31][C:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH3:19])=[CH:27][C:28]=1[CH3:35])=[O:7])=[O:18]
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: NCC(O)c1cccc(O)c1
Reactant: Cc1cc(-c2ccccc2C)ccc1C(=O)O
Product: CON=C1C[C@@H](C(=O)NCC(O)c2cccc(O)c2)N(C(=O)c2ccc(-c3ccccc3C)cc2C)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 2′,3-dimethyl[1,1′-biphenyl]-4-carboxylic acid, and 3-[(1RS)-2-amino-1-hydroxyethyl]phenol, the title compound was obtained in 91% purity by HPLC. MS(ESI+): m/z=502.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3]([Cl:5])=[O:4].[Cl:8][C:9]1[CH:34]=[CH:33][C:12]2[N:13]3[C:17]([CH2:18][NH:19][CH2:20][C:11]=2[CH:10]=1)=[N:16][N:15]=[C:14]3[CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:23][CH2:22]1>>[ClH:5].[ClH:8].[Cl:8][C:9]1[CH:34]=[CH:33][C:12]2[N:13]3[C:17]([CH2:18][N:19]([C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])[CH2:20][C:11]=2[CH:10]=1)=[N:16][N:15]=[C:14]3[CH:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:25][CH2:26]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Product: CC(C)(C)C(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ccccn3)CC2)C1
Product: Cl
Yield: 54 %

Procedure:
The title compound was prepared from 2,2-Dimethyl-propionyl chloride and the amine of example 4, in 54% yield, using the procedure described in example 8.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Cl)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].O.[SH-:13].[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1[C:10]([SH:13])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1nccnc1Cl
Reactant: [SH-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1nccnc1S
Temperature: 25 °C
Reaction time: 9 h
Yield: 89.4 %

Procedure:
After 3-chloro-pyrazine-2-carboxylic acid methyl ester (0.4 g, 2.3 mmol) was dissolved in MeOH (46 mL), sodium hydrosulfide monohydrate (0.65 g, 6.9 mmol) was added thereto, and the mixture was stirred at room temperature for 9 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure, and 1N HCl aqueous solution was used to adjust the pH of the reactant to 3. The reactant was extracted with EtOAc, and the organic layer was separated to obtain the title compound (0.35 g, 89%).
Reaction SMILES: I[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([CH3:15])[C:3]=1[C:16]#[N:17].[CH3:18][C:19]1[C:23]([Sn](CCCC)(CCCC)CCCC)=[C:22]([CH3:37])[O:21][N:20]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][C:19]1[C:23]([C:2]2[N:6]([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=3)[N:5]=[C:4]([CH3:15])[C:3]=2[C:16]#[N:17])=[C:22]([CH3:37])[O:21][N:20]=1
Reactant: COc1ccc(-n2nc(C)c(C#N)c2I)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(C)noc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: COc1ccc(-n2nc(C)c(C#N)c2-c2c(C)noc2C)cc1
Reaction time: 0.5 h
Yield: 135.3 %

Procedure:
5-iodo-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (450 mg, 1.33 mmol), 3,5-dimethyl-4-(tributylstannyl)isoxazole (907 mg, 2.35 mmol) and PdCl2(PPh3)2 (186 mg, 0.27 mmol), were mixed with 1 mL degassed dioxane and 1 mL degassed DME under nitrogen in a microwave vial. The reaction was run at 145° C. in the microwave for 30 min. Water was added, extracted with CH2Cl2, filtered through a phase separator. The organic phase was evaporated and the residue was purified using silica to give 5-(3,5-dimethylisoxazol-4-yl)-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (555 mg, >100%) which was used as such in the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C@H:6]([C:7]#[N:8])[N:5]2[C:9](=[O:12])[C@H:10](Br)[C@H:4]2[S:3]1.[CH3:14][N:15]([CH3:24])[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1>O1CCCC1.C(OCC)(=O)C.[Zn]>[CH3:1][C:2]1([CH3:13])[C@H:6]([C:7]#[N:8])[N:5]2[C:9](=[O:12])[C@H:10]([CH:20]([OH:21])[C:19]3[CH:18]=[CH:17][C:16]([N:15]([CH3:14])[CH3:24])=[CH:23][CH:22]=3)[C@H:4]2[S:3]1.[CH3:1][C:2]1([CH3:13])[C@H:6]([C:7]#[N:8])[N:5]2[C:9](=[O:12])[C@@H:10]([CH:20]([OH:21])[C:19]3[CH:18]=[CH:17][C:16]([N:15]([CH3:14])[CH3:24])=[CH:23][CH:22]=3)[C@H:4]2[S:3]1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CC1(C)S[C@@H]2[C@@H](Br)C(=O)N2[C@H]1C#N
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)c1ccc(C(O)[C@@H]2C(=O)N3[C@@H]2SC(C)(C)[C@@H]3C#N)cc1
Product: CN(C)c1ccc(C(O)[C@H]2C(=O)N3[C@@H]2SC(C)(C)[C@@H]3C#N)cc1

