Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].C[C:11]1[C:16]([C:17]([O-:19])=O)=[C:15](C)[C:14]([C:21]([O-:23])=O)=[C:13](C)[C:12]=1[C:25]([O-:27])=O.Cl>CC(C)=O.O1CCCC1>[CH3:6][C:5]([CH3:8])([CH3:7])[C:4](=[O:9])[CH2:3][C:25]([C:12]1[CH:11]=[C:16]([C:17](=[O:19])[CH2:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])[CH:15]=[C:14]([C:21](=[O:23])[CH2:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])[CH:13]=1)=[O:27]
Reactant: Cc1c(C(=O)[O-])c(C)c(C(=O)[O-])c(C)c1C(=O)[O-]
Reactant: CC(=O)C(C)(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)CC(=O)c1cc(C(=O)CC(=O)C(C)(C)C)cc(C(=O)CC(=O)C(C)(C)C)c1
Reaction time: 7 h
Yield: 52.7 %

Procedure:
In a 100 ml three-necked flask equipped with a mechanical stirrer, dropping funnel, reflux condenser, and a nitogen-inlet tube, 2.29 gm (57 mmol) of 60% sodium hydride, 5.24 gm (52 mmol) of pinacolone, 4.0 gm (15.8 mmol) of trimethyl-1,3,5-benzenetricarboxylate, and 40 ml of anhydrous tetrahydrofuran were mixed with stirring under nitrogen stream, and the refluxing under heat was continued for 7 hours. After cooling the reaction mixture, 30 ml of 2N aqueous hydrochloric acid was added, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was removed by evaporation to give a crude product. Acetone was added to the crude product, and recrystallization afforded 3.8 gm of the target compound as yellow crystals (yield: 52%).
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:15][N:14]=1>CN(C)C(=O)C>[S:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:13]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2][CH2:3]2)=[N:14]1
Reactant: Clc1nsc2ccccc12
Reactant: CCOC(=O)N1CCNCC1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)N1CCN(c2nsc3ccccc23)CC1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
A mixture of 32 parts of ethyl 1-piperazinecarboxylate, 17 parts of 3-chloro-1,2-benzisothiazole and 45 parts of N,N-dimethylacetamide was stirred for 0.5 hours at 150° C. After cooling to 50° C., the reaction mixture was poured into ice water. The aqueous layer was decanted and the oily layer was stirred in water. The product from the oil layer was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 13 parts (44%) of ethyl 4-(1,2-benzisothiazol-3-yl)-1-piperazinecarboxylate as a residue (int. 3).
Reaction SMILES: C[O:2][C:3]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[C:26]([CH3:27])=[CH:25][C:24]([N+:28]([O-:30])=[O:29])=[C:23]3[C:19]=2[CH2:20][CH2:21][CH2:22]3)=[CH:13][C:4]=1[CH2:5][C:6]1[CH:7]=[CH:8][C:9](=[O:12])[NH:10][N:11]=1.Br.O>C(O)(=O)C>[OH:2][C:3]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[C:26]([CH3:27])=[CH:25][C:24]([N+:28]([O-:30])=[O:29])=[C:23]3[C:19]=2[CH2:20][CH2:21][CH2:22]3)=[CH:13][C:4]=1[CH2:5][C:6]1[CH:7]=[CH:8][C:9](=[O:12])[NH:10][N:11]=1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1Cc1ccc(=O)[nH]n1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(O)c(Cc3ccc(=O)[nH]n3)c1)CCC2
Yield: 39.7 %

Procedure:
