Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([N:19]2[CH2:23][CH2:22][CH2:21][C@@H:20]2[CH2:24][OH:25])[CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=[O:6].B(O)(O)[C:27]1[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].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>[CH3:15][C:12]1[N:11]=[CH:10][C:9]([CH2:8][NH:7][C:5]([C:4]2[CH:3]=[C:2]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[CH:18]=[C:17]([N:19]3[CH2:23][CH2:22][CH2:21][C@@H:20]3[CH2:24][OH:25])[CH:16]=2)=[O:6])=[CH:14][CH:13]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cc1ccc(CNC(=O)c2cc(Br)cc(N3CCC[C@@H]3CO)c2)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: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C)nc3)cc(N3CCC[C@@H]3CO)c2)cc1

Procedure:
To a mixture of (R)-3-bromo-5-(2-(hydroxymethyl)pyrrolidin-1-yl)-N-((6-methylpyridin-3-yl)methyl)benzamide (45 mg, 0.11 mmol), p-tolylboronic acid (16 mg, 0.12 mmol), Toluene (3 mL, 30 mmol), cesium carbonate (4.0E1 mg, 0.12 mmol), and Water (0.2 mL, 8 mmol) under argon was added Tetrakis(triphenylphosphine)palladium(0) (6.4 mg, 0.0055 mmol). The mixture was heated under reflux for 5 h. After cooling, the mixture was filtered through Celite and the filter cake was washed with EtOAc. The filtrate was washed with brine, dried (Na2SO4), and concentrated. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 30-80% CH3CN/water [10 mM Et2NH]) to afford a white foam. LC-MS: 2.09 min, 416.5 [M+1]+; HPLC: 9.12 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: C1CCNC1
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)N2CCCC2)cc1
Temperature: 0 °C
Yield: 91.6 %

Procedure:
4-Methoxy-benzenesulfonyl chloride (3.00 g, 14.52 mmol) was slowly added to a solution of pyrrolidine (5.15 g, 72.6 mmol) in CHCl3 (15 mL) with stirring at 0° C. The reaction mixture was allowed to warm up to room temperature and then stirred for 1 hour. After that the reaction mixture was concentrated in vacuo. The residue was dissolved in toluene and washed with aqueous H3PO4 solution, and then aqueous KHCO3 solution. The organic phase was dried with Na2SO4, and filtered. The solvents were removed in vacuo and the residue crystallized from ether and heptane to provide the title compound (3.21 g, m.p. 88-89° C.).
Reaction SMILES: [C:1]([CH2:4][C:5]1[C:6]([F:16])=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)(=O)[CH3:2].C([O-])(=O)C.[NH4+]>CC(C)=O.[Cl-].[Cl-].[Cl-].[Ti+3]>[F:16][C:6]1[C:7]([O:14][CH3:15])=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[C:1]([CH3:2])[NH:11]2
Reactant: COc1ccc([N+](=O)[O-])c(CC(C)=O)c1F
Agent: [Ti+3]
Agent: CC(=O)[O-]
Agent: [Cl-]
Solvent: CC(C)=O
Product: COc1ccc2[nH]c(C)cc2c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
To a solution of 3-acetylmethyl-2-fluoro-1-methoxy-4-nitrobenzene (11.36 g, 50 mmol) in acetone (200 ml) was added 4M aqueous ammonium acetate (700 ml) followed by a solution of titanium trichloride (15% in water, 340 ml) dropwise. The mixture was stirred for 10 minutes at ambient temperature and the mixture was extracted with ether. The organic layer was washed with 0.5N aqueous sodium hydroxide followed by water, brine, dried (MgSO4) and the volatiles were removed under vacuum. The residue was purified by column chromatography eluting with methylene chloride to give 4-fluoro-5-methoxy-2-methylindole (8.15 g, 90%).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[H-].[Na+].[CH3:22][CH:23]1[CH:27]([CH3:28])OS(=O)(=O)[N:24]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>CN(C=O)C>[C:34]([O:33][C:31]([NH:24][CH:23]([CH3:22])[CH:27]([N:1]1[C:5]2=[N:6][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:28])=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC1OS(=O)(=O)N(C(=O)OC(C)(C)C)C1C
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)C(C)NC(=O)OC(C)(C)C)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 106.5 %

