Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[C:2]1([N:8]([C:13]2([CH2:27][O:28]CC3C=CC=CC=3)[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:15][CH2:14]2)[C:9](=[O:12])[CH2:10][CH3:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[ClH:1].[OH:28][CH2:27][C:13]1([N:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:12])[CH2:10][CH3:11])[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:18]1
Reactant: CCC(=O)N(c1ccccc1)C1(COCc2ccccc2)CCN(CCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCC(=O)N(c1ccccc1)C1(CO)CCN(CCc2ccccc2)CC1

Procedure:
A mixture of 5.9 parts of N-phenyl-N-[1-(2-phenylethyl)-4-(phenylmethoxymethyl)-4-piperidinyl]propanamide hydrochloride and 120 parts of methanol is hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and washed on the filter with methanol. The filtrate is evaporated. The oily residue solidifies on scratching. The solid product is crystallized from 20 parts of 2-propanone at room temperature. It is filtered off and recrystallized from 2-propanol at 0° C., yielding N-[4-(hydroxymethyl)-1-(2-phenylethyl)-4-piperidinyl]-N-phenylpropanamide hydrochloride; mp. 218.4° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[F:17][CH:18]([F:29])[O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=O)=[CH:22][CH:21]=1>>[F:17][CH:18]([F:29])[O:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]2[O:14][C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:15][N:16]=2)=[CH:22][CH:21]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: O=C(O)c1ccc(OC(F)F)cc1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(OC(F)F)cc2)o1
Yield: 25 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 4-difluoromethoxy-benzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 85 mg, 25%) which was obtained as a white solid. MS: m/e=369.9 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]4[C:32]=3[NH:31][CH:30]=[C:29]4[CH2:33][CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]4[C:32]=3[NH:31][CH:30]=[C:29]4[CH2:33][CH2:34][C:35]([OH:37])=[O:36])[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:17])[CH3:18]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)OC(C)(C)C)c[nH]c34)no2)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Yield: 84.9 %

Procedure:
Trifluoroacetic acid (0.32 mL) was added to a solution of 1,1-dimethylethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoate (D7) (40 mg) in dichloromethane (0.5 mL) at RT for 1 hour. The reaction mixture was concentrated. The residue was recrystallized from dichloromethane/ether to afford 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanoic acid (E1) (30 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 2.65 (2H, q), 3.01 (2H, t), 4.91 (1H, m), 7.22 (1H, t), 7.28 (1H, d), 7.46 (1H, d), 7.83 (1H, d), 7.95 (1H, dd), 8.21 (1H, dd), 8.39 (1H, d), 10.86 (1H, s), 12.12 (1H, br s). MS (ES): C22H20ClN3O4 requires 425; found 425.9 (M+H+).
Reaction SMILES: [C:1]([C:6]1(CC)[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])([O:3][CH2:4][CH3:5])=[O:2].[O-][CH2:15][CH3:16].[Na+]>>[CH2:15]([CH:8]1[CH2:9][CH2:10][CH:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[C:7]1=[O:11])[CH3:16]
Reactant: CC[O-]
Reactant: CCOC(=O)C1(CC)CCCC1=O
Agent: [Na+]
Product: CCOC(=O)C1CCC(CC)C1=O

Procedure:
2-Carboethoxy-2-ethyl-cyclopentanone is reacted with sodium ethoxide to produce 2-ethyl-5-carboethoxycyclopentanone. (J. Org. Chem. 29, 2782 (1964))
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[C:4]2[CH:14]=[C:15]([C:17]([OH:19])=O)[S:16][C:3]1=2.O=S(Cl)Cl.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.Cl.N1CCOCC1>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[C:4]2[CH:14]=[C:15]([C:17]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:19])[S:16][C:3]1=2
Reactant: C1COCCN1
Reactant: Cn1c2ccc([N+](=O)[O-])cc2c2cc(C(=O)O)sc21
Agent: Cl
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cn1c2ccc([N+](=O)[O-])cc2c2cc(C(=O)N3CCOCC3)sc21
Reaction time: 1 h

