Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13](=[O:30])[CH2:14][O:15][C:16]1[CH:29]=[CH:28][C:19]([CH:20]=[C:21]2[S:25][C:24](=[O:26])[NH:23][C:22]2=[O:27])=[CH:18][CH:17]=1>[Pd].O1CCOCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:13](=[O:30])[CH2:14][O:15][C:16]1[CH:29]=[CH:28][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[NH:23][C:22]2=[O:27])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1C(=O)COc1ccc(C=C2SC(=O)NC2=O)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: Cc1oc(-c2ccccc2)nc1C(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reaction time: 4 h

Procedure:
A stirred mixture of 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-oxoethoxy]benzylidene}-2,4-thiazolidinedione (1.0 g), Pd-black (3 g) and dioxane (100 ml) was hydrogenated at 40° C. and at atmospheric pressure. After 4 hours, another Pd-black (3 g) was added and hydrogenation was continued for 4 hours. The catalyst was filtered off and the filtrate was concentrated to yield 5-{4-[2-(5-methyl-2-phenyl-4-oxazolyl)-2-oxoethoxy]benzyl}-2,4-thiazolidinedione (the same compound as that obtained in Example 48) as crystals (0.95 g, 94.1%). Recrystallization from ethyl acetate-hexane gave colorless needles, m.p. 168°-169° C.
Reaction SMILES: [CH3:1]OC(OC)N(C)C.[CH:9]([N:22]1[CH2:25][C:24]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:26]([NH2:28])=[O:27])[CH2:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH:9]([N:22]1[CH2:23][C:24]2([C:26](=[O:27])[N:28]=[CH:1][N:29]2[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:25]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(OC)N(C)C
Reactant: NC(=O)C1(NCc2ccccc2)CN(C(c2ccccc2)c2ccccc2)C1
Product: O=C1N=CN(Cc2ccccc2)C12CN(C(c1ccccc1)c1ccccc1)C2
Reaction time: 4 h
Yield: 61.7 %

Procedure:
N,N-Dimethylformamide dimethyl acetal (16 ml, 121 mmol) was combined with 1-benzhydryl-3-benzylaminoazetidine-3-carboxylic acid amide (I-3A-50b; 3.03 g, 8.16 mmol) and heated to reflux. After 4 hours, the suspension was cooled and extracted from saturated aqueous NaHCO3 with ethyl acetate. The combined extracts were dried (Na2SO4) and concentrated, in vacuo, to give a crude solid (3.50 g). Purification of the residue on a Biotage™ Flash 40M column using 0-3% methanol in methylene chloride as eluant afforded I-3A-50c as a yellowish solid (1.92 g, 62%): +ESI MS (M+1) 382.3; 1H NMR (400 MHz, CD3OD) δ 8.66 (s, 1H), 7.59 (d, J=7.1 Hz, 2H), 7.49-7.11 (m, 13H), 5.12 (s, 2H), 4.44 (s, 1H), 3.31 (d, J=9.6 Hz, 2H), 3.20 (d, J=9.6 Hz, 2H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13](B(O)O)=[C:12]([F:19])[CH:11]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].Br[C:21]1[S:25][C:24]([CH:26]=[O:27])=[CH:23][CH:22]=1>>[F:19][C:12]1[CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=2)[CH:15]=[CH:14][C:13]=1[C:21]1[S:25][C:24]([CH:26]=[O:27])=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: CCCc1ccc(-c2ccc(B(O)O)c(F)c2)cc1
Product: CCCc1ccc(-c2ccc(-c3ccc(C=O)s3)c(F)c2)cc1

Procedure:
5-(3-Fluoro-4′-propylbiphenyl-4-yl)thiophene-2-carbaldehyde is prepared analogously to Example 3 by Suzuki coupling of 4′-propyl-3-fluoro-4-biphenylboronic acid to 5-bromothiophene-2-carbaldehyde.
Reaction SMILES: C[O:2][C:3](=[O:28])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:24](=[CH:25][CH:26]=1)[O:23][C:11]1([CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12]1)[CH2:10][C:9]2=[O:27].Cl>CC(O)=O>[CH2:16]([N:13]1[CH2:14][CH2:15][C:11]2([CH2:10][C:9](=[O:27])[C:8]3[C:24](=[CH:25][CH:26]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:28])=[O:2])[CH:7]=3)[O:23]2)[CH2:12]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)C1)O2
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3ccccc3)C1)O2
Yield: 85.7 %

