Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]2[C:10]([CH2:11][CH3:12])=[N:9][NH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:25]([CH3:27])[CH3:26]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]2[C:10]([CH2:11][CH3:12])=[N:9][N:8]([CH:25]([CH3:27])[CH3:26])[C:6]=2[N:7]=1
Reactant: CCOC(=O)c1cc(Br)nc2[nH]nc(CC)c12
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cc(Br)nc2c1c(CC)nn2C(C)C
Yield: 77.9 %

Procedure:
Ethyl 6-bromo-3-ethyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (0.45 g, 1.51 mmol) was suspended in acetonitrile (5 mL) and K2CO3 (0.312 g, 2.26 mmol) and 2-bromopropane (0.372 g, 3.02 mmol) was added to it. The reaction mixture was refluxed for overnight. On completion of reaction, acetonitrile was removed under reduced pressure and water was added to it. Extraction was carried out using ethyl acetate; the combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. Solvent was removed under reduced pressure and residue was purified by silica gel column chromatography to give the desired intermediate (0.4 g, 87.7%).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[CH3:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13][NH2:14]>C(O)C>[CH3:9][C:10]1[CH:11]=[C:12]([CH2:13][NH:14][C:4](=[O:6])[CH2:3][C:1]#[N:2])[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cccc(CN)c1
Reactant: CCOC(=O)CC#N
Solvent: CCO
Product: Cc1cccc(CNC(=O)CC#N)c1
Yield: 51.5 %

Procedure:
5.6 g of ethyl cyanoacetate and 6.06 g of 3-methylbenzylamine are refluxed for 9 h in 40 ml of ethanol to give a solution. After cooling, this solution gives a precipitate which is filtered off and washed with ethanol and ether to give 4.8 g of N-(3-methylphenyl)methylcyanoacetamide in the form of a white solid melting at 115° C. Yield 51%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:23]=[O:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=3[Cl:22])[CH2:12][CH2:13][N:7]21.[CH2:25]([Mg]Br)[CH3:26].O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:14]4[C:19]([CH3:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:15]=4[Cl:22])[CH2:12][CH2:13][N:7]3[C:6]=2[C:5]([CH:23]([OH:24])[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: Cc1cc(Cl)cc(Cl)c1N1CCn2c1nc1c(Cl)ccc(C=O)c12
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCN3c1c(C)cc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a solution of 8-chloro-1-(2,4-dichloro-6-methylphenyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole-5-carbaldehyde (140 mg, 0.368 mmol) in tetrahydrofuran (30 mL) was added ethylmagnesium bromide (3.0 M solution in diethyl ether, 0.50 mL, 15.0 mmol) at 0° C. The mixture was stirred at 0° C. for 2 hr. Water was added to the reaction mixture at 0° C. and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (150 mg).
Reaction SMILES: C([O:8][CH:9]1[CH2:12][N:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:10]1)C1C=CC=CC=1>[Ni].C(O)C>[C:13]([N:11]1[CH2:12][CH:9]([OH:8])[CH2:10]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)N1CC(OCc2ccccc2)C1
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)N1CC(O)C1
Temperature: 40 °C
Reaction time: 15 h
Yield: 76 %

Procedure:
A solution of 4.4 parts of 3-benzyloxy-1-(tert.butyl)azetidine in 30 parts of ethanol was taken into an autoclave together with 2 parts of Raney nickel as catalyst. Under a hydrogen gas pressure of 100 atmospheres, the mixture was stirred at 40° C. for 15 hours to perform the reduction. The catalyst was separated by filtration, and the remaining ethanol solution was concentrated to dryness. The resulting oily substance was dissolved in n-hexane and cooled. As a result 2.0 parts of 1-(tert.-butyl)-3-azetidinol melting at 42° - 43° C. The yield was 76%. The results of infra-red spectrum analysis and nuclear magnetic resonance analysis of the product are as follows:
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]([NH:11][CH:12]([CH:19]([CH3:21])[CH3:20])[CH:13]([OH:18])[C:14]([F:17])([F:16])[F:15])=[O:10])[C:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:5][CH:4]=[C:3]1[NH:28][C:29]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)=[O:30]>CO.ClCCl>[O:1]=[C:2]1[N:7]([CH2:8][C:9]([NH:11][CH:12]([CH:19]([CH3:21])[CH3:20])[C:13](=[O:18])[C:14]([F:15])([F:17])[F:16])=[O:10])[C:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:5][CH:4]=[C:3]1[NH:28][C:29]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)=[O:30]
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)NCc2ccncc2)c1=O)C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)NCc2ccncc2)c1=O)C(=O)C(F)(F)F

