Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.[NH2:18][C:19]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)[CH:29]=[CH:28][C:20]=1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[Cl:38][C:34]1[CH:33]=[C:32]([C:30]2[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[C:19]([NH:18][C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:8]=3[CH3:7])[CH:31]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cccc(Cl)c2)cc1N
Reactant: Cc1cccc(C(=O)O)c1C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)Nc2cc(-c3cccc(Cl)c3)ccc2C(=O)OC(C)(C)C)c1C
Reaction time: 1 h

Procedure:
1.7 mL of methylene chloride, 1.0 μl of N,N-dimethylformamide and, 0.025 mL of oxalyl chloride were added to 41 mg of 2,3-dimethylbenzoic acid at room temperature sequentially and stirred at the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 49 mg of tert-butyl 2-amino-4-(3-chlorophenyl)benzoate, 2.8 mL of methylene chloride and 0.36 mL of triethylamine and stirred at room temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane: ethyl acetate=4:1]to obtain tert-butyl 4-(3-chlorophenyl)-2-(2,3-dimethylbenzamido)benzoate.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([O:10][CH3:11])=[O:9].Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: COC(=O)Cc1cccn1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc([N+](=O)[O-])cc1)c1cccn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
Methyl 1-methylpyrrole-2-acetate (5.0 g, 32.0 mmol) and 4-chloronitrobenzene (10.3 g, 65.0 mmol) were dissolved in DMF (30 ml) and the mixture was cooled in an ice bath under argon. Sodium hydride, 50% in mineral oil, (3.1 g, 64.0 mmol) was added in portions. After stirring for 1 h at room temperature the reaction mixture was poured into 1 M HCl/ice and the product was extracted into ethyl acetate. The organic extracts were washed with water, dried over sodium sulfate, and concentrated to dryness. Purification on a Florisil® column (methylene chloride) gave methyl 2-(1-methylpyrrol-2-yl)-2-(4-nitrophenyl)acetate (4.13 g, 46%) as a solid. ##STR38##
Reaction SMILES: Cl.[CH2:2]([O:6][NH2:7])[CH:3]([CH3:5])[CH3:4].[NH2:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[C:16]=2[F:24])[N:12]=[C:11]([C:25](O)=[O:26])[C:10]=1[Cl:28].Cl.C(N=C=NCCCN(C)C)C.C(O)(=O)C>CN(C)C1C=CN=CC=1.ClCCCl>[NH2:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[C:16]=2[F:24])[N:12]=[C:11]([C:25]([NH:7][O:6][CH2:2][CH:3]([CH3:5])[CH3:4])=[O:26])[C:10]=1[Cl:28]
Reactant: COc1c(Cl)ccc(-c2cc(N)c(Cl)c(C(=O)O)n2)c1F
Reactant: CC(C)CON
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1c(Cl)ccc(-c2cc(N)c(Cl)c(C(=O)NOCC(C)C)n2)c1F
Temperature: 23 °C
Reaction time: 18 h
Yield: 61 %

Procedure:
O-iso-Butylhydroxylamine hydrochloride (380 mg, 3.0 mmol, 2.0 equiv) and 4-(dimethylamino)pyridine (740 mg, 6.0 mmol, 4.0 equiv) were sequentially added to a stirred suspension of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinic acid (prepared as in Balko et al., U.S. Pat. No. 7,314,849 B2; 500 mg, 1.5 mmol, 1.0 equiv) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (1.2 g, 6.0 mmol, 4.0 equiv) in 1,2-dichloroethane (5.0 mL) at 23° C. The resulting tan suspension was stirred at 23° C. for 18 h. The reaction mixture was quenched with glacial acetic acid (430 μL, 7.5 mmol, 5.0 equiv) and concentrated by a nitrogen stream. The residue was directly subjected to silica gel column chromatography (50% EtOAc in hexane) to afford a white powder (370 mg, 61%): mp 145-148° C.; 1H NMR (300 MHz, CDCl3) δ 9.87 (br s, 1H), 7.53 (t, J=8 Hz, 1H), 7.26 (m, 1H), 7.18 (d, J=2 Hz, 1H), 4.95 (br s, 2H), 3.99 (d, J=1 Hz, 3H), 3.83 (d, J=7 Hz, 2H), 2.07 (m, 1H), 1.01 (d, J=6 Hz, 6H); IR (neat film) 3221 (m), 2941 (w), 2878 (w), 1653 (s) cm−1; ESIMS m/z 402.2 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C@@H:7]([OH:8])[C:5](=[O:6])[O:4][CH2:3]1.[OH-:10].[Na+:11]>>[Na+:11].[C:5]([O-:10])(=[O:6])[C@@H:7]([C:2]([CH2:3][OH:4])([CH3:9])[CH3:1])[OH:8]
Reactant: CC1(C)COC(=O)[C@@H]1O
Reactant: [OH-]
Agent: [Na+]
Product: CC(C)(CO)[C@@H](O)C(=O)[O-]