Procedure:
280 mg of (68) was added to 25 ml of THF, 0.5 ml of SOCl2 was added, and the reaction left with stirring for 1 hour. 1 ml of morpholine was added in portions, and stirring continued . The precipitated morpholine hydrochloride was filtrered off, and the solvent evaporated. The residue was purified by column chromatography on silica gel, using MeOH in CH2Cl2, 1+9 as the eluent. MeOH was added to the pooled fractions to precipitate the product, giving after filtration and drying 50 mg of (69). M.p. 250°-2° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21](O)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH2:26]([NH2:34])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([NH:34][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:22])=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: NCCc1ccccc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)O)cc2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)NCCc3ccccc3)cc2)=C(C)C1=O
Yield: 24.1 %

Procedure:
3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (200 mg, 0.58 mmol) obtained in Example 1 and phenethylamine (91 mg, 0.75 mmol) were used, and a method similar to that described in Example 3 was employed to obtain the title compound (61 mg, 0.14 mmol, yield 24%).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[CH:27]=[CH:26][CH:25]=[CH:24][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:21]#[C:22][CH3:23])[CH2:17][C:18]([NH2:20])=O)=[CH:12][CH:11]=1>CN(C=O)C>[CH3:5][C:6]1[CH:27]=[CH:26][CH:25]=[CH:24][C:7]=1[CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:21]#[C:22][CH3:23])[CH2:17][C:18]#[N:20])=[CH:12][CH:11]=1
Reactant: CC#CC(CC(N)=O)c1ccc(OCc2ccccc2C)cc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC#CC(CC#N)c1ccc(OCc2ccccc2C)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 71.6 %

Procedure:
An oven-dried 50 mL round-bottomed flask was charged with DMF (8 mL) and a stir bar. The solution was cooled to 0° C. in an ice bath. Thionyl chloride (160 μL, 1.0 mmol) was added slowly via syringe. The mixture was stirred at 0° C. for an additional 45 minutes. Nitrile 23.2 (300 mg, 0.98 mmol) was then added to the mixture as solution in DMF (2 mL). The reaction was stirred at 0° C. for an hour, and was then allowed to gradually warm to room temperature overnight. The reaction mixture was partitioned between ice water and ethyl acetate. The aqueous layer was extracted 2 additional times with 25 mL ethyl acetate. Saturated NaHCO3 was then added to the aqueous layer and the aqueous layer was extracted a third time with ethyl acetate. The combined organic layers were washed with saturated NaHCO3 and concentrated under reduced pressure. The resulting residue was purified via radial chromatography (15% ethyl acetate in hexanes) to yield 203 mg (72%) of 3-[4-(2-Methyl-benzyloxy)-phenyl]-hex-4-ynenitrile (23.3). 1H NMR (400 MHz) (acetone-d6) δ 7.44 (3H, m), 7.24 (3H, m), 7.05 (2H, m), 5.13 (2H, s), 4.09 (1H, m), 2.89 (2H, m), 2.39 (3H, s), 1.88 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH2:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:33]([N:40]=[C:41]=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[C:1]([O:5][C:6](=[O:32])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][C@@H:13]([OH:31])[C@@H:14]([NH:22][C:23](=[O:30])[C@H:24]([CH2:26][C:27](=[O:29])[NH2:28])[NH:25][C:41](=[O:42])[NH:40][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)NCc1ccccc1
Yield: 48 %

Procedure:
A solution of 0.28 g of N-[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester, and 0.083 g of benzyl isocyanate in 5 ml of dichloromethane was stirred at 20° C. for 2 hours. The solvent was then removed by evaporation and the residue was triturated with diethyl ether to give 0.174 g of N-[3(S)-[[N-(benzylcarbamoyl)-L -asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-L-proline tert.butyl ester as a white solid; MS: m/e 582 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH2:15]([C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24](Cl)[N:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[C:24]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=3)=[CH:9][CH:10]=2)[N:23]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Reactant: Cc1cc(-c2ccc(N)cc2)ccn1
Product: Cc1cc(-c2ccc(Nc3nc(C)cc(Cc4ccccc4)n3)cc2)ccn1