To a solution of 6-[2-methoxy-5-(5-methyl-7-nitroindan-4-yloxy)benzyl]-2H-pyridazine-3-one (704 mg) in acetic acid (10 mL) was added hydrobromic acid (48%, 10 mL). The mixture was heated at reflux temperature under an argon atmosphere overnight. After adding water, the reaction mixture was extracted with dichloromethane. The organic layer was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was crystallized from a small amount of ethyl acetate to give the title compound (270 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2)([O-:3])=[O:2].Cl.[NH2:15]O.C(O)C.[OH-].[Na+]>CO>[NH2:15][C:11]1[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[C:5]2[C:10]=1[CH:9]=[N:8][CH:7]=[CH:6]2
Reactant: NO
Reactant: O=[N+]([O-])c1cccc2cnccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: Nc1ccc([N+](=O)[O-])c2ccncc12
Temperature: 0 °C
Yield: 57.5 %

Procedure:
To 5-nitroisoquinoline (2.0 g) were added hydroxylamine hydrochloride (5.0 g) and ethanol (120 ml). A solution of sodium hydroxide (10 g) in methanol (65 ml) was slowly added at 50° C. over 90 min. The reaction mixture was poured into ice water (700 g) and the resulting precipitate was collected by filtration. The residue was washed with ethanol and dried under reduced pressure to give 8-amino-5-nitroisoquinoline (1.25 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])/[CH:5]=[C:6](\[NH2:14])/[C@H:7]([CH3:13])[C@H:8]([CH3:12])[CH2:9][CH2:10][CH3:11])[CH3:2].[C:16](Cl)(=[O:18])[CH3:17].N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])/[CH:5]=[C:6](\[NH:14][C:16](=[O:18])[CH3:17])/[C@H:7]([CH3:13])[C@H:8]([CH3:12])[CH2:9][CH2:10][CH3:11])[CH3:2]
Reactant: CCC[C@@H](C)[C@@H](C)/C(N)=C/C(=O)OCC
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC[C@@H](C)[C@@H](C)/C(=C/C(=O)OCC)NC(C)=O
Temperature: -20 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a 1 L 3-necked round bottom flask equipped with an overhead stirrer, thermocouple, addition funnel, and nitrogen inlet, was charged 150 g (0.70 mol) of (4R,5R)-3-amino-4,5-dimethyl-(Z)-oct-2-enoic acid ethyl ester and 50 mL of dry CH2Cl2. The reaction mixture was cooled to −20° C. To the mixture was added, successively, acetyl chloride (60 mL, 0.84 mol) and pyridine (66.8 g, 0.84 mol) over 0.5-hour time intervals. After the additions, the mixture was stirred at −20° C. to 0° C. for 2 hours and then filtered to remove the pyridine.HCl salt. The filtrate was diluted with 200 mL of CH2Cl2 and washed 2× with aliquots of aq NH4Cl. The organic solution was treated with silica gel (50 g), MgSO4 (20 g) and charcoal (20 g), and stirred at room temperature for 0.5 hours. The solids were filtered off and the filtrate was concentrated under reduced pressure to give 166.5 g (93% yield) of the titled compound as an oil: 1H NMR (400 MHz, CHLOROFORM-D) 0.85 (t, J=7.4 Hz, 3 H), 0.95 (d, J=6.8 Hz, 3 H), 1.00 (d, J=7.0 Hz, 3 H), 1.11 (m, 1 H) 1.29 (t, J=5.8 Hz, 3 H), 1.40–1.25 (m, 2 H), 1.65 (m, 1 H) 2.13 (s, 3 H), 3.80 (m, 1 H) 4.2–4.14 (m, 3 H), 5.01(s, 1 H), 11.28(s, 1 H).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[C:28]([CH3:39])=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[C:28]([CH3:39])=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: Cc1c(NC(=O)C(C)C)cccc1C1CCN(CCCN)CC1
Product: Cc1c(NC(=O)C(C)C)cccc1C1CCN(CCCNC(=O)C(c2ccccc2)c2ccccc2)CC1

Procedure:
