Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5]([C:14]#[N:15])=[C:4]([CH:16]=[CH2:17])[N:3]=1.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[N:3]=[C:4]([CH2:16][CH3:17])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: [H][H]
Reactant: C=Cc1nc(N)nc(-c2ccccc2)c1C#N
Agent: [Pd]
Solvent: CCO
Product: CCc1nc(N)nc(-c2ccccc2)c1C#N
Yield: 34.7 %

Procedure:
A solution of 100 mg (0.45 mmol) 2-amino-4-phenyl-6-vinyl-pyrimidine-5-carbonitrile in 10 ml ethanol was stirred with a spatula end of 10% palladium on charcoal under 1 atm of hydrogen for 16 h at room temperature. After filtration to remove the catalyst, the reaction mixture was concentrated in vacuo and the residue triturated in ether to afford 35 mg (35%) 2-amino-4-ethyl-6-phenyl-pyrimidine-5-carbonitrile as a white crystalline solid. EI-MS m/e (%): 224 (M+, 44), 223 ([M—H]+, 100).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][NH:12][CH2:13][CH2:14][OH:15]>C(OCC)(=O)C>[CH3:11][N:12]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH2:13][CH2:14][OH:15]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CNCCO
Solvent: CCOC(C)=O
Product: CN(CCO)c1ccc([N+](=O)[O-])cc1
Reaction time: 12 h

Procedure:
A mixture of 4-fluoronitrobenzene (20 g) and 2-methylaminoethanol (56 mL) was left to stand for 12 hours and then diluted with ethyl acetate. It was washed with water. The organic phase was dried and concentrated. The product with the molecular weight of 196.21 (C9H12N2O3);
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(O)(=O)/C=C/C(O)=O.[CH3:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[NH:25][C:26](=O)[CH2:27][CH2:28][CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>CO.CCOCC>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[CH3:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH3:17])[C:19]=1[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: Cc1cccc(C)c1NC(=O)CCCn1ccnc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Solvent: CO
Product: Cc1cccc(C)c1NCCCCn1ccnc1

Procedure:
A solution of 27.27 g of N-(2,6-dimethylphenyl)-1H-imidazole-butanamide hydrobromide salt in 250 ml of dry tetrahydrofuran was added dropwise with stirring to 530 ml of 1 molar borane in tetrahydrofuran and the resulting solution was heated to reflux for 2 hours. After cooling, excess methanol was added to decompose the remaining borane and the solution was evaporated to dryness. The residue was acidified by the cautious addition of 285 ml of 2N hydrochloric acid and was warmed on the steam bath for 20 minutes. The resulting solution was cooled, made strongly basic with sodium hydroxide solution and was extracted with dichloromethane. The combined organic layers were dried with potassium carbonate and concentrated to give 25.1 g of N-(2,6-dimethylphenyl)-1H-imidazole-1-butanamine as an oil which was dissolved in 200 ml of methanol, treated with 23.9 g of fumaric acid and diluted with 600 ml of ether. The resulting solid amounted to 37.0 g of N-(2,6-dimethylphenyl)-1H-imidazole-1-butanamide (E)-2-butenedioate(1:2) salt, mp 146°-147° C. Recrystallization from methanol-ether gave the analytical sample, mp 148°-149° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([C:9]1[S:13][C:12]([C:14](O)=[O:15])=[CH:11][CH:10]=1)=[O:8].C(Cl)(=O)C([Cl:24])=O>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([C:9]1[S:13][C:12]([C:14]([Cl:24])=[O:15])=[CH:11][CH:10]=1)=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)s1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(C(=O)NCc2ccc(Cl)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A stirring solution of (12(b)) (495 mg; 1.5 mmole) in dichloromethane (25 mL) was cooled in an ice bath and DMF (1 drop) and oxalyl chloride (0.175 mL; 2.0 mmole) added dropwise. The solution was stirred at ambient temperature under argon for 4 hours. The dichloromethane and excess oxalyl chloride were removed in vacuo. The residue was azeotroped uith toluene (2×15 mL) to give 5-(3,4-dichlorobenzyl-carbamoyl)-thiophene-2-carbonyl-chloride (12(c)) which was used crude in the next step.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[N:12]([CH2:13][C:14]([C:16]3[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[O:15])[C@H:11]([C:23]([F:26])([F:25])[F:24])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.Cl.[C@H:28]12[CH2:34][C@H:31]([NH:32][CH2:33]1)[CH2:30][O:29]2.C(N(CC)CC)C>>[CH3:22][C:19]1[N:18]=[CH:17][C:16]([C:14](=[O:15])[CH2:13][N:12]2[C:4]3=[N:3][C:2]([N:32]4[CH2:33][C@@H:28]5[CH2:34][C@H:31]4[CH2:30][O:29]5)=[CH:7][C:6](=[O:8])[N:5]3[CH2:9][CH2:10][C@H:11]2[C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=1
Reactant: Cc1ccc(C(=O)CN2c3nc(Cl)cc(=O)n3CC[C@H]2C(F)(F)F)cn1
Reactant: C1O[C@@H]2CN[C@H]1C2
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)CN2c3nc(N4C[C@@H]5C[C@H]4CO5)cc(=O)n3CC[C@H]2C(F)(F)F)cn1

