Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH:3]([OH:5])[CH3:4].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[CH3:17][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:6][CH2:1][CH2:2][CH:3]([OH:5])[CH3:4])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: CC(O)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC(C)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 110.6 %

Procedure:
To a solution of butane-1,3-diol (1 g, 11.1 mmol), TEA (4.6 mL, 33.2 mmol) and DMAP (30 mg, 0.25 mmol) in DCM (20 mL) was added p-toluenesulfonyl chloride (2.75 g, 14.4 mmol) at 0° C. The resulting mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give 3-hydroxybutyl 4-methylbenzenesulfonate (3 g, 100% yield) as yellow oil, which was used without purification. Product tlc [DCM/methanol (100:1) developed with potassium permanganate, Rf 0.4]
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[C:19]4[CH:20]=[C:21]([C:24]#[N:25])[CH:22]=[CH:23][C:18]=4[O:17][C:16]([CH3:27])([CH3:26])[CH:15]=3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.C(OCC)(=[O:30])C>>[C:24]([C:21]1[CH:22]=[CH:23][C:18]2[O:17][C:16]([CH3:27])([CH3:26])[CH:15]=[C:14]([C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=4)=[CH:13][N+:12]=3[O-:30])[C:19]=2[CH:20]=1)#[N:25]
Reactant: CCOC(C)=O
Reactant: Cc1ccc(-c2ccc(C3=CC(C)(C)Oc4ccc(C#N)cc43)nc2)cc1
Product: Cc1ccc(-c2ccc(C3=CC(C)(C)Oc4ccc(C#N)cc43)[n+]([O-])c2)cc1

Procedure:
In an analogous manner to that described in the first paragraph of Example 6, from 4-[5-(4-methylphenyl)-2-pyridyl]-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile there was obtained 2-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-5-(4-methylphenyl)pyridine N-oxide of melting point 173°-175° C. (decomposition) (from ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13]CC)=[O:12])=[C:4]2[CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CCO>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:4]2[CH:3]=1
Reactant: CCOC(=O)c1cnn2ccc(C)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccn2ncc(C(=O)O)c2c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
To a solution of ethyl 5-methylpyrazolo[1,5-a]pyridine-3-carboxylate (2.73 g) in THF/EtOH (30/15 mL) was added 1N aqueous sodium hydroxide solution (20 mL), and the mixture was stirred at 80° C. for 4 hr. To the reaction mixture was added 1N hydrochloric acid at 0° C., and the mixture was extracted with THF/EtOAc. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with cooled hexane/IPE to give the title compound (2.11 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[C:15]([CH3:16])=[N:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][C@@H:19]1[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:7]([C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[N:11]2[C:15]([CH3:16])=[N:14][CH:13]=[N:12]2)=[O:9])[C@@H:19]1[CH2:24][NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][N:27]=1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1ccc(C(F)(F)F)cn1
Reactant: Cc1ccc(-n2ncnc2C)c(C(=O)O)c1
Product: Cc1ccc(-n2ncnc2C)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using 5-methyl-2-(5-methyl-1H-1,2,4-triazol-1-yl)benzoic acid and N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)-5-(trifluoromethyl)pyridin-2-amine. ESI-MS (m/z): 473 [M+1]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[CH2:17]([N+:21]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH3:20]>O.CC(O)C>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1)[O-:13].[CH2:30]([N+:21]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:31][CH2:32][CH3:33]
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: [O-]c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
To a flask were added 1.0 g 3,5-bis(trifluoromethyl)phenol, 1.8 g of a 55-60% solution of tetrabutylammonium hydroxide in water and 10 ml 2-propanol. After heating to 50 C under nitrogen for 1 hour, the solvent was removed and another 10 ml of 2-propanol were added and removed by distillation under reduced pressure. An oil was obtained which crystallized on standing.
Reaction SMILES: [C:1]1([CH2:11]O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:13]([CH2:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C[N+]([O-])=O>[C:1]1([CH2:11][CH:21]([C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:29])[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Reactant: OCc1cccc2ccccc12
Solvent: C[N+](=O)[O-]
Product: O=C(c1ccccc1)C(Cc1cccc2ccccc12)C(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of naphthalen-1-ylmethanol (XXII) (0.75 mmol) in CH3NO2 (1 mL) was added slowly over a period of 45 min to a solution of dibenzoylmethane (XXI) (2.27 mmol) and Bi(OTf)2 (0.008 mmol) in CH3NO2 heated at 100° C. The solution was further stirred at 100° C. for 2 h. The solution was cooled and the solvent was removed under vacuum. The residue was purified by column chromatography to produce 2-(naphthalen-1-ylmethyl)-1,3-diphenylpropane-1,3-dione 19 as a yellow solid (75% yield). 1H NMR (DMSO-d6, 400 MHz): δ ppm 3.75 (d, J=7 Hz, 2H), 6.23 (t, J=7 Hz, 1H), 7.24-7.38 (m, 6H), 7.50-7.55 (m, 4H), 7.57 (m, 1H), 7.81-7.87 (m, 5H), 8.14 (m, 1H); ESIMS found C26H20O2 m/z 365 (M+H).
Reaction SMILES: CO[C:3]([CH:5]1[C:9](=O)[CH2:8][O:7][CH2:6]1)=[O:4].[F:11][C:12]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:13]=1[C:14]([NH2:16])=[NH:15]>C(O)C>[Cl:21][C:18]1[CH:19]=[CH:20][C:12]([F:11])=[C:13]([C:14]2[N:16]=[C:3]([OH:4])[C:5]3[CH2:6][O:7][CH2:8][C:9]=3[N:15]=2)[CH:17]=1
Reactant: COC(=O)C1COCC1=O
Reactant: N=C(N)c1cc(Cl)ccc1F
Solvent: CCO
Product: Oc1nc(-c2cc(Cl)ccc2F)nc2c1COC2
Temperature: 80 °C
Yield: 29.7 %