Procedure:
(+)-(E)-3-[1′Benzyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester (40 mg, 0.106 mmol) was hydrolyzed in aqueous 20% HCl solution and AcOH following the procedure described in Example 1, Step A, giving (+)-(E)-3-[1′-benzyl-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid (33 mg) as a white solid (hydrochloride salt).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6](/[CH:7]=[N:8]/[C@@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[OH:15])=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:27](Cl)(=[O:30])[O:28][CH3:29]>CO>[OH:15][C@H:10]1[C@H:9](/[N:8]=[CH:7]/[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:17][CH:16]=2)[CH2:14][CH2:13][N:12]([C:27]([O:28][CH3:29])=[O:30])[CH2:11]1
Reactant: COc1ccc(/C=N/[C@@H]2CCNC[C@H]2O)cc1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)N1CC[C@@H](/N=C/c2ccc(OC)cc2)[C@H](O)C1
Reaction time: 12 h
Yield: 100 %

Procedure:
A solution of (3R,4R)-4-((E)-(4-methoxybenzylidene)amino)piperidin-3-ol (400 mg, 1.707 mmol) and DIPEA (0.447 mL, 2.56 mmol) in MeOH (50 mL) at 0° C. (ice bath) was treated with Methyl Chlorocarbonate (1 mL, 12.94 mmol). The reaction was stirred for 12 hour, and then the mixture was concentrated. The crude material was diluted with MeOH and applied on a SCX column (Phenomenex, Strata XC). The column was eluted with 2N ammonia in methanol and solvent removed to afford (3R,4R)-methyl 3-hydroxy-4-((E)-(4-methoxybenzylidene)amino)piperidine-1-carboxylate (499 mg).
Reaction SMILES: [OH:1][C:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:16])[CH2:7][CH:8]=[CH:9][C:10]([CH3:15])=[CH:11][C:12]([OH:14])=O.[CH2:19]([Li])[CH3:20].[Cl-].[NH4+]>C1C=CC=CC=1.CCOCC>[OH:1][C:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:16])[CH2:7][CH:8]=[CH:9][C:10]([CH3:15])=[CH:11][C:12](=[O:14])[CH2:19][CH3:20]
Reactant: CC(C=CCC(C)CCCC(C)(C)O)=CC(=O)O
Reactant: [Li]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCC(=O)C=C(C)C=CCC(C)CCCC(C)(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3.35 g. of 11-hydroxy-3,7,11-trimethyldodeca-2,4-dienoic acid in 50 ml. ether at -20°C under nitrogen is added dropwise 59.1 ml. of a 0.67 molar solution of ethyllithium in benzene. The reaction mixture is allowed to warm to room temperature and is stirred overnight. The reaction mixture is then taken up in a mixture of ether and saturated aqueous ammonium chloride. The organic layer is separated, is washed with saturated aqueous ammonium chloride, 5% aqueous sodium bicarbonate, water, and saturated sodium chloride, is dried over calcium sulfate, and the solvent is removed to yield 13-hydroxy-5,9,13-trimethyltetradeca-4,6-dien-3-one which is purified by preparative thin layer chromatography (50% ether/hexane).
Reaction SMILES: [Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C@H:4]1[C@H:6]([C:7](O)=[O:8])[C:5]1([CH3:11])[CH3:10].S(Cl)([Cl:18])=O>>[Cl:18][C:7]([C@H:6]1[C@H:4]([CH:3]=[C:2]([Cl:1])[C:12]([F:15])([F:14])[F:13])[C:5]1([CH3:11])[CH3:10])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)[C@@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)O
Product: CC1(C)[C@@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl

Procedure:
A mixture of (+)-cis/trans-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane carboxylic acid (0.4 g) and thionyl chloride (5.0 ml) was heated at the reflux temperature for a period of 2 hours, after which the excess thionyl chloride was removed by distillation under reduced pressure, leaving (+)-cis/trans-1-chlorocarbonyl-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([S:21]([Cl:24])(=[O:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)[CH:6]([CH3:8])[CH3:7].CCOCC>C(OC(=O)C)(=O)C>[CH2:5]([C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16]([S:21]([Cl:24])(=[O:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:13][C:14]=1[N+:1]([O-:4])=[O:2])[CH:6]([CH3:8])[CH3:7]
Reactant: O=[N+]([O-])O
Reactant: CC(C)Cc1ccc(-c2ccccc2S(=O)(=O)Cl)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CC(C)Cc1ccc(-c2ccccc2S(=O)(=O)Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Fuming nitric acid (0.8 ml) was added over 10 minutes to a stirred solution of 4'-isobutyl-2-biphenylsulphonyl chloride (3.09 g) in acetic anhydride (18 ml) at -20° C. The solution was kept at -20° C. for 1.5 hours and then allowed to warm to ambient temperature. The solution was stirred for 1.5 hours and then added to ice (300 g) with vigorous sextracted with ether 30 minutes and extracted with ether (3×100 ml) while still below 10° C. The ethereal solution was dried (MgSO4) and the solvent was removed by evaporation. The resulting oil was purified by flash chromatography, eluting with ethyl acetate/hexane (1:9 v/v), to give 4'-isobutyl-3'-nitro-2-biphenylsulphonyl chloride (2.01 g); 1H NMR (CDCl3): 0.95 (d,6H), 1.9-2.05 (m,1H), 2.9 (d,2H), 7.35-7.5 (m,2H), 7.6 (d,1H), 7.7 (d,1H), 7.8 (t,1H), 8.0 (s,1H), 8.25 (d,1H); mass spectrum (EI): 353(M+).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][NH:41][C@@H:40]([CH3:44])[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:30])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:16])([CH3:17])[C:10]=3[CH:18]=2)[C@@H:40]([CH3:44])[CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O

Procedure:
Under the same conditions as the method for synthesizing Compound B2-10, the title compound was prepared from Compound B1 and (S)-3-methylpiperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[CH3:18][N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1.O>C1COCC1>[CH3:18][N:19]1[CH2:24][CH2:23][C:22](=[CH:9][C:7]#[N:8])[CH2:21][CH2:20]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CN1CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(=CC#N)CC1

Procedure:
9.36 g of K2CO3 and 8.89 ml of diethyl (cyanomethyl)phosphonate are placed in 12 ml of THF in a round-bottomed flask equipped with a magnetic stirrer, and under a stream of nitrogen, and the mixture is left to react for 15 minutes at room temperature and then refluxed for 20 minutes. The resulting mixture is allowed to cool and 6.5 ml of 1-methyl-4-piperidone are added dropwise. This mixture is refluxed for 16 hours. The reaction mixture is then poured into water and extracted with ethyl acetate. The organic phase is dried over Na2SO4, filtered and evaporated under vacuum. 6.8 g of oil are obtained.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[N:20]=[CH:19][CH:18]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1>C(O)C>[F:28][C:25]1[CH:24]=[CH:23][C:22]([N:21]2[C:17]([C:11]3[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([OH:8])[CH:10]=3)=[CH:18][CH:19]=[N:20]2)=[CH:27][CH:26]=1
Reactant: COc1ccc(-c2ccnn2-c2ccc(F)cc2)cc1OCc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2ccnn2-c2ccc(F)cc2)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
Into a 1-neck round-bottom flask was added 5-[3-(benzyloxy)-4-methoxyphenyl]-1-(4-fluorophenyl)-1H-pyrazole (3.5 g, 9.3 mmol) and 100 mL of ethanol. The flask was flushed with nitrogen for 10 minutes and 350 mg of 10% Pd/C was added. The reaction was then stirred under one atmosphere of hydrogen at room temperature overnight. The reaction was degassed under reduced pressure, flushed with argon for 5 minutes, filtered through Celite and concentrated to yield 2.6 g (98%) of 5-[1-(4-fluorophenyl)-1H-pyrazol-5-yl]-2-methoxyphenol as a grey oil. m/z 285.0 (M++1). 1H NMR(CDCl3 300 MHz) δ 3.9 (s, 3H); 5.6 (s, 1H); 6.4 (s, 1H); 6.8 (d, 1H); 7.0 (d, 2H); 7.4 (d, 2H); 7.6 (m, 2H); 7.7 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.Cl[CH2:21][C:22]1[CH:23]=[C:24]([CH:39]=[CH:40][CH:41]=1)[O:25][CH2:26][C:27]1[N:28]=[C:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:30][C:31]=1[CH3:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:32][C:31]1[O:30][C:29]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[N:28][C:27]=1[CH2:26][O:25][C:24]1[CH:23]=[C:22]([CH:41]=[CH:40][CH:39]=1)[CH2:21][O:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:4]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1
Reactant: CCOC(=O)CCc1cc(O)nn1-c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cc(OCc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)nn1-c1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 90.2 %

