Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:3]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])([CH3:16])[CH:4]1[CH3:25])C.Br.C(O)(=O)C.C(OC(OCC)C=C)C>C(O)C>[CH3:25][C:4]1[C:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])([CH3:16])[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([S:12]([OH:15])(=[O:14])=[O:13])[CH:7]=2)[N:3]=1
Reactant: CCN1c2ccc(S(=O)(=O)O)cc2C(C)(CCCCCC(=O)O)C1C
Agent: Br
Agent: C=CC(OCC)OCC
Solvent: CCO
Solvent: CC(=O)O
Product: CC1=Nc2ccc(S(=O)(=O)O)cc2C1(C)CCCCCC(=O)O
Temperature: 70 °C

Procedure:
6-(2,3-Dimethyl-5-sulfo-3H-indol-3-yl)hexanoic acid was synthesised as described in Example 5. To a stirred solution of 6-(1-ethyl-2,3-dimethyl-5-sulfo-3H-indol-3-yl)hexanoic acid (1.8 g, 5.3 mmol) in ethanol (200 ml) at ambient temperature was added hydrobromic acid (10 ml 48% aqueous solution). After 1 Hr the reaction solvent was removed in vacuo. The hydrobromide salt was re-dissolved in acetonitrile (150 ml) and acetic acid (1.54 ml) and acrolein diethyl acetal (6.6 g, 51 mmol). The reaction mixture was heated to 70° C. for 30 minutes. The solution was cooled and the solvent removed in vacuum. The product was rapidly purified by preparative HPLC on reverse phase C18 column using gradient elution of water containing 10% acetonitrile to acetonitrile (containing 0.1% TFA) as solvent over 30 minutes. All fractions were monitored by MALDI-TOF mass spectrometry (M/Z=498). Fractions containing product mass were pooled. Evaporation of the solvent gave a sticky mass (162 mg 11%). It was immediately used for the next reaction.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=1)=[O:7].S(Cl)([Cl:18])=O>C1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][Cl:18])=[CH:10][CH:9]=1)=[O:7]
Reactant: O=S(Cl)Cl
Reactant: O=C(c1ccc(CO)cc1)c1cccs1
Solvent: c1ccccc1
Product: O=C(c1ccc(CCl)cc1)c1cccs1
Reaction time: 8 h

Procedure:
To a stirred and cooled suspension of 31 parts of α-hydroxy-p-tolyl 2-thienyl ketone in 160 parts of dry benzene are added dropwise 24 parts of thionyl chloride at 10° C. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is evaporated and the residue is evaporated twice more from toluene. The latter residue is triturated in petroleumether. The product is filtered off and dissolved in 320 parts of ether. This solution is stirred with charcoal, filtered and the filtrate is evaporated. The residue is crystallized from ethanol at -20° C, yielding α-chloro-p-tolyl 2 -thienyl ketone.
Reaction SMILES: FC(F)(F)C(O)=O.[ClH:8].[Cl:9][C:10]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([F:38])[C:11]=1[O:12][C:13]1[CH:29]=[CH:28][C:16]2[N:17]([CH3:27])[C:18](=[O:26])[C:19]([C:22](=[O:25])[CH2:23]O)([CH3:21])[O:20][C:15]=2[CH:14]=1>ClCCl>[Cl:9][C:10]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([F:38])[C:11]=1[O:12][C:13]1[CH:29]=[CH:28][C:16]2[N:17]([CH3:27])[C:18](=[O:26])[C:19]([C:22](=[O:25])[CH2:23][Cl:8])([CH3:21])[O:20][C:15]=2[CH:14]=1
Reactant: Cl
Reactant: CN1C(=O)C(C)(C(=O)CO)Oc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)C(C)(C(=O)CCl)Oc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc21

Procedure:
In Example 15, dichloromethane was used as the solvent, and trifluoroacetic acid or conc. hydrochloric acid was used in place of hydroiodic acid, and 7-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2,4-dimethyl-2-hydroxyacetyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine (Compound 95) and 7-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2,4-dimethyl-2-chloroacetyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine (Compound 97) were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6](C1C=CC=CC=1)[C:5]2(OCC)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl.N[OH:30]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N+:6]([O-:30])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NO
Reactant: CCOC1(c2ccccc2)c2cc(Cl)ccc2NC(=O)N1c1ccccc1
Agent: Cl
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)[n+]1[O-]
Yield: 71.8 %