Procedure:
A solution of 100 mg 2,2-dimethyl-3α-cyano-6α-bromopenam in 40 ml dry tetrahydrofuran is stirred with 60 mg p-dimethylaminobenzaldehyde and 500 mg zinc for about 12 hours at room temperature. The reaction mixture is then diluted in ethyl acetate, washed with aqueous sodium chloride and dried over anhydrous sodium sulfate. Chromatography of the mixture on silica gel affords, in 11:1 ratio, 2,2-dimethyl-3α-cyano-6α-(p-dimethylamino-α-hydroxybenzyl)penam and 2,2-dimethyl-3α-cyano-6β-(p-dimethylamino-α-hydroxybenzyl)penam. The 6α-compound has the following formula: ##STR39##
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15](=[O:17])[CH3:16])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]([N:32]3[C:44]4[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=4[C:38]4[C:33]3=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:29]=[CH:30][CH:31]=2)O1>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[CH:34]1[C:33]2[N:32]([C:28]3[CH:27]=[C:26]([C:2]4[CH:3]=[CH:4][C:5]5[N:6]([C:15](=[O:17])[CH3:16])[C:7]6[C:12]([C:13]=5[CH:14]=4)=[CH:11][CH:10]=[CH:9][CH:8]=6)[CH:31]=[CH:30][CH:29]=3)[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38]=2[CH:37]=[CH:36][CH:35]=1
Reactant: CC1(C)OB(c2cccc(-n3c4ccccc4c4ccccc43)c2)OC1(C)C
Reactant: CC(=O)n1c2ccccc2c2cc(Br)ccc21
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)n1c2ccccc2c2cc(-c3cccc(-n4c5ccccc5c5ccccc54)c3)ccc21
Temperature: 25 °C
Yield: 92.8 %

Procedure:
A solution of 1-(3-bromo-9H-carbazol-9-yl)ethanone (2.000 g, 6.94 mmol), 9-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-9H-carbazole (2.56 g, 6.94 mmol), Pd2(dba)3 (0.064 g, 0.069 mmol), SPhos (0.057 g, 0.139 mmol) and potassium phosphate tribasic hydrate (4.80 g, 20.82 mmol) in toluene (100 mL) and water (10 mL) was stirred at 70° C. under nitrogen overnight. After cooling to room temperature, the organic phase was isolated. Upon evaporation of the solvent, the residue was purified by column chromatography on silica gel with hexane:DCM (1:4, v/v) as eluent to yield 1-(3-(3-(9H-carbazol-9-yl)phenyl)-9H-carbazol-9-yl)ethanone (2.9 g, 94%) as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:18]Cl)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1.[F:20][C:21]1[CH:26]=[C:25]([F:27])[N:24]=[C:23]([NH2:28])[N:22]=1>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:18][NH:28][C:23]3[N:24]=[C:25]([F:27])[CH:26]=[C:21]([F:20])[N:22]=3)=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:8]=1
Reactant: Nc1nc(F)cc(F)n1
Reactant: ClCc1c(-c2ccccc2)nc2ccc(Cl)cn12
Agent: Cl
Product: Fc1cc(F)nc(NCc2c(-c3ccccc3)nc3ccc(Cl)cn23)n1
Yield: 43 %

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 6-chloro-3-(chloromethyl)-2-phenylimidazo[1,2-a]pyridine hydrochloride and 4,6-difluoropyrimidin-2-amine. ((0.26 g, 43% yield), M/e+ 372.2 for C18H12ClF2N5 (M+H)+.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH2:9])([CH3:5])([CH3:4])[CH3:3].Br[CH:13]1[CH2:18][CH2:17][O:16][C:14]1=[O:15].C(N(CC)CC)C.O>CN(C)C=O>[C:2]([O:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH:9][CH:13]1[CH2:18][CH2:17][O:16][C:14]1=[O:15])([CH3:5])([CH3:4])[CH3:3]
Reactant: O=C1OCCC1Br
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](NC1CCOC1=O)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 5 h
Yield: 58 %

