Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14]/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C/C=C/c2ccc(C(F)(F)F)cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CCCc2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-[(E)-3-(4-Trifluoromethylphenyl)allyl]piperidine-1-carboxylic acid tert-butyl ester (13.4 g, 36.2 mmol) and 10% palladium on carbon (1.4 g, 1.3 mmol) were suspended in ethanol (120 ml), followed by stirring under a hydrogen atmosphere (atmospheric pressure) at room temperature for 5 hours. Thereafter the insoluble matter was removed by filtration, and the resulting solution was concentrated to afford the title compound as a colorless oil (crude).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1B1OC(C)(C)C(C)(C)O1>>[F:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:20])[F:19])=[CH:14][CH:15]=2)=[O:8])[CH:21]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2cnccc2F)OC1(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cnccc2F)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 7 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and 4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine to afford a solid. UPLC-MS (Condition 3), tR=0.97 min, m/z=463.3 [M+H]+; 1H-NMR (400 MHz, DMSO-d6), δ ppm 1.66-1.76 (m, 1H) 1.77-1.89 (m, 1H) 2.87-2.97 (m, 1H) 3.14-3.21 (m, 1H) 3.30 (s, 2H) 4.14-4.23 (m, 1H) 4.82-4.92 (m, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.41-7.49 (m, 1H) 7.83 (d, J=8.99 Hz, 2H) 8.03 (d, J=2.35 Hz, 1H) 8.61-8.67 (m, 1H) 8.68-8.77 (m, 1H) 8.79 (d, J=2.35 Hz, 1H) 10.15 (s, 1H).
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[SH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:1](=[O:10])[S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:3][CH:4]=1
Reactant: Sc1ccccn1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Sc2ccccn2)cc1

Procedure:
Following the general procedure described above, reaction of p-anisoyl chloride (4.70 g, 30.0 mmol) with 2-mercaptopyridine (3.33 g, 30.0 mmol) in THF (30 mL) for 30 min at room temperature afforded pale yellow solid after precipitation (6.70 g, 91%): mp 73° C.; 1H NMR δ 3.88 (s, 3H), 6.93-7.00 (m, 2H), 7.30-7.34 (m, 1H), 7.70-7.74 (m, 2H), 7.75-7.80 (m, 1H), 7.97-8.02 (m, 1H), 8.64-8.69 (m, 1H); Anal. Calcd for C13H11NO2S: C, 63.65; H, 4.52; N, 5.71. Found: C, 63.78; H, 4.59; N, 5.66.
Reaction SMILES: O=[C:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[NH2:17][C:18]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:19]=1[CH:20]=O>CO.[OH-].[Na+]>[Br:26][C:23]1[CH:22]=[C:19]2[C:18](=[CH:25][CH:24]=1)[N:17]=[C:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]([CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:20]2
Reactant: O=C(O)CCCCCC(=O)c1ccccc1
Reactant: Nc1ccc(Br)cc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCCc1cc2cc(Br)ccc2nc1-c1ccccc1
Temperature: 110 °C
Yield: 102.8 %

Procedure:
7-Oxo-7-phenylheptanoic acid (5.00 g, 22.7 mmol) and 2-amino-5-bromobenzaldehyde (5.45 g, 27.2 mmol) were dissolved in a solution of methanol (100 mL) and 2 M NaOH (30 mL). The reaction mixture was heated to 110° C. in an oil bath and refluxed overnight. The reaction was concentrated, acidified with 10% aq. HCl to pH 1 and diluted with DCM. The biphasic solution was separated and the aqueous layer was extracted with DCM (3×). The combined organic phase was dried over anhydrous sodium sulfate and concentrated to provide 5-(6-bromo-2-phenylquinolin-3-yl)pentanoic acid (1A, 8.97 g, LCMS (M+H)=384).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10](N)=[C:9]([OH:14])[CH:8]=1)[CH3:2].N([O-])=O.[Na+].[ClH:20]>O.[Cu]Cl>[CH2:1]([O:3][C:4](=[O:15])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([Cl:20])=[C:9]([OH:14])[CH:8]=1)[CH3:2]
Reactant: Cl
Reactant: CCOC(=O)/C=C/c1ccc(N)c(O)c1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(Cl)c(O)c1
Temperature: 25 °C