Procedure:
480 mg (1.24 mmol) of (8S)-2-chloro-9-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, 201.94 mg (1.49 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride and 313.97 mg (3.10 mmol) of triethylamine were used in the reaction. After purification by chromatography on silica gel (eluent A/B: heptane/EtOAc, gradient A/B: t 0 min 30% B, t 35 min 60% B, t 40 min 60% B), 335 mg of (8S)-9-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one were obtained, corresponding to the following characteristics:
Reaction SMILES: [C:1]([NH:11][C@@H:12]([C:14]([OH:16])=[O:15])[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(=O)(=O)(O)O.[CH3:22][C:23]1[CH2:27][CH2:26][CH2:25][CH:24]=1>ClCCl>[CH3:22][C:23]1([O:15][C:14](=[O:16])[C@@H:12]([CH3:13])[NH:11][C:1]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC1=CCCC1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: C[C@@H](NC(=O)OCc1ccccc1)C(=O)OC1(C)CCCC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a magnetically stirred solution of 22.3 g (0.1 mol) N-Cbz-D-alanine in 50 mls of dry dichloromethane containing 0.5 mls of concentrated sulfuric acid at 0° C., was added dropwise a 10 g (0.1 mol) sample of 1-methylcyclopentene in 50 mls of dichloromethane. After 5 days of stirring at room temperature, the mixture was heated to reflux for 4 hours, after which the reaction was cooled to room temperature, washed with 100 mls of saturated NaHCO3, 100 mls of water and dried over MgSO4. Filtration followed by evaporation of the solvent yielded 1.81 g of the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](=[O:9])[CH:7]=[CH:6][NH:5][C:4]=1[CH3:10].[CH2:11](I)[CH2:12][CH3:13]>CN(C)C=O.C(Cl)(Cl)Cl.[Ag]=O>[CH3:1][O:2][C:3]1[C:4]([CH3:10])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:11][CH2:12][CH3:13]
Reactant: CCCI
Reactant: COc1c(C)[nH]ccc1=O
Agent: O=[Ag]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCOc1ccnc(C)c1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-Methoxy-2-methyl-4(1H)-pyridone(1.39 g) and propyl iodide (2.0 ml) were dissolved in dimethylformamide (20 ml), to which silver oxide (2.31 g) was added in small portions and stirred vigorously at room temperature for 5 hours. The reaction mixture was diluted with chloroform (100 ml), washed with water, dried and evaporated. The residue was purified by flash chromatography (chloroform) on silica gel, to give 3-methoxy-2-methyl-4-propoxypyridine (1.7 g) as a light brown oil.
Reaction SMILES: [C:1]1(C)[C:2]([C:7]#[N:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O(Cl)Cl.[C:13]([Cl:17])(Cl)([Cl:15])[Cl:14]>>[Cl:14][C:13]([Cl:17])([Cl:15])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[N:8]
Reactant: Cc1ccccc1C#N
Reactant: ClC(Cl)(Cl)Cl
Agent: ClOCl
Product: N#Cc1ccccc1C(Cl)(Cl)Cl
Yield: 100 %