Procedure:
Dissolved in 30 ml of dimethylformamide were 2.54 g of L-alanine t-butyl ester hydrochloride and 2.38 g of 2-bromo-γ-butyrolactone. After a dropwise addition of 2.83 g of triethylamine, the resultant mixture was heated and stirred at 70° C. for 5 hours. The reaction mixture was poured into chilled water, followed by extraction with ethyl acetate. The extract was washed successivley with water, a 2% aqueous solution of sodium hydrogencarbonate, and water. After drying the extract over anhydrous sodium sulfate, it was distilled under reduced pressure. The residue was isolated and purified by chromatography on a silica gel column (toluene:ethyl acetate=20:1), thereby obtaining 1.86 g of N-(2-oxo-3-tetrahydrofuranyl)-L-alanine t-butyl ester as a colorless oily substance.
Reaction SMILES: C([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[S:13])=[CH:10][CH:9]=1)C1C=CC=CC=1.[Cl:16][CH2:17][CH2:18][O:19][CH2:20][Mg]Cl.[Cl-].[NH4+].Cl.C([O:29][CH2:30][CH3:31])(=O)C>O1CCCC1>[CH2:12]([S:13][C:8]1[CH:15]=[CH:14][C:31]([CH:30]([OH:29])[CH2:20][O:19][CH2:18][CH2:17][Cl:16])=[CH:10][CH:9]=1)[C:11]1[CH:10]=[CH:9][CH:8]=[CH:15][CH:14]=1
Reactant: S=Cc1ccc(Cc2ccccc2)cc1
Reactant: CCOC(C)=O
Reactant: ClCCOC[Mg]Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(COCCCl)c1ccc(SCc2ccccc2)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
1.19 g of 4-benzylthiobenzaldehyde was dissolved in 20 ml of tetrahydrofuran. The solution was cooled to -10° C. Thereto was dropwise added 10 ml of a tetrahydrofuran solution containing 2M of 2-chloroethoxymethylmagnesium chloride in 10 minutes. The resulting mixture was stirred for 1 hour with ice cooling. The reaction mixture was added to a mixture of 50 ml of ice water, 50 ml of ethyl acetate and 1 g of ammonium chloride. The resulting mixture was adjusted to pH 2 with 6N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography [eluant: toluene/ethyl acetate=20/1] to obtain 1.34 g of 1-(4-benzylthiophenyl)-2-(2-chloroethoxy)ethanol.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8](=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=1.Cl[C:22]([O:24]C)=[O:23].O.N1C=CC=C[CH:28]=1>>[C:22]([O:24][NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8](=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=2)[N:6]=1)(=[O:23])[CH3:28]
Reactant: COC(=O)Cl
Reactant: c1ccncc1
Reactant: Nc1nc(CC(=O)Nc2cccc(C(F)(F)F)c2)cs1
Solvent: O
Product: CC(=O)ONc1nc(CC(=O)Nc2cccc(C(F)(F)F)c2)cs1

Procedure:
To a solution of 5.0 g (0.017 mole) of 2-amino-4-(3-trifluoromethylphenylcarbamoylmethyl)thiazole in 22 ml of pyridine, there was added dropwise 2.8 g (0.03 mole) of methyl chloroformate. The solution was stirred and heated at 40°-45° for eighteen hours. The mixture was poured into 300 ml of cold water and stirring induced crystal formation. The solid was collected and the filter cake was washed with water. There was obtained 4.9 g of product, m.p. 137°-40°. N.M.R. (dimethyl-d6 sulfoxide) ∂ 3.6-3.9 (OCH3, CH2), 6.8 (hetero-aromatic), 7.3-8.1 (aromatic), 10.4 (HNC=0).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([CH3:17])[C:14]([CH:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22][CH:21]=2)[OH:19])=[C:13]([O:30][CH3:31])[CH:12]=1)[CH3:2].[H-].[Na+].I[CH2:35][CH3:36]>CN(C=O)C>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:11]1[N:16]=[C:15]([CH3:17])[C:14]([CH:18]([O:19][CH2:35][CH3:36])[CH:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22][CH2:21]2)=[C:13]([O:30][CH3:31])[CH:12]=1)[CH3:10]
Reactant: CCc1cccc(CC)c1-c1cc(OC)c(C(O)C2=CCCc3ccccc32)c(C)n1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(c1c(OC)cc(-c2c(CC)cccc2CC)nc1C)C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of [6-(2,6-diethyl-phenyl)-4-methoxy-2-methyl-pyridin-3-yl]-(3,4-dihydro-naphthalen-1-yl)-methanol (75 mg, 0.18 mmol) in DMF (1 mL) is added to a suspension of NaH (22 mg, 0.90 mmol) in DMF (5 mL). The mixture is stirred for 1 hour at room temperature. Iodoethane 10.14 mL, 1.8 mmol) is added and the resulting mixture is stirred for 18 hours at room temperature, quenched with water, and extracted with ether. The combined extracts are washed with saturated brine, dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel to give 6-(2,6-diethyl-phenyl)-3-[ethoxy-(1,2,3,4-tetrahydro-naphthalen-1-yl)-methyl]-4-methoxy-2-methyl-pyridine as a colorless oil. 1H NMR (CDCl3) 7.71-7.68 (m, 1H), 7.32-7.26 (m, 1H), 7.21-7.10 (m, 5H), 6.67 (s, 1H), 5.04 (d, 1H), 3.80 (s, 3H), 3.51-3.46 (m, 1H), 3.36-3.19 (m, 2H), 2.89-2.2.72 (m, 2H), 2.75 (s, 3H), 2.47-2.38 (m, 4H), 1.90-1.81 (m, 1H), 1.69-1.59 (m, 2H), 1.41-1.1.32 (m, 1H), 1.17-1.08 (m, 9H).