Procedure:
To a suspension of 4-oxo-tetrahydrofuran-3-carboxylic acid methyl ester (prepared according to Dowd, P.; Choi, S-C. Tetrahedron, 1991, 47, 4847-4860; 800 mg, 5.55 mmol, 1 eq) in ethanol (20 ml) was added a solution of 2-fluoro-5-chloro-benzamidine (961 mg, 5.55 mmol, 1 eq) in EtOH (10 ml). The reaction mixture was heated to 80° C. overnight. The reaction mixture was cooled to r.t. and the white precipitate was filtered and washed with cold ethyl actetate (2×20 ml). The crude residue was partitioned between chloroform and water. The aqueous layer was acidified to pH 4 and the product was extracted with chloroform (3×50 ml). The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give a crude solid which was purified by flash column chromatography (5% MeOH in EtOAc) to give a white solid 2-(5-chloro-2-fluoro-phenyl)-5,7-dihydrofuro[3,4-d]pyrimidin-4-ol (440 mg, 30%).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]([NH2:11])=O)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)(Cl)=O>>[CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:9]#[N:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cc(C(N)=O)cc(S(N)(=O)=O)c1Oc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCNc1cc(C#N)cc(S(N)(=O)=O)c1Oc1ccccc1
Temperature: 120 °C

Procedure:
A mixture of 3-n-butylamino-4-phenoxy-5-sulfamylbenzamide (8.5g) and phosphorus oxychloride (25 ml) is heated at 120° C. for 2 hours. The mixture is then evaporated in vacuo and the residue is triturated with icewater (120 ml) to yield crude 3-n-butylamino-4-phenoxy5-sulfamylbenzonitrile. After filtration, carefully washing with water, drying and recrystallization from methanol, it is obtained with a melting point of 217°-218° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[O:5][C@H:6]1[CH2:9][CH2:8][C@H:7]1[OH:10].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([O:10][C@@H:7]1[CH2:8][CH2:9][C@@H:6]1[O:5][C:4]1[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=1[C:2]([F:15])([F:16])[F:1])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@@H]1CC[C@@H]1Oc1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O[C@@H]1CC[C@@H]1Oc1ccccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of C7 (484 mg, 2.08 mmol), triethylamine (0.87 mL, 6.3 mmol) and dichloromethane (30 mL) was cooled to 0° C. and methanesulfonyl chloride (0.32 mL, 4.2 mmol) was added drop-wise over 15 minutes. After an additional 30 minutes at 0° C., the reaction was quenched with saturated aqueous sodium bicarbonate solution (50 mL), and the mixture was extracted with dichloromethane (2×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to provide the title compound as a colorless oil. Yield: 640 mg, 2.06 mmol, 99%. 1H NMR (400 MHz, CDCl3) δ 7.60 (br dd, J=7.8, 1.2 Hz, 1H), 7.45-7.51 (m, 1H), 7.06 (br dd, J=7.7, 7.6 Hz, 1H), 6.88 (br d, J=8.4 Hz, 1H), 5.26-5.32 (m, 1H), 5.01-5.06 (m, 1H), 2.95 (s, 3H), 2.53-2.63 (m, 1H), 2.37-2.46 (m, 1H), 2.18-2.30 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:20]4[C:28]5[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=5)[C:22]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:35](=[O:38])([O-])[O-:36].[K+].[K+]>CN(C)C=O>[CH2:14]([O:36][C:35]([CH2:2][CH2:1][CH2:3][O:29][C:25]1[CH:24]=[C:23]2[C:28](=[CH:27][CH:26]=1)[N:20]([CH2:19][C:16]1[CH:17]=[CH:18][C:12]3[O:11][C:10]([C:7]4[S:8][CH:9]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[N:6]=4)=[CH:14][C:13]=3[CH:15]=1)[CH:21]=[C:22]2[CH2:30][C:31]([O:33][CH3:34])=[O:32])=[O:38])[C:13]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Cc1cn(Cc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)c2ccc(O)cc12
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(Cc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)c2ccc(OCCCC(=O)OCc3ccccc3)cc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 110.8 %