Procedure:
A mixture of 3.51 g (0.0093 mole) of 6-chloro-4-ethoxy-3,4-dihydro-3,4-diphenyl-2(1H)-quinazolinone and 2.09 g (0.03 mole) of hydroxylamine hydrochloride in 50 ml alcohol was refluxed for 4 days, and then cooled. The solid that formed was collected on a filter, washed with ethanol, and dried in air to give 1.82 g (72%) of 6-chloro-4-phenyl-2(1H)-quinazolinone 3-oxide as yellow crystals, mp 267°-269°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:21])=[C:11]([CH2:13][CH2:14][CH:15]3SCCCS3)[N:12]=2)=[CH:4][CH:3]=1.C1C[O:25]CC1.C(Cl)Cl>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:21])=[C:11]([CH2:13][CH2:14][CH:15]=[O:25])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCC1SCCCS1
Reactant: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCC=O
Reaction time: 6 h
Yield: 86 %

Procedure:
Add HgClO4.4H2O (1.49 g, 4.00 mmol) to a solution of 2-(4-bromo-phenyl)-4-(2-[1,3]dithian-2-yl-ethyl)-5-methyl-oxazole (0.672 g, 1.75 mmol) in 1:1 THF:CH2Cl2 (16 mL) and water (1.6 mL). After 6 hours, filter and wash the solids with dichloromethane. Concentrate to give 3-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-propionaldehyde (0.445 g, 86%). MS (m/e): 294 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH:25]1([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37][O:38]S(C3C=CC(C)=CC=3)(=O)=O)[N:35]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37][O:38][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([O:15][C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=4)([CH3:14])[C:4]([OH:24])=[O:3])=[CH:12][CH:11]=3)[N:35]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(OC)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Product: COc1cccc(OC(C)(Cc2ccc(OCCc3nc(C4CCCCC4)oc3C)cc2)C(=O)O)c1

Procedure:
The title compound was prepared from 3-(4-hydroxy-phenyl)-2-(3-methoxy-phenoxy)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyl-oxazol-4-yl)-ethyl ester using the procedure of Example 74.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1
Reactant: Clc1ccccn1
Reactant: OCC1CCNCC1
Product: OCC1CCN(c2ccccn2)CC1
Yield: 80 %

Procedure:
The title compound (2.7 g, 80%) was prepared as a syrupy liquid from 2-chloropyridine (6.5 ml) and 4-piperidinyl methanol (2 g) by an analogous procedure to that described in preparation 1.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4](O)=O.[NH:13]([C:15](=[S:17])[NH2:16])[NH2:14].O=P(Cl)(Cl)Cl>O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:3]=1[C:4]1[S:17][C:15]([NH2:16])=[N:13][N:14]=1
Reactant: COc1cccc(F)c1C(=O)O
Reactant: NNC(N)=S
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1cccc(F)c1-c1nnc(N)s1
Temperature: 78 °C
Reaction time: 3 h
Yield: 93.6 %

Procedure:
A stirred mixture of 2-fluoro-6-methoxybenzoic acid (2 g, 11.7 6 mmol) and hydrazinecarbothioamide (1.607 g, 17.63 mmol) was cooled under nitrogen atmosphere in an ice bath and POCl3 (3.29 mL, 35.3 mmol) was added drop-wise. On completion of the addition, the reaction mixture was stirred at 78° C. for 3 hours. The reaction mixture was cooled in an ice bath and quenched by addition of ice water (˜50 mL) to give a solid/gum-like mass. This solid was sonicated for 1.5 hours and the resulting suspension was diluted with a further 50 mL of water then slurried at room temperature for ˜16 hours. The solid was collected by vacuum filtration, rinsed with water, re-suspended in saturated NaHCO3(aq) (˜100 mL) and slurried for ˜30 minutes. The resulting solid was collected by vacuum filtration, then rinsed with water to afford the crude product as an off-white solid. The crude material was pre-absorbed onto silica gel and purified by flash chromatography using a 120 g silica cartridge with a 0-10% MeOH/DCM gradient as the eluent to afford the title compound as a pale yellow solid (1.265 g, 45% yield). LC-MS: Rt 0.77 min; MS m/z 226.1 [M+H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.48 (td, J=8.34, 6.57 Hz, 1H), 7.29 (s, 2H), 7.02 (d, J=8.08 Hz, 1H), 6.91-6.99 (m, 1H), 3.85 (s, 3H).
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:15]([NH:16][C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[C:20]#[N:21])=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][CH2:11]2.[C:25](Cl)(=[O:30])[CH2:26][C:27](Cl)=[O:28]>CO>[C:20]([C:19]1[CH:18]=[C:17]([N:16]2[C:27](=[O:28])[CH2:26][C:25](=[O:30])[NH:6][C:7]3[C:8]4[CH2:9][CH2:10][CH2:11][C:12]=4[CH:13]=[CH:14][C:15]2=3)[CH:24]=[CH:23][CH:22]=1)#[N:21]
Reactant: N#Cc1cccc(Nc2ccc3c(c2N)CCC3)c1
Reactant: O=C(Cl)CC(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCC2)c1
Reaction time: 1 h
Yield: 29.4 %