Procedure:
A mixture of ethyl 3-(3-hydroxy-1-phenyl-1H-pyrazol-5-yl)propionate (460 mg), 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (550 mg), potassium carbonate (350 mg) and N,N-dimethylformamide. (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-5-yl]propionate (850 mg, yield 90%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](N1C=CN=C1)=[C:6]2[CH3:17].[H-].[Na+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]>CN(C)C=O.O>[C:26]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[C:6]([CH3:17])=[CH:7]1)([OH:28])=[O:27]
Reactant: COc1ccc2[nH]c(-n3ccnc3)c(C)c2c1
Reactant: O=C(O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(C)cn2CCCCCC(=O)O

Procedure:
A solution of 5-methoxy-3-methyl-2-(1-imidazolyl)indole (0.57 g) in dimethylformamide (4 ml) is added dropwise to a suspension of sodium hydride (50% dispersion in mineral oil), 0.27 g in dimethylformamide (5 ml) while stirring under N2 at 0°-5°. The mixture is stirred at 5° for 1/2 hour. A solution of 6-bromohexanoic acid (0.55 g) in dimethylformamide (4 ml) is added dropwise to the reaction mixture while stirring at 0°-5°. The mixture is stirred at 0°-5° for 1/2 hour and then overnight at room temperature. The thick suspension is diluted with water (50 ml) and the mixture is washed with ether (2×25 ml). The aqueous layer is acidified to pH 5.6 with 1N hydrochloric acid and extracted with ethyl acetate (3×30 ml). The organic extract is dried over magnesium sulfate, filtered, and concentrated in vacuo to give an oil which becomes partially crystalline. This material is triturated with ether and the solid is collected to give 1-(5-carboxypentyl)-5-methoxy-3-methylindole, m.p. 134°-137°.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=12>CO.[Pt]=O>[N:1]1[CH:2]=[CH:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=12
Reactant: c1cn2ccnc2cn1
Agent: O=[Pt]
Solvent: CO
Product: c1cn2c(n1)CNCC2
Yield: 99 %

Procedure:
The title compound was prepared from imidazo[1,2-a]pyrazine (500 mg, 4.20 mmol, from Step A) and platinum oxide (250 mg) in methanol (50 mL), using a procedure analogous to that described in Example 1, Step B. Concentration gave the title compound (512 mg) as a viscous oil. 1H NMR (500 MHz, CD3OD) δ 3.37 (t, 1H, J=5.5 Hz), 4.18 (t, 2H, J=5.6 Hz), 4.88 (s, 1H), 7.27 (d, J=1.6 Hz, 1H), 7.33 (d, 1H).
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[C:11]([NH:15][C:16]([CH:18]1[CH2:20][C:19]1([CH3:22])[CH3:21])=[O:17])[C:12]([OH:14])=[O:13]>CO>[CH3:21][C:19]1([CH3:22])[CH2:20][CH:18]1[C:16]([NH:15]/[C:11](=[CH:10]\[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:2][CH3:1])/[C:12]([OH:14])=[O:13])=[O:17]
Reactant: CC1(C)CC1C(=O)NC(=CCCCCCBr)C(=O)O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COCCCCC/C=C(\NC(=O)C1CC1(C)C)C(=O)O
Yield: 49.4 %

