Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[CH:6][CH2:5][C:4]([CH3:9])([CH3:8])[CH:3]1[C:10](=[O:14])[CH:11]=[CH:12][CH3:13].[NH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][CH2:25][CH2:26][NH2:27]>C(O)C>[CH3:13][CH:12]([NH:27][CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][CH2:16][NH:15][CH:12]([CH3:13])[CH2:11][C:10]([CH:3]1[C:4]([CH3:9])([CH3:8])[CH2:5][CH:6]=[CH:7][CH:2]1[CH3:1])=[O:14])[CH2:11][C:10](=[O:14])[CH:3]1[C:4]([CH3:8])([CH3:9])[CH2:5][CH:6]=[CH:7][CH:2]1[CH3:1]
Reactant: NCCCNCCCNCCCN
Reactant: CC=CC(=O)C1C(C)C=CCC1(C)C
Solvent: CCO
Product: CC(CC(=O)C1C(C)C=CCC1(C)C)NCCCNCCCNCCCNC(C)CC(=O)C1C(C)C=CCC1(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 0° C. stirred solution of 96 g (0.50 mol) of 1-(2,6,6-trimethyl-cyclohex-3-enyl)-but-2-en-1-one (δ-damascone) in 250 mL of ethanol is added 47 g (0.25 mol) of N1-[3-(3-Amino-propylamino)-propyl]-propane-1,3-diamine. The reaction is allowed to warm to room temperature. After stirring for 24 h, the ethanol is concentrated by rotary evaporation to give 3-[3-(3-{3-[1-methyl-3-oxo-3-(2,6,6-trimethyl-cyclohex-3-enyl)-propylamino]-propylamino}-propylamino)-propylamino]-1-(2,6,6-trimethyl-cyclohex-3-enyl)-butan-1-one (bis-Michael adduct 14) as an oil.
Reaction SMILES: Cl.[C:2]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]([C:18]([NH:20][C@H:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH2:22][OH:23])=[O:19])[NH2:17])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C(N([CH2:37][CH3:38])CC)C>C(Cl)Cl>[C:2]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]([C:18]([NH:20][C@H:21]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)[CH2:22][OH:23])=[O:19])[NH:17][C:22](=[O:23])[CH:21]([C:38]1[CH:37]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:3]
Reactant: CCN(CC)CC
Reactant: COc1ccc([C@H](CO)NC(=O)[C@H](N)CCCNC(=O)OCc2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc([C@H](CO)NC(=O)[C@@H](CCCNC(=O)OCc2ccccc2)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Yield: 28 %

Procedure:
Prepared according to the method described in Example 1(d) above from (R)-N5 -(Cbz)-(R)-N-[2-hydroxy-1-(4-methoxyphenyl)ethyl]ornithine amide hydrochloride (3.33 g; 7.37 mmol; from step (b) above), 2-nitrophenyl diphenyl acetate (2.60 g; 8.10 mmol; see Example 1(c) above), triethylamine (2.23 g; 22.11 mmol) and CH2Cl2 (200 mL), reaction time 60 hours. The resulting yellow solution was submitted to aqueous work up, dried, filtered and concentrated to give the crude product as an off-white solid (4.76 g). The crude product was chromatographed twice on silica gel eluting with CH2Cl2 :MeOH (98:2). Concentration of the product containing fractions gave the sub-title compound as a white solid (0.63 g).
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9](O)(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].Cl.[C:15]1([N:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22](=[O:25])[NH:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([N:21]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:22](=[O:25])[NH:23][N:24]=[C:9]2[C:10](=[O:11])[C:4]3[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=3)[C:7]2=[O:8])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: NNC(=O)N(c1ccccc1)c1ccccc1
Agent: Cl
Product: O=C(NN=c1c(=O)c2ccccc2c1=O)N(c1ccccc1)c1ccccc1

Procedure:
ninhydrin, 4,4-diphenyl semicarbazide hydrochloride
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH2:8][CH2:7][C:6]2([CH3:15])[CH3:14])#[CH:2].[CH2:16]([O:18][C:19](=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][C:22]=1[F:28])[CH3:17].C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:16]([O:18][C:19](=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]#[C:1][C:3]2[CH:12]=[CH:11][C:10]3[C:9](=[O:13])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=3[CH:4]=2)=[CH:23][C:22]=1[F:28])[CH3:17]
Reactant: CCOC(=O)Cc1ccc(I)cc1F
Reactant: C#Cc1ccc2c(c1)C(C)(C)CCC2=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1F