Procedure:
To a dry tetrahydrofuran (75 mL) solution of 3-(4-aminoindan-5-ylamino)benzonitrile (0.75 g, 3.00 mmol) was added malonyl chloride (0.35 mL, 3.60 mmol) while stirring in ice-bath. The mixture was stirred under cooling in ice-bath for 1 hour and at room temperature for 1 hour. To the mixture was added methanol (5 mL) while stirring in ice-bath. The mixture was stirred under cooling in ice-bath for 1 hour and at room temperature for 1 hour. To the reaction mixture was added methanol (25 mL) while stirring in ice-bath. The mixture was stirred under cooling in ice-bath for 1 hour and at room temperature for 1 hour. The solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/1-4/1) to slightly yellow crystal (0.40 g). The crystal was recrystallized from ethyl acetate to give the titled compound as white crystal (0.28 g, yield 29%).
Reaction SMILES: [CH2:1](Cl)[CH2:2][OH:3].[OH:5][C:6]1[C:15]([CH2:16][CH3:17])=[N:14][C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[N:7]=1.[OH-].[Na+]>C(O)(C)(C)C>[OH:3][CH2:2][CH2:1][N:7]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[N:14]=[C:15]([CH2:16][CH3:17])[C:6]1=[O:5]
Reactant: OCCCl
Reactant: CCc1nc2c(nc1O)CCCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: CCc1nc2c(n(CCO)c1=O)CCCC2
Temperature: 60 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
Ethylene chlorohydrin (20.2 g, 0.25M) was added to a solution of 2-hydroxy-3-ethyl-5,6,7,8-tetrahydro quinoxaline (8.90 g, 50 mM) in dilute aqueous 5N NaOH (50 ml) and t-butanol (150 ml), and stirred at 60° C. for 3 hours. The t-butanol was distilled off in vacuo. Water was added to the residue, which residue was then extracted three times with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 170 g) packed with chloroform, and eluted with chloroform-methanol (100:1) to obtain compound 646 (9.30 g, yield: 83.8%).
Reaction SMILES: [C:1](=O)=O.[CH:4]1([C:7]2[C:12]([CH:13]=[O:14])=[CH:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:8]=2)[CH2:6][CH2:5]1.C[Mg]Br>C1COCC1.CCOCC>[CH:4]1([C:7]2[C:12]([CH:13]([OH:14])[CH3:1])=[CH:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=3)[N:8]=2)[CH2:6][CH2:5]1
Reactant: O=Cc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Reactant: O=C=O
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a dry ice chilled solution of 0.75 g (2.57 mmol) 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbaldehyde in 5 ml THF was dropped a solution of 1.11 ml (3.33 mmol) 3M methylmagnesium bromide in 2.5 ml THF. The reaction mixture was allowed to warm to RT and it was stirred for 15 min at this temperature. The reaction mixture was then taken up in ether and washed with 1N HCl and water. The crude product was purified by chromatography over silica gel with AcOEt/dichloromethane 1:6, to give 384 mg of pure [rac]-1-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethanol.
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].C([O-])(=O)C.[Na+].[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([N+:28]#[N:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>C(O)C.O>[CH3:18][S:19]([C:22]1[CH:23]=[CH:24][C:25]([NH:28]/[N:29]=[C:8](\[C:2](=[O:1])[CH2:3][C:4]([O:6][CH3:7])=[O:5])/[C:9]([O:11][CH3:12])=[O:10])=[CH:26][CH:27]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)c1ccc([N+]#N)cc1
Reactant: COC(=O)CC(=O)CC(=O)OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)CC(=O)/C(=N\Nc1ccc(S(C)(=O)=O)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a mixture of dimethyl 3-oxopentanedioate (3.48 g, 20 mmol) in ethanol (12 mL) and water (40 mL) at room temperature was added sodium acetate (12.0 g, 146 mmol), and was followed by addition of 4-(methylsulfonyl)benzenediazonium solution (20 mmol). The resulting reaction mixture was stirred at room temperature for 1 h. The product was collected by filtration, then washed with water (˜50 mL) and dried overnight under reduce pressure to yield 7.0 g (83%) of (E)-dimethyl 2-(2-(4-(methylsulfonyl)phenyl)hydrazono)-3-oxopentanedioate as a yellow solid. MS (ESI) 357 (M+H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18](N)=[O:19])=[CH:16][C:10]=3[C:9](=[O:22])[CH2:8][C:7]=2[CH:23]=1.Br.C(O)(=[O:27])C>CCCCCC>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18]([OH:19])=[O:27])=[CH:16][C:10]=3[C:9](=[O:22])[CH2:8][C:7]=2[CH:23]=1
Reactant: COc1ccc2c(c1)CC(=O)c1cc(C(C)C(N)=O)ccc1S2
Reactant: CC(=O)O
Agent: Br
Solvent: CCCCCC
Product: CC(C(=O)O)c1ccc2c(c1)C(=O)Cc1cc(O)ccc1S2
Reaction time: 3 h
Yield: 82 %