Procedure:
390.5 mg of D-pantolactone was dissolved in 30 ml of a 0.1 N aqueous sodium hydroxide solution and reacted at room temperature for 3 hours to form an aqueous pantoic acid sodium salt solution. Separately, 321 mg of cis-dinitrato-diammine platinum (II) was dissolved in 50 ml of water, and thereto was added the previously prepared aqueous pantoic acid sodium salt solution. After 48-hour reaction at room temperature, water was evaporated away under reduced pressure. Methanol was added to the residue and the produced platinum complex was extracted. Then methanol was removed under reduced pressure to obtain a crude powdery product. This product was again dissolved in methanol and added with acetone, causing reprecipitation. The precipitate was filtered out and dried under reduced pressure to obtain 510 mg of the compound No. 1.
Reaction SMILES: C(NC1C=CC=CC=1C1CCC2C(=CC=C(OC)C=2)C1)C.Cl.N1(CCOC2C=CC(C(O)=O)=CC=2)CCCCC1.[CH2:41]([N:43]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=1[CH:66]1[CH2:75][CH2:74][C:73]2[C:68](=[CH:69][CH:70]=[C:71]([O:76]C)[CH:72]=2)[CH2:67]1)[CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH2:53][N:54]2[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]2)=[CH:47][CH:46]=1)[CH3:42]>>[CH2:41]([N:43]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH2:53][N:54]2[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]2)=[CH:47][CH:46]=1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=1[CH:66]1[CH2:75][CH2:74][C:73]2[CH:72]=[C:71]([OH:76])[CH:70]=[CH:69][C:68]=2[CH2:67]1)[CH3:42]
Reactant: CCN(Cc1ccc(OCCN2CCCCC2)cc1)c1ccccc1C1CCc2cc(OC)ccc2C1
Agent: CCNc1ccccc1C1CCc2cc(OC)ccc2C1
Agent: Cl
Agent: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Product: CCN(Cc1ccc(OCCN2CCCCC2)cc1)c1ccccc1C1CCc2cc(O)ccc2C1
Yield: 80 %

Procedure:
Synthesized from ethyl[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine and 4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride according to an analogous synthetic method to Example 152, ethyl[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl][4-(2-piperidin-1-ylethoxy)benzyl]amine (507 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (394 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[O:24]1[C:29]2[CH:30]=[CH:31][C:32]([CH2:34][N:35]([CH:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:33][C:28]=2[O:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O.C(O)(=O)C.ClCCl>[C:38]([O:37][C:36]([N:35]([CH2:34][C:32]1[CH:31]=[CH:30][C:29]2[O:24][CH2:25][CH2:26][O:27][C:28]=2[CH:33]=1)[CH:43]1[CH2:48][CH2:47][N:46]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[C:7](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:8][C:9]2=[O:16])[CH2:45][CH2:44]1)=[O:42])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: CCOC(=O)/C=C/c1cc(=O)n(CC=O)c2cc(OC)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)/C=C/c1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(OC)ccc12
Reaction time: 1 h
Yield: 63.7 %