Procedure:
(E)-3-(4-Amino-3-hydroxy-phenyl)-acrylic acid ethyl ester (236 g, 13.3 mmol) was suspended in HCl solution (6N, 4 ml), and sodium nitrite solution in water (960 mg, 14 mmol) was added at 0° C. The resulting suspension was added at 0° C. to a solution of copper (I) chloride (2 g, 16 mmol) in concentrated HCl (4 ml). The mixture was slowly warmed to RT and heated to 60° C. for 30 min., shaking occasionally. Then it was cooled to RT, diluted with water and extracted with DCM, which was dried and evaporated. The residue was purified by silica gel column chromatography, eluant petroleum ether/AcOEt 90:10, to give 1.46 g of (E)-3-(4-chloro-3-hydroxy-phenyl)-acrylic acid ethyl ester as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH3:9])=[CH:6][N:5]=[C:4]2[N:10]([CH2:13][CH3:14])[N:11]=[CH:12][C:3]=12.CCN(C(C)C)C(C)C.[F:24][C:25]([F:43])([F:42])[C:26]1[CH:27]=[C:28]([C:36]([CH3:41])([CH3:40])[C:37](Cl)=[O:38])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1>C(Cl)Cl>[F:43][C:25]([F:24])([F:42])[C:26]1[CH:27]=[C:28]([C:36]([CH3:41])([CH3:40])[C:37]([N:8]([C:7]2[C:2]([Cl:1])=[C:3]3[CH:12]=[N:11][N:10]([CH2:13][CH3:14])[C:4]3=[N:5][CH:6]=2)[CH3:9])=[O:38])[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1
Reactant: CCn1ncc2c(Cl)c(NC)cnc21
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCn1ncc2c(Cl)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cnc21
Temperature: 40 °C
Yield: 94.7 %

Procedure:
To a solution of (4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-methyl-amine (2.24 g, 10.63 mmol) in CH2Cl2 (50 mL) was added iPr2NEt (3.69 mL, 21.20 mmol) and 2-(3,5-Bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride (described in J. Org. Chem, 2006, 71, 2000-2008, 4.38 g, 13.70 mmol). The reaction mixture was heated at 40° C. for 2 hours, diluted with CH2Cl2 (100 mL), and washed with H2O. The organic phase was dried over Na2SO4, concentrated under vacuo, and column chromatography (SiO2, EtOAc/Heptane 1/4) afforded 4.96 g (95%) of the title compound as a light yellow solid. ES-MS m/e: 493.2 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:15][CH3:16])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]#[N:14])[N:12]=2)[C:8]=1[CH3:9])[CH3:2].C(Cl)(Cl)Cl.[OH2:21]>>[CH2:1]([C:3]1[C:4]([O:15][CH3:16])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]([NH2:14])=[O:21])[N:12]=2)[C:8]=1[CH3:9])[CH3:2]
Reactant: O
Reactant: CCc1c(OC)nc2nc(C#N)cn2c1C
Solvent: ClC(Cl)Cl
Product: CCc1c(OC)nc2nc(C(N)=O)cn2c1C
Yield: 97 %

Procedure:
A suspension of 10.0 g of 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-carbonitrile of Step A and 20.0 g of Amberlite IRA-400 (base form) in 200 ml of water was stirred rapidly at reflux and after 41/2 hours, the mixture was cooled. Chloroform was added to dissolve the precipitated product and the two phase mixture was filtered to remove the Amberlite. The layers were separated and the aqueous phase was extracted with chloroform. The combined chloroform layers were dried over MgSO4, filtered and evaporated to dryness. The solid product was crystallized from methanol to obtain 10.5 g (97% yield) of 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-carboxamide as white needles melting at 256°-259° C.
Reaction SMILES: [CH:1]1([C:4](=[O:19])[CH2:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:9]=2[F:18])=[O:7])[CH2:3][CH2:2]1.[CH:20](OCC)(OCC)[O:21][CH2:22][CH3:23].C(OC(=O)C)(=O)C>>[CH:1]1([C:4](=[O:19])[C:5](=[CH:20][O:21][CH2:22][CH3:23])[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:10][C:9]=2[F:18])=[O:7])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(C(=O)CC(=O)C2CC2)c(F)c1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc(S(C)(=O)=O)cc1F)C(=O)C1CC1
Yield: 99.3 %