Procedure:
o-Tolunitrile (1.83 g, 0.0156 mole) and dichlorine monoxide (6.79 g, 0.078 mole) in carbon tetrachloride were heated at 75° for 18.5 hrs in a Carrius tube following the procedure described in Example 6. The reaction mixture was dried (MgSO4) and the solvent removed on a rotary evaporator to give a white crystalline solid (4.09 g, purity by HPLC 85.45%, yield 100%). The product was combined with that of a similar run and recrystallized from cyclohexane to give substantially pure 2-trichloromethylbenzonitrile mp 98.9°-100° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH3:16][N:17]([CH3:35])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]2[CH:27]=[N:28][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:31]=2)=[CH:20][CH:19]=1>>[CH3:16][N:17]([CH3:35])[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]([C:26]2[CH:27]=[N:28][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:30][CH:31]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:22][CH:23]=1
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cn1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)C)nc1)CCC2
Yield: 14.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.41 g) and [(4-dimethylaminophenyl)methyl](6-isopropylpyridin-3-yl)amine (0.54 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-N-(6-isopropylpyridin-3-yl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.13 g) was obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[O:6][C:5]1([CH:8]1[CH:15]([O:16][CH3:17])[CH:14]([O:18][C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:13][CH2:12][C:9]21[O:11][CH2:10]2)[CH3:7].[H-].[Na+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>C1(C)C=CC=CC=1.CN(C)C=O>[CH2:34]([O:33][C:31]([CH2:30][O:1][CH2:2][CH2:3][CH:4]1[O:6][C:5]1([CH:8]1[CH:15]([O:16][CH3:17])[CH:14]([O:18][C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:13][CH2:12][C:9]21[O:11][CH2:10]2)[CH3:7])=[O:32])[CH3:35]
Reactant: COC1C(OC(=O)N2CCOCC2)CCC2(CO2)C1C1(C)OC1CCO
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)COCCC1OC1(C)C1C(OC)C(OC(=O)N2CCOCC2)CCC12CO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.3 %

Procedure:
To a solution of 4-[3-(2-hydroxyethyl)-2-methyloxiranyl]-5-methoxy-6-(morpholinocarbonyloxy)-1-oxaspiro[2,5]octane (76.2 mg) in a mixture of toluene (2 ml) and N,N-dimethylformamide (1 ml) was added sodium hydride (20.5 mg) in one portion under ice cooling. The mixture was stirred for half an hour at the same temperature and ethyl bromoacetate (68.5 mg) was added. After stirred for 3 hours at ambient temperature, the reaction mixture was quenched with aqueous saturated ammonium chloride solution (2 ml). The organic layer was washed with brine, dried, and evaporated in vacuo. The residue was purified by column chromatography on silica gel (diethyl ether) to give 4-[3-(2-ethoxycarbonylmethoxyethyl)-2-methyl-oxiranyl]-5-methoxy-6-(morpholinocarbonyloxy)-1-oxaspiro-[2,5]octane (66.9 mg).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:8]=[O:9].N12CCC(CC1)CN2.Cl>O.CS(C)=O>[OH:9][CH2:8][C:2](=[CH2:3])[C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: C=O
Reactant: C=CC(=O)OCC
Agent: C1CN2CCC1CN2
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: C=C(CO)C(=O)OCC
Temperature: 100 °C

Procedure:
Into a 2-liter separable flask fitted with a stirrer, a reflux condenser and a thermometer, dimethylsulfoxide (500 parts), water (170 parts), ethyl acrylate (200 parts), paraformaldehyde (purity: 80%, 72.5 parts) and diazabicyclo (2.2.2) octane (15.6 parts) were charged. They were heated to 100° C., and subjected to a reaction for 4 hours. Although the contents were not homogeneous at the time of the charging, they turned into a homogeneous clear mixture around 60° C. Dilute hydrochloric acid (500 parts) was then added, followed by extraction twice with diethylether (200 parts, each). The extract was dried over anhydrous magnesium sulfate. After the thus-dried extract was concentrated in an evaporator, the concentrate was subjected to distillation under reduced pressure. Ethyl 2-(hydroxymethyl)acrylate was obtained (yield: 193 parts). The reaction product was identified to be the target compound by IR and NMR, and its purity was determined to be 98.7% by GC.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[C:9]2=[O:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1C2C=CC(O)=CC=2OC1.[Br:35][C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1>>[Br:35][C:36]1[CH:37]=[CH:38][C:39]([OH:42])=[C:40]([C:10]2([OH:17])[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]2=[O:18])[CH:41]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: Oc1ccc(Br)cc1
Agent: Oc1ccc2c(c1)OCO2
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc(Br)ccc1O

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations to replace1-(2-cyclopropylethyl)-1H-indole-2,3-dione with 1-(diphenylmethyl)-1H-indole-2,3-dione, and 1,3-benzodioxol-5-ol with 4-bromophenol, the title compound was obtained (90%) as an orange solid: MS (ES+) m/z 486.2 (M+1), 488.2 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](O)=[O:9])([CH3:4])[CH3:3].[NH3:19]>O1CCCC1>[CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([NH2:19])=[O:9])([CH3:4])[CH3:3]
Reactant: N
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(N)=O)cc(C(C)(C)C)c1O
Temperature: 26 °C
Reaction time: 2 h

