Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:16][CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18])([CH2:5][C:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)[CH3:4]>CCO>[NH2:1][CH2:2][C:3]([NH:16][CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18])([CH3:4])[CH2:5][CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1
Reactant: CC(NC(C)(CN)CC1=Cc2ccccc2CC1)c1ccccc1
Solvent: CCO
Product: CC(NC(C)(CN)CC1CCc2ccccc2C1)c1ccccc1

Procedure:
A suspension of 0.52 g (1.62 mmol) of the compound obtained in Step 2 (diastereoisomer 1) and of 0.1 g of Pd/Al2O3 in 60 ml of EtOH is hydrogenated at 20° C. under 1 bar for 16 hours. The mixture is then filtered and concentrated in vacuo to yield the title compound in the form of a foam.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([O:18]CC)=[O:17])=[CH:8]1.[OH-].[Na+]>O1CCCC1>[C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([OH:18])=[O:17])=[CH:8]1
Reactant: CCOC(=O)c1cn(-c2ccccc2C)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccccc1-n1cc(C(=O)O)c2ccccc21
Temperature: 60 °C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
A mixture of ethyl 1-(o-tolyl)-1H-indole-3-carboxylate (0.789 g, 2.82 mmol), 4N sodium hydroxide aqueous (20 mL) and tetrahydrofuran (20 mL) was stirred at 60° C. for 18 hours. Most solvent was removed and the rest was acidified with 10% hydrochloric acid aqueous to adjust to pH=5. Pale yellow precipitate formed and was collected by filtration. The solid was washed with petroleum ether, dried in vacuo to give 1-(o-tolyl)-1H-indole-3-carboxylic acid as a pale yellow solid (0.675 g, 95%). LRMS (M+H) m/z: calcd 251.09. found 251.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][C:12]=1[I:13].[CH2:14]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].ClCC(Cl)(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-].S(=O)(=O)(O)O>>[Br:1][C:2]1[C:12]([I:13])=[CH:11][C:5]2[C:6](=[O:8])[C:30]3[C:29](=[CH:28][C:27]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[C:26]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:31]=3)[C:9](=[O:10])[C:4]=2[CH:3]=1
Reactant: CCCCCCCCCCCCc1ccccc1CCCCCCCCCCCC
Reactant: O=C1OC(=O)c2cc(I)c(Br)cc21
Agent: ClCC(Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Agent: [Al+3]
Product: CCCCCCCCCCCCc1cc2c(cc1CCCCCCCCCCCC)C(=O)c1cc(I)c(Br)cc1C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.9 %

Procedure:
To a 100 ml three-necked flask were added 1.00 g (2.83=mol) of 4-bromo-5-iodophthalic anhydride synthesized in the above, 1.29 g (3.11 mmol) of 1,2-didodecylbenzene, and 4 ml of tetrachloroethane. Thereto was added 0.82 g (6.15 mmol) of aluminum chloride, followed by 3 hours of stirring at room temperature. Ice was added portionwise to the resulting reaction mixture to quench the reaction, followed by extraction with toluene. The extract was concentrated under reduced pressure to obtain 2.5 g of a viscous matter. To the viscous matter was added 8 ml of sulfuric acid, followed by 2 hours of stirring at 80° C. The resulting reaction mixture was cooled to room temperature and ice was added. The mixture was extracted with toluene and the organic phase was dried over sodium sulfate. Then, the phase was filtrated and concentrated under reduced pressure to obtain 678 mg of 2-bromo-3-iodo-6,7-didodecylanthraquinone (yield 35%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[C:7]([OH:9])=O)[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.O[NH:38]/[C:39](=[N:56]\[H])/[C:40]1[CH:41]=[CH:42][CH:43]=[C:44]2[C:48]=1[NH:47][CH:46]=[C:45]2[CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7]2[O:9][N:56]=[C:39]([C:40]3[CH:41]=[CH:42][CH:43]=[C:44]4[C:48]=3[NH:47][CH:46]=[C:45]4[CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])[N:38]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH3:2]
Reactant: [H]/N=C(\NO)c1cccc2c(CCC(=O)OCC)c[nH]c12
Reactant: CCOc1ccc(C(=O)O)cc1OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OCC)c(OCC)c4)n3)cccc12
Reaction time: 2 h
Yield: 78.5 %