Procedure:
A mixture of 3-cyclopropyl-1-(2-fluoro-4-methylsulphonylphenyl)-propan-1,3-dione (7.4 g), triethyl orthoformate (8.5 g) and acetic anhydride was stirred and heated at reflux for 4 hours. The mixture was evaporated to dryness. Xylene was added and the mixture was re-evaporated to give 3-cyclopropyl-2-ethoxymethylene-1-(2-fluoro-4-methylsulphonylphenyl)-propan-1,3-dione (8.8 g) as a red oil which was not further purified.
Reaction SMILES: Cl.[CH2:2]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH3:28][S:29]([NH2:32])(=[O:31])=[O:30]>N1C=CC=CC=1>[CH2:2]([NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:32][S:29]([CH3:28])(=[O:31])=[O:30])=[O:24])=[CH:21][CH:20]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Cl)cc1
Reactant: CS(N)(=O)=O
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)NS(C)(=O)=O)cc1

Procedure:
A solution of 25.2 g. of 4-(hexadecylamino)benzoyl chloride hydrochloride and 5.8 g. of methanesulfonamide in 250 ml. of pyridine was stirred under reflux for 2 hours and then concentrated in vacuo. The residue was partitioned between water and diethyl ether; the aqueous layer acidified with 1 N HCl, and the organic layer separated, dried (MgSO4), and evaporated. Crystallization of the residual white solid from 60% aqueous acetic acid followed by CH2Cl2 -hexane afforded the product as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([N+:24]([O-])=O)[CH:20]=4)[N:15]=3)[CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-])=O>C(O)C.[H][H].[Pd]>[NH2:1][C:4]1[CH:28]=[CH:27][C:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([NH2:24])[CH:20]=4)[N:15]=3)[CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN(Cc1ccc3cc([N+](=O)[O-])ccc3n1)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)CCN(Cc1ccc3cc(N)ccc3n1)CC2

Procedure:
The title compound was prepared similarly to the procedure of Preparation 5 by the hydrogenation of 7-nitro-3-(6-nitroquinol-2-ylmethyl)-1,2,4,5-tetrahydro-3H-3-benzazepine using H2 /Pd/C in ethanol.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[O:12][C@@H:11]([N:23]2[C:36]3[N:35]=[C:30]([NH:31][C:32](=[O:34])[NH2:33])[NH:29][C:27](=[O:28])[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:46]1([N:52]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:53](Cl)=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>N1C=CC=CC=1>[Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:17])[CH3:18])[O:12][C@@H:11]([N:23]2[C:36]3[N:35]=[C:30]([NH:31][C:32](=[O:34])[NH2:33])[N:29]=[C:27]([O:28][C:53](=[O:54])[N:52]([C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=4)[C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(NC(N)=O)nc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(OC(=O)N(c4ccccc4)c4ccccc4)nc(NC(N)=O)nc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
The above-obtained 3′,5′-bis-O-(tert-butyldimethylsilyl)-2-N-carbamoyldeoxyguanosine (1.23 g, 2.29 mmol) was azeotroped with anhydrous pyridine three times and then dissolved in anhydrous pyridine (23 mL). To the resulting solution, diisopropylethylamine (797 μL, 4.58 mmol) and then diphenylcarbamoyl chloride (689 mg, 2.98 mmol) were added, and the mixture was stirred at room temperature for 0.5 hours. Then, the reaction was terminated by adding sodium bicarbonate water (5 ml) thereto. The reaction solution was extracted with ethyl acetate (180 mL)/sodium bicarbonate water (150 mL) once and then with ethyl acetate (180 mL)/brine (100 mL) twice. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (C200) with ethyl acetate/50% to 60% hexane to give 3′,5′-bis-O-(tert-butyldimethylsilyl)-2-N-carbamoyl-6-O-diphenylcarbamoyldeoxyguanosine (1.53 g, 91%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH:10]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[CH:27][C:28](O)=[N:29][CH:30]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:28]2[CH:27]=[CH:26][C:25]([Cl:24])=[CH:30][N:29]=2)[CH:10]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C(c2ccc(F)c(F)c2)C1
Reactant: Oc1ccc(Cl)cn1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(Cl)cn2)C(c2ccc(F)c(F)c2)C1
Temperature: 25 °C