Procedure:
Following general procedure F and using 6-ethynyl-4,4-dimethyl-1,2,3,4-tetrahydro-naphthalene-1-one (Intermediate 13, 0.298 g, 1.43 mmol), 2-fluoro-4-iodo Phenyl Acetic Acid ethyl ester (Reagent C, 0.44 g, 1.43 mmol), triethyl amine (Intermediate 13, 3 mL), anhydrous tetrahydrofiran (7 mL), copper(I)iodide (0.04 g, 0.2 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.15 g, 0.213 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 14-16% ethyl acetate in hexane as the eluent, the title compound was obtained as an oil (0.43 g, 77%).
Reaction SMILES: P(Cl)(Cl)Cl.[C:5]([O:9][C:10](=[O:31])[C@H:11]([CH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)([CH3:8])([CH3:7])[CH3:6].[CH2:32]([NH:50][C:51]([O:53][CH:54]([CH2:62][O:63][C:64](=[O:84])[NH:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH3:83])[CH2:55][S:56][CH2:57][CH2:58][C:59](O)=[O:60])=[O:52])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]>N1C=CC=CC=1>[C:5]([O:9][C:10](=[O:31])[C@H:11]([CH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:59](=[O:60])[CH2:58][CH2:57][S:56][CH2:55][CH:54]([O:53][C:51](=[O:52])[NH:50][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH2:62][O:63][C:64](=[O:84])[NH:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH3:83])=[CH:16][CH:15]=1)([CH3:7])([CH3:8])[CH3:6]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CSCCC(=O)O)OC(=O)NCCCCCCCCCCCCCCCCCC
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(N)cc1)C(=O)OC(C)(C)C
Solvent: ClP(Cl)Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CSCCC(=O)Nc1ccc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OC(=O)NCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
To a solution of phosphorus trichloride (19 mg) in pyridine (4 ml), 4-aminobenzoyl-glutamic acid di-t-butyl ester (106 mg) was added, followed by stirring at room temperature for 1 hour. To this mixture, 6,7-bis(octadecylcarbamoyloxy)-4-thiaheptanoic acid as obtained in Reference Example 10 (216 mg) was added, followed by stirring at 50° C. for 1 hour. After solvent concentration under reduced pressure, the resulting residue was purified by silica gel preparative TLC (dichloromethane:methanol=50:1×3) to yield the title compound (102 mg, yield 32%) as a colorless solid.
Reaction SMILES: O.[OH-].[Li+].[F:4][CH2:5][CH:6]([O:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=1)[C:13]([O:15]C)=[O:14])[CH2:7][F:8]>O.C1COCC1>[F:4][CH2:5][CH:6]([O:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=1)[C:13]([OH:15])=[O:14])[CH2:7][F:8]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(OC(CF)CF)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(OCc2ccccc2)cc(OC(CF)CF)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
A solution of lithium hydroxide monohydrate (2.32 g, 55.1 mmol) in water (100 mL) was added to a solution of methyl 3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-[(phenylmethyl)oxy]benzoate (7.41 g, 22.0 mmol) in THF (200 mL) and the mixture allowed to stir at RT overnight. The THF was removed in vacuo and the resulting solution partitioned between water (100 mL) and ethyl acetate (250 mL). The ethyl acetate layer was separated, washed with brine and dried (MgSO4). The aqueous layer was then adjusted to pH 7 by addition of 1M hydrochloric acid and extracted with ethyl acetate (75 mL). The ethyl acetate layer was separated, washed with brine and dried (MgSO4). The ethyl acetate layers were combined and evaporated to give the required product (6.404 g).
Reaction SMILES: C(=O)([O-])O.[NH4+:5].Cl[CH2:7][C:8]([NH:10][C@H:11]([C:20]([OH:22])=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:9]>N.O>[NH2:5][CH2:7][C:8]([NH:10][C@H:11]([C:20]([OH:22])=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)=[O:9]
Reactant: O=C(CCl)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: [NH4+]
Agent: N
Agent: O=C([O-])O
Solvent: O
Product: NCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Temperature: 40 °C
Reaction time: 5 h

Procedure:
Ammonium hydrogencarbonate (1289 g) was dissolved in a mixture of 4000 ml of 28% aqueous ammonia and 1000 ml of distilled water at 35° C. To the solution were added 700 g (2.72 mol) of N-chloroacetyl-L-tyrosine and 700 ml of distilled water, followed by stirring at 40° C. for 5 hours. The reaction mixture was concentrated under reduced pressure to remove excess ammonia and then adjusted to pH 5.5 with concentrated hydrochloric acid at 45° C., followed by gradual cooling. After crystals were deposited, the mixture was ice-cooled and the crystals were isolated by filtration to give 600 g (489 g on anhydrous basis, 2.05 mol, 75.4%) of crude crystals of N-glycyl-L-tyrosine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[CH2:9][NH:10][C:11]([CH:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]2)=[O:12])=[CH:4][CH:3]=1.C[CH2:24][OH:25].C(=O)(O)[O-].[Na+].C=O>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:22])[CH:9]([NH:10][C:11]([CH:13]2[CH2:14][CH2:15][N:16]([C:19](=[O:21])[CH3:20])[CH2:17][CH2:18]2)=[O:12])[CH2:24][OH:25])=[CH:6][CH:7]=1
Reactant: CC(=O)N1CCC(C(=O)NCC(=O)c2ccc(F)cc2)CC1
Reactant: CCO
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)N1CCC(C(=O)NC(CO)C(=O)c2ccc(F)cc2)CC1
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
To a 250 mL 3-neck flask under n2 is added 8.00 g (26.1 mmol) of 1-Acetyl-piperidine-4-carboxylic acid [2-(4-fluoro-phenyl)-2-oxo-ethyl]amide, prepared as in Part A, to a 3:1 solution of EtOH:H2O (40 mL). While stirring the resultant solution at room temperature, 500 mg (5.95 mmol) of sodium bicarbonate is added followed by subsequent addition of 4.24 mL (52.23 mmol) of 37% formaldehyde over 5 min. The mixture is stirred for 1.5 h and then 20 mL of H2O is added. The reaction is cooled to -5° C. at which point a precipitate formed and is filtered. The mother liquor is again cooled to give a second crop of product and the combined lots are dried in-vacuo overnight at 65° C. to yield 1-Acetyl-piperidine-4-carboxylic acid [2-(4-fluoro-phenyl)-1-hydroxymethyl-2-oxo-ethyl]-amide as a white solid.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][S:19]([C:22]2[S:23][C:24]([Cl:27])=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[O:17])=[CH:11][C:10]=1[CH3:28])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][S:19]([C:22]2[S:23][C:24]([Cl:27])=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[O:17])=[CH:11][C:10]=1[CH3:28]
Reactant: Cc1cc(NC(=O)NS(=O)(=O)c2ccc(Cl)s2)ccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(NC(=O)NS(=O)(=O)c2ccc(Cl)s2)ccc1N
Reaction time: 1.5 h
Yield: 136.7 %

Procedure:
To a chilled solution of N-{4-[(tert-butoxy)carbonylamino]-3-methylphenyl}{[(5-chloro(2-thienyl))sulfonyl]amino}carboxamide (0.246 g, 0.55 mmol) in CH2Cl2 (5 mL) was added neat TFA (1.11 mL). The reaction mixture was stirred cold for 1.5 hr, concentrated in vacuo, azeotroped with heptane and dried to give N-(4-amino-3-methylphenyl){[(5-chloro(2-thienyl))sulfonyl]amino}-carboxamide (0.26 g) as the mono TFA salt. ES-MS (M+H)+=346.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([NH2:14])[C:11]([C:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH:18]2[CH2:22][OH:23])=[O:16])=[CH:10][C:9]=1[O:24][CH3:25].N1C=CC=CC=1.Cl[C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([NH:14][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[C:11]([C:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH:18]2[CH2:22][OH:23])=[O:16])=[CH:10][C:9]=1[O:24][CH3:25]
Reactant: C=CCOC(=O)Cl
Reactant: COC(=O)CCCOc1cc(N)c(C(=O)N2CCCC2CO)cc1OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)Nc1cc(OCCCC(=O)OC)c(OC)cc1C(=O)N1CCCC1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A batch of the amine 15 (22.5 g, 61.5 mmol) was dissolved in anhydrous DCM (300 mL) in the presence of anhydrous pyridine (10.9 mL, 134 mmol) at 0° C. Allyl chloroformate (7.17 mL, 67.5 mmol) diluted in anhydrous DCM (200 mL) was added dropwise at 0° C. The resulting solution was allowed to stir overnight at room temperature. It was then washed with cold 1N aqueous HCl (200 ml), water (200 mL), saturated aqueous NaHCO3 (200 mL), and brine (200 mL). The solution was then dried (MgSO4), and the solvent was removed in vacuo to provide 16, slightly contaminated by the product of diacylation (27 g, quantitative yield). A sample was columned (EtOAc/Hexane) to provide the analytical data. 1H NMR (CDCl3) δ 8.78 (1H, bs), 7.75 (1H, s), 6.82 (1H, s), 5.97 (1H, m), 5.38-5.34 (1H, dd, J=1.5, 17.2 Hz), 5.27-5.24 (1H, dd, J=1.3, 10.4 Hz, 1H), 4.63 (2H, m), 4.40 (2H, bs), 4.11 (2H, t, J=6.3 Hz), 3.82 (3H, s), 3.69 (4H, m), 3.61-3.49 (2H, m), 2.54 (2H, t, J=7.4 Hz), 2.18 (2H, p, J=6.7 Hz), 1.92-1.70 (4H, m); 13C NMR (CDCl3) δ 173.4, 170.9, 153.6, 150.5, 144.0, 132.5, 132.0, 118.1, 115.4, 111.6, 105.6, 67.7, 66.6, 65.8, 61.1, 60.4, 56.6, 51.7, 30.5, 28.3, 25.1, 24.3; MS (FAB+) m/z 50 (451, M+H); IR (golden gate) vmax 2949, 2359, 1728, 1596, 1521, 1433, 1202, 1173, 1119, 998, 844, 652 cm−1; [α]26D=−67° (c=0.45, CHCl3).
Reaction SMILES: [ClH:1].[C:2]([CH:5]([CH2:17]O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)([OH:4])=[O:3]>P(=O)(O)(O)O>[ClH:1].[C:2]([C:5](=[CH2:17])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1)([OH:4])=[O:3]
Reactant: O=C(O)C(CO)CCCCCCn1ccnc1
Agent: Cl
Agent: O=P(O)(O)O
Product: C=C(CCCCCCn1ccnc1)C(=O)O
Yield: 46.4 %

Procedure:
To 180 mg of 1-(7-carboxy-7-hydroxymethylheptyl)imidazole hydrochloride (prepared in Example 6(b)) was added 2 or 3 drops of phosphoric acid, and the mixture was reacted under reduced pressure at 160° C. for 5 hours. The reaction mixture was purified by column chromatography on cellulose using a mixture of n-butanol, water and acetic acid (8:10:1), and the obtained fraction was adjusted to pH 8 with a 1 N solution of sodium hydride in order to remove the contaminated phosphoric acid, and the resulting crystals was removed off. The same purification by column chromatography on cellulose was repeated to give 78 mg of the title compound having the following physical characteristics:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[NH:10][CH:9]=[C:8]([C:11]([O:13]CC)=[O:12])[C:7](=[O:16])[N:6]2[CH:17]=1)[CH3:2].[OH-].[Na+]>CO>[CH2:1]([C:3]1[CH:4]=[C:5]2[NH:10][CH:9]=[C:8]([C:11]([OH:13])=[O:12])[C:7](=[O:16])[N:6]2[CH:17]=1)[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2cc(CC)cn2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc2[nH]cc(C(=O)O)c(=O)n2c1
Temperature: 25 °C

Procedure:
Ethyl 7-ethyl-4-oxo-1,4-dihydropyrrolo[1,2-a]pyrimidine-3-carboxylate (0.63 g, 2.711 mmol) was dissolved in a solution of methanol (8 mL)/sodium hydroxide (13.56 mL, 2.0 M, 27.11 mmol) and heated at reflux for 3 hours. The mixture was allowed to cool to room temperature and methanol was removed in vacuo. The aqueous solution was cooled to 0° C. and concentrated HCl was slowly added until a precipitate formed (pH 4). The precipitate was filtered, washed with water and dried to give 7-ethyl-4-oxo-1,4-dihydropyrrolo[1,2-a]pyrimidine-3-carboxylic acid; 0.43 g (77%). LC/MS (10-99% CH3CN/0.05% TFA in H2O/0.05% TFA gradient over 3 min): M+H m/z 207.1, retention time 1.10 minutes. 1H NMR (400.0 MHz, DMSO) δ 13.42 (bs, 1H), 12.89 (bs, 1H), 8.51 (s, 1H), 7.29 (t, J=0.8 Hz, 1H), 6.17 (d, J=1.8 Hz, 1H), 2.61-2.50 (m, 2H) and 1.20 (t, J=7.5 Hz, 3H).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH:9]([C:25]1[N:26]=[N:27][N:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[N:29]=1)[C:10]([NH:12][C:13]1[C:18]([CH:19]([CH3:21])[CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=1[CH:22]([CH3:24])[CH3:23])=[O:11].[C:42](Cl)(=[O:44])[CH3:43]>C1COCC1.C(OCC)(=O)C>[CH:22]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([CH:19]([CH3:21])[CH3:20])[C:13]=1[NH:12][C:10](=[O:11])[CH:9]([C:25]1[N:26]=[N:27][N:28]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[N:29]=1)[NH:8][C:42](=[O:44])[CH3:43])([CH3:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: CCCCCCCCCCCCn1nnc(C(N)C(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCn1nnc(C(NC(C)=O)C(=O)Nc2c(C(C)C)cccc2C(C)C)n1
Temperature: 24 °C
Reaction time: 0.25 h
Yield: 46.1 %

Procedure:
Triethylamine (0.27 g, 2.75 mmol) was added in one portion to a stirred solution of 1.3 g (2.75 mmol) of (±)-N-(2,6-diisopropylphenyl)-2-(2-dodecyl-2H-tetrazol -5-yl)-2-amino-acetamide (prepared as in Example 10) in 50 mL of THF. To the solution was added in one portion 0.23 g (3.0 mmol) of acetyl chloride. The mixture was stirred at 24° C. for 15 minutes, diluted with 50 mL of ethyl acetate, washed with 50 mL of 1N hydrochloric acid, then with 50 mL of 1N sodium hydroxide, brine, and finally dried over MgSO4. The solution was filtered and concentrated by removing the solvents in vacuo to afford an oil. The oil was further purified by chromatography over silica gel (eluting with 1:1 ethyl acetate/hexane) to provide 0.65 g of (±)-N-(2,6-diisopropylphenyl)-2-(2-dodecyl-2H-tetrazol -5-yl)-2-acetylamino-acetamide;
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][CH2:12][CH2:11]3)[CH2:5][C:4](=[O:17])[CH:3]=1.N1C=CC=CC=1.[C:24](Cl)(=[O:27])[CH2:25][CH3:26].[Cl-].[Cl-].[Cl-].[Al+3].Cl>ClCCl.ClCCCl.O>[OH:17][C:4]1[CH2:5][CH:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[CH2:13][CH2:12][CH2:11]3)[CH2:7][C:2](=[O:1])[C:3]=1[C:24](=[O:27])[CH2:25][CH3:26]
Reactant: CCC(=O)Cl
Reactant: O=C1C=C(O)CC(c2ccc3c(c2)CCC3)C1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: ClCCCl
Product: CCC(=O)C1=C(O)CC(c2ccc3c(c2)CCC3)CC1=O
Reaction time: 1 h

Procedure:
A mixture of 3-hydroxy-5-(5-indanyl)cyclohex-2-en-1-one (5.0 g; 22 mmole) in dichloromethane (100 ml) and pyridine (1.74 g; 22 mmole) was stirred at room temperature whilst propionyl chloride (1.92 g; 22 mmole) was added dropwise over a period of two minutes. Stirring was continued for 1 hour after which the organic solution was washed with water (2×100 ml), dried over anhydrous sodium sulphate, and the solvent was removed under reduced pressure using a rotary evaporator. The resulting brown oil was immediately dissolved in 1,2-dichloroethane (50 ml) and added dropwise to a mixture of aluminium trichloride (5.85 g; 44 mmole) in 1,2-dichloroethane (50 ml) over 30 min at such a rate that the temperature did not exceed 30° C. After stirring for 30 min at room temperature, the solution was poured into 100 ml of a 1:1 mixture of concentrated hydrochloric acid and water. The organic solution was washed with water (2×200 ml), dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure using a rotary evaporator. The resulting yellow oil was purified by chromatography over silica gel (eluant dichloromethane) to give 3-hydroxy-5-(5-indanyl)-2-propionylcyclohex-2-en-1-one, (1.71 g; 27%) as a yellow solid, mp 98° C.
Reaction SMILES: ClC1C=C(C=CC=1NC(=O)CC1CCCC1)C(NC1SC=CN=1)=O.ClC[O:27][C:28]([CH:30]1[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]1)=[O:29]>>[NH:33]1[CH2:34][CH2:35][CH:30]([C:28]([OH:29])=[O:27])[CH2:31][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)OCCl)CC1
Agent: O=C(CC1CCCC1)Nc1ccc(C(=O)Nc2nccs2)cc1Cl
Product: O=C(O)C1CCNCC1