Procedure:
To 0.16 g of ethyl (2E)-3-(1-(1,3-dioxolan-2-ylmethyl)-7-methoxy-2-oxo-1,2-dihydroquinolin-4-yl)acrylate, 2 mL of 90% aqueous trifluoroacetic acid solution was added and stirred for 2 hours. The solvent was removed under reduced pressure, and aqueous saturated sodium hydrogen carbonate solution and chloroform were added. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (eluent; chloroform) to give 84 mg of ethyl (2E)-3-(7-methoxy-2-oxo-1-(2-oxoethyl)-1,2-dihydroquinolin-4-yl)acrylate as a yellow oil. (2) To 3 mL of a dichloromethane solution containing 84 mg of ethyl (2E)-3-(7-methoxy-2-oxo-1-(2-oxoethyl)-1,2-dihydroquinolin-4-yl)acrylate, 98 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 14 μL of acetic acid were added and stirred for 1 hour. To the reaction mixture, 81 mg of sodium triacetoxyborohydride was added and stirred for 2 hours. Water, ethyl acetate and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=100:1] to give 0.11 g of ethyl (2E)-3-(1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinolin-4-yl)acrylate as a yellow oil.
Reaction SMILES: [O:1]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[OH:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>>[NH2:6][C:5]1[CH:4]=[CH:3][C:2]([O:1][C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:27](=[O:28])[C:26]3[CH:25]=[CH:24][C:23]([N:20]4[CH2:21][CH2:22][CH:17]([OH:16])[CH2:18][CH2:19]4)=[CH:31][CH:30]=3)=[CH:11][CH:10]=2)=[CH:8][CH:7]=1
Reactant: O=C(O)c1ccc(N2CCC(O)CC2)cc1
Reactant: Nc1ccc(Oc2ccc(N)cc2)cc1
Product: Nc1ccc(Oc2ccc(NC(=O)c3ccc(N4CCC(O)CC4)cc3)cc2)cc1

Procedure:
Compound 919 was prepared according to the procedure described in Scheme IV from 4,4′-oxydianiline and 4-(4-hydroxypiperidin-1-yl)benzoic acid. [M+H]+ calcd for C24H25N3O3: 404.19; found 404.05.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]3)=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:26][C:27]1[NH:28][C:29]2[C:34]([C:35]=1[CH3:36])=[CH:33][C:32]([OH:37])=[CH:31][CH:30]=2>>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][S:21](=[O:25])(=[O:24])[CH2:20][CH2:19]1)[N:5]=[CH:4][CH:3]=[C:2]2[O:37][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH3:26])=[C:35]2[CH3:36])#[N:13]
Reactant: Cc1[nH]c2ccc(O)cc2c1C
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCCCN1CCS(=O)(=O)CC1
Product: Cc1[nH]c2ccc(Oc3ccnc4cc(OCCCN5CCS(=O)(=O)CC5)c(C#N)cc34)cc2c1C
Yield: 64.8 %

Procedure:
Using an analogous procedure to that described in Example 7, 4chloro-6-cyano-7-(3-(1,1-dioxothiomorpholino)propoxy)quinoline (100 mg, 0.26 mmol) was reacted with 2,3-dimethyl-5-hydroxyindole (51 mg, 0.32 mmol), (Arch. Pharm. 1972, 305, 159), to give 6-cyano-4-(2,3-dimethylindol-5-yloxy)-7-(3-(1,1-dioxothiomorpholino)propoxy)quinoline (85 mg, 64%).
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:34])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[N:28]=[C:27]([NH2:29])[C:26]4[C:21](=[CH:22][C:23]([O:32][CH3:33])=[C:24]([O:30][CH3:31])[CH:25]=4)[N:20]=3)[CH2:15][CH2:14]2)=[N:8][CH:7]=1>CO.O>[NH2:29][C:27]1[C:26]2[C:21](=[CH:22][C:23]([O:32][CH3:33])=[C:24]([O:30][CH3:31])[CH:25]=2)[N:20]=[C:19]([N:16]2[CH2:17][CH2:18][CH:13]([NH:12][C:9]3[CH:10]=[CH:11][C:6]([C:5]([OH:34])=[O:4])=[CH:7][N:8]=3)[CH2:14][CH2:15]2)[N:28]=1
Reactant: COC(=O)c1ccc(NC2CCN(c3nc(N)c4cc(OC)c(OC)cc4n3)CC2)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2nc(N3CCC(Nc4ccc(C(=O)O)cn4)CC3)nc(N)c2cc1OC
Temperature: 85 °C
Yield: 103.2 %