Procedure:
To a solution of diethyl 1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate (Intermediate D, 3.40 g, 13.0 mmol) in DMF (15 mL) cooled to 0° C. is added 60% sodium hydride in mineral oil (570 mg, 14.3 mmol). The mixture is stirred at 0° C. for 20 min after which a solution of tert-butyl 4,5-dimethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (5.35 g, 14.3 mmol) in DMF (10 mL) is added. The mixture is stirred at 0° C. for 30 min after which the reaction was allowed to warm and stir at ambient temperature overnight. The reaction is quenched with H2O and was stirred for 15 min. The mixture is extracted with ethyl acetate and the combined organic phases are washed with brine, and are dried (Na2SO4). The solvent is removed in vacuo and the crude material is purified via flash column chromatography using a gradient elution of 0-20% ethyl acetate/heptane to afford the title compound as a colorless oil (6.00 g, quantitative). LCMS: 434.83 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:46])[CH2:4][C:5](=[O:45])[CH2:6][CH:7]([O:37][Si](C(C)(C)C)(C)C)[CH:8]=[CH:9][C:10]1[N:11]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:12]=[C:13]([C:18](=[O:29])[N:19]([CH3:28])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[C:14]=1[CH:15]([CH3:17])[CH3:16].CCOC(C)=O>CC#N.O>[CH3:1][O:2][C:3](=[O:46])[CH2:4][C:5](=[O:45])[CH2:6][CH:7]([OH:37])[CH:8]=[CH:9][C:10]1[N:11]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[N:12]=[C:13]([C:18](=[O:29])[N:19]([CH3:28])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[C:14]=1[CH:15]([CH3:16])[CH3:17]
Reactant: COC(=O)CC(=O)CC(C=Cc1c(C(C)C)c(C(=O)N(C)Cc2ccccc2C)nn1-c1ccc(F)cc1)O[Si](C)(C)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: COC(=O)CC(=O)CC(O)C=Cc1c(C(C)C)c(C(=O)N(C)Cc2ccccc2C)nn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.2 %

Procedure:
To a solution of 5-(tert-butyl-dimethyl-silanyloxy)-7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-3-oxo-hept-6-enoic acid methyl ester (2.48 g, 3.82 mmol) in MeCN (40 mL) at 25° C. was added HF (2.5 mL of 48% in water). Reaction was stirred at 25° C. for 16 hrs. Subsequently, EtOAc (100 mL) and water (100 mL) were added and the organic layer was separated, dried and concentrated. Product was purified by column chromatography (30%-50% EtOAc-Hex) to afford 7-{2-(4-fluoro-phenyl)-4-isopropyl-5-[methyl-(2-methyl-benzyl)-carbamoyl]-2H-pyrazol-3-yl}-5-hydroxy-3-oxo-hept-6-enoic acid methyl ester (2.03 g, 98.0%): MS(APCI+) 536.4 m/z (M+H).
Reaction SMILES: [NH2:1][C:2]1[O:3][C@H:4]([C:26]([F:29])([F:28])[F:27])[CH2:5][C@:6]([C:9]2[CH:10]=[C:11]([NH:16][C:17](=O)[C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=3)[CH:12]=[N:13][C:14]=2[F:15])([CH3:8])[N:7]=1.ClC1C2N=CC(Cl)=CC=2[N:34]=[CH:35][N:36]=1>>[Cl:24][C:21]1[CH:20]=[N:19][C:18]2[C:17]([NH:16][C:11]3[CH:10]=[C:9]([C@:6]4([CH3:8])[CH2:5][C@@H:4]([C:26]([F:29])([F:28])[F:27])[O:3][C:2]([NH2:1])=[N:7]4)[C:14]([F:15])=[N:13][CH:12]=3)=[N:36][CH:35]=[N:34][C:23]=2[CH:22]=1
Reactant: C[C@@]1(c2cc(NC(=O)c3ccc(Cl)cn3)cnc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: Clc1cnc2c(Cl)ncnc2c1
Product: C[C@@]1(c2cc(Nc3ncnc4cc(Cl)cnc34)cnc2F)C[C@@H](C(F)(F)F)OC(N)=N1

Procedure:
The title compound was synthesized using steps and procedures analogous to those described in Method B (step 2) above, but using (4S,6S)-4-(5