Procedure:
A mixture of 1 g (3 mmol) (3SR,4SR)-3-(3,4-Difluoro-phenyl)-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester, 0.59 g (4.5 mmol) 5-chloro-2-hydroxy pyridine, 1.1 g (4.8 mmol) di-tert-butyl azodicarboxylate and 2.42 g (5 mmol) triphenylphosphine (polymer bound) in 70 mL THF was stirred at room temperature over night. the mixture was filtered through decalite and evaporated to dryness. The residue was subjected to column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane to afford after evaporation of the product containing fractions 1.2 g (91%) of the title compound as viscous colorless oil. MS (m/e): 439.1 [(M+H)+].
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH3:13])=[O:12])=[CH:6][CH:5]=1)=O.BrBr.[NH2:16][C:17]1[S:18][CH2:19][CH2:20][N:21]=1>C(Cl)Cl.O>[C:11]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]2[N:16]=[C:17]3[N:21]([CH:1]=2)[CH2:20][CH2:19][S:18]3)=[CH:5][CH:6]=1)(=[O:12])[CH3:13]
Reactant: NC1=NCCS1
Reactant: CC(=O)Nc1ccc(C(C)=O)cc1
Agent: BrBr
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1ccc(-c2cn3c(n2)SCC3)cc1
Reaction time: 8 h

Procedure:
4-Acetamidoacetophenone (44 g, 0.25 mole) was suspended in 500 ml methylene chloride and treated with bromine (44 g, 0.275 mole). The reaction mixture was stirred overnight, then evaporated in vacuo. The residue was suspended in 200 ml of absolute EtOH and treated with 2-amino-4,5-dihydrothiazole (60 g, 0.59 mole). The reaction was stirred for 2 days, then taken up in water and extracted with methylene chloride. The organic phase was washed with water and then brine, and then dried over sodium sulfate. Flash column chromatography (silica, eluting with methylene chloride/methanol, 98/2) gave 6-(4-acetamidophenyl)-2,3-dihydroimidazo[2,1-b]thiazole.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]([N:8]([CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:7])(O)=[O:2].[Cl:30][C:31]1[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:30][C:31]1[CH:37]=[CH:36][C:34]([NH:35][C:1]([CH2:4][CH2:5][C:6]([N:8]([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=2)[C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[O:7])=[O:2])=[CH:33][CH:32]=1
Reactant: COC(=O)c1ccc(OCCCN(C(=O)CCC(=O)O)c2ccc(Cl)cc2)cc1
Reactant: Nc1ccc(Cl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(OCCCN(C(=O)CCC(=O)Nc2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 52 h
Yield: 84.3 %

Procedure:
Methyl 4-[3-[N-(3-carboxypropionyl)-N-(4-chlorophenyl)amino]propoxy]benzoate (1.6 g), p-chloroaniline (0.54 g), DCC (0.87 g) and 4-dimethylaminopyridine (47 mg) were dissolved in methylene chloride (40 ml), and the mixture was stirred at room temperature for 52 hours, and concentrated under reduced pressure. The residue was dissolved in a small amount of DMF, and filtered. To this filtrate were added water and ethyl acetate and it was separated into layers. The organic layer was washed with water 3 times and concentrated under reduced pressure. The oily product thus obtained was subjected to column chromatography on silica gel and eluted with a mixed solvent of chloroform/methanol [30:1 (v/v)], and then concentrated under reduced pressure. The residue was crushed in aqueous methanol and collected by filtration to give the subject product (1.70 g). mp. 128°-130° C.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][N:5]2[C:7](=[O:10])[CH2:8][CH2:9][CH:4]2[N:3]1[CH2:11][C:12]([O:14]CC)=O.[NH3:17]>CO>[O:1]=[C:2]1[CH2:6][N:5]2[C:7](=[O:10])[CH2:8][CH2:9][CH:4]2[N:3]1[CH2:11][C:12]([NH2:17])=[O:14]
Reactant: CCOC(=O)CN1C(=O)CN2C(=O)CCC12
Reactant: N
Solvent: CO
Product: NC(=O)CN1C(=O)CN2C(=O)CCC12
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
A solution of ethyl 2,5-dioxohexahydropyrrolo[1,2-a]imidazole-1-acetate (1.4 g, 6.18 mmol), in methanol (25 ml) was saturated with ammonia at 0° C. After stirring at room temperature for 16 hours the precipitate was collected, washed with methanol and dried to yield 0.9 g (75%) of the title compound, m.p. 182°-185° C. NMR (DMSO-d6): deltaH =7.50 and 7.10 (2s, 2H, CONH2); 5.25 (c.a. 1H, N--CH--N); 3.94 and 3.55 (ABq, J=16 Hz, 2H, N--CH2CO); 3.85 and 3.70 (ABq, J=16.5 Hz, 2H, N--CH2CONH2); 2.90 and 1.90 (c.a., 4H, CH2CH2). MS (E.I., 70 eV, 1.5 mA) m/z=139 (M--CH2CONH2)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:12][CH:13]2[CH2:16][NH:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.CCN(CC)CC.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[CH3:35])=[O:27]>CC#N>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:26](=[O:27])[CH2:25][N:15]2[CH2:16][CH:13]([CH2:12][S:9]([C:6]3[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[CH2:14]2)=[C:29]([CH3:35])[CH:30]=1
Reactant: Cc1cc(F)ccc1C(=O)CBr
Reactant: O=S(=O)(CC1CNC1)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(F)ccc1C(=O)CN1CC(CS(=O)(=O)c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
A mixture of 3-{[(4-fluorophenyl)sulfonyl]methyl}azetidine hydrochloride (75 mg, 0.28 mmol) in MeCN (5 mL) was treated with Et3N (97 μL, 0.7 mmol) and 2-bromo-1-(4-fluoro-2-methylphenyl)ethanone (72 mg, 0.31 mmol) and stirred for 30 min at room temperature. The reaction was evaporated and the residue dissolved in DCM and purified using 10 g silica bond-elute cartridge on the personal flash master. The column was eluted with 0.5% MeOH/DCM then 1% MeOH/DCM to give the title compound as a cream solid (60 mg, 56%). 1H NMR (500 MHz, CDCl3)δ2.49 (3H, s), 2.93–2.98 (1H, m), 3.08 (2H, t, J=7.4 Hz), 3.41 (2H, d, J=7.4 Hz), 3.62 (2H, t, J=7.4 Hz), 3.77 (2H, s), 6.89–6.95 (2H, m), 7.23–7.27 (2H, t, J=8.8 Hz), 7.61 (1H, dd, J=5.8 & 8.5 Hz), 7.90–7.92 (2H, dd, J=5.2 & 8.8 Hz). m/z (ES+) 380 (M+H)+.
Reaction SMILES: [C:1]1([N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:23][C:24]1[CH:29]=[N:28][C:27](Br)=[CH:26][N:25]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:23][C:24]1[N:25]=[CH:26][C:27]([C:11]2[CH:12]=[CH:13][C:8]([N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:9][CH:10]=2)=[N:28][CH:29]=1
Reactant: OB(O)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: Brc1cnc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Brc1cnc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)cn1
Temperature: 85 °C
Yield: 68.2 %