Procedure:
To a solution of 3,4-bis(ethyloxy)benzoic acid (631 mg) in tetrahydrofuran (15 mL) stirred at room temperature was added EDCI (767 mg) and HOBT (613 mg). The reaction mixture was stirred for 2 h. Then ethyl 3-{7-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D35) (551 mg) was added. The reaction mixture was stirred at 60° C. for 2 h, and then TBAF (2092 mg) was added. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 130° C. for 3 h. After cooling the reaction, the solvent was removed. Water (90 mL) and ethanol (30 mL) was added to the residue, a yellow solid was formed, filtered and dried in vacuo to afford the product ethyl 3-(7-{5-[3,4-bis(ethyloxy)phenyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (D66) (706 mg). δH (CDCl3, 400 MHz): 1.26 (3H, t), 1.52-1.57 (6H, m), 2.76 (2H, t), 3.18 (2H, t), 4.16 (2H, q), 4.19-4.28 (4H, m), 7.02 (1H, d), 7.20 (1H, d), 7.28 (1H, t), 7.74 (1H, d), 7.81 (1H, d), 7.86 (1H, dd), 8.14 (1H, dd), 9.64 (1H, s). MS (ES): C25H27N3O5 requires 449. found 450.2 (M+H+).
Reaction SMILES: CS[C:3]1[NH:12][C:11](=[O:13])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(O)CC(C)C>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][N:25]([C:3]2[NH:12][C:11](=[O:13])[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[N:4]=2)[CH2:24][CH2:23]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CSc1nc2c(c(=O)[nH]1)CCCC2
Solvent: CC(C)CCO
Product: COc1ccccc1N1CCN(c2nc3c(c(=O)[nH]2)CCCC3)CC1

Procedure:
2-Methylsulfanyl-5,6,7,8-tetrahydro-3H-quinazolin-4-one (100 mg; 0.51 mmol) and 1-(2-methoxyphenyl)piperazine (98 mg; 0.51 mmol) are reacted in isoamyl alcohol (1 ml) in accordance with the procedure for Example 1 (reaction time 4 h) and worked up; yield: 52 mg (30%), crystals;
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[F:25][C:26]([F:42])([F:41])[C:27]1[CH:32]=[CH:31][C:30](/[CH:33]=[CH:34]/[CH:35]=[CH:36]/[CH:37]=[CH:38]/[CH:39]=O)=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][C@@H:19]1[CH2:20][O:21][C@@H:39](/[CH:38]=[CH:37]/[CH:36]=[CH:35]/[CH:34]=[CH:33]/[C:30]2[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:41])[F:42])=[CH:32][CH:31]=2)[O:23][CH2:22]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=C/C=C/C=C/C=C/c1ccc(C(F)(F)F)cc1
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/C=C/C=C/c2ccc(C(F)(F)F)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 65 %

Procedure:
Reaction was carried out in the same manner as in Example 4 using (2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol and (2E,4E,6E)-7-[4-(trifluoromethyl)phenyl]-2,4,6-heptatrienal as described in Reference example 28 to obtain the title compound, a major product as an oil in a yield of 65%.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([O:11][CH3:12])=[CH:7][CH:8]=2)[C:3]1=[O:13].[O:14]1[C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:18]=2[O:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[O:14]1[C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([N:24]3[CH2:29][CH2:28][N:27]([CH:2]4[CH2:10][C:9]5[C:4](=[CH:5][C:6]([O:11][CH3:12])=[CH:7][CH:8]=5)[C:3]4=[O:13])[CH2:26][CH2:25]3)[C:18]=2[O:17][CH2:16][CH2:15]1
Reactant: COc1ccc2c(c1)C(=O)C(Br)C2
Reactant: c1cc2c(c(N3CCNCC3)c1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C(=O)C(N1CCN(c3cccc4c3OCCO4)CC1)C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 73.9 %