Example 33 was prepared from diphenyl acetyl chloride and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-2-methyl phenyl}-2-methylpropanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 7.49 (d, 1H, J=8.0 Hz), 7.35–7.19 (m, 11H), 7.09–7.02 (m, 3H), 4.90 (s, 1H), 3.41 (dd, 2H, J=5.6, 11.6 Hz), 2.99 (d, 2H, J=12.8 Hz), 2.72 (m, 1H), 2.59 (m, 1H), 2.43 (t, 2H, J=6.4 Hz), 2.19 (s, 3H), 2.06–2.00 (m, 2H), 1.75–1.60 (m, 6H), 1.30 (d, 6H, J=6.8 Hz); ESMS m/e: 512.5 (M+H)+.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=2)[CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([NH:20][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1cc(-c2cncc(F)c2)cc(C)n1
Product: Cc1cc(-c2cncc(F)c2)cc(C(=O)Nc2ccccc2)n1

Procedure:
The title compound, was prepared from 5-Fluoro-6′-methyl-[3,4′]bipyridinyl-2′-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using Aniline instead of 3-chloroaniline to yield the final compound as a white solid, MS (ISP): m/e=308.3, 309.3 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([C:16](=[O:18])[CH3:17])C(OCC)=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].[OH2:19]>Cl>[O:18]=[C:16]([CH3:17])[CH2:10][CH2:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]([NH2:2])=[O:19]
Reactant: CCOC(=O)C(Cc1cccc(C#N)c1)C(C)=O
Reactant: O
Agent: Cl
Product: CC(=O)CCc1cccc(C(N)=O)c1

Procedure:
38.2 g of ethyl 2-(3'-cyanophenylmethyl)-3-oxobutyrate was heated for 2 hours under reflux in 500 ml of concentrated hydrochloric acid. To the reaction solution was added 500 ml of water, followed by extraction three times with 500 ml portions of ethyl acetate. The organic phase was washed with water and dried with anhydrous sodium sulfate, after which the solvent was distilled off. The resultant 3-(3'-oxobutyl)benzoic acid was admixed with 500 ml of benzene and 17 ml of thionyl chloride and heated for 2 hours under reflux. The reaction solution was dropped into ice-cooled concentrated ammonia water and the resultant amide extracted three times with 500 ml portions of ethyl acetate. The organic phase was washed with a saturated saline solution and dried with anhydrous sodium sulfate. The solvent was distilled off and the residue recrystallized from ethyl acetate-n-hexane to obtained 23.1 g of 3-(3'-oxobutyl)benzamide, melting point 122°-125° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([N:21]3[CH2:25][CH2:24][CH2:23][C@H:22]3[CH2:26][O:27][CH:28]3[CH2:33][CH2:32][CH:31]([C:34]([O:36]C)=[O:35])[CH2:30][CH2:29]3)=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1.[OH-].[Na+]>C1COCC1.CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][C:11]2[CH:17]=[C:16]([CH2:18][C:19]([N:21]3[CH2:25][CH2:24][CH2:23][C@H:22]3[CH2:26][O:27][CH:28]3[CH2:29][CH2:30][CH:31]([C:34]([OH:36])=[O:35])[CH2:32][CH2:33]3)=[O:20])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: COC(=O)C1CCC(OC[C@@H]2CCCN2C(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)N3CCC[C@H]3COC3CCC(C(=O)O)CC3)cc2o1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
In THF (10 ml) and methanol (5 ml) was dissolved methyl 4-(1-(2-(2-methylphenylamino)-6-benzoxazolylacetyl)-(2S)-pyrrolidinylmethoxy)cyclohexanecarboxylate (580 mg, 1.1 mmol), that is, a mixture of two diastereomers (cis and trans forms). After addition of 1N NaOH (1.5 ml, 1.5 mmol), the mixture was stirred at 70° C. for 24 hours. The residue obtained by distilling off the solvent under reduced pressure, was acidified weakly with 1N HCl. The crystals thus precipitated were collected by filtration under reduced pressure. The resulting crystals were washed with water and dried under reduced pressure, whereby 