Procedure:
A mixture of methyl 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-5-hydroxyindole-3-acetate (0.474 g), benzyl 4-bromobutylate (0.34 g) and potassium carbonate (0.19 g) in N,N-dimethylformamide (5 ml) was stirred at 50° C. for 8 hours. After being cooled to room temperature, the mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of n-hexane and ethyl acetate. The fractions containing the objective compound were combined and concentrated under reduced pressure to give methyl 5-[3-(benzyloxycarbonyl)propoxy]-1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}indole-3-acetate (0.36 g).
Reaction SMILES: O1CCCC1.[S:6]1[CH:10]=[CH:9][C:8]2[CH:11]([N:15]=[C:16]=[S:17])[CH2:12][CH2:13][CH2:14][C:7]1=2.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CCOCC>[S:6]1[CH:10]=[CH:9][C:8]2[CH:11]([NH:15][C:16]([CH:21]3[CH2:22][CH2:23][NH:18][CH2:19][CH2:20]3)=[S:17])[CH2:12][CH2:13][CH2:14][C:7]1=2
Reactant: S=C=NC1CCCc2sccc21
Reactant: C1CCNCC1
Solvent: C1CCOC1
Solvent: CCOCC
Product: S=C(NC1CCCc2sccc21)C1CCNCC1
Reaction time: 2.5 h

Procedure:
In 50 ml. of tetrahydrofuran, 5.85 grams of 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isothiocyanate is stirred and 2.81 grams of piperidine is added. An exotherm is observed and the temperature rises to about 40° C. to 50° C. After 2.5 hours, the mixture is heated at reflux temperature for 3.5 hours. After stirring overnight, the mixture is evaporated to dryness to afford a sticky yellow-brown solid. Ether is added to this material and the off-white, insoluble product is collected. The crude product, 5.25 grams, melts at 102° C. to 104° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][N:16]=[CH:15][C:14]=3[CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:28]O>>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[O:17][N:16]=[CH:15][C:14]=3[CH2:18][CH2:19][C:20]([O:22][CH3:28])=[O:21])=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCc1cnoc1-c1ccc(-c2ccccc2)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCc1cnoc1-c1ccc(-c2ccccc2)cc1
Yield: 94 %

Procedure:
A mixture of 3-[5-(4-phenylphenyl)-4-isoxazolyl]propionic acid (6.00 g), conc. sulfuric acid (0.1 ml) and methanol (100 ml) was refluxed for 4 hr. The reaction mixture was concentrated, water was added to the residue 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 methyl 3-[5-(4-phenylphenyl)-4-isoxazolyl]propionate (5.91 g, yield 94%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:3, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 103–104° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C([Li])CCC.[CH3:15][Si:16]([CH3:19])([CH3:18])Cl.C(N(CC)CC)C>COCCOCCOC>[CH3:15][Si:16]([CH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6])([CH3:19])[CH3:18]
Reactant: Cc1cccc(CO)c1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: COCCOCCOC
Solvent: CCN(CC)CC
Product: C[Si](C)(C)Cc1cccc(CO)c1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-methylbenzylalcohol (6.10 g, 50 mmol) in anhydrous diglyme (200 ml) at -78° C. was added 1.5M butyllithium (100 ml) over 20 min. The resulting mixture was allowed to warm to -20° C. and stirred for 30 min. Then a mixture of trimethylchlorosilane (19.0 g, 175.0 mmol) and triethylamine (5.05 g, 50 mmol) was added and the final solution was stirred at room temperature for 3 hours. The reaction mixture was treated with ice water (200 ml), extracted three times with diethyl ether (100 ml) and the extracts washed twice with water, brine, dried over MgSO4 and concentrated. The crude product was dissolved in 90% aqueous methanol (200 ml) and refluxed for 1 hour. Then the solvents were removed and 3-trimethylsilylmethylbenzylalcohol was purified by fractional distillation.
Reaction SMILES: C([O:3][C:4](=O)/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][N:10]2[CH:13]=[CH:14][N:15]=[C:9]2[CH:8]=1)C.[H-].C([Al+]CC(C)C)C(C)C.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1.ClCCl>[N:15]1[CH:14]=[CH:13][N:10]2[CH:11]=[CH:12][C:7](/[CH:6]=[CH:5]/[CH2:4][OH:3])=[CH:8][C:9]=12
Reactant: CCOC(=O)/C=C/c1ccn2ccnc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: OC/C=C/c1ccn2ccnc2c1
Temperature: 25 °C
Yield: 78.2 %