Procedure:
Prepared from 3-chloro-4-(2-cyclopentyl-acetylamino)-N-thiazol-2-yl-benzamide and piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-chloromethyl ester followed by deprotection.
Reaction SMILES: C([O:8][C:9]1[C:14]([O:15]CC2C=CC=CC=2)=[C:13]([O:23][CH3:24])[CH:12]=[CH:11][C:10]=1[C:25]([C:27]1[C:33]2[CH:34]=[C:35]([O:42][CH3:43])[C:36]([O:40][CH3:41])=[C:37]([O:38][CH3:39])[C:32]=2[CH2:31][CH2:30][CH2:29][CH:28]=1)=[O:26])C1C=CC=CC=1.C1CC=CCC=1.CC(=O)OCC>CCO.[Pd]>[OH:8][C:9]1[C:14]([OH:15])=[C:13]([O:23][CH3:24])[CH:12]=[CH:11][C:10]=1[C:25]([C:27]1[C:33]2[CH:34]=[C:35]([O:42][CH3:43])[C:36]([O:40][CH3:41])=[C:37]([O:38][CH3:39])[C:32]=2[CH2:31][CH2:30][CH2:29][CH:28]=1)=[O:26]
Reactant: COc1ccc(C(=O)C2=CCCCc3c2cc(OC)c(OC)c3OC)c(OCc2ccccc2)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1=CCC=CC1
Solvent: CCO
Product: COc1ccc(C(=O)C2=CCCCc3c2cc(OC)c(OC)c3OC)c(O)c1O
Temperature: 25 °C
Reaction time: 7 h
Yield: 63 %

Procedure:
95 (0.69 g, 1.19 mmol) was dissolved in 20 mL of anhydrous EtOH under nitrogen and the reaction mixture was immersed in a water bath to maintain a temperature of 25° C. 1.2 g of Pd—C was added followed by 1,4-cyclohexadiene (1.13 mL, 11.90 mmol) and the reaction mixture was stirred for 7 h. The reaction mixture was monitored for completion by TLC (Rf: 0.32, 60:40 Hex:EA). The reaction mixture was filtered through celite, washed with ethylacetate, rotavaped and purified by column chromatography (20:80 EtOAc:Hexanes) to obtain 0.3 g (63%) of 23 as yellow oil.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:21][CH2:22][CH:23]1[CH:27]([CH3:28])[CH2:26][NH:25][CH2:24]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:21][CH2:22][CH:23]1[CH:27]([CH3:28])[CH2:26][N:25]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:16])[CH2:24]1
Reactant: CC1CNCC1CN
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1CN
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.6 g), anhydrous acetonitrile (5 ml), 3-aminomethyl-4-methylpyrrolidine (0.29 g) and DBU (0.33 g) was refluxed for an hour and then stirred at room temperature for 2 hours and allowed to stand overnight. The resulting precipitate was collected by filtration and recrystallized from chloroform-methanol-concentrated aqueous ammonia (10:10:1) to give the title compound (0.45 g) as colorless prisms, mp 249°-252.5° C.
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)(Cl)Cl>[CH3:1][O:2][CH:3]=[CH:4][CH2:5][C:6]12[O:20][CH:7]1[CH:8]=[CH:9][CH:10]=[CH:11]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC=CCc1ccccc1
Solvent: ClC(Cl)Cl
Product: COC=CCC12C=CC=CC1O2
Reaction time: 55 h
Yield: 109 %

Procedure:
22.2 g of o-methoxyallylbenzene was dissolved in 200 ml of chloroform and to the mixture was added dropwise, while maintaining the temperature at 0° - 5° C, 31.3 g of m-chloroperbenzoic acid dissolved in 1l of chloroform. The thus obtained mixture was allowed to stand for 55 hours at the same temperature. After separated m-chlorobenzoic acid was filtered off, the filtrate was washed with 5% sodium hydroxide solution, then with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtained the residue, which was distilled under reduced pressure, there was obtained 26.8 g (yield 54.5%) of o-methoxyallylbenzene oxide having a boiling point of 88.5° - 89.5° C/1 mmHg.