Procedure:
A suspension prepared from 25.3 g (100 mmol) of the compound obtained in Step 1, 22.0 g (100 mmol) of (2,3-dihydro[1,4]benzodioxin-5-yl)piperazine, 13.8 g (100 mmol) of potassium carbonate and 140 ml of dimethylformamide is stirred at room temperature for 20 hours. The mixture is then poured into 1.5 litres of water, and the solid that forms (violet) is filtered off, rinsed with water and dried in vacuo to obtain 28.1 g of the expected product.
Reaction SMILES: [C:1]([C:3]1([OH:13])[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][CH2:5][C:4]1([CH3:12])[CH3:11])#[CH:2].Br[C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH:18]=[CH:19][CH:20]=1>>[F:27][C:26]([F:28])([F:29])[C:25]([NH:24][CH2:23][CH2:22][CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:2]#[C:1][C:3]2([OH:13])[C:4]([CH3:12])([CH3:11])[CH2:5][CH2:6][CH2:7][C:8]2([CH3:9])[CH3:10])[CH:16]=1)=[O:30]
Reactant: O=C(NCCCc1cccc(Br)c1)C(F)(F)F
Reactant: C#CC1(O)C(C)(C)CCCC1(C)C
Product: CC1(C)CCCC(C)(C)C1(O)C#Cc1cccc(CCCNC(=O)C(F)(F)F)c1

Procedure:
Coupling of 1-ethynyl-2,2,6,6-tetramethylcyclohexanol with bromide 10 following the method used in Example 4 gave 2,2,2-trifluoro-N-(3-(3-((1-hydroxy-2,2,6,6-tetramethylcyclohexyl)ethynyl)phenyl)propyl)acetamide as a light brown foam. Yield (0.192 g, 84%): 1H NMR (400 MHz, DMSO-d6) δ 9.40 (br s, 1H), 7.27 (t, J=7.6 Hz, 1H), 7.18-7.23 (m, 3H), 4.92 (s, 1H), 3.18 (q, J=6.8 Hz, 2H), 2.57 (t, J=7.2 Hz, 2H), 1.76 (quint, J=7.6 Hz, 2H), 1.22-1.50 (m, 6H), 1.14 (s, 6H), 1.04 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)[CH3:20]>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:24]2[CH:25]=[CH:26][C:21]([CH2:19][CH3:20])=[CH:22][CH:23]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Reactant: CCc1ccc(B(O)O)cc1
Product: CCc1ccc(-c2ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c2)cc1

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) and 4-ethylbenzene boronic acid according to the general procedure B. Obtained as an orange solid (689 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:13]=[CH:12][N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:10]=2)[N:5]=[C:4]([C:22](OC)=[O:23])[CH:3]=1.[BH4-].[Li+]>O1CCCC1.CO>[OH:23][CH2:22][C:4]1[CH:3]=[C:2]([OH:1])[CH:7]=[C:6]([NH:8][C:9]2[CH:13]=[CH:12][N:11]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:10]=2)[N:5]=1
Reactant: COC(=O)c1cc(O)cc(Nc2ccn(COCC[Si](C)(C)C)n2)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc(Nc2cc(O)cc(CO)n2)n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To 16 g of methyl 4-hydroxy-6-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)pyridine-2-carboxylate dissolved in 200 ml of tetrahydrofuran, 2.0 M of lithium borohydride dissolved in 30 ml of tetrahydrofuran solution was added, and the mixture was stirred at 60° C. for 1 hour. The resulting mixture was cooled to 0° C., and then 10% hydrochrolic acid in methanol was added thereto to adjust the pH of the solution to 4. After stirred 30 minutes at room temperature, the mixture was concentrated to give the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:9]1)=O)(C)(C)C.C[Si]([N:26]=[C:27]=[O:28])(C)C>C(Cl)Cl.C(O)(C)C>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][N:13]([C@@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[C:27]([NH2:26])=[O:28])=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NCc2ccc(Cl)cc2)C1
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Solvent: CC(C)O
Product: NC(=O)N(Cc1ccc(Cl)cc1)[C@@H]1CCNC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(R)-3-(4-Chloro-benzylamino)-pyrrolidine-1-carboxylic acid tert-butylester (0.690 g, 2.2 mmol) was dissolved in CH2Cl2 with a few drops of isopropanol and trimethylsilylisocyanate (0.365 mL, 2.6 mmol) were added. The solution was allowed to stir at room temperature for 12 h, the reaction was concentrated down and used directly in the next reaction. ESI-MS m/z: 354 (M+1), retention time 2.15.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[C:15]([C:23](OC)=[O:24])[C:16](=[CH:21][CH:22]=2)[C:17](OC)=[O:18])[CH:6]=[CH:7][C:8]=1[OH:9])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].Cl>C(OCC)C.O>[OH:24][CH2:23][C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][CH2:10][C:5]2[CH:6]=[CH:7][C:8]([OH:9])=[C:3]([CH2:1][CH3:2])[CH:4]=2)[CH:22]=[CH:21][C:16]=1[CH2:17][OH:18]
Reactant: CCc1cc(CCCc2ccc(C(=O)OC)c(C(=O)OC)c2)ccc1O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CCc1cc(CCCc2ccc(CO)c(CO)c2)ccc1O
Reaction time: 0.5 h