Procedure:
In a 22 L Morton flask, 749 g (3.0 mol) of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acid, 533 g (3.3 mol) carbonylcuiimidazole and tetrahydrofuran (THF) were combined and heated slowly to reflux and allowed to reflux for 2.5 hours. The reaction mixture was cooled to 26° C. and concentrated aqueous ammonia was added. Stirring was continued for 2 hours and the reaction mixture was allowed to stand overnight. The contents were transferred to a flask and rinsed with tetrahydrofuran (250 mL). The mixture was stirred, layers were separated, and the aqueous layer was saved. The organic layer was washed with brine (2.5 L) followed by brine/deionized (DI) water (1 L/1.5 L). The organic layer was washed with 9.7 M hydrochloric acid (HCl)/deionized water (0.25 L/2.25 L), followed by 9.7 M hydrochloric acid/deionized water (0.5 L/2.8 L), and 9.7 M hydrochloric acid/deionized water/brine (0.5 L/1.5 L/1.5 L). The organic layer was set aside while the combined aqueous layers were washed with tetrahydrofuran. The combined organic layers were washed with brine, dried with sodium sulfate (855 g) and filtered. The filtrate was evaporated to 1011 g of a wet (water), white solid. Methylene chloride was added and removed in vacuo. This procedure was repeated with ethyl acetate (6 L, then 2 L) to produce a solid residue (779 g). The residue was slurried in ethyl acetate and heptane, filtered, and dried in a vacuum oven to yield the desired amide (736 g, 98.7%) as a white solid
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[CH2:11][C:12]1[CH2:13][S:14](=[O:46])[C@@H:15]2[CH:35]([NH:36][C:37](=[O:44])[CH2:38][C:39]3[S:40][CH:41]=[CH:42][CH:43]=3)[C:34](=[O:45])[N:16]2[C:17]=1[C:18]([O:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].O>C(Cl)Cl>[F:7][CH2:11][C:12]1[CH2:13][S:14](=[O:46])[C@@H:15]2[CH:35]([NH:36][C:37](=[O:44])[CH2:38][C:39]3[S:40][CH:41]=[CH:42][CH:43]=3)[C:34](=[O:45])[N:16]2[C:17]=1[C:18]([O:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS(=O)[C@H]12
Reactant: CCN(CC)S(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CF)CS(=O)[C@H]12
Reaction time: 0.5 h
Yield: 5.9 %

Procedure:
To a solution of 0.483 g (3.0 mmoles) of diethylaminosulfur trifluoride in 10 ml of CH2Cl2 at -78° under N2 was added a solution of 1.61 g (3.0 mmoles) of benzhydryl 3-hydroxymethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate-1-oxide in 50 ml of CH2Cl2 and the mixture was stirred at -78° for 0.5 hr, then poured into 100 ml of water. The CH2Cl2 layer was dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel with 9:1 CH2Cl2 -acetone to yield 0.095 g of benzhydryl 3-fluoromethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate-1-oxide in fractions 12-15, rf = 0.60 on tlc with 9:1 CH2Cl2 -acetone; mp 205.5°-207.5° d; ir (CHCl3) 3450 (amide N--H), 1805 (β -lactam C=O), 1725 (ester C=O), 1680 (amide C=O), 1495 ("amide II" band), and 700 (aromatic) cm-1.
Reaction SMILES: Br[C:2]1[C:3]([NH:12][C@H:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[CH:26]1(B(O)O)[CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:26]1([C:2]2[C:3]([NH:12][C@H:13]3[CH2:17][CH2:16][CH2:15][C@@H:14]3[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=2)[CH2:28][CH2:27]1
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1C1CC1

Procedure:
A suspension of tert-butyl N-[(1S,2S)-2-{[3-bromo-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]carbamate (2.44 g, 5.73 mmol), cyclopropylboronic acid (2.46 g, 28.6 mmol), potassium carbonate (3.17 g, 22.9 mmol) and tetrakis(triphenylphosphine)palladium (0.662 g, 0.57 mmol) in 1,4-dioxane (15 ml) and water (4 ml) was subjected to microwave irradiation at 140° C. for 2 hours. The reaction was partitioned between ethyl acetate (20 ml) and water (20 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml) and combined organics were washed with brine (50 ml), filtered through a hydrophobic frit and concentrated in vacuo. The crude product was purified by column chromatography (silica, 0-50% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:11]=[C:12](Cl)[C:13]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:14]=2[N:15]=1>>[Cl:9][C:10]1[N:11]=[C:12]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:14]=2[N:15]=1
Reactant: CCc1cc2c(Cl)nc(Cl)nc2s1
Reactant: NCc1ccccc1
Product: CCc1cc2c(NCc3ccccc3)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of benzylamine with 2,4-dichloro-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-ethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[N:21]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>CS(C)=O>[N:21]1([NH:27][C:2]2[N:7]=[C:6]([C:8]3[CH:20]=[CH:19][C:11]4[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=4[CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Reactant: NN1CCCCC1
Solvent: CS(C)=O
Product: CC(=O)Nc1nc2ccc(-c3ccnc(NN4CCCCC4)n3)cc2s1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 9 %