Procedure:
Potassium hydroxide (1.18 g, 21.1 mmol) was added to a solution of (3) (0.5 g, 1.05 mmol) in MeOH/H2O (20 mL, 10%; v/v). The reaction mixture was heated to 85° C. for 12 h, then cooled to room temperature. The mixture was concentrated, acidified with HCl (aq) (20 mL, 3M) and the desired product was filtered and rinsed with cold H2O to give 0.46 g (quantitative yield) of the title compound: 1H NMR (DMSO) δ 12.36 (br s, 1H), 9.56 (br s, 1H), 8.78 (br s, 2H), 8.36 (s, 1H), 8.07 (d, 1H, J=9.2), 7.75 (s, 1H), 7.61 (s, 1H), 7.11 (d, 1H, J=9.3), 4.64 (m, 2H), 4.29 (m, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.37 (m, 2H), 2.12 (m, 2H), 1.60 (m, 2H); 13C NMR (DMSO) δ 164.7, 161.3, 155.2, 154.4, 151.0, 146.7, 141.8, 140.1, 136.3, 115.2, 112.4, 105.2, 101.6, 99.3, 56.3, 56.0, 48.4, 43.3, 30.4; HRMS (FAB) m/z 425.1948 (M+H)+ (C21H24N6O4 requires 425.1937); Anal. (C21H24N6O4 ·2HCl·2H2O) C, H, N.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[N:11]=[C:10]([Cl:12])[CH:9]=[C:8]([O:13]C)[N:7]=1)[CH3:2].C(#N)C.[I-].[K+].C[Si](C)(C)Cl>O>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[NH:7][C:8](=[O:13])[CH:9]=[C:10]([Cl:12])[N:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1nc(Cl)cc(OC)n1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)Cc1nc(Cl)cc(=O)[nH]1
Temperature: 100 °C
Yield: 81 %

Procedure:
33 g of (4-chloro-6-methoxypyrimidin-2-yl)acetic acid ethyl ester (example 8b, step 2b) and 750 ml of acetonitrile are placed in a 1000 ml autoclave and then 71.2 g of potassium iodide and 55.85 ml of trimethylchlorosilane are added; an orangey-colored heterogeneous solution is obtained, which is stirred while heating under an argon pressure of 10 bar at 100° C. for 2 hours. The reaction medium is drawn off and then the insoluble material is filtered off and washed with 3 times approximately 100 ml of EtOAc, and the filtrate is concentrated until a pasty residue is obtained, which is taken up in 500 ml of water. After stirring and extraction with 3 times approximately 350 ml of ethyl acetate, the combined organic extracts are washed with 500 ml of saturated NaCl solution, dried over MgSO4, filtered through a VF filter, and concentrated under vacuum. The compound obtained is purified by chromatography on silica gel (40-63 μm), elution being carried out with a mixture of 2/8 v/v EtOAc/n-heptane. The fractions containing the expected compound are combined and evaporated. A solid is isolated, which is triturated from diisopropyl ether, filtered through sintered glass and dried. (4-Chloro-6-oxo-1,6-dihydropyrimidin-2-yl)acetic acid ethyl ester is isolated in the form of a beige solid: 25.2 g; yield 81%
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH:10]=[N:9][CH:8]=[N:7][C:6]=2[NH:5][CH:4]=1)#[CH:2]>C(O)C.[OH-].[Pd+2].[OH-]>[CH2:1]([C:3]1[C:11]2[CH:10]=[N:9][CH:8]=[N:7][C:6]=2[NH:5][CH:4]=1)[CH3:2]
Reactant: C#Cc1c[nH]c2ncncc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCc1c[nH]c2ncncc12
Yield: 86.2 %