Procedure:
2-[6-Oxo-2-phenyl-5-[3-(4-pyridylmethyl)ureido]-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-2-hydroxy-1-isopropylpropyl)acetamide was subjected to a procedure similar to that described in Example 1. Chromatography, with methanol:dichloromethane (10:90) as the eluent, gave 2-[6-oxo-2-phenyl-5-[3-(4-pyridylmethyl)ureido]-1,6-dihydro-1-pyrimidinyl]-N-(3,3,3-trifluoro-1-isopropyl-2-oxopropyl)acetamide as a white solid; NMR (DMSO/D2O): 8.58 (s,1), 8.46 (bs, 2), 7.41 (m,5), 7.27 (d,2), 4.56 (d,1), 4.37 (d,1), 4.32 (s,2), 4.00 (d,1), 2.20 (m,1), 0.79 (d,3), 0.73 (d,3); MS: m/z=531(M+1).
Reaction SMILES: [NH3:1].C[O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:6]=1[CH2:14]Br>CO>[N+:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]2[C:6]=1[CH2:14][NH:1][C:4]2=[O:3])([O-:13])=[O:12]
Reactant: N
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Solvent: CO
Product: O=C1NCc2c1cccc2[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NH3 (2.0 M in MeOH, 50 ml) was slowly added to the solution of 2-bromomethyl-3-nitro-benzoic acid methyl ester (4.46 g, contaminated with a small amount of assumed starting material, 16.3 mmol) in 30 ml of MeOH at RT. The resulting mixture was stirred at RT overnight, to provide the title compound as a white solid. MS (ES+): 179.2 (M+H)+. Calc'd for C8H6N2O3—178.14.
Reaction SMILES: [CH:1](=[N:8]/[OH:9])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10]N1C(=O)CCC1=O.O>C(Cl)Cl>[Cl:10][C:2]1([CH:7]=[CH:6][CH:5]=[CH:4][CH2:3]1)/[CH:1]=[N:8]/[OH:9]
Reactant: O/N=C/c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: ClCCl
Product: O/N=C/C1(Cl)C=CC=CC1
Yield: 83.8 %

Procedure:
After dissolving (E)-benzaldehyde oxime (3.0 g, 25 mmol) in CH2Cl2 (30 ml), N-chlorosuccinimide (3.4 g, 25 mmol) was slowly added at 0° C. After stirring reaction solution for 2 hours, the reaction was completed by adding water (20 ml), and the reaction solution was extracted with dichloromethane. A pure compound of (E)-1-chloro-benzaldehyde oxime (3.30 g, 85%) was obtained by separating the residue with silica gel column chromatography. After dissolving the (E)- and (Z)-oxime mixtures (1.5 g, 9.64 mmol) in CH2Cl2 (30 ml), benzoylchloride (1.45 ml, 12.53 mmol) was slowly added at 0° C. under the presence of triethylamine (1.75 ml, 12.53 mmol). After stirring reaction solution for 1 hour, the reaction was quenched by 1 N hydrochloric acid, and the reaction solution was extracted with dichloromethane. A pure compound of (E)-1-chloro-benzaldehyde O-benzoyloxime (15) (1.9 g, 76%) was obtained by separating the residue with silica gel column chromatography.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH3:24][C:25]1[N:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>CN(C=O)C>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:28]5[CH:29]=[N:30][C:25]([CH3:24])=[CH:26][CH:27]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: Cc1ccc(B(O)O)cn1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)sc2CCO3)cn1
Yield: 23 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 6-methylpyridin-3-ylboronic acid were reacted. The crude material was diluted with DMF and the solids were collected by filtration to provide 135 (58 mg, 23%). 1H NMR (400 MHz, DMSO) δ 8.73 (dd, J=32.7, 2.1, 2H), 8.11 (s, 1H), 7.96 (dd, J=8.1, 2.4, 1H), 7.65 (dd, J=8.4, 2.3, 1H), 7.38 (d, J=8.1, 1H), 7.20 (d, J=8.4, 1H), 5.78 (dt, J=13.0, 6.5, 1H), 4.52-4.32 (m, 2H), 3.48 (t, J=4.9, 2H), 2.52 (s, 3H), 1.57 (d, J=6.6, 6H). MS (ESI(+)): m/z 404.1 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[F:11][C:12]([F:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:13][NH2:14].C([O-])(O)=O.[Na+]>CCO.O>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:14][CH2:13][C:12]([F:11])([F:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=1
Reactant: NCC(F)(F)c1ccccc1
Reactant: COc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1nc(Cl)cc(NCC(F)(F)c2ccccc2)n1
Temperature: 85 °C
Reaction time: 5 h
Yield: 52.4 %

Procedure:
A mixture of 4,6-dichloro-2-methoxy-pyrimidine (0.66 g, 3.69 mmol), 2,2-difluoro-2-phenyl-ethylamine (0.58 g, 3.69 mmol), and NaHCO3 (0.93 g, 11.1 mmol) in 95% EtOH (10 mL) is heated to reflux. After stirred at 85° C. for 5 h. The mixture is diluted with water, filtered, washed (water), and dried to afford (6-chloro-2-methoxy-pyrimidin-4-yl)-(2,2-difluoro-2-phenyl-ethyl)-amine as a solid (0.58 g). LCMS: RT=3.17 minutes, MS: 300 (M+H). 1H NMR (300 MHz, CDCl3) □7.57-7.45 (5H, m), 6.1 (1H, s), 5.2 (1H, s), 4.2-4 (2H, m), 3.92 (3H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]([C:5]1[N:28]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[O:21])=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].Br[CH2:36][CH2:37][OH:38]>>[CH3:1][N:2]([CH3:34])[C:3]([C:5]1[N:28]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([N:22]4[CH2:27][CH2:26][N:25]([CH2:36][CH2:37][OH:38])[CH2:24][CH2:23]4)=[O:21])=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CCNCC4)cn3)nc2n1C1CCCC1
Reactant: OCCBr
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CCN(CCO)CC4)cn3)nc2n1C1CCCC1
Yield: 45.9 %

Procedure:
Following General Procedure D, 7-cyclopentyl-2-[5-(piperazine-1-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (200 mL, 0.43 mmol) and 2-bromo ethanol (37 mg, 0.52 mmol) to give 7-cyclopentyl-2-{5-[4-(2-hydroxy-ethyl)-piperazine-1-carbonyl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 48%). MS (ESI) m/z 478.3 (M+H)+
Reaction SMILES: [ClH:1].CCOC(C)=O.C(OC(=O)[NH:14][C:15]1([CH3:32])[CH2:18][N:17]([CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16]1)(C)(C)C>>[ClH:1].[CH:19]([N:17]1[CH2:18][C:15]([NH2:14])([CH3:32])[CH2:16]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC1(NC(=O)OC(C)(C)C)CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC1(N)CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of HCl in EtOAc (4M, 10 mL, 40 mmol) was added (1-benzhydryl-3-methyl-azetidin-3-yl)-carbamic acid tert-butyl ester (0.750 g, 2.128 mmol) and the mixture was stirred for 2 h. The mixture was concentrated to give 1-benzhydryl-3-methyl-azetidin-3-ylamine hydrochloride salt as solid (0.600 g, 2.077 mmol, 98%). 1H NMR (CDCl3, 400 MHz): δ 9.04 (m, 3H), 7.46-7.67 (m, 4H), 7.21-7.42 (m, 6H), 4.35 (m, 2H), 3.89 (m, 2H), 1.52-1.65 (m, 3H).
Reaction SMILES: C([Li])CCC.[O:6]1CC[CH2:9][CH2:8][CH:7]1OCC#C.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH:21]=[O:22].[Cl-].[NH4+]>O1CCCC1.CCOCC>[OH:6][CH2:7][C:8]#[C:9][C:21]([C:20]1[CH:23]=[C:24]([O:28][CH3:29])[C:25]([O:26][CH3:27])=[C:18]([O:17][CH3:16])[CH:19]=1)=[O:22]
Reactant: C#CCOC1CCCCO1
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(C(=O)C#CCO)cc(OC)c1OC
Reaction time: 0.5 h

Procedure:
44.6 ml of n-butyllithium solution (1.6M in hexane) were added to a solution of 10.0 g (71.3 mmol) of 3-[(tetrahydro-2H-pyran-2-yl)oxy]1-propyne in 150 ml of absolute tetrahydrofuran at -78° . The reaction mixture was stirred at -40° for 30 minutes and then treated with 14.0 g (71.3 mmol) of 3,4,5-trimethoxybenzaldehyde in 50 ml of tetrahydrofuran. The reaction mixture was subsequently stirred at 0° for 1 hour and then treated with 100 ml of saturated ammonium chloride solution and 200 ml of ether. The aqueous phase was extracted twice with ether, whereupon the combined organic phases were dried over magnesium sulphate and the solvent was distilled off. The residue was dissolved in 150 ml of methylene chloride and added dropwise at 0° to a suspension of 186 g of manganese dioxide in 300 ml of methylene chloride. The reaction mixture was stirred at room temperature for 30 minutes, filtered over magnesium sulphate and evaporated. The residue was dissolved in 300 ml of tetrahydrofuran/ethanol (1:1) and treated with 2.4 g of pyridinium p-toluenesulphonate. The mixture was stirred at room temperature for 24 hours, 100 ml of water and 200 ml of ether were then added, the aqueous phase was extracted twice with ether, the combined organic phases were dried over magnesium sulphate and the solvent was distilled off. Crystallization from ethyl acetate/hexane yielded 4-hydroxy 1-(3,4,5 -trimethoxyphenyl)-2-butyn- 1-one of melting point 104°-105°.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[C:20](=[O:31])[CH2:19]3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.Cl.Cl[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.C(=O)(O)[O-].[Na+]>>[N:3]1([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH:25]4[CH2:30][CH2:29][N:28]([C:38]5[CH:37]=[CH:36][N:35]=[CH:34][CH:39]=5)[CH2:27][CH2:26]4)[C:20](=[O:31])[CH2:19]3)(=[O:16])=[O:17])=[CH:13][CH:14]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: O=C1CN(S(=O)(=O)c2ccc(Cn3ccnc3)cc2)CCN1CC1CCNCC1
Reactant: Clc1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1CN(S(=O)(=O)c2ccc(Cn3ccnc3)cc2)CCN1CC1CCN(c2ccncc2)CC1
Reaction time: 15 h
Yield: 48.4 %

Procedure:
A mixture of 4-[4-(1H-imidazol-1-ylmethyl)benzenesulfonyl]-1-(piperidin-4-ylmethyl)-2-piperazinone dihydrochloride (209 mg) and chloropyridine hydrochloride (93 mg) was added to sodium bicarbonate solution, and the mixture was extracted with dichloromethane (twice), dried and concentrated. To the residue was added isoamylalcohol (10 ml), and the mixture was stirred at 130% for 15 hours. The reaction solution was concentrated, and the residue was dissolved in dichloromethane. The solution was washed with 1N sodium hydroxide solution, dried and concentrated, and the residue was purified with silica gel column chromatography (dichloromethane:methanol containing 10% ammonia solution=7:1) to give colorless solid of 4-[4-(1H-imidazol-1-ylmethyl)benzenesulfonyl]-1-[1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone (102 mg). The obtained 4-[4-(1H-imidazol-1-ylmethyl)benzenesulfonyl]-1-[1-(4-pyridyl)piperidin-4-ylmethyl]-2-piperazinone was dissolved in ethyl acetate (5 ml), and to the solution was added a solution of 4N hydrochloric acid in ethyl acetate. Precipitates were filtered, washed with ethyl acetate and dried to give colorless solid of the title compound (103 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.C(=O)([O-])[O-].[K+].[K+].[OH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CN(C)C=O.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:22]1[CH2:23][CH2:24][CH:19]([OH:18])[CH2:20][CH2:21]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1ccc(N2CCC(O)CC2)c(F)c1
Temperature: 120 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of 4.77 g (30.0 mmol) of 3,4-difluoronitrobenzene in 100 mL of N,N-dimethylformamide were added 5.33 g (40.0 mmol) of potassium carbonate and 3.03 g (30.0 mmol) of 4-hydroxypiperidine and the mixture was stirred for 1 hour at 120° C. After the reaction mixture was cooled to room temperature, the reaction mixture was diluted with chloroform and insoluble substances were removed off by filtration. The filtrate was condensed and the residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=1.5/1) to give 3.1 g (43%) of the title compound.
Reaction SMILES: N[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[BrH:13].S(=O)(=O)(O)O.N([O-])=O.[Na+]>O>[C:4]1([CH2:3][C@H:2]([Br:13])[C:10]([OH:12])=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Br
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@@H](Br)Cc1ccccc1
Reaction time: 8 h
Yield: 79.4 %

Procedure:
Slurry L-phenylalanine (23.6 g, 143 mmol), 49% hydrobromic acid (500 g), water (500 mL) and concentrated sulfuric acid (50 mL) and cool to -5° C. Add, by dropwise addition, a solution of sodium nitrite (9.87 g, 143 mmol) in water (70 mL) over a period of about 1 hour. Stir at -5° C. to 0° C. overnight extract into ethyl ether (3×250 mL), combine the organic phases and wash with water (1×) and brine (2×). Dry (MgSO4) and evaporate the solvent in vacuo to give 3-phenyl-2(S)-bromopropionic acid as a yellow oil (26 g, 80%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.NC(N)=[S:22]>C(O)C>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:11]2[C:2](=[S:22])[NH:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:13][CH:14]=1)#[N:19]
Reactant: N#Cc1ccc(-c2cc3ccccc3nc2Cl)cc1
Reactant: NC(N)=S
Solvent: CCO
Product: N#Cc1ccc(-c2cc3ccccc3[nH]c2=S)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2-chloro-3-(p-cyanophenyl)quinoline (6.25 g., see Example 30) and thiourea (1.8 g.) in ethanol (30 ml.) was heated under reflux for 2 hr. The solution was allowed to cool to ambient temperature, the solid which precipitated was filtered off, dispersed in 1 M-sodium hydroxide solution (100 ml.) and the dispersion heated on a steam bath for 20 min. The mixture was acidified with 2 M-hydrochloric acid solution. The resulting mixture was filtered, the solid residue was stirred with hot ethanol (75 ml.) for 5 min., and the mixture was then filtered. There was thus obtained as the solid residue 3-(p-cyanophenyl)quinolin-2-thione, m.p. 284°-9°.
Reaction SMILES: [I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH3:9].[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=O.C(O)C.[OH-].[K+]>O>[I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH:9]=[CH:15][C:11]1[S:10][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1cccs1
Reactant: CC1N(C)C=C[NH+]1C
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1C=C[NH+](C)C1C=Cc1cccs1

Procedure:
A mixture of 5.0 g of 1,2,3-trimethyl-1H-imidazolium iodide, 2ml of 2-thiophenecarboxaldehyde, 20 ml of absolute ethanol and 1 g of potassium hydroxide is refluxed for 25 minutes. Water is added to the cooled mixture and the resulting solid is filtered off. Recrystallization from ethanol yields 3.8 g of the title compound, melting point 309°-311° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:21]([C:27](O)=[O:28])=[N:22][CH:23]=[C:24]([Cl:26])[N:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:21]3[C:20]([Cl:19])=[N:25][C:24]([Cl:26])=[CH:23][N:22]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1ncc(Cl)nc1Cl
Product: C[C@]1(c2cc(NC(=O)c3ncc(Cl)nc3Cl)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 3,5-dichloro-pyrazine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=434.1 [M+H]+, 436.1 [M+2+H]+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4](/[CH:7]=[CH:8]/[CH2:9]O)=[CH:5][CH:6]=1.[CH3:11][C:12]([CH3:16])=[CH:13][CH:14]=[O:15].C1(C)C=CC=CC=1>C(O)(=O)C>[CH3:11][C:12]([CH2:16][CH2:9][CH:8]=[CH:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)=[CH:13][CH:14]=[O:15]
Reactant: OC/C=C/c1ccccc1
Reactant: CC(C)=CC=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(=CC=O)CCC=Cc1ccccc1
Yield: 81 %

Procedure:
A mixture of 187 parts of cinnamic alcohol, 360 parts of 3,3-dimethylacrolein and 550 parts of toluene is heated with 33 parts of glacial acetic acid in a V4A steel stirred vessel having a capacity of 5 liters for six hours at 140° C. at a pressure of 2 atmospheres, the water forming being continuously removed as an azeotropic mixture with toluene. The product is distilled. 149 parts of 3-methyl-7-phenyl-2,6-heptadien-1-al is obtained having a boiling point of 118° to 120° C. at 10-3 mm. The yield is 81% of theory (based on cinnamic alcohol) at a conversion of 66%.
Reaction SMILES: [O:1]=[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:17][CH:16]([C:18]([NH:20][CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[O:19])[O:15][C:14]3=[O:27])=[CH:9][CH:8]=2)[NH:3]1.CO.C(=O)([O-])[O-].[K+].[K+]>O>[O:1]=[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH2:17][CH:16]([C:18]([NH:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:19])[O:15][C:14]3=[O:27])=[CH:11][CH:12]=2)[NH:3]1
Reactant: COC(=O)CCNC(=O)C1CN(c2ccc(-c3noc(=O)[nH]3)cc2)C(=O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)CCNC(=O)C1CN(c2ccc(-c3noc(=O)[nH]3)cc2)C(=O)O1

Procedure:
1.12 g of methyl 3-{3-[4-(5-oxo-1,2,4-oxadiazolin-3-yl)phenyl]-2-oxo-5-oxazolidinylcarbonylamino}propionate [obtainable according to Example 4] are stirred at room temperature for 3 h in 13.5 ml of water and 30 ml of methanol with the addition of 1.35 g of potassium carbonate. The reaction solution is then given the customary workup. 3-{3-[4-(5-Oxo-1,2,4-oxadiazolin-3-yl)phenyl]-2-oxo-5-oxazolidinylcarbonylamino)propionic acid is obtained, m.p. 221°-223°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:14]#[N:15])[C:10]([O:12][CH3:13])=[O:11].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([C:14]#[N:15])([C:10]([O:12][CH3:13])=[O:11])[CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)CBr
Reactant: COC(=O)C(C#N)Cc1ccccc1Cl
Product: COC(=O)CC(C#N)(Cc1ccccc1Cl)C(=O)OC

Procedure:
In the same manner as Example 1-(b), 100 g of methyl 3-(2-chlorophenyl)-2-cyanopropionate was reacted with methyl bromoacetate to obtain methyl 4-(2-chlorophenyl)-3-cyano-3-methoxycarbonylbutyrate.