Procedure:
A mixture of 130 mg of 2-(10,11-dihydro-8-methoxy-11-oxodibenzo[b,f]thiepin-2-yl)-propionamide, 20 ml of hydrobromic acid and 8 ml of acetic acid was refluxed with stirring for 3 hours. The solvent was distilled off to obtain a residue, which was extracted with chloroform. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain crude crystals, which were recrystallized from ethyl acetate--n-hexane to obtain 102 mg (yield: 82%) of 2-(10,11-dihydro-8-hydroxy-11-oxodibenzo[b,f]thiepin-2-yl)-propionic acid as a light yellow powder having a melting point of 216°-217° C.
Reaction SMILES: [C:1]1(=O)[O:7][C:5](=[O:6])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[NH2:13]C(N)=O>O>[C:1]1(=[O:7])[NH:13][C:5](=[O:6])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1
Reactant: NC(N)=O
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: O
Product: O=C1Cc2ccccc2C(=O)N1
Yield: 52.8 %

Procedure:
Homophthalic anhydride (20 g) and urea (60 g) were reacted at 170° C. for 1 hr. The reaction mixture was cooled, water (500 ml) was added thereto, and then the resulting precipitates were collected by filtration. The precipitate were washed with water and dried in hot air, to give 10.5 g of homophthalimide as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:18])[CH2:14][CH2:15][CH:16](Br)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2].[CH3:19][NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:18])[CH2:14][CH:15]=[C:16]([N:20]([CH3:19])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CNc1ccccc1
Reactant: CCOC(=O)c1cnc2n(c1=O)C(C)CCC2Br
Solvent: CCO
Product: CCOC(=O)c1cnc2n(c1=O)C(C)CC=C2N(C)c1ccccc1
Reaction time: 8 h
Yield: 25.9 %

Procedure:
10.0 g. (31.83 mmoles) of 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid ethyl ester are dissolved in 100 ml. anhydrous ethanol. 6.9 ml. (63.66 mmoles) of N-methylaniline are added to the solution, whereafter the reaction mixture is boiled under reflux for 8 hours. When the reaction is completed the solvent is distilled off at reduced pressure. To the residue 100 cm3 5% by weight aqueous solution of hydrochloric acid is added followed by extraction of the product twice with 30 ml. chloroform. The combined organic layers are dried above calcinated sodium sulfate and evaporated in vacuo. The residue is dissolved in 25 cm3 of methanol and allowed to stand overnight in a refrigerator. The precipitated crystals are filtered and washed with some methanol. 2.8 g. (25.9%) of 9-(N-methyl-anilino)-6-methyl-4-oxo-6,7-dihydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid ethyl ester is obtained which after recrystallization from methanol melts at 131°-133° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[S:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[O:21][CH:22]=1>>[Cl:28][C:25]1[S:24][C:23]([C:20]2[O:21][CH:22]=[C:18]([CH2:17][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:19]=2)=[CH:27][CH:26]=1
Reactant: ClCc1coc(-c2ccc(Cl)s2)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: Clc1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)s1
Yield: 68 %