Procedure:
5-ethynyl-7H-pyrrolo[2,3-d]pyrimidine (0.293 g, 2.05 mmol) and palladium hydroxide [20 weight percent (dry basis)] on carbon [moist] (0.0644 g, 0.0458 mmol) were stirred in ethanol (10 mL) under an atmosphere of hydrogen for 18 hours. The mixture was filtered through a pad of celite and concentrated to give the title compound as an orange solid (0.260 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[NH2:16]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:14]=[C:13]([Cl:12])[CH:19]=[C:18]([Cl:20])[CH:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1cc(Cl)cc(Cl)c1
Product: O=C(Nc1cc(Cl)cc(Cl)c1)c1cc(Cl)ccc1O
Yield: 41.2 %

Procedure:
Using 5-chlorosalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: Cl[C:2]1C=C(C)C2C(=CC=C(C#CC3C=CC(C4C=CC(Cl)=CC=4)=CN=3)C=2)[N:3]=1.Br[C:29]1[CH:38]=[C:37]([CH3:39])[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:40]#[C:41][C:42]3[CH:47]=[CH:46][C:45]([C:48]4[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=4)=[CH:44][N:43]=3)[CH:35]=2)[N:30]=1>CN1C(=O)CCC1.CN(C=O)C>[Cl:54][C:51]1[CH:52]=[CH:53][C:48]([C:45]2[CH:46]=[CH:47][C:42]([C:41]#[C:40][C:34]3[CH:35]=[C:36]4[C:31](=[CH:32][CH:33]=3)[N:30]=[C:29]([CH2:2][NH2:3])[CH:38]=[C:37]4[CH3:39])=[N:43][CH:44]=2)=[CH:49][CH:50]=1
Reactant: Cc1cc(Cl)nc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc12
Reactant: Cc1cc(Br)nc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc12
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: Cc1cc(CN)nc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc12

Procedure:
Analogously to Example 1k, the following Examples may be prepared starting from 2-chloro-6-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-4-methylquinoline (Example 1h) or 2-bromo-6-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-4-methylquinoline (Example 1i) and the corresponding amines: Examples 1.8-1.9, 1.11, 1.15-1.21, 1.23 and 1.28 were prepared by heating in NMP in the microwave (300 W, 190° C.; 30-60 min); Example 1.13 was prepared by heating in DMF in the microwave (150 W, 170° C.; 10 min); and Example 1.51 was obtained as a by-product.
Reaction SMILES: BrC1C=C(CC(=O)C(NC([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=3)[N:16]=2)=O)C)C=CC=1>O=P(Cl)(Cl)Cl>[F:30][C:27]([F:28])([F:29])[O:26][C:23]1[CH:22]=[CH:21][C:20]([C:17]2[N:16]=[CH:15][O:19][N:18]=2)=[CH:25][CH:24]=1
Reactant: CC(NC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)no1)C(=O)Cc1cccc(Br)c1
Solvent: O=P(Cl)(Cl)Cl
Product: FC(F)(F)Oc1ccc(-c2ncon2)cc1
Temperature: 25 °C
Yield: 108.6 %

Procedure:
A solution of N-(4-(3-bromophenyl)-3-oxobutan-2-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole-5-carboxamide (200 mg, 0.4 mmol) in POCl3 (5 mL) was stirred at 110° C. for 5 h, cooled to RT, concentrated, and neutralized with aqueous K2CO3 (˜8M). The residue was diluted with H2O, and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (Petroleum ether:EtOAc=5:1) to afford 545-(3-bromobenzyl)-4-methyloxazol-2-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (100 mg, 52%) as a white solid. MS (ES+) C20H13BrF3N2O2 requires: 479, 481, found: no desired peak; 1H NMR (500 MHz, CDCl3) δ 8.23 (d, J=9.0 Hz, 2H), 7.42-7.31 (m, 4H), 7.23-7.
Reaction SMILES: [C:1]([C:3]1[C:7]2[CH2:8][CH2:9][C:10](=O)[CH2:11][C:6]=2[S:5][C:4]=1[NH:13][C:14](=[O:20])[CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])#[N:2].[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[CH2:29][NH2:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[C:1]([C:3]1[C:7]2[CH2:8][CH2:9][CH:10]([NH:30][CH2:29][C:23]3[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=3[Cl:21])[CH2:11][C:6]=2[S:5][C:4]=1[NH:13][C:14](=[O:20])[CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])#[N:2]
Reactant: CCC(CC)C(=O)Nc1sc2c(c1C#N)CCC(=O)C2
Reactant: NCc1ccc(Cl)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC(CC)C(=O)Nc1sc2c(c1C#N)CCC(NCc1ccc(Cl)cc1Cl)C2
Reaction time: 16 h