Procedure:
To a solution of 2.43 mmoles of sodium methoxide in 5 ml of methanol was added 332 mg (1 mmole) of 8-bromo-2-(2,2-dimethylcyclopropanecarboxamido)-2-octenoic acid. The solution was heated under reflux in a nitrogen atmosphere for 1 hr. The reaction mixture was evaporated under reduced pressure, the residue dissolved in water and acidified with 2.5 N hydrochloric acid. The oil which precipitated was extracted with ether (3X). The ether extracts were washed with water, and saturated brine and dried over MgSO4. Removal of the ether under reduced pressure gave a colorless oil that crystallized upon standing. It was recrystallized from ether-hexane to give 140 mg of Z-2-(2,2-dimethylcyclopropanecarboxamido)-8-methoxy-2-octenoic acid, m.p. 71°-72° C. Homogeneous by TLC (toluene-HOAc, 4:1). The NMR spectrum was in accord with the desired structure.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]([CH2:12][CH3:13])[C:8]([NH:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[F:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH2:19][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH2:12][CH3:13])[C:8]([NH:10][CH3:11])=[O:9])=[CH:14][CH:15]=1
Reactant: Fc1ccccc1CBr
Reactant: CCC(Oc1ccc(O)cc1)C(=O)NC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCC(Oc1ccc(OCc2ccccc2F)cc1)C(=O)NC

Procedure:
In analogy to the procedure described in Example 3 b), the alkylation of (RS)-2-(4-hydroxy-phenoxy)-N-methyl-butyramide with 2-fluoro-benzylbromide in 2-butanone using potassium carbonate as the base yielded the (RS)-2-[4-(2-fluoro-benzyloxy)-phenoxy]-N-methyl-butyramide as a white solid; MS: m/e=318 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][C:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:25]>CC#N>[CH2:27]([N:26]([CH2:29][CH3:30])[C:24](=[O:25])[CH2:23][N:8]1[C:9](=[O:11])[C:10]2[C:2]([CH3:1])=[C:3]([C:12]([O:14][CH3:15])=[O:13])[S:4][C:5]=2[N:6]=[CH:7]1)[CH3:28]
Reactant: COC(=O)c1sc2nc[nH]c(=O)c2c1C
Reactant: CCN(CC)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CC)C(=O)Cn1cnc2sc(C(=O)OC)c(C)c2c1=O
Yield: 97.8 %

Procedure:
To a suspension of methyl 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate (2.24 g, 10 mmol) in CH3CN (20 mL) was added K2CO3 (1.38 g, 10 mmol), KI (1.61 g, 10 mmol), and 2-chloro-N,N-diethylacetamide (1.4 mL, 10 mmol). The reaction mixture was refluxed overnight and quenched with H2O (50 mL). The resulting precipitate was filtered and dried to afford 3.3 g of methyl 3-(2-(diethylamino)-2-oxoethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate as a solid (yield: quantitative).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([CH:9]=[C:10]1[NH:15][CH2:14][CH2:13][CH2:12][S:11]1)([O-:8])=[O:7].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([N:15]1[CH2:14][CH2:13][CH2:12][S:11][C:10]1=[CH:9][N+:6]([O-:8])=[O:7])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=[N+]([O-])C=C1NCCCS1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCCSC1=C[N+](=O)[O-]
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
A solution of 20 g of methanesulfonyl chloride in 150 ml of methylene chloride was added drop-by-drop over a 55 minute period to a stirred mixture of 20 g of 2-(nitromethylene)-tetrahydro-2H-1,3-thiazine and 40 ml of triethylamine in 150 ml of methylene chloride, at -30° C., in a nitrogen atmosphere. The resulting mixture was stirred for 30 minutes at -30° C., and then washed with 2% hydrochloric acid. The aqueous phase was washed twice with methylene chloride. The resulting organic phases were combined, dried (Na2SO4), concentrated to about 50 ml, cooled to 0° C., and filtered. The crystalline solid was triturated with cold methylene chloride, to give N-(methylsulfonyl)-2-(nitromethylene)-tetrahydro-2H-1,3-thiazine (1A), as a crystalline solid, m.p.: 144-145° C. (with decomposition).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH2:13])[N:4]=1)[CH3:2].[F:14][C:15]1[CH:16]=[CH:17][C:18]([O:33][CH3:34])=[C:19]([C:21]([CH3:32])([CH3:31])[CH2:22][C:23]([OH:30])([C:26]([F:29])([F:28])[F:27])[CH:24]=O)[CH:20]=1>C(O)(=O)C.C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N:13]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])([OH:30])[CH2:22][C:21]([C:19]2[CH:20]=[C:15]([F:14])[CH:16]=[CH:17][C:18]=2[O:33][CH3:34])([CH3:31])[CH3:32])[N:4]=1)[CH3:2]
Reactant: CCc1ccc2c(N)cccc2n1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCc1ccc2c(N=CC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1
Yield: 80.1 %