Procedure:
(E)-3-Imidazo[1,2-a]pyridin-7-yl-acrylic acid ethyl ester (prepared according to Procedure H1 to H4 using triethylphosphono acetate, 519 mg, 2.4 mmol) was dissolved in a mixture of toluene/dichloromethane (1:1, 12 ml) and cooled on a dry ice/acetone bath. Diisobutylaluminium hydride (1 M in toluene, 3 ml) was added dropwise. After 45 minutes the reaction was transferred to a salt/ice bath and further portions of DIBAL were added until the reaction was complete. The reaction was quenched by the cautious addition of methanol and was allowed to warm to room temperature. The reaction was concentrated in vacuo and 2N sodium hydroxide solution was added. This was extracted twice with dichloromethane and the combined liquors were dried and concentrated to furnish the desired monomer (327 mg) as a yellow solid MS: [M+H]+=175
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][N:8]2[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9]2)=[CH:5][CH:4]=1)#[N:2].[C:17](O)([CH3:20])([CH3:19])[CH3:18].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClC(Cl)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:9][CH:10]([C:12]([O:14][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:13])[CH2:11]2)=[CH:15][CH:16]=1)#[N:2]
Reactant: N#Cc1ccc(CN2CC(C(=O)O)C2)cc1
Reactant: CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(C#N)cc2)C1
Yield: 86 %

Procedure:
To a mixture of 1-(4-cyanobenzyl)azetidine-3-carboxylic acid (3.25 g, 15.0 mmol), DMAP (1.84 g, 15.0 mmol), and tert-butanol (14.1 mL, 150 mmol) in dichloroethane (150 mL) was added EDCI (4.32 g, 22.5 mmol), and the reaction mixture was allowed to stir over the weekend. The volatiles were removed under reduced pressure, and the residue was partitioned between ethyl acetate (250 mL) and a saturated aqueous solution of sodium bicarbonate (250 mL). The organic layer was washed with water (250 mL), washed with brine (100 mL), and dried over anhydrous magnesium sulfate. Concentration under reduced pressure afforded a light yellow oil which was chromatographed on a 5×15 cm silica gel column, eluting with a 0-40% ethyl acetate/hexane gradient to give tert-butyl 1-(4-cyanobenzyl)azetidine-3-carboxylate (3.5 g, 12.9 mmol, 86% yield) as a colorless liquid. HPLC retention time=1.38 minutes−Column: YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+H)=273.18. 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (s, 9H), 3.26 (m, 3H), 3.52 (m, 2H), 3.66 (s, 2H), 7.39 (d, J=8.3 Hz, 2H), and 7.60 (d, J=8.3 Hz, 2H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[S:10]([CH3:13])(=[O:12])=[O:11])=[CH:5][CH:4]=1>Cl.O1CCOCC1.O>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][C:15]([OH:17])=[O:16])[S:10]([CH3:13])(=[O:12])=[O:11])=[CH:5][CH:4]=1
Reactant: CSc1ccc(N(CC(=O)OC(C)(C)C)S(C)(=O)=O)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CSc1ccc(N(CC(=O)O)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
Tert-butyl 2-(N-(4-(methylthio)phenyl)methylsulfonamido)acetate (220 mg, 0.664 mmol) was dissolved in HCl 4M in Dioxane (4 ml). The reaction was stirred at RT for 8 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated under vacuum, and the crude product was triturated with Petroleum Ether to give 2-(N-(4-(methylthio)phenyl)methyl-sulfonamido)acetic acid (150 mg, 82% yield).
Reaction SMILES: CS[C:3](=[NH:5])[NH2:4].[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12].[H-].[Na+]>O1CCCC1>[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:3](=[NH:5])[NH2:4]
Reactant: NCCCCCO
Reactant: CSC(=N)N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N=C(N)OCCCCCN