Procedure:
1.7 g (4.8 mmol) of dimethyl 4-[3-(3-ethyl-4-hydroxyphenyl)propyl]phthalate (Example 1f are dissolved in 50 ml of ethyl ether, and this solution is slowly added to a suspension of 435 mg (11.4 mmol) of lithium aluminum hydride. The medium is stirred for 30 minutes and is then sequentially treated with 450 μl of water, 450 μl of 15% sodium hydroxide and 1.5 ml of water. The reaction medium is poured into a 1N hydrochloric acid solution, and extracted with ethyl ether. A white solid is obtained (m=1.2 g, m.p.=82° C., y=84%).
Reaction SMILES: ClC1C=CC2[C:6](=[O:16])C3C(NC=2C=1)=CC=CC=3.Cl[C:18]1[CH:19]=[CH:20][C:21]2[C:22](=[O:34])[C:23]3[C:28]([N:29]([CH2:32][CH3:33])[C:30]=2[CH:31]=1)=[CH:27][CH:26]=[CH:25][CH:24]=3>C(OCC)(=O)C>[CH3:6][O:16][C:25]1[CH:26]=[CH:27][C:28]2[N:29]([CH2:32][CH3:33])[C:30]3[C:21](=[CH:20][CH:19]=[CH:18][CH:31]=3)[C:22](=[O:34])[C:23]=2[CH:24]=1
Reactant: O=c1c2ccccc2[nH]c2cc(Cl)ccc12
Reactant: CCn1c2ccccc2c(=O)c2ccc(Cl)cc21
Solvent: CCOC(C)=O
Product: CCn1c2ccccc2c(=O)c2cc(OC)ccc21

Procedure:
Similarly, there was prepared, from 3-chloro-9(10H)-acridinone and ethyl acetate, 3-chloro-10-ethyl-9(10H)-acridinone, m.p. 169°-171° C.
Reaction SMILES: [C:1]1([CH:7]([NH:14][C:15]2[S:16][CH:17]=[C:18]([CH:20]=O)[N:19]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:22]1[CH2:28][C:26](=[O:27])[N:25]([CH2:29][C:30]([OH:32])=[O:31])[C:23]1=[S:24].[Cl-].[NH4+].N>C(O)C>[C:8]1([CH:7]([NH:14][C:15]2[S:16][CH:17]=[C:18]([CH:20]=[C:28]3[S:22][C:23](=[S:24])[N:25]([CH2:29][C:30]([OH:32])=[O:31])[C:26]3=[O:27])[N:19]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1csc(NC(c2ccccc2)c2ccccc2)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(O)CN1C(=O)C(=Cc2csc(NC(c3ccccc3)c3ccccc3)n2)SC1=S

