Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[C:23]([Br:24])=[CH:22][CH:21]=[CH:20][N:19]=1>>[Br:24][C:23]1[C:18]2[N:19]([CH:2]=[C:3]([C:5]3[C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][O:8][C:9]=3[CH3:10])[N:17]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Reactant: Nc1ncccc1Br
Product: Cc1onc(-c2ccccc2)c1-c1cn2cccc(Br)c2n1
Yield: 48 %

Procedure:
As described for Example 1, 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (140 mg, 0.5 mmol) was converted, using 2-amino-3-bromopyridine instead of 2-aminopyridine, to the title compound (85 mg, 48%) which was obtained as a yellow gum. MS: m/e=354.0/356.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[H-].[Na+].[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:13]=1[C:14](Cl)=[O:15].CCOCC.CCCCCC>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:14](=[O:15])[C:13]2[C:12]([Cl:11])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:21])[CH:3]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(Nc1cc(Cl)ncn1)c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.5 %

Procedure:
To a cooled (0° C.) solution of 6-chloropyrimidin-4-amine (1.295 g, 10 mmol) in DMF (25 mL) was added sodium hydride (1.2 g, 30 mmol, 60% dispersion in mineral oil) in one portion. The mixture was stirred at 0° C. for 10 min and then 2,6-dichlorobenzoyl chloride (2.304 g, 11 mmol) was added dropwise. The mixture was warmed to room temperature and stirred under nitrogen overnight. The mixture was quenched with ice water and the resulting precipitate was collected by filtration. The solid was washed with water, then 1:1 ether/hexane (10 mL,) to give N-(6-chloropyrimidin-4-yl)-2,6-dichlorobenzamide (1.95 g, yield: 64%). 1H NMR (500 MHz, DMSO) δ 12.09 (s, 1H), 8.84 (s, 1H), 8.24 (s, 1H), 7.61-7.56 (m, 2H), 7.53 (dd, J=9.2, 6.8 Hz, 1H). LCMS (ESI) m/z: 302.1 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.N12CCCN=C1CCCCC2.[F:23][CH:24]([F:43])[O:25][C:26]1[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([N:33](C2C=CC=CC=2)[C:34](=O)[O-:35])[N:27]=1>O1CCOCC1>[Cl:1][C:2]1[C:7]([S:8]([NH:11][C:34]([NH:33][C:28]2[N:27]=[C:26]([O:25][CH:24]([F:43])[F:23])[CH:31]=[C:30]([CH3:32])[N:29]=2)=[O:35])(=[O:9])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(OC(F)F)nc(N(C(=O)[O-])c2ccccc2)n1
Reactant: NS(=O)(=O)c1cccnc1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: Cc1cc(OC(F)F)nc(NC(=O)NS(=O)(=O)c2cccnc2Cl)n1
Reaction time: 2 h
Yield: 90 %

Procedure:
To a mixture of 0.652 g of 2-chloro-3-pyridinylsulfonamide and 0.55 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene in 10 ml of absolute dioxan is added, at 25° C., 1 g of N-(4-difluoromethoxy-6-methylpyrimidin-2-yl)phenylcarbamate. The reaction mixture is stirred for another 2 hours at the same temperature and then concentrated. The residue is taken up in ice/water and neutralised with 1.86 ml of 2N hydrochloric acid. The precipitate is isolated, washed with water and dreid, affording 1.2 g (90%) of N-(2-chloro-3-pyridinylsulfonyl)-N'-(4-difluoromethoxy-6-methylpyrimidin-2-yl)urea (compound 1.15) with a melting point of 161°-162° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:16]([CH3:18])[CH3:17].CN(C)C=O>[I-].[Na+].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:16]([CH3:18])[CH3:17])=[CH:4][CH:3]=1
Reactant: CC(C)Br
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1ccc(Br)cc1
Temperature: 60 °C
Yield: 17052 %

Procedure:
A mixture of 4-bromophenol (30.0 g, 173 mmol), potassium carbonate (26.3 g, 190 mol), sodium iodide (0.60 g, 4 mmol), 2-bromopropane (85.1 g, 0.692 mmol), and N,N-dimethylformamide (173 mL) was warmed at 60° C. for 17 hours. The solution was cooled to room temperature and water (300 mL) was added. The solution was extracted with diethyl ether. The extract was washed with aqueous sodium hydroxide, water, and aqueous sodium chloride, dried (Na2SO4), filtered, and concentrated. The product was purified by vacuum distillation to give 4-bromo-isopropoxybenzene (25.3 g, 118 mmol) as a colorless liquid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:53][CH3:54])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2[O:20][C@@H:21]1[CH2:25][N:24]([C:26]([NH:28][C@:29]2([C:34](=[O:42])[NH:35][S:36]([CH:39]3[CH2:41][CH2:40]3)(=[O:38])=[O:37])[CH2:31][C@H:30]2C=C)=[O:27])[C@H:23]([C:43]([N:45]([CH2:47][CH2:48][CH2:49][CH2:50][CH:51]=[CH2:52])[CH3:46])=[O:44])[CH2:22]1.SC1N=CC=CC=1C(O)=O>ClC(Cl)C>[Cl:1][C:2]1[C:3]([O:53][CH3:54])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:18])[CH3:19])[N:16]=1)[CH:8]=[C:7]2[O:20][C@@H:21]1[CH2:25][N:24]2[C@H:23]([C:43](=[O:44])[N:45]([CH3:46])[CH2:47][CH2:48][CH2:49][CH2:50][CH:51]=[CH:52][C@H:31]3[C@:29]([C:34]([NH:35][S:36]([CH:39]4[CH2:41][CH2:40]4)(=[O:37])=[O:38])=[O:42])([NH:28][C:26]2=[O:27])[CH2:30]3)[CH2:22]1
Reactant: C=CCCCCN(C)C(=O)[C@@H]1C[C@H](Oc2cc(-c3nc(C(C)C)cs3)nc3c(Cl)c(OC)ccc23)CN1C(=O)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C
Agent: COc1ccc2c(O[C@H]3C[C@H]4C(=O)N(C)CCCC/C=C\[C@@H]5C[C@@]5(C(=O)NS(=O)(=O)C5CC5)NC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Agent: O=C(O)c1cccnc1S
Solvent: CC(Cl)Cl
Product: COc1ccc2c(O[C@H]3C[C@H]4C(=O)N(C)CCCCC=C[C@@H]5C[C@@]5(C(=O)NS(=O)(=O)C5CC5)NC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Temperature: 75 °C
Reaction time: 0.42 h

Procedure:
Compound 137 (5.5 g) was dissolved in dichloroethane (1.375 mL) under Ar at room temperature. The solution was degassed with argon and then heated at 73-77° C. Zhan 1B catalyst (1%) in dichloroethane was slowly added to the reaction solution. At 25 min, another 1% of the catalyst in DCE was added. At 45 min, 2-mercaptonicotinic acid (0.5 eq.) was added. The reaction mixture was cooled down to room temperature, concentrated under vacuum to ˜130 mL, and then washed with 0.5M aqueous NaHCO3. To the separated organic phase was added MNA (0.5 eq.) and the mixture was stirred at room temperature for 55-65 min. The mixture was washed twice with aqueous 0.5M NaHCO3, dried over Na2SO4, and filtered. Charcoal (5.5 g) was added to the organic solution and the mixture was stirred at room temperature for 15 hrs. The mixture was concentrated under vacuum to ˜10-15 mL and filtered through a silica plug. The crude solid was crystallized from hot methanol and DCE to give compound 62d (2.87 g) as a white solid in 54% yield and 98% purity. More product was obtained similarly from the filtrate to give 487 mg of a white solid. Thus, the total yield was 63%.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:5]=[CH:4][N:3]=1.[Br:21][C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1>ClCCl>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[C:11]=2[C:2]([NH:1][C:29]([NH:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([Br:21])[CH:23]=2)=[O:30])=[N:3][CH:4]=[N:5]3)=[CH:14][CH:15]=1
Reactant: O=C=Nc1cccc(Br)c1
Reactant: COc1ccc(Oc2cccc3ncnc(N)c23)cc1
Solvent: ClCCl
Product: COc1ccc(Oc2cccc3ncnc(NC(=O)Nc4cccc(Br)c4)c23)cc1
Yield: 82.7 %