Procedure:
The title compound was prepared in analogy to example 62 from 4-(2-methyl-pyridin-4-yl)-phenylamine and 4-benzyl-2-chloro-6-methyl-pyrimidine (example 43a). Obtained as a yellowish solid (Yield=48%). MS ISP (m/e): 367.1 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.77 (s, 1H), 8.45 (d, 1H), 7.93 (d, 2H), 7.71 (d, 2H), 7.55 (s, 1H), 7.47 (d, 1H), 7.35-7.20 (m, 5H), 6.67 (s, 1H), 3.95 (s, 2H), 2.51 (s, 3H), 2.33 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][C:14](O)=O.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[O:38]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[O:41][CH2:40][CH:39]1[CH2:48][NH2:49]>CN(C=O)C>[O:38]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[O:41][CH2:40][CH:39]1[CH2:48][NH:49][CH2:14][CH2:13][CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][CH:6]=1
Reactant: NCC1COc2ccccc2O1
Reactant: O=C(O)CCCc1c[nH]c2ccc(F)cc12
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc2[nH]cc(CCCCNCC3COc4ccccc4O3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
5-Fluoroindole-3-butyric acid (1.5 g, 6.8 mmole), 1-hydroxybenzotriazole hydrate (1.1 g, 8.2 mmole) and 1,3-diisopropylcarbodiimide (2.6 ml, 16.3 mmole) were combined in 150 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 2,3-dihydro-1,4-benzodioxin-2-methanamine hydrochloride (1.4 g, 6.8 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Fractions of the products were concentrated and washed with a minimum amount of THF to remove a by-product and to give 1.5 g (60%) of the desired product, (2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-4-(5-fluoro-1H-indole-3yl)-butanamide, as an oil.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:30]([OH:32])=O)[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([O:27][CH3:28])=[C:22]([CH3:29])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[O:66]1[CH2:71][CH2:70][CH:69]([N:72]2[CH2:77][CH2:76][NH:75][CH2:74][CH2:73]2)[CH2:68][CH2:67]1>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:21]=[C:22]([CH3:29])[C:23]([O:27][CH3:28])=[C:24]([CH3:26])[CH:25]=3)[C:30](=[O:32])[N:75]3[CH2:74][CH2:73][N:72]([CH:69]4[CH2:70][CH2:71][O:66][CH2:67][CH2:68]4)[CH2:77][CH2:76]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:33]=[CH:34][CH:35]=[CH:36][C:4]=2[NH:3]1
Reactant: COc1c(C)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C
Reactant: C1CN(C2CCOCC2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1c(C)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 40 mg (0.08 mmol) (R)-2-(4-methoxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 29 mg (0.09 mmol) TBTU and 14 μL (0.10 mmol) triethylamine in 1 mL DMF was stirred for 1 h at RT. Then 15 mg (0.09 mmol) 1-(tetrahydropyran-4-yl)-piperazine was added and the mixture was stirred for a further 16 h at RT. The reaction solution was purified by HPLC without any further working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[O:9][CH2:10][C:11]([OH:13])=O)=[O:5])C.[C@@H:17]1([NH2:21])[CH2:19][C@H:18]1[NH2:20]>>[C@@H:17]1([NH:21][C:11](=[O:13])[CH2:10][O:9][C:8]2[CH:7]=[C:6]([CH:16]=[CH:15][CH:14]=2)[C:4]([OH:3])=[O:5])[CH2:19][C@H:18]1[NH:20][C:11](=[O:13])[CH2:10][O:9][C:8]1[CH:7]=[C:6]([CH:16]=[CH:15][CH:14]=1)[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cccc(OCC(=O)O)c1
Reactant: N[C@@H]1C[C@H]1N
Product: O=C(COc1cccc(C(=O)O)c1)N[C@@H]1C[C@H]1NC(=O)COc1cccc(C(=O)O)c1

Procedure:
By following the processes described in stages A to C of Example R13, Example R35 is prepared by dimerization of [3-(ethoxycarbonyl)phenoxy]acetic acid with 1,2-trans-cyclopropanediamine (CAS 758637-65-9). A white powder is obtained.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)=[CH:16][CH:15]=1.[OH-].[Na+]>CCO.C1COCC1>[Cl:30][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:5]3[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=3[C:3]([OH:31])=[O:2])=[CH:19][CH:18]=2)[CH:28]=[CH:27][C:26]=1[Cl:29]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Nc1ccc(CCCc2ccc(Cl)c(Cl)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cc([N+](=O)[O-])ccc1Nc1ccc(CCCc2ccc(Cl)c(Cl)c2)cc1
Yield: 100.9 %

Procedure:
The title compound was 2-{4-[3-(3,4-dichlorophenyl)-propyl]phenylamino}-5-nitrobenzoic acid methyl ester (0.50 g, 1.09 mmol), 2N NaOH (5.0 mL) in EtOH (2 mL) and THF (4 mL) using the procedure described in Example 2. This procedure yielded an orange solid, 0.49 g (1.10 mmol, 100%) of the desired product. mp 153-155° C.
Reaction SMILES: [C:1]12([NH:11][C:12]3[CH:17]=[C:16]([Cl:18])[N:15]=[C:14](Cl)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:20][C:21]12[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2>C(O)CCC>[C:21]12([NH:20][C:14]3[N:13]=[C:12]([NH:11][C:1]45[CH2:2][CH:3]6[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]6)[CH2:8]4)[CH2:10]5)[CH:17]=[C:16]([Cl:18])[N:15]=3)[CH2:22][CH:23]3[CH2:29][CH:27]([CH2:26][CH:25]([CH2:24]3)[CH2:30]1)[CH2:28]2
Reactant: Clc1cc(NC23CC4CC(CC(C4)C2)C3)nc(Cl)n1
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: CCCCO
Product: Clc1cc(NC23CC4CC(CC(C4)C2)C3)nc(NC23CC4CC(CC(C4)C2)C3)n1
Reaction time: 75 h

Procedure:
26.0 g (87.25 mmoles) of 4-(1-adamantylamino)-2,6-dichloropyrimidine and 39.5 g (261.6 mmoles) of 1-aminoadamantane are dissolved in 200 ml of n-butanol, the reaction mixture is boiled for 75 hours and evaporated. The residue is suspended in 400 ml of ether and filtered. The filtered substance is chromatographed after drying on a silica gel column by using chloroform as eluent. The substance obtained is a mixture of the title isomers. The isomers are separated on a silica gel column by using as eluent a 49:1 mixture of hexane and ethyl acetate. 2,4-Bis(1-adamantylamino)-6-chloropyrimidine is obtained which is recrystallized from hexane to obtain a yield of 21.67 g (60.14%). Its melting point and 1H-NMR are identical to those of the product according to Example 11.
Reaction SMILES: N[C@@H:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=[O:4].[BrH:10].N([O-])=O.[Na+]>O>[Br:10][C@@H:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=[O:4]
Reactant: CCCC[C@H](N)C(=O)O
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCCC[C@H](Br)C(=O)O
Reaction time: 2 h

Procedure:
(S)-2-aminohexanoic acid (FW 131.2, also known as L-norleucine) (1 g, 7.62 mmol, which is commercially available from Sigma Chemical Co at Sigmaaldrich.com, is dissolved in a mixture of HBr 48% (7.0 mL, 61 mmol) and H2O (10 mL). At 0° C., a solution of NaNO2 (1.7 g, 24 mmol) in H2O (5 mL) is added over a period of 30 min. The reaction is stirred for two hours. The reaction mixture is degassed in vacuo and extracted with EtOAc (2×20mL). The extracts are washed with water (15 mL), dried (Na2SO4), filtered and evaporated to give (S)-2-bromohexanoic acid.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].[C:10]1([C:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:1]([N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[C:16]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[OH:17])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Reactant: CCCCn1ccnc1
Product: CCCCn1ccnc1C(O)(c1ccccc1)c1ccc(F)cc1