4-(1-(2-(2-methylphenylamino)-6-benzoxazolylacetyl)-(2S)-pyrrolidinylmethoxy)cyclohexanecarboxylic acid was obtained as a mixture of two diasteromers. The mixture was separated by HPLC (C18 column, eluting with 0.02N acetate buffer-acetonitrile (1:1, v/v)), whereby Isomer A (150 mg, 27%) was obtained as a white crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:16])C(=O)C1>CC#N.CCOC(C)=O>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([Br:16])=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncccc1F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Nc1ncc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-3-fluoro-pyridine (9.4 g, 83.1 mmol, 1 eq.) in MeCN (470 mL) under argon at 0° C. was added NBS (7.4 g, 41.5 mmol, 0.5 eq.). The reaction mixture was stirred at r.t. for 1 h then cooled to 0° C. before introducing additional NBS (7.39 g, 41.5 mmol, 0.5 eq.). The reaction mixture was stirred at r.t. for 1 h then diluted in EtOAc. The organic layer was washed with a saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated in vacuo. The residue was diluted in DCM, washed with a 1 N NaOH solution. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to afford Intermediate Gen-1-a (2-amino-5-bromo-3-fluoropyridine).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:27]([O-:29])=[O:28])[C:18]([NH:19][C@H:20]4[CH2:25][CH2:24][CH2:23][C@H:22]([OH:26])[CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[C:39](Cl)(=[O:41])[CH3:40]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:27]([O-:29])=[O:28])[C:18]([NH:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH:22]([O:26][C:39](=[O:41])[CH3:40])[CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1N[C@H]1CCC[C@H](O)C1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC1CCCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C

Procedure:
To a solution of Trans (racemic) 3-(1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-cyclohexanol (8.84 g, 21.2 mmol) dissolved in DCM (5 ml) was added N,N-diisopropylethylamine (3.88 ml, 22.28 mmol), followed by 4-Dimethylamino pyridine (420.3 mg, 3.44 mmol) at room temperature. To this was added Acetyl chloride (6.04 ml, 84.90 mmol) dropwise with stirring at room temperature. The mixture was stirred for 4 hours at room temperature and concentrated under reduced pressure to give an oil, which was used, as is, for the next step. LCMS (Method M, ESI): RT=3.07 min, m+H=459.3.
Reaction SMILES: [NH2:1][C:2]1[N:6](C)[N:5]=[C:4](C)[CH:3]=1.F[C:10]1[CH:27]=CC(C=C(C(=O)C(C)C)C(OCC)=O)=C[CH:11]=1>>[NH:6]1[C:2]2=[N:1][CH:11]=[CH:10][CH:27]=[C:3]2[CH2:4][NH:5]1
Reactant: Cc1cc(N)n(C)n1
Reactant: CCOC(=O)C(=Cc1ccc(F)cc1)C(=O)C(C)C
Product: c1cnc2c(c1)CNN2
Temperature: 130 °C

Procedure:
2.22 g (0.02 mol) of 5-amino-1,3-dimethylpyrazole and 5.3 g (0.02 mol) of ethyl 2-(4'-fluorobenzylidene)-4-methyl-3-oxo-pentanoate were mixed and heated at about 130° C. for one hour. Substances having a low boiling point were distilled off under reduced pressure by a rotary evaporator. Then, the reaction mixture was dissolved in chloroform, washed with a sodium carbonate aqueous solution and with water and dried over anhydrous magnesium sulfate. Chloroform was evaporated, and the residual oil was purified by silica gel column chromatography to obtain dihydropyrazolo[3,4-b]pyridine (XI 1).