Procedure:
4-Amino-5-(4-methoxyphenoxy)quinazoline (0.35 g, 1.3 mmol) and 3-bromophenyl isocyanate (0.31 g, 1.6 mmol) were reacted in 20 ml of dichloromethane according to procedure E to give 1-[5-(4-methoxyphenoxy)quinazolin-4-yl]-3-(3-bromophenyl)urea (0.5 g, 83.3%, m.p. 249-251° C.)
Reaction SMILES: C([O:3][C:4](=[O:25])[CH:5]([O:22][CH2:23][CH3:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:21])([CH3:20])[O:14][SiH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:9][CH:8]=1)C.C(C1C=C(CC(OCC)C(O)=O)C=CC=1O)C1C=CC=CC=1>>[C:16]([SiH2:15][O:14][C:13]([CH3:20])([CH3:21])[C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:22][CH2:23][CH3:24])[C:4]([OH:25])=[O:3])=[CH:8][CH:9]=1)([CH3:18])([CH3:19])[CH3:17]
Reactant: CCOC(=O)C(Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1)OCC
Agent: CCOC(Cc1ccc(O)c(Cc2ccccc2)c1)C(=O)O
Product: CCOC(Cc1ccc(C(C)(C)O[SiH2]C(C)(C)C)cc1)C(=O)O

Procedure:
The title compound was prepared from 3-[4-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-2-ethoxy-propionic acid ethyl ester (1.1 g, 3.0 mmol) in the same manner as described for 3-(3-benzyl-4-hydroxy-phenyl)-2-ethoxy-propionic acid. The crude product was obtained as a solid and used in the next step without further purification (0.73 g, 65%). 1H NMR (400 MHz, CDCl3): δ 7.11-7.18 (m, 4H), 4.63 (s, 2H), 3.96-3.99 (m, 1H), 3.48-3.52 (m, 1H), 3.31-3.37 (m, 1H), 3.01-3.05 (dd, 1H), 2.87-2.92 (dd, 1H), 1.07 (t, 3H), 0.85 (s, 9H), 0.00 (s, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.S(Cl)(Cl)=O.C[N:22](C)C=O>>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:22])=[O:13])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(Nc2ccncc2)cc1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1ccc(Nc2ccncc2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
4-(4-Pyridinylamino)benzoic acid (43 g), 400 ml of thionyl chloride and 0.4 ml of dimethylformamide were mixed at 0° C. The mixture was heated on a steam bath for about 19 hours. The excess thionyl chloride was removed under reduced pressure and the residue azeotroped twice with toluene. The resulting acid chloride was suspended in 300 ml of acetonitrile. The suspension was cooled to 0° C. and an ice-cold solution of 0.8 ml of ammonia in 250 ml of acetonitrile was added dropwise over a period of 20 minutes. The reaction mixture was stirred for four hours and the solid material collected by filtration. The latter was slurried in 1 liter of water and 25 ml of saturated aqueous potassium carbonate was added. The solid product was collected and recrystallized twice from methanol to give 22 g of 4-(4-pyridinylamino)benzamide, m.p. 223°-226° C. A further recrystallization gave a sample with the m.p. 225.5°-227.5° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:10][CH:11]1[CH2:20][CH:19]([N:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22](=[O:24])[CH3:23])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12]1.C(N(C(C)C)C(C)C)C.ClCCl>O1CCOCC1>[CH3:10][C@H:11]1[CH2:20][C@@H:19]([N:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:22](=[O:24])[CH3:23])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]1[C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:8]
Reactant: CC(=O)N(c1ccccc1)C1CC(C)Nc2ccccc21
Reactant: O=C(Cl)c1cccnc1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2cccnc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Nicotinoyl chloride (1.1 eq) was added to a solution of N-(2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-phenylacetamide (100 mg) and N-ethyl-N,N-diisopropylamine (2.2 eq) in dioxane (1 ml). The mixture was stirred overnight at room temperature. Dichloromethane was added and the organic layer was washed by water and sodium carbonate solution and dried over sodium sulfate. The solvent was removed and the mixture was purified by chromatography on silica gel (dichloromethane and ethanol (99:1)) to afford the title compound (30 mg).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[CH3:13][C:14]1([C:20]([OH:22])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(O)(C)C>[CH3:13][C:14]1([C:20]([OH:22])=[O:21])[CH2:19][CH2:18][N:17]([C:2]2[C:3]3[C:10]([CH3:11])=[CH:9][NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:16][CH2:15]1
Reactant: CC1(C(=O)O)CCNCC1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1c[nH]c2ncnc(N3CCC(C)(C(=O)O)CC3)c12
Temperature: 180 °C
Yield: 93.4 %