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 1.95 g of 2-diphenylmethylaminothiazole-4-carbaldehyde. 1.32 g of rhodanine-3-acetic acid, 0.4 g of ammonium chloride, 0.4 ml of 28% v/v aqueous ammonia and 20 ml of ethanol. The resulting product was a reddish-brown powder having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]Br)=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH:13]([OH:15])[CH3:14]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:11][CH2:12][CH:13]([OH:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: CC(O)CN
Reactant: Clc1ccc(CCBr)cc1
Product: CC(O)CNCCc1ccc(Cl)cc1

Procedure:
reacting the 2-(4-chlorophenyl)ethyl bromide with 1-aminopropan-2-ol to form 1-(4-chlorophenethylamino)propan-2-ol; and
Reaction SMILES: [Br:1][C:2]1[CH2:7][C:6]([F:9])(I)[CH:5]=[CH:4][C:3]=1[F:10].[CH2:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]#[CH:22])=[CH:17][CH:16]=1)[CH2:12][CH2:13][CH3:14].Cl>C(NCC)C.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.[Cu]I>[Br:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([C:22]#[C:21][C:18]2[CH:19]=[CH:20][C:15]([CH2:11][CH2:12][CH2:13][CH3:14])=[CH:16][CH:17]=2)=[C:6]([F:9])[CH:7]=1
Reactant: FC1=C(Br)CC(F)(I)C=C1
Reactant: C#Cc1ccc(CCCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCNCC
Product: CCCCc1ccc(C#Cc2cc(F)c(Br)cc2F)cc1
Temperature: 5 °C
Yield: 66.8 %

Procedure:
2-Bromo-1,4-difluoro-4-iodobenzene (11 g) was dissolved in diethylamine (16 ml) under nitrogen atmosphere, and then bis(triphenylphosphine)palladium(II) chloride (0.03 g) and copper(I) iodide (0.03 g) were added thereto, followed by stirring. The flask was cooled to 5° C. or lower, and then 4-butylphenylacetylene (6.2 g) was added dropwise thereto. After stirring at room temperature for 5 hours, the reaction solution was poured into a mixture of concentrated hydrochloric acid (9 ml) and ice (20 g). After extraction with chloroform, the resultant was washed with water twice, followed by distilling off chloroform. The residue was distilled under reduced pressure (b.p. 170° to 180° C./5 mmHg) to give 4-bromo-2,5-difluoro-4'-butyltolane (8 g).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:20])[C:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][CH2:15][C:16]#[N:17])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:18][C:12]([CH3:19])([C:11](=[O:20])[C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:25]3[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=3)[N:3]=2)[NH:8][CH:9]=1)[CH2:13][CH2:14][CH2:15][C:16]#[N:17]
Reactant: CC(C)(CCCC#N)C(=O)c1c[nH]c2ncc(Br)nc12
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(-c2cnc3[nH]cc(C(=O)C(C)(C)CCCC#N)c3n2)cc(OC)c1OC
Reaction time: 1 h
Yield: 4 %

Procedure:
A mixture of 6-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-5,5-dimethyl-6-oxo-hexanenitrile (0.079 g, 0.236 mmol), 3,4,5-trimethoxyphenylboronic acid (0.055 g, 0.26 mmol), potassium carbonate (0.098 g, 0.71 mmol) and Pd(dppf)Cl2.CH2Cl2 (0.019 g, 0.024 mmol) in 2.4 mL of 1,4-dioxane and 0.4 mL of water was stirred at 120° C. in a microwave for 1 h, then at 130° C. in a microwave for 1 h. The resulting mixture was partitioned between 50 mL of ethyl acetate and 25 mL of water. The organic layer was dried over MgSO4, filtered, and concentrated to a residue. Column chromatography (0→100% EtOAc/hexanes) afforded 0.004 g (4%) of 5,5-dimethyl-6-oxo-6-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-hexanenitrile as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[CH:19]=[CH:20][NH:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1.CC1[O:25]C2CCNC(C)C=2N=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[O:25][C:20]([CH3:19])=[N:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1
Reactant: CC1c2[nH]ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1
Reactant: Cc1nc2c(o1)CCNC2C
Product: Cc1nc2c(o1)CCN(C(=O)c1cc3ncc(Br)cn3n1)C2C

Procedure:
(6-Bromo-pyrazolo[1,5-a]pyrimidin-2-yl)-(7-methyl-1,4,5,7-tetrahydro-pyrrolo[2,3-c]pyridin-6-yl)-methanone is reacted with 2,4-dimethyl-4,5,6,7-tetrahydro-oxazolo[4,5-c]pyridine to provide the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:16]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([N+:22]([O-])=O)[CH:7]=1.[H][H]>CCOC(C)=O.[Pd]>[NH2:22][C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[C:16]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: [H][H]
Reactant: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1N
Yield: 92 %

Procedure:
According to the procedure described in Example 6A Step 3, a mixture of ethyl 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate (8.53 g, 24.8 mmol) and Pd/C (10%, 0.85 g) in EtOAc (150 mL) was stirred under 1 atmosphere of hydrogen at room temperature overnight, to afford ethyl 2-amino-4,5-bis(2-methoxyethoxy)benzoate as an oil (7.15 g, 92%). 1H NMR (300 MHz, CDCl3) δ 7.44 (s, 1H), 6.15 (s, 1H), 5.60 (br, 2H), 4.30 (q, 2H), 4.13 (t, 2H), 4.08 (t, 2H), 3.78 (t, 2H), 3.73 (t, 2H), 3.45 (s, 6H), 1.36 (t, 3H); LC-MS (ESI) m/z 314 (M+H)+.
Reaction SMILES: BrC[CH2:3][C:4]1([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)OCCO1.[C:17](=O)([O-:19])[O-:18].[Ca+2].C(N)=O>O>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([CH:4]([CH3:3])[C:17]([OH:19])=[O:18])=[CH:14][CH:13]=1
Reactant: COc1ccc(C2(CCBr)OCCO2)cc1
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: NC=O
Solvent: O
Product: COc1ccc(C(C)C(=O)O)cc1
Temperature: 120 °C
Reaction time: 6 h
Yield: 83 %

Procedure:
A mixture of 2-(bromoethyl)-2-(4-methoxyphenyl)-1,3-dioxolane (2.87 g; 10 mmol), calcium carbonate (1.2 g; 12 mmol), formamide (44 ml) and water (4 ml) is heated at 120° C., under stirring, for 6 h. The reaction mixture is worked up as described in example 1a to give 2-(4-methoxyphenyl)-propionic acid (1.67 g; 8.3 mmol; yield 83%), m.p. 55°-57° C.
Reaction SMILES: CN([CH:4]=[C:5]1[C:11](=O)[C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[NH:8][C:7](=[O:17])[CH2:6]1)C.Cl.[C:19]([NH2:22])(=[NH:21])[CH3:20]>>[CH3:20][C:19]1[N:21]=[CH:4][C:5]2[CH2:6][C:7](=[O:17])[NH:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]=2[N:22]=1
Reactant: CN(C)C=C1CC(=O)Nc2ccccc2C1=O
Reactant: CC(=N)N
Agent: Cl
Product: Cc1ncc2c(n1)-c1ccccc1NC(=O)C2
Yield: 44 %

Procedure:
Analogous to Scheme 1, from 4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and acetamidine hydrochloride. Yield: 44%.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23]>>[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:23]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: Cc1ccc(Cn2cnc(N)c2C(N)=O)cc1
Product: Cc1ccc(Cn2cnc(NC(=O)c3cccc(F)c3)c2C(N)=O)cc1
Yield: 88 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 1, using 2.30 g (9.99 mmol) of 4-amino-1-(4-methylbenzyl)-5-imidazolecarboxamide prepared in the same manner as in Example 87 and 3-fluorobenzoyl chloride instead of benzoyl chloride to obtain 3.11 g of 4-(3-fluorobenzoylamino)-1-(4-methylbenzyl)-5-imidazole carboxamide (yield 88%).