Procedure:
To a solution of the intermediate isolated in Step C in 100 mL of dichloromethane was added 1.41 mL (12.0 mL) of 1-(2,4-dichlorophenyl)methanamine, followed by 2.54 g (12.0 mmol) of sodium triacetoxyborohydride, and 0.960 mL (16.0 mmol) of acetic acid. After 16 h at ambient temperature, the reaction was quenched with an equal volume of saturated aqueous NaHCO3. The mixture was extracted twice with dichloromethane, and the combined organic layers were dried (Na2SO4), and concentrated in vacuo, affording a yellow solid. Purification by flash chromatography (15% EtOAc in hexane) afforded the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:18](=[O:19])[C:13]2=[CH:14][CH2:15][CH2:16][CH2:17][N:12]2[C:11]1=[O:20].CI.[C:23](=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:23])=[CH:4][C:3]=1[N:10]1[C:18](=[O:19])[C:13]2=[CH:14][CH2:15][CH2:16][CH2:17][N:12]2[C:11]1=[O:20]
Reactant: Cc1cc(Cl)c(N2C(=O)C3=CCCCN3C2=O)cc1O
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: CC#N
Product: COc1cc(N2C(=O)C3=CCCCN3C2=O)c(Cl)cc1C
Yield: 64.6 %

Procedure:
An acetonitrile (10 mL) solution of 2-(2-chloro-4-methyl-5-hydroxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.34 g, 1.11 mmol), methyliodide (0.08 mL, 1.22 mmol) and potassium carbonate (0.15 g, 1.11 mmol) was stirred for 30 minutes under reflux. A saturated ammonium chloride solution (20 mL) was added to the resulting mixture and the organic layer was separated. The aqueous layer was extracted with diethyl ether (10 mL×2 times), and the organic layer combined was washed with a saturated sodium chloride solution (40 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane=1/2) to obtain a white solid of 2-(2-chloro-4-methyl-5-methoxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.22 g, yield:61.1%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:13])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2[CH:25]=[CH:26][CH:27]=[N:28]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1(N)CC1>CN(C)C=O.C(=O)(O)[O-].[Na+].CCOCC.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([NH:28][CH:27]2[CH2:25][CH2:26]2)=[O:13])=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(Br)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NC1CC1)[C@@H]1C[C@H]1c1ccc(Br)cc1
Reaction time: 8 h

Procedure:
To a solution of (1R,2R)-2-(4-bromophenyl)cyclopropanecarboxylic acid from Step 1 (300 mg, 1.24 mmoles) in dimethylformamide (5 mL) at room temperature was added HATU (500 mg, 1.31 mmoles) followed by cyclopropylamine (0.44 mL, 6.2 mmoles). The reaction mixture was stirred overnight and diluted with half-saturated sodium bicarbonate aqueous solution (50 mL), ether (50 mL) and ethyl acetate (50 mL). The phases were separated and the organic layer was washed with water twice (30 mL each portion), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified onto a short column of silica gel using 50% ethyl acetate diethyl ether to give the title compound.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([O:10]CC1C=CC=CC=1)=[O:9])[CH3:2]>[Pd]>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]([OH:10])=[O:9])[CH3:2]
Reactant: CCN1CCC[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Product: CCN1CCC[C@H]1C(=O)O
Reaction time: 3 h
Yield: 102.1 %

Procedure:
Palladium on carbon (10%, 0.2 g) was added to a solution of benzyl (S)—N-ethylpyrrolidine-2-carboxylate (Intermediate 107, 0.603 g) under an atmosphere of nitrogen. The mixture was then hydrogenated at 4 Bar for 3 hours. The mixture was filtered through Celite and the filtrate was evaporated to dryness to give (S)—N-ethylpyrrolidine-2-carboxylic acid (0.378 g) as a straw coloured gummy solid.