Procedure:
To a solution of 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.274 g, 1.64 mmol) in isopropanol (10 mL) were added 4-methylpiperidine 4-carboxylic acid hydrochloric acid from step A (0.294 g, 1.64 mmol) and triethylamine (0.654 mL, 4.92 mmol). The reaction was heated to 180° C. for 1 hour under microwave conditions, concentrated, taken up with ice water, and neutralized to pH 3 with 6 N aq. HCl to precipitate the product. The product was collected by filtration and dried under vacuum overnight to give the title compound (0.42 g, 75%) as a gray solid. MS (ES+) [M+H]+=275.2.
Reaction SMILES: [NH2:1][C:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=[S:3].Br[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C>CN(C)C=O>[CH2:23]([O:22][C:20]([C:19]1[N:1]=[C:2]([CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)[S:3][CH:18]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Reaction time: 8 h
Yield: 70.8 %

Procedure:
tert-Butyl 4-(aminocarbothioyl)tetrahydropyridine-1(2H)-carboxylate (May-bridge) (85 mmol; 20.8 g) is dissolved in 250 ml of dimethylformamide and placed at 5° C. Ethyl bromopyruvate (1 eq.; 85 mmol; 16.6 g) dissolved in 50 ml of dimethylformamide is added dropwise. The reaction medium is stirred overnight and excess triethylamine is then added dropwise. The reaction medium is evaporated and the residual brown oil is taken up in ethyl acetate and washed with water (twice) and then with saturated sodium chloride solution (twice). The organic phase is dried over sodium sulfate and evaporated to dryness. The crude product is chromatographed on silica, eluting with dichloromethane to dichloromethane/3% methanol, to give 20.5 g of the expected product in the form of oily crystals. TLC: 1/1 ethyl acetate/hexane: Rf=0.55
Reaction SMILES: [N:1]1([C:7](=[S:9])[NH2:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:10][CH:11](Cl)[C:12](=O)[CH3:13]>C(O)C>[Cl:10][CH2:11][C:12]1[N:8]=[C:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[S:9][CH:13]=1
Reactant: NC(=S)N1CCOCC1
Reactant: CC(=O)C(Cl)Cl
Solvent: CCO
Product: ClCc1csc(N2CCOCC2)n1

Procedure:
11.51 g (78.76 mmol) of 4-morpholinecarbothioamide and 10.00 g (78.76 mmol) of dichloroacetone in 100 ml of ethanol are heated under reflux for one hour. The colourless solid which precipitates from the pink solution is, after cooling, filtered off with suction and washed twice with ethanol. This gives 12.96 g (75% of theory) of product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1Br.[C:10]1(=[O:14])[CH2:13][CH2:12][CH2:11]1.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:10]1([OH:14])[CH2:13][CH2:12][CH2:11]1
Reactant: Brc1ccc(Br)c(Br)c1
Reactant: O=C1CCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(c2cc(Br)ccc2Br)CCC1
Temperature: -45 °C
Reaction time: 1 h