Reaction SMILES: Cl.[O:2]([CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:19][S:20](O)(=[O:22])=[O:21]>ClCCl>[Cl:19][S:20]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[O:11])=[CH:4][CH:5]=1)(=[O:22])=[O:21]
Reactant: O=C(COc1ccccc1)Nc1ccccn1
Reactant: O=S(=O)(O)Cl
Agent: Cl
Solvent: ClCCl
Product: O=C(COc1ccc(S(=O)(=O)Cl)cc1)Nc1ccccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.32 g of 2-(phenoxyacetyl)aminopyridine HCl salt (5 mmole) was resuspended in 10 ml of dichloromethane and 2 ml of chlorosulfonic acid was added in ice-bath to give clear solution. The solution was stirred at room temperature for 3 hr. The reaction mixture was added to ice-water with good stirring to give white solids. The solids were filtered, washed with acetonitrile, and dried in vacuo. 0.65 g of solid was obtained. M. P. 170-175° C. (decomposition)
Reaction SMILES: [Na].[CH2:2]([OH:5])[CH:3]=[CH2:4].[Cl:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11](Cl)[CH:12]=1.CS(C)=O>O>[CH2:2]([O:5][C:11]1[CH:10]=[N:9][CH:8]=[C:7]([Cl:6])[CH:12]=1)[CH:3]=[CH2:4]
Reactant: Clc1cncc(Cl)c1
Reactant: C=CCO
Agent: [Na]
Solvent: CS(C)=O
Solvent: O
Product: C=CCOc1cncc(Cl)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Sodium (4.7 g, 203 mmol) was added to allyl alcohol (57.5 ml, 84.5 mmol). After complete reaction, the excess of allyl alcohol was evaporated. 3,5-Dichloropyridine (25.0 g, 169 mmol) and dimethyl sulfoxide (75 ml) were added to the crude mixture. The mixture was stirred at 60° C. overnight. Water (100 ml) was added followed by extraction twice with ethyl acetate (100 ml). The product was isolated in quantitative yield.
Reaction SMILES: [C:1]1([CH:7]2[NH:11][CH:10]([C:12](OCC3CC3)=[O:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:33])[NH:28][CH2:29][C:30]([OH:32])=[O:31])[CH:23]=[CH:24][CH:25]=1>ClCCCl.S(Cl)(Cl)=O>[CH3:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:33])[NH:28][CH2:29][C:30]([O:32][C:12](=[O:13])[C@@H:10]2[CH2:9][CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:11]2)=[O:31])[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(OCC1CC1)C1CCC(c2ccccc2)N1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: Cc1cccc(NC(=O)NCC(=O)OC(=O)[C@@H]2CCC(c3ccccc3)N2)c1

Procedure:
By proceeding in a fashion similar to that described in Example 1, but starting from 2 g of cyclopropyl-methyl (2RS,5SR)-5-phenylprolinate, 1.7 g of 2-[3-(3-methylphenyl)ureido]acetic acid in suspension in 50 cm3 of anhydrous 1,2-dichloroethane and 0.6 cm3 of sulphinyl chloride, 1.1 g of cyclopropylmethyl (2RS,5SR)-1-{2-[3-(3-methylphenyl)ureido}acetyl-5-phenylprolinate, melting at 130° C., are obtained after recrystallization in acetonitrile.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[N:11]=O.[OH-].[Na+].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[Pd].O>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[N:11]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cn1c(=O)[nH]c(N)c(N=O)c1=O
Reactant: O=Cc1ccccc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1c(=O)[nH]c(N)c(N=Cc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
6-amino-3-methyl-5-nitrosopyrimidine-2,4-dione (37.5 g=0.22 mol) with 10% palladium on carbon (Pd/C) (1.9 g) and 25% NaOH (25 ml) in 0.75L water. Hydrogenate at 50 psi for 3 hr, filter through Celite, and dilute to 1.5L with water. Adjust to pH 4.5 with HOAc and add benzaldehyde (35 g=0.34 mol). Add 0.5 kg ice, collect the solid, wash with water, then acetonitrile, and dry to give the title compound as a yellow powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:14][CH3:15])[C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[N:6][CH:7]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)C(C)C)(C)C.[C:47](#[N:50])[CH:48]=[CH2:49]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[CH3:15][O:14][C:4]1[CH:3]=[C:2](/[CH:49]=[CH:48]/[C:47]#[N:50])[CH:7]=[N:6][C:5]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1