Procedure:
A mixture of (4-(diphenylamino)phenyl)boronic acid (3.26 g, 11.3 mmol), 2,5-dibromopyrazine (5.82 g, 22.6 mmol), Pd(PPh3)4 (0.635 g, 0.55 mmol), K2CO3 (3.45 g, 25 mmol) in dioxane/water (100 mL/16 mL) was degassed and heated at about 85° C. for about 20 hours. The resulting mixture was poured into ethyl acetate (250 mL), washed with brine, dried over Na2SO4, loaded on silica gel and purified by flash column using eluents of hexanes to hexanes/dichloromethane 4:1. After removal of solvent, a yellow solid (Compound 19) was obtained (3.1 g, in 68.2% yield).
Reaction SMILES: [C:1]1([C:13]2[C:14](=[O:28])[NH:15][C:16](=[O:27])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[H][H]>[Pd].CO>[C:1]1([C@H:13]2[C@@H:17]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[C:16](=[O:27])[NH:15][C:14]2=[O:28])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@H]1c1c[nH]c2ccccc12
Yield: 57.1 %

Procedure:
A suspension of 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrole-2,5-dione (16 g, 43.6 mmol) and 10% palladium on carbon (Pd/C, wet catalyst) (8 g) were stirred under 1 atmosphere of hydrogen in methanol (600 ml) at room temperature for 48 hours. The catalyst was then filtered through a bed of C elite and the filtrate evaporated to dryness. The residue was re-dissolved in methanol and the product precipitated by the addition of cold water. The precipitate was filtered, washed with water and dried under vacuum to yield (±)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione (9.2 g). 1H NMR (DMSO-d6) 400 MHz δ: 11.56 (s, 1H), 10.66 (s, 1H), 7.43 (d, 1H, J=7.6 Hz), 7.14 (d, 2H, J=8 Hz), 6.86-6.97 (m, 4H), 6.78 (t, 1H, J=7.2 Hz), 6.69 (d, 1H, J=6.8 Hz), 4.88 (dd, 2H, J=9.2 and 45.6 Hz), 3.88 (m, 2H), 2.76 (t, 2H, J=5.6 Hz), 1.94 (t, 2H, J=6 Hz).