Procedure:
21.09 g (67 mmol) of 1,2,4-tribromobenzene are initially introduced in 100 ml of THF under nitrogen, cooled to −45° C., and a solution (1.3 M) of 51.54 ml (67 mmol) of isopropylmagnesium chloride/lithium chloride complex in THF is added dropwise. After 1 hour, the batch is warmed to −10° C., and 5 ml (66.34 ml) of cyclobutanone are added dropwise at this temperature. The batch is allowed to thaw, and sat. NH4Cl solution is added, the mixture is extracted with methyl t-butyl ether, the organic phase is dried over sodium sulfate and filtered, the solvent is removed in vacuo, and the residue is filtered through silica gel with dichloromethane, giving 4, which is employed in the next step without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3](C)C.N(C(C1C=CC=CC=1)=O)[C@H](C(OC)=O)C.[OH-].[Na+].N(C(C1C=CC=CC=1)=O)[C@H](C([NH:31][C@H:32]([C:36]([OH:38])=[O:37])[CH:33]([CH3:35])[CH3:34])=O)C>Cl>[NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH3:3].[NH2:31][C@H:32]([C:36]([OH:38])=[O:37])[CH:33]([CH3:35])[CH3:34]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)c1ccccc1)C(=O)O
Agent: CC(C)[C@H](N)C(=O)O
Agent: COC(=O)[C@H](C)NC(=O)c1ccccc1
Agent: Cl
Product: C[C@H](N)C(=O)O

Procedure:
A solution of 2 ml of 0.6 M Valine-0.1 M KCl-1 mM EDTA, pH 9.8 was mixed with 100 μl (0.1 mmole) of a 1 M Bz-Ala-OMe (dissolved in 96% ethanol) solution. The reaction was carried out in a pH-stat at 35° C. and pH 9.8, the pH-value being kept constant by automatic addition of 0.5 M NaOH. The reaction was initiated by adding 0.7 mg of carboxypeptidase Y (150 U/mg, prepared by De Forenede Bryggerier). After a reaction time of 30 minutes, the reaction was discontinued by adjusting pH to about pH=1 with 6 M HCl. The reaction product was purified and isolated by means of high pressure chromatography. The yield of Bz-Ala-Val-OH was 40%. Quantitative amino acid analysis after hydrolysis of the product in 6 M HCl for 24 hours gave relatively 1.0 mole of Alanine and 1.0 mole of Valine.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([S:7]([S:10][C@H:11]2[N:14]([C:15](=[C:29](OS(C)(=O)=O)[CH3:30])[C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:17])[C:13](=[O:36])[C@H:12]2[NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:49](N(CC)CC)C>C(Cl)(Cl)Cl>[C:5]1([CH3:49])[C:4]([S:7]([S:10][C@H:11]2[N:14]([C:15](=[C:29]=[CH2:30])[C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=3)=[O:17])[C:13](=[O:36])[C@H:12]2[NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)(=[O:8])=[O:9])=[CH:3][CH:2]=[CH:1][CH:6]=1
Reactant: CC(OS(C)(=O)=O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SS(=O)(=O)c1ccc(C)cc1
Reactant: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=C=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SS(=O)(=O)c1ccccc1C
Reaction time: 1 h
Yield: 98.6 %

Procedure:
A solution of 4-nitrobenzyl 2-[(3R,4R)-4-(p-toluenesulfonylthio)-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-3-methanesulfonyloxy-2-butenoate (XXc, 0.0714 g, 0.00010 mole) in chloroform (1 mL) was treated with triethylamine (0.014 mL, 0.00010 mole) at room temperature. After a period of 1 h, reverse-phase C-18 HPLC indicated consumption of the starting material with formation of a single new peak (65% acetonitrile and 0.01M phosphate pH 6.5 buffer). Dilute hydrochloric acid (chilled at 0° C.) and ethyl acetate were added. The organic layer was washed with cold water, dried (sodium sulfate) and concentrated to give 0.0615 g (ca 100%) of the title compound as a foam. The product was characterized by its 1H-NMR spectrum.
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@H:17]([OH:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:30]1[CH2:34][CH2:33][CH:32]([O:35][CH2:36][C:37]#[CH:38])[CH2:31]1)C1C=CC=CC=1.C(N(CC)CC)C.N>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.[Cu]I.C(OCC)(=O)C.O.CN(C)C=O.CO>[CH2:1]([C:8]1[C:13]([CH2:38][CH2:37][CH2:36][O:35][CH:32]2[CH2:33][CH2:34][NH:30][CH2:31]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([O:20][CH3:21])[C@H:17]([OH:22])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1O
Reactant: C#CCOC1CCN(Cc2ccccc2)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CO[C@@H]1CN(c2ccc(CCCOC3CCNC3)c(Cc3ccccc3)n2)C[C@H]1O
Temperature: 75 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
A mixture of 742 mg of 2-benzyl-3-iodo-6-[(3R,4R)-3-hydroxy-4-methoxypyrrolidin-1-yl]pyridine (Production Example 1), 389 mg of 1-benzyl-3-(2-propynyloxy)pyrrolidine (Production Example 16), 62.7 mg of tetrakis(triphenylphosphine)palladium (0), 51.7 mg of copper (I) iodide, 757 μl of triethylamine, 4 ml of methanol and 4 ml of N,N-dimethylformamide was stirred under nitrogen atmosphere at 75° C. for 2 hours. After standing to cool, water, ethyl acetate and aqueous ammonia were added to the reaction mixture. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate, filtered through NH-silica gel and the solvent was removed. After 10 ml of methanol, 1 ml of acetic acid and 50 mg of 10% palladium carbon were added to the residue and hydrogen substitution was performed, the mixture was stirred at room temperature overnight. After the reaction mixture was nitrogen-purged, it was filtered through Celite. The solvent was removed, and then the residue was purified by silica gel column chromatography with ethyl acetate/methanol/aqueous ammonia (100/5/2), to give 465 mg of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)(=[O:14])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>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.CCO>[CH3:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:7]=[CH:6][N:5]3[CH:8]=[CH:9][N:10]=[C:4]3[CH:3]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Clc1ccn2ccnc2c1
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: [Cs+]
Solvent: COCCOC
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2ccn3ccnc3c2)cc1
Temperature: 25 °C
Yield: 361.2 %

Procedure:
Heat a mixture of 7-chloro-imidazo[1,2-a]pyridine (100 g, 152.5 mmol, 1 eq), 4-methylsulfonylphenyl boronic acid (157.3 g, 786.8 mmol, 1.2 eq), Pd(PPh3)4 (19 g, 16.3 mmol, 0.025 eq) and cesium carbonate (472.4 g, 1.44 mol, 2.2 eq) in a mixture of anhydrous DME (2000 mL) and EtOH (1000 mL) at 80° C. under N2 atmosphere for 24 hours. Cool the mixture to room temperature and filter through Celite® to remove Pd catalyst. Add water (5000 mL) and extract this solution with CH2Cl2 (3×2000 mL). Dry the organic phase over MgSO4 and evaporate. Add to the crude 2000 mL of CH2Cl2 and heat to reflux. Remove insoluble materials by filtration and evaporate the solvent to afford a yellow solid. Wash the solid with ethyl ether to give 150 g of the desired compound as a light yellow solid. (Yield: 85%). MS (ES), m/z 273 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]CC)=O.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH2:17]>>[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][NH:17][C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: CCOC(=O)CN1CCCC1=O
Reactant: CN(C)CCN
Product: CN(C)CCNC(=O)CN1CCCC1=O

Procedure:
From 8.5 g. of ethyl 2-oxo-1-pyrrolidineacetate and 8.8 g. of 2-(dimethylamino)ethylamine, following the procedure of Example 1, there is obtained N-[2-(dimethylamino)ethyl]-2-oxo-1-pyrrolidineacetamide; b.p. 146°-147° C./0.1 mm.