Procedure:
S-Methylisothiourea is reacted with 5-aminopentanol and sodium hydride in tetrahydrofuran to give O-(5-aminopentyl)isourea, which is reacted with 2-nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone in refluxing ethanol to give 2-[5-(O-isoureido)pentylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.BrBr.O>C(O)(=O)C>[C:4]1([C:3]#[C:2][C:1]([OH:11])=[O:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)C=Cc1ccccc1
Agent: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)C#Cc1ccccc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 75.3 %

Procedure:
Cinnamic acid (29.6 g) was dissolved in acetic acid (80 ml) under heating and then bromine (32 g) was added dropwise. After stirring at 50° C. for 15 minutes, the resulting mixture was allowed to cool under standing and water (100 ml) was gradually added. The white crystals formed were filtered, washed with water and dried (yield: 56 g). Potassium hydroxide (56 g) was dissolved into methanol (20 ml) and then the above crystals were added in small portions to this solution. The methanol was removed under stirring with heating over a water bath. The residue was dissolved into 200 ml of water and neutralized with a diluted sulfuric acid under ice cooling. Freed pale yellow oil rapidly solidified. The solidified crystals were filtered and recrystallized from water to afford phenylpropiolic acid (22 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([NH:7][CH2:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=O)[CH3:2].P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[C:10]([C:9]1[O:14][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])=[N:7][CH:8]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOC(=O)C(=O)NCC(=O)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ncc(C(C)(C)C)o1
Temperature: 120 °C
Yield: 87.6 %

Procedure:
To a mixture of ethyl[(3,3-dimethyl-2-oxobutyl)amino](oxo)acetate (40 g, 162 mmol) in toluene (350 mL) is added phosphorous oxychloride (75 g, 488 mmol). The reaction mixture is heated at 120° C. for 14 h. Then the solvent is removed and the residue is diluted with ether. The ether layer is washed with saturated aqueous NaHCO3 solution, brine, dried (Na2SO4) and concentrated to afford the title compound (28 g, 87%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[NH:15][C:14]=2[CH3:24])[C:7]=1[F:25])[CH3:2].I[C:28]1[CH:29]=[N:30][N:31]([CH2:33][CH2:34][CH3:35])[CH:32]=1>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12][C:13]2[C:21]3[C:16](=[C:17]([F:23])[C:18]([Cl:22])=[CH:19][CH:20]=3)[N:15]([C:28]3[CH:29]=[N:30][N:31]([CH2:33][CH2:34][CH3:35])[CH:32]=3)[C:14]=2[CH3:24])[C:7]=1[F:25])[CH3:2]
Reactant: CCCn1cc(I)cn1
Reactant: CCOC(=O)Cc1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1F
Product: CCCn1cc(-n2c(C)c(Sc3cccc(CC(=O)OCC)c3F)c3ccc(Cl)c(F)c32)cn1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: [3-(6-Chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-2-fluoro-phenyl]-acetic acid ethyl ester and 4-iodo-1-propyl-1H-pyrazole.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]1[N:11]=[C:12]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][N:13]2[C:14](=[O:19])[C:15]=1[CH2:16][CH2:17][CH3:18].Cl[CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]1[N:11]=[C:12]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH2:28][CH2:29][N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[O:25])=[CH:20][N:13]2[C:14](=[O:19])[C:15]=1[CH2:16][CH2:17][CH3:18]
Reactant: CCCc1c(/C=C/c2ccccc2C)nc2ccc(C(=O)O)cn2c1=O
Reactant: CCN(CC)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(/C=C/c2ccccc2C)nc2ccc(C(=O)OCCN(CC)CC)cn2c1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 45.4 %

Procedure:
2-trans-[2-(2-methyl-phenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid (3.6 g) was reacted with 1-chloro-2-(diethylamino)ethane (2.7 g) and anhydrous K2CO3 (2.8 g) in dimethylformamide (40 ml) under stirring at 50° C. for 8 hours. After dilution with water, the precipitate was filtered off and washed with water until neutral: crystallization from isopropyl ether gave 2.1 g of 2-trans-[2-(2-methylphenyl)-ethenyl]-3-propyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-7-carboxylic acid, 2-diethylamino-ethyl ester. By proceeding analogously, the following compounds were prepared: