Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][NH:11]C(=O)OC(C)(C)C)=[CH:8][N:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2].[ClH:19]>C(Cl)Cl>[ClH:19].[ClH:19].[CH:1]([C:4]1[C:9]([CH2:10][NH2:11])=[CH:8][N:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ncncc1CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)c1ncncc1CN
Temperature: 0 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
tert-Butyl ((4-isopropylpyrimidin-5-yl)methyl)carbamate (1.0 equiv.) was combined in DCM (3.8 M) and cooled to 0° C. Hydrogen chloride (4 M) in dioxanes (3.1 equiv.) was then added via syringe. The solution was allowed to stir at ambient temperature. After 5 h, additional solution of hydrogen chloride (4 M) in dioxanes was added and stirring continued. After another 2 h, the volatile organic solvents were removed under reduced pressure to afford (4-isopropylpyrimidin-5-yl)methanamine dihydrochloride (95% yield) as a bis hydrochloride salt. MS (ESI) m/z 151.3 [M+1]+.
Reaction SMILES: [OH:1][C:2]1([C:14](O)=[O:15])[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH2:3]1.C(OCC)(=O)C.O.Cl>O1CCCC1>[OH:1][C:2]1([CH2:14][OH:15])[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH2:7]1
Reactant: O=C(O)C1(O)C=CC(c2ccccc2)=CC1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCC1(O)C=CC(c2ccccc2)=CC1
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To a solution of 4-hydroxy-4-biphenylcarboxylic acid (2.14 g) in tetrahydrofuran (25 ml) under an argon atmosphere was added slowly 1M borane-THF complex (50 ml). The resulting mixture was stirred for 18 hours before the addition of ethyl acetate (10 ml) and water (100 ml). The resulting mixture was acidified with 2N hydrochloric acid and stirred for 30 minutes. The aqueous layer was extracted with ethyl acetate (2×100 ml). The organic extracts were combined, dried (MgSO4) and evaporated . Recrystallisation from a small volume of ethyl acetate gave 4-hydroxy-4-biphenylmethanol (580 mg): NMR (d6DMSO), δ4.5(s,2H), 6.85(d,2H), 7.35(d,2H), 7.45-7.55(dd,4H), 9.45(s,1H); m/e 201(M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19].[Cl-].C([NH+](CC)CC)C.[OH-].[Na+]>O1CCCC1.O>[CH:15]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[CH:16][CH2:17][CH2:18][CH3:19]
Reactant: C=CCCCBr
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC=Cn1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 69 %

Procedure:
Carbazole (30.1 g, 0.18 mol), 5-bromo-1-pentene (25.5 g, 0.17 mol), and triethylammonium chloride (6 g, 0.026 mol) were combined in tetrahydrofuran (200 mL), and a solution of sodium hydroxide (14 g, 0.35 mol) in water (60 mL) was added. The mixture was heated at reflux with stirring for 6 hours, then cooled to room temperature and left overnight. The aqueous layer was separated and the organic phase was concentrated to dryness. The crude product was redissolved in diethyl ether (100 mL) and washed with water (2×50 mL), dried (Na2SO4,) and then concentrated in vacuo. Recrystallization from methanol afforded N-pentenyl-carbazole as cream-colored needles (27.6 g, 65%), m.p.=47° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]C)=O.[NH2:19][C:20]1[C:21](=[O:28])[CH:22]=[CH:23][CH:24]=[C:25]([CH3:27])[CH:26]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:14])[C:3]=1[C:15]([NH:19][C:20]1[C:21](=[O:28])[CH:22]=[CH:23][CH:24]=[C:25]([CH3:27])[CH:26]=1)=[O:17]
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reactant: Cc1cccc(=O)c(N)c1
Solvent: Cc1ccccc1C
Product: Cc1cccc(=O)c(NC(=O)C2=C(O)c3ccccc3S(=O)(=O)N2C)c1
Reaction time: 8 h
Yield: 24.1 %

Procedure:
A solution of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (2.4 g) and 2-amino-4-methyl-2,4,6-cycloheptatrien-1-one (1.3 g) in xylene (50 ml) is refluxed for 7 hours. The reaction mixture is then allowed to stand at room temperature overnight. The resulting crystals (1.0 g) are collected by filtration and recrystallized from dioxane to give 4-hydroxy-2-methyl-N-(4-methyl-1-oxo-2,4,6-cycloheptatrien-2-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (0.8 g), m.p. 235°-242° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH2:11][CH3:12])[S:4]([N:7]=[C:8]=[S:9])(=[O:6])=[O:5])[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:23][NH:22][N:21]=2)=[CH:16][CH:15]=1>ClCCl>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:23][N:22]([C:8](=[S:9])[NH:7][S:4]([N:3]([CH2:1][CH3:2])[CH2:10][CH2:11][CH3:12])(=[O:6])=[O:5])[N:21]=2)=[CH:18][CH:19]=1
Reactant: CCCN(CC)S(=O)(=O)N=C=S
Reactant: Clc1ccc(C2=NNCC2c2ccccc2)cc1
Solvent: ClCCl
Product: CCCN(CC)S(=O)(=O)NC(=S)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Reaction time: 1.5 h
Yield: 55.6 %

Procedure:
Part A: To a stirred solution of ((ethyl)propylamino)sulfonyl isothiocyanate (5.98 gram, 25.4 mmol) in dry dichloromethane in a nitrogen atmosphere is added of 3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazole (6.52 gram, 25.4 mmol). After stirring for 90 minutes the resulting solution is concentrated in vacuo and purified by column chromatography (CH2Cl2, silicagel, Rf ˜0.45). The resulting solid is recrystallized from diethyl ether to give 3-(4-chlorophenyl)-N-(((ethyl)propylamino)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyra-zole-1-thiocarboxamide (6.57 gram, 56% yield). Melting point: 144-146° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])=[CH:6][CH:5]=1)([O-])=O>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])=[CH:6][CH:5]=1
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(NC(=O)OC(C)(C)C)c1ccc(N)cc1
Reaction time: 3 h

Procedure:
A suspension of 10% Pd/C (1.25 g) and tert-butyl (1-(4-nitrophenyl)ethyl)carbamate (A130) (3.78 g, 14.2 mmol) in EtOAc (50 mL) was stirred under a hydrogen atmosphere for 3 hours. The resulting solution was filtered through a pad of Celite, washing with EtOAc, then the filtrate was concentrated in vacuo to give the title compound A131 as a viscous oil (3.01 g, 89%); 1H NMR (300 MHz, CDCl3) δ 7.11 (d, J=8.1 Hz, 2H), 6.70 (d, J=8.0 Hz, 2H), 4.70 (brs, 2H), 1.44 (m, 14H). LCMS-B: 4.444 min; m/z 237 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH3:10][O:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:14]([N:16]=[C:17]=[O:18])=[O:15].C([O-])(=O)/C=C/C([O-])=O>>[N:4]12[CH2:9][CH2:8][CH:7]([CH2:6][CH2:5]1)[C@H:2]([NH:1][C:17]([NH:16][C:14](=[O:15])[C:13]1[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=1[O:11][CH3:10])=[O:18])[CH2:3]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: COc1ccccc1C(=O)N=C=O
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: COc1ccccc1C(=O)NC(=O)N[C@@H]1CN2CCC1CC2

Procedure:
The above compound was prepared, following the procedure of Example 1, from (S)-3-aminoquinuclidine (0.63 g, 5 mmol) and 2-methoxybenzoyl isocyanate (1.26 g, 7 mmol). The product (1.44 g) was converted to the 1:1 fumarate, mp 158°-159° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14](=[O:16])[CH3:15])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:19]=1[C:20](O)=[O:21]>>[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:19]=1[C:20]([N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([C:14](=[O:16])[CH3:15])=[CH:3][C:2]=2[F:1])[CH2:9][CH2:10]1)=[O:21]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3Cl)CC2)c(F)c1

Procedure:
The title compound was prepared according to the procedure D described for example 2 from 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone and 2-chloro-5-nitro-benzoic acid (CAS: 2516-96-3); MS (ISP): 406.2 MH+.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C@H:8]([CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][CH:24]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]5[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=5)=[CH:30][CH:29]=4)[CH2:23][CH2:22]3)=[CH:17][CH:16]=1)[O:7]2)([O-:3])=[O:2].C=O.[C:48]([BH3-])#N.[Na+].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.CO>[CH3:48][N:27]([CH:24]1[CH2:25][CH2:26][N:21]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@@H:8]3[O:7][C:6]4=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][N:11]4[CH2:10][CH2:9]3)=[CH:16][CH:17]=2)[CH2:22][CH2:23]1)[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=2)=[CH:30][CH:29]=1
Reactant: O=[N+]([O-])c1cn2c(n1)O[C@@H](COc1ccc(N3CCC(Nc4ccc(OCc5ccc(C(F)(F)F)cc5)cc4)CC3)cc1)CC2
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(c1ccc(OCc2ccc(C(F)(F)F)cc2)cc1)C1CCN(c2ccc(OC[C@H]3CCn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
N-{1-[4-((R)-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-7-ylmethoxy)phenyl]piperidin-4-yl}-N-[4-(4-trifluoromethylbenzyloxy)phenyl]amine (0.40 g) and methanol (3 ml) were mixed. A 37% formaldehyde aqueous solution (0.47 g), sodium cyanoborohydride (0.36 g) and acetic acid (3 ml) were added to the mixture and stirred at room temperature overnight. The reaction mixture was added to a potassium carbonate aqueous solution, followed by extraction with methylene chloride. The organic layer was washed with water and dried over sodium sulfate. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride:methanol=1:0→methylene chloride:methanol=9:1) to afford the title compound as a yellow powder (0.26 g).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:20]([O:22][C:23](=[O:28])[CH2:24][C:25]([OH:27])=O)[CH3:21].CCN=C=NCCCN(C)C.Cl.[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42]>CN(C=O)C.O>[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][N:51]([C:25](=[O:27])[CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:28])[CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:42])[CH3:43]
Reactant: CCOC(=O)CC(=O)O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 10 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
HOBt (3.48 g, 25.8 mmol) and DIPEA (6.94 g, 53.8 mmol) were added to a stirred solution of malonic acid monoethyl ester (2.84 g, 21.5 mmol) in DMF (10 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (4.95 g, 25.8 mmol) followed by piperazine-1-carboxylic acid tert-butyl ester (4 g, 21.5 mmol) were added. The reaction mixture was stirred at room temperature overnight then diluted with water. The product was extracted with ethyl acetate and the ethyl acetate was washed with brine solution, dried over Na2SO4 and concentrated to afford 5.2 g (84%) of 4-(2-ethoxycarbonyl-acetyl)-piperazine-1-carboxylic acid tert-butyl ester. LCMS: 301.17 (M+1)+ 84.5%. 1H NMR: (CDCl3): δ 4.0 (q, 2H), 3.45 (m, 2H), 3.3 (m, 8H), 1.25 (s, 9H), 1.1 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:24])([CH3:23])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=3)[NH:10][C:11]=2[CH:12]=[CH:13][C:14]=1[Cl:15])=[O:4].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][C:8]([CH3:24])([CH3:23])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:17]=3)[NH:10][C:11]=2[CH:12]=[CH:13][C:14]=1[Cl:15])=[O:4]
Reactant: COC(=O)c1c(Cl)ccc2c1CC(C)(C)C(c1cccc(Br)c1)N2
Reactant: C1COCCN1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: COC(=O)c1c(Cl)ccc2c1CC(C)(C)C(c1cccc(N3CCOCC3)c1)N2
Temperature: 120 °C
Reaction time: 16 h
Yield: 79.8 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (1.2 g, 2.94 mmol), morpholine (1.3 mL, 14.7 mmol), copper(I) iodide (140 mg, 0.7 mmol), N,N-dimethylglycine hydrochloride (206 mg, 1.5 mmol) and potassium carbonate (1.2 g, 8.8 mmol) in dimethyl sulfoxide (15 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 6-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-5-carboxylic acid methyl ester (973 mg, 80%) as a white solid which was used for next step without further purification: LC/MS m/e calcd for C23H27ClN2O3 (M+H)+: 415.94, observed: 415.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[C:28](=[O:30])[CH3:29].Cl>O1CCCC1.CCCCCC.C(OCC)C.C(OCC)(=O)C.O>[C:28]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)N(C)C
Reactant: CCCCCCCc1ccc(-c2ccc(Br)cc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCCCCCc1ccc(-c2ccc(C(C)=O)cc2)cc1
Temperature: -60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-4′-n-heptylbiphenyl (5.1 g) in tetrahydrofuran (60 ml) was added a solution of #n-butyllithium in a mixture of n-hexane and diethyl ether (1.6M, 9.7 ml) at −60° C. After stirring at −60° C. for 30 minutes, to the mixture was added N,N-dimethylacetamide (4.3 ml) and the reaction mixture was allowed to warm to 0° C. The reaction mixture was taken up into a mixture of cold water and ethyl acetate, and the pH was adjusted to around 1 with 1N hydrochloric acid. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel (150 ml) eluting with a mixture of n-hexane and ethyl acetate (20:1, V/V) to give 4-Acetyl-4′-n-heptylbiphenyl (1.60 g).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:39])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH3:36])=[O:28])=[C:22]([O:37][CH3:38])[CH:21]=3)=[CH:13][CH:12]=2)[CH2:9][N:8]([C:40](=[O:42])[CH3:41])[CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C>[C:40]([N:8]1[CH2:9][CH:10]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:39])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH3:36])=[O:28])=[C:22]([O:37][CH3:38])[CH:21]=3)=[CH:13][CH:12]=2)[CH:6]([C:4]([OH:5])=[O:3])[CH2:7]1)(=[O:42])[CH3:41]
Reactant: CCOC(=O)C1CN(C(C)=O)CC1c1ccc(NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(CC(=O)Nc2ccc(C3CN(C(C)=O)CC3C(=O)O)cc2)ccc1NC(=O)Nc1ccccc1C
Temperature: 23 °C
Reaction time: 15 h

Procedure:
A solution of 1-acetyl-4-(4-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-phenyl)-pyrrolidine-3-carboxylic acid ethyl ester (1.62 g, Reference Example 1) in anhydrous ethanol (60 ml) was treated dropwise with sodium hydroxide solution (48 ml, 0.1 M). After stirring for 15 hours at 23° C. the mixture was evaporated (40° C. and 2.7 kPa). The residue was diluted with distilled water (200 ml), then cooled to 5° C. and then the pH of the mixture was adjusted to 2 by dropwise addition of hydrochloric acid (1N) resulting in the precipitation of a white solid. After stirring at 23° C. for 15 hours the mixture was filtered. The white solid was dried under reduced pressure (2.7 kPa) then triturated with ether affording the title compound (1 g) as a white solid, m.p. 242° C. 1H-NMR [600 MHz, (CD3)2SO]: δ 1.95 and 1.98 (2 s, 3H); 2.25 (s, 3H); 3.10 to 3.95 (m, 6H); 3.58 (s, 2H); 3.89 (s, 3H); 6.85 (bd, J=8 Hz, 1H); 6.95 (t, J=7.5 Hz, 1H); 7.02 (bs, 1H); 7.13 (t, J=7.5 Hz, 1H); 7.17 (d, J=7.5 Hz, 1H); 7.25 and 7.28 (2 d, J=8 Hz, 2H); 7.50 to 7.60 (m, 2H); 7.80 (d, J=7.5 Hz, 1H); 8.04 (d, J=8 Hz, 1H); 8.48 (s, 1H); 8.59 (s, 1H). MS [FAB (meta-nitrobenzylalcohol)]: 545 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([OH:7])=O)[CH3:3].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:15]=[C:16]([C@@H:20]([NH2:22])[CH3:21])[CH:17]=[CH:18][CH:19]=2)[CH:9]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH3:1][N:2]([CH3:3])[CH2:4][C:5]([NH:22][C@H:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:10]2[CH:9]=[N:8][CH:13]=[CH:12][CH:11]=2)[CH:15]=1)[CH3:21])=[O:7]
Reactant: C[C@H](N)c1cccc(-c2cccnc2)c1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)CN(C)C)c1cccc(-c2cccnc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of dimethylamino-acetic acid (0.083 mmol), (S)-1-(3-pyridin-3-yl-phenyl)-ethylamine (12.7 mg, 0.064 mmol), EDAC.HCl (18.4 mg, 0.096 mmol), HOBT (13 mg, 0.096 mmol) and diisopropylethylamine (33 μL, 0.192 mmol) in DMF (2 mL) was stirred at room temperature for 18 h, and the reaction mixture was purified by preparative HPLC (5 mM NH4OAc buffer; gradient 0% to 100% B in 10 min (A: 10% CH3CN/H2O ; B: 90% CH3CN/H2O; column: Primesphere C18 HC 21.2×100 mm) to afford the title product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[C:28]([CH3:30])=[CH2:29])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:32])[C:19](=[O:31])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[CH:28]([CH3:29])[CH3:30])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:32])[C:19](=[O:31])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)c1cc2c(cc1C1CCN(C(=O)OC(C)(C)C)CC1)N1C(=NNC(=O)C1C)CO2
Agent: [Pd]
Solvent: CO
Product: CC(C)c1cc2c(cc1C1CCN(C(=O)OC(C)(C)C)CC1)N1C(=NNC(=O)C1C)CO2
Reaction time: 10 h
Yield: 2.9 %