Reactant: C=CC#N
Reactant: COc1cc(Br)cnc1-n1cnc(C)c1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(/C=C/C#N)cnc1-n1cnc(C)c1
Temperature: 110 °C
Reaction time: 5 h

Procedure:
A mixture of 5-bromo-3-methoxy-2-(4-methyl-1H-imidazol-1-yl)pyridine (3.8 g), tris(dibenzylideneacetone)dipalladium (650 mg), tri-o-tolylphosphine (433 mg), N,N-diisopropylethylamine (4.86 mL), DMF (14.1 mL) and acrylonitrile (2.82 mL) was stirred in a nitrogen atmosphere at 110° C. for five hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. The residue was diluted with ethyl acetate and then filtered through celite, and the filtrate was washed with water. The organic layer was concentrated under reduced pressure, and the precipitated crystals were hot dissolved in ethyl acetate. After leaving to cool to room temperature, the precipitated crystals were collected by filtration and air-dried to obtain 1.79 g of the title compound. The filtrate was concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography (heptane-ethyl acetate system) and then recrystallized from ethyl acetate to obtain 0.312 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=1.I[CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCCC1.CN1CCCN(C)C1=O.CN1CCCN(C)C1=O>[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]([CH2:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=1
Reactant: ICC1CCCC1
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: O=C(O)C(CC1CCCC1)c1cccc(Cl)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (141.3 mL of a 0.32M stock solution, 45.0 mmol) cooled to −78° C. was treated with (3-chloro-phenyl)-acetic acid (3.41 g, 20.0 mmol) in tetrahydrofuran/1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (49.7 mL, 3:1). The resulting reaction solution was stirred at −78° C. for 1 h. Iodomethylcyclopentane (4.64 g, 22.08 mmol) was then added in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4.64 mL). The reaction mixture was stirred at −78° C. for 4 h. The reaction was then warmed to 25° C. and was stirred at 25° C. for 48 h. The solution was then quenched by the slow addition of the reaction mixture to a 2N aqueous hydrochloric acid solution (50 mL). The product was extracted into ethyl acetate (1×150 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 85/15 hexanes/ethyl acetate) afforded 2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid (3.68 g, 72.9%) as a yellow solid: mp 70-72° C.; EI-HRMS m/e calcd for C14H17ClO2 (M+) 252.0917, found 252.0915.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:27]=[C:28]([C:32]([OH:34])=O)[CH:29]=[N:30][CH:31]=1.CCN(C(C)C)C(C)C.[CH3:44][C@@H:45]1[NH:50][CH2:49][CH2:48][N:47]([S:51]([C:54]2[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:56][CH:55]=2)(=[O:53])=[O:52])[CH2:46]1>CN(C=O)C>[Br:25][C:26]1[CH:27]=[C:28]([C:32]([N:50]2[CH2:49][CH2:48][N:47]([S:51]([C:54]3[CH:55]=[CH:56][C:57]([C:60]([F:63])([F:61])[F:62])=[CH:58][CH:59]=3)(=[O:52])=[O:53])[CH2:46][C@@H:45]2[CH3:44])=[O:34])[CH:29]=[N:30][CH:31]=1
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Reactant: O=C(O)c1cncc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
HATU (458 mg, 1.21 mmol) was added to a solution of 5-bromo-3-pyridinecarboxylic acid (supplied by Aldrich) (203 mg, 1.01 mmol) in DMF (4 ml) and the mixture was treated with DIPEA (0.438 ml, 2.51 mmol). This mixture was stirred for ca. 10 min at ambient temperature. (3S)-3-Methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Description 2) (372 mg, 1.21 mmol) was added and stirring was continued for 1.5 h. The reaction mixture was partitioned between DCM and sat aq. NaHCO3 solution (20 ml each). The layers were separated and the aqueous was washed with further DCM (2×20 ml). The combined organic layers were concentrated to leave an dark brown gum.