Procedure:
Procedure as described in 1), only using N-n-butylimidazole and 4-fluorophenyl phenyl ketone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([CH:16]=1)[CH2:14][CH2:13][S:12]2.[Br:17]N1C(=O)CCC1=O>CN(C)C=O.O>[Br:17][C:16]1[N:15]2[C:11]([S:12][CH2:13][CH2:14]2)=[N:10][C:9]=1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: Clc1ccc(-c2cn3c(n2)SCC3)c(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(-c2nc3n(c2Br)CCS3)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The 6-(2,4-dichlorophenyl)-2,3-dihydroimidazo[2,1-b]thiazole (0.6 g) prepared above and N-bromosuccinimide (0.45 g) were dissolved in dimethylformamide (5 ml). The mixture was heated to reflux and stirred for 18 h at room temperature. The mixture was diluted with water (60 ml) and allowed to crystallize. The liquid was decanted and the residue was dissolved in methylene chloride and dried with magnesium sulfate. The organic residue was chromatographed on silica gel with hexanes/ethyl acetate (3:1) as eluent to give the desired product as a solid (m.p. 200°-202° C.); NMR (CDCl3, 200 MHz) δ: 7.4-7.2 (3H), 4.2 (m, 2H), 3.9 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:18]#[N:19])=[CH:4][C:5]2[N:6]([C:8]([S:14](O)(=[O:16])=[O:15])=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=2)[CH:7]=1.C(N(CC)CC)C.P(Cl)(Cl)([Cl:29])=O>ClC(Cl)C>[Cl:1][C:2]1[C:3]([C:18]#[N:19])=[CH:4][C:5]2[N:6]([C:8]([S:14]([Cl:29])(=[O:16])=[O:15])=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=2)[CH:7]=1
Reactant: CC(C)c1nc2cc(C#N)c(Cl)cn2c1S(=O)(=O)O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(C)c1nc2cc(C#N)c(Cl)cn2c1S(=O)(=O)Cl
Temperature: 100 °C
Reaction time: 4 h
Yield: 75 %

Procedure:
6-Chloro-7-cyano-2-isopropylimidazo[1,2-a]pyridine-3-sulfonic acid (2.16 g, 7.21 mmol) obtained in step 2 was dissolved in dichloroethane (20 mL), and the solution was stirred at 100° C. for 4 hours after adding triethylamine (2.01 mL, 14.4 mmol) and phosphorus oxychloride (1.34 mL, 14.4 mL). The reaction mixture was extracted with chloroform after adding water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→80/20) to give 6-chloro-7-cyano-2-isopropylimidazo[1,2-a]pyridine-3-sulfonylchloride (1.73 g, yield 75%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[NH2:12][C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1>>[CH3:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:12][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Cc1ccccc1N
Reactant: O=C(O)Cc1ccccc1Br
Product: Cc1ccccc1Nc1ccccc1CC(=O)O

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with o-toluidine to yield 2-[(2-methylphenyl)amino]phenylacetic acid.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].Cl[S:10]([C:13]1[CH:17]=[CH:16][S:15][C:14]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH2:26][O:27][C:21]=2[CH:20]=1)(=[O:12])=[O:11]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:10]([C:13]1[CH:17]=[CH:16][S:15][C:14]=1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH2:26][O:27][C:21]=2[CH:20]=1)(=[O:12])=[O:11]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccsc1Cc1ccc2c(c1)OCO2
Product: Cc1noc(NS(=O)(=O)c2ccsc2Cc2ccc3c(c2)OCO3)c1Br
Yield: 37 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(3,4-methylenedioxy)benzyl]thiophene-3-sulfonamide was prepared in the same manner as described in Example 2 by reacting 5-amino-4-bromo-3-methylisoxazole and 3-chlorosulfonyl-2-[(3,4-methylenedioxy)benzyl]thiophene. The crude product was purified by HPLC, 37% yield.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:25])[CH2:14][CH2:15][C:16](=[N:17][NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]2=[N:8][CH:7]=1)=[O:5])C.O.[NH2:27][NH2:28]>C(O)C>[C:19]1([NH:18][N:17]=[C:16]2[C:9]3=[N:8][CH:7]=[C:6]([C:4]([NH:27][NH2:28])=[O:5])[C:11](=[O:12])[N:10]3[CH:13]([CH3:25])[CH2:14][CH2:15]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NN
Reactant: CCOC(=O)c1cnc2n(c1=O)C(C)CCC2=NNc1ccccc1
Solvent: CCO
Solvent: O
Product: CC1CCC(=NNc2ccccc2)c2ncc(C(=O)NN)c(=O)n21
Yield: 82.7 %

Procedure:
7.8 g. (0.02 mole) of ethyl-9-(phenyl-hydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxylate are dissolved in 100 ml. of ethanol. To the solution 6.0 ml. of 98% hydrazine-hydrate are added and the reaction mixture is refluxed for 2 hours. On cooling the precipitation of crystals begins. The crystals are filtered off and washed with ethanol. Thus 5.4 g. (82.7%) of 9-(phenyl-hydrazono)-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-prido(1,2-a)pyrimidine-3-carbohydrazide are obtained. Mp.: 205°-207° C.