Procedure:
To a solution of 4-(7-isopropenyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.035 g, 2.76 mmol) in MeOH (15 mL) was added Pd/C (10%, 0.005 g, 0.005 mmol). The reaction mixture was stirred under an H2 atmosphere (50 psi) for 10 h. The catalyst was removed by filtration and washed with methanol (3×5 mL). The filtrate was concentrated in vacuo to give 4-(7-isopropyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.035 g, 100%). LC/MS (Table 1, Method 5) Rt=3.554 min.; MS m/z: 443 [M+H]+.
Reaction SMILES: C([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[N+:27]([O-])=O)[CH:13]([C:30]([OH:32])=O)[CH2:12]1)(OCC1C=CC=CC=1)=O.C(=O)(O)[O-].[K+].O>[Ni].C(O)C>[F:24][C:23]([F:26])([F:25])[C:20]1[CH:19]=[C:18]2[C:17](=[CH:22][CH:21]=1)[N:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH:13]1[C:30](=[O:32])[NH:27]2
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Ni]
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1Nc2cc(C(F)(F)F)ccc2N2CCNCC12
Reaction time: 0.75 h

Procedure:
A solution of 7.5 g. of 4-carbobenzoxy-1-(4-trifluoromethyl-2-nitrophenyl)piperazine-2-carboxylic acid, 4.0 g. of potassium bicarbonate, 150 ml. of water and 50 ml. of ethanol is hydrogenated over three teaspoons of Raney nickel catalyst at 50 p.s.i. for 45 minutes. The catalyst is filtered and the filtrate is acidified and extracted with ethylacetate. The aqueous phase is then basified with dilute sodium hydroxide and extracted with ethyl acetate. Concentration of the organic phase gives 1.2 g. of pale yellow solid product, m.p. 193°-195°. This solid is converted to its hydrogen chloride salt in ethanol giving 0.78 g., m.p. 275°-277° dec.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1.C([O:23][C:24]([N:26]1[CH2:31][CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH2:28][CH2:27]1)=[O:25])(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:29]2[CH2:30][CH2:31][N:26]([C:24]([OH:25])=[O:23])[CH2:27][CH:28]=2)=[C:3]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[CH:4]=1
Reactant: O=C(Nc1cc(Cl)ccc1Br)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cc(Cl)ccc1C1=CCN(C(=O)O)CC1)c1cccc(Cl)c1
Temperature: 100 °C
Yield: 88.8 %

Procedure:
In a 20 mL microwave tube is added N-(2-bromo-5-chloro-phenyl)-3-chloro-benzamide (0.500 g, 1.45 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.532 g, 1.74 mmol), bis(triphenylphosphine) palladium(II) chloride (0.102 g, 0.145 mmol), 2N Na2CO3 aqueous solution (3.62 mL, 7.25 mmol) and DMF (10 mL). The resulting mixture is placed in a microwave oven and heated to 100° C. for 30 min. The reaction turns black. The reaction mixture is poured into water (30 mL) and filtered. The cake is washed with 10 mL water and air dried. The cake is then dissolved in minimum dichloromethane and purified via flash chromatography using 0-30% EtOAc/hexane. The compound comes at 30% EtOAc. Removal of the solvent under vacuum gives 0.504 g of 4-[4-chloro-2-(3-chloro-benzoylamino)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tent-butyl ester in 78% yield.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=2)[CH:19]=O)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.CC[O:26][C:27](/[CH:29]=[C:30](/[CH2:32]P(OCC)(OCC)=O)\[CH3:31])=[O:28]>>[CH3:31][C:30]([CH:32]=[CH:19][C:18]1[CH:21]=[CH:22][CH:23]=[C:16]([C:3]2[C:2]([CH3:1])=[CH:11][C:10]3[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=3[CH:4]=2)[CH:17]=1)=[CH:29][C:27]([OH:26])=[O:28]
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Reactant: Cc1cc2c(cc1-c1cccc(C=O)c1)C(C)(C)CCC2(C)C
Product: CC(C=Cc1cccc(-c2cc3c(cc2C)C(C)(C)CCC3(C)C)c1)=CC(=O)O
Yield: 70.9 %

Procedure:
In a manner similar to that of Example 2(c), by reaction of 2.0 g (6.53 mmol) of 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)benzaldehyde obtained in the preceding example and 1.90 g (7.20 mmol) of triethyl 3-methyl-4-phosphonocrotonate, 1.80 g (66%) of the expected compound was obtained in the form of a white powder having a melting point of 83°-85° C.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH2:30][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:24][CH:23]=1)([S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:6][CH2:7][CH2:8][CH3:9])C>CO.[OH-].[Na+]>[CH2:34]([N:31]([CH2:32][CH3:33])[CH2:30][CH2:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C:5]([S:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)(=[O:11])=[O:12])([CH2:6][CH2:7][CH2:8][CH3:9])[C:4]([OH:36])=[O:3])=[CH:27][CH:26]=1)[CH3:35]
Reactant: CCCCC(Cc1ccc(OCCN(CC)CC)cc1)(C(=O)OCC)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCC(Cc1ccc(OCCN(CC)CC)cc1)(C(=O)O)S(=O)(=O)c1ccc(OC)cc1

Procedure:
2-[4-(2-Diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-hexanoic acid was prepared starting from 2-[4-(2-diethylamino-ethoxy)-benzyl]-2-(4-methoxy-benzenesulfonyl)-hexanoic acid ethyl ester (8 g, 15.4 mmol) dissolved in methanol (200 ml) and 10 N NaOH (30 ml). The resulting mixture was worked up as outlined in example 1. Yield 3.88 g crude (51%); brown oil; MS: 492 (M+H)+.