Procedure:
In substantially the same manner as in Working Example 109, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(5-chloro-2-thienyl)oxazole to give 2-(5-chloro-2-thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 68%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 77-78° C.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:14](O)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[OH:31])[CH2:26][NH2:27]>>[C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:14]([NH:27][CH2:26][C:25]3[CH:28]=[CH:29][C:30]([OH:31])=[C:23]([OH:22])[CH:24]=3)=[O:15])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: COc1ccc(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Reactant: NCc1ccc(O)c(O)c1
Product: COc1ccc(C(=O)NCc2ccc(O)c(O)c2)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
0.02 g of the target compound is obtained as solid of a light color in substantially the same manner as in (2) of Example 1, except for using 3-adamantan-1-yl-4-methoxybenzoic acid instead of 5-adamantan-1-yl-2,4-dihydroxybenzoic acid and using 3,4-dihydroxybenzylamine instead of dopamine.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:11][CH:10]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:28][OH:29]>C(O)C.N1C=CC=CC=1>[CH:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:11][CH:10]=2)=[N:28][OH:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCC1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C(c1ccc(OCc2ccc3ccccc3n2)cc1)C1CCCCC1

Procedure:
A solution of 15.9 g (46 mmol) of 4-(quinolin-2-yl-methoxy)phenyl cyclohexyl ketone in 100 ml of ethanol and 33 ml of pyridine is stirred at room temperature for 18 h after addition of 4.77 g (68.6 mmol) of hydroxylamine hydrochloride. For working up, the mixture is concentrated in vacuo and the residue is taken up in dichloromethane. The organic phase is washed with water, dried over sodium sulphate and concentrated to dryness in vacuo.
Reaction SMILES: C[O:2][C:3]([CH:5]1[N:9]([CH2:10][C:11]#[C:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:8](=[O:19])[CH2:7][CH2:6]1)=O.[NH3:20]>CO>[O:19]=[C:8]1[N:9]([CH2:10][C:11]#[C:12][CH2:13][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:5]([C:3]([NH2:20])=[O:2])[CH2:6][CH2:7]1
Reactant: COC(=O)C1CCC(=O)N1CC#CCN1CCCC1
Reactant: N
Solvent: CO
Product: NC(=O)C1CCC(=O)N1CC#CCN1CCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
An ice water chilled solution of 5-methoxycarbonyl-1-[4-(1-pyrrolidinyl)-2-butynyl]-2-pyrrolidinone (5.52 g) in sieve dried methanol (175 ml) was treated with anhydrous ammonia for fifteen minutes and was allowed to stand at ambient temperature overnight. The solution was concentrated to a brown solid (3.33 g). The solid was recrystallized from toluene (100 ml) to give 2.03 g of slightly brown crystals, mp 146°-147.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[CH:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:27][CH:26]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(O)(=O)C>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:23][C:25]3[CH:26]=[CH:27][C:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:30]=3)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COC(=O)Cc1ccc(C=O)cc1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNCc1ccc(CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.9 %

Procedure:
To the product from step (iv) (1.25 g) in THF (100 mL), methyl 2-(4-formylphenyl)acetate (0.818 g) was addded followed by sodium triacetoxyborohydride (0.885 g) and acetic acid (3 drops) and stirred at rt for 16 h. The reaction was quenched with water, extracted with DCM washed with sat. NaHCO3 (200 mL), dried and solvent removed. The resulting residue was dissolved in methanol and purified on SCX to give the subtitle compound (0.73 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Cl[CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)=[O:12].C([O-])([O-])=O.[Cs+].[Cs+].CC#N>C(Cl)Cl>[F:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11](=[O:12])[CH2:10][N:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]2)=[N:15][CH:16]=1
Reactant: O=C(CCl)Nc1ccc(F)cn1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Product: O=C(Cn1cc([N+](=O)[O-])cn1)Nc1ccc(F)cn1
Temperature: 80 °C

Procedure:
A flask was charged with 4-nitro-1H-pyrazole (230 mg, 2.03 mmol), 2-chloro-N-(5-fluoropyridin-2-yl)acetamide (2.24 mmol), Cs2CO3 (729 g, 2.24 mmol) and MeCN (11.5 mL). The resulting reaction mixture was stirred at reflux (80° C.) for 2 h, then allowed to reach rt. The mixture was diluted with DCM, filtered, the filter cake was washed with DCM. The filtercake was redisolved in DCM and water, the org. layer was separated and the aq. layer was extracted with DCM (2×). The combined org. layers were washed with brine, dried (MgSO4), filtered and concentrated to yield N-(5-fluoropyridin-2-yl)-2-(4-nitro-1H-pyrazol-1-yl)acetamide as a crude which was used in the next step without further purification. LC-MS conditions A: tR=0.67 min, [M+H]+=266.32.