Procedure:
A mixture of N-(6-(2-chloropyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (0.100 g, 0.3 mmol) and piperidin-1-amine (0.03 g, 0.3 mmol) in DMSO (0.03 g, 0.3 mmol) was heated under microwave (CEM) at 80° C. and 130 W (Powermax® off) for 20 min. Then, the mixture was diluted with 1 ml of DMSO and purified by HPLC (5-50% CH3CN in water) to give a light yellow solid (10 mg) as a TFA salt. MS (ESI pos. ion) Found m/z: 369, (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:6]#[N:7])=[C:4](S(C)=O)[N:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][NH2:25]>COCCOC>[NH2:1][C:2]1[CH:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:5]([C:6]#[N:7])=[C:4]([NH:25][CH2:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=2)[N:3]=1
Reactant: NCc1ccccn1
Reactant: CS(=O)c1nc(N)cc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(-c2ccco2)cc(N)nc1NCc1ccccn1
Temperature: 100 °C
Yield: 34 %

Procedure:
To a stirred suspension of 250 mg (1.01 mmol) 6-amino-4-furan-2-yl-2-methanesulfinyl-nicotinonitrile in 10 ml DME was added 0.41 ml (4.04 mmol) 2-picolylamine and the mixture heated at 100° C. for 16 hours. The reaction mixture was then cooled to room temperature and partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate and concentrated in vacuo. Chromatography (ethyl acetate) followed by trituration in ether afforded 100 mg (34%) 6-amino-4-furan-2-yl-2-[(pyridin-2-ylmethyl)-amino]-nicotinonitrile as an off-white crystalline solid. ES-MS m/e (%): 292 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7](B(O)O)[N:8]2[CH3:11])=[CH:4][CH:3]=1.Br[C:16]1[CH:17]=[C:18]([CH2:22][N:23]2[C:31](=[O:32])[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]2=[O:33])[CH:19]=[N:20][CH:21]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:16]3[CH:17]=[C:18]([CH2:22][N:23]4[C:24](=[O:33])[C:25]5[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=5)[C:31]4=[O:32])[CH:19]=[N:20][CH:21]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1c(B(O)O)cc2ccc(Cl)cc21
Reactant: O=C1c2ccccc2C(=O)N1Cc1cncc(Br)c1
Product: Cn1c(-c2cncc(CN3C(=O)c4ccccc4C3=O)c2)cc2ccc(Cl)cc21

Procedure:
6-Chloro-1-methyl-indole-2-boronic acid and 2-(5-bromo-pyridin-3-ylmethyl)-isoindole-1,3-dione are processed according to the method described in Example 100 to give 2-[5-(6-chloro-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]isoindole-1,3-dione. MS (ESI) m/z 402.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][C:5]1([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[O:9][CH:8]([CH2:10]Cl)[CH2:7][O:6]1.[CH3:23][O-:24].[Na+].[I-].[Na+].O>CS(C)=O>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[CH2:4][C:5]1([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[O:9][CH:8]([CH2:10][O:24][CH3:23])[CH2:7][O:6]1
Reactant: ClCC1COC(Cc2ccc(Cl)cc2Cl)(c2cccnc2)O1
Reactant: C[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COCC1COC(Cc2ccc(Cl)cc2Cl)(c2cccnc2)O1
Temperature: 25 °C

Procedure:
6.0 g of 3-[2-(2,4-dichlorobenzyl)-4-chloromethyl-1,3-dioxolan-2-yl] pyridine, 1.8 g of sodium methylate and a catalytically acting amount of sodium iodide are stirred in 50 ml of dimethyl sulfoxide for 20 h at an internal temperature of +120° C. After cooling to RT, the reaction mixture is poured into 400 ml of water, and extracted twice with 120 ml of ethyl acetate each time. The organic phases are combined, washed with 150 ml of water, dried over sodium sulfate, treated with active charcoal and filtered, and the solvent is evaporated off. The oily residue is purified by chromatography on silica gel with ether. The compound is obtained as colourless oil; nD22.5 :1.4774.