Procedure:
Analogously to Example 37, 334 mg (1.94 mmol) of 2-ethylquinolin-5-ylamine is reacted with 500 mg (1.62 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentanal in 2.20 ml of concentrated acetic acid and 15 ml of toluene. After purification on silica gel with hexane-ethyl acetate (0-100%), 600 mg (80% of theory) of the corresponding imine is obtained.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][CH:14]([CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:20]=1)[C:15]([OH:17])=O.[CH3:35][NH:36][CH:37]([CH3:39])[CH3:38]>O1CCCC1>[CH:37]([N:36]([CH3:35])[C:15](=[O:17])[CH:14]([CH3:13])[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[C:21]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:20]=1)([CH3:39])[CH3:38]
Reactant: CNC(C)C
Reactant: CC(Cc1nc(-c2ccccc2)nc2ccccc12)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(Cc1nc(-c2ccccc2)nc2ccccc12)C(=O)N(C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Carbonyldiimidazole (1.65 g) is added to a stirred solution of dextrorotatory α-methyl-2-phenyl-4-quinazolinepropanoic acid (2 g) in tetrahydrofuran (20 cc). The mixture is stirred for one hour at room temperature (until the evolution of gas has ceased) and N-methylisopropylamine (1.03 cc) is then added. The mixture is stirred for three days at room temperature (approximately 20° C.), then heated under reflux for 6 hours, N-methylisopropylamine (1.03 cc) is added and the mixture is heated under reflux for a further 12 hours. The treatment is then similar to that described in Example 85. After two recrystallizations in acetonitrile, laevorotatory N-isopropyl-N-methyl-α-methyl-2-phenyl-4-quinazolinepropanamide (19 g), m.p. 171.2° C., is isolated; αD at 0.5% in EtOH at 23° C.=-12.1°±2°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14](=[O:32])[NH:15][C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].F[C:35]1[CH:42]=[CH:41][C:38]([CH:39]=[O:40])=[CH:37][CH:36]=1>>[C:1]([O:5][C:6](=[O:33])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14](=[O:32])[NH:15][C:16]2[CH:21]=[C:20]([O:22][C:35]3[CH:42]=[CH:41][C:38]([CH:39]=[O:40])=[CH:37][CH:36]=3)[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)Nc2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Reactant: O=Cc1ccc(F)cc1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)Nc2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C=O)cc3)c2)CC1

Procedure:
Following the procedure of Example 42(b) {trans-4-[3-(4-cyano-phenoxy)-5-hydroxy-phenylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester (1.0 g, 2.21 mmol) and 4-fluorobenzaldehyde (0.475 ml, 4.43 mmol) were used to afford 0.4 g of the required product. 1H NMR (DMSO-d6): δ 1.11 (4H, m), 1.29 (9H, s), 1.8 (4H, m), 2.11 (1H, m), 3.15 (1H, m), 6.82 (1H, d), 7.34 (6H, m), 7.86 (2H, d), 7.92 (2H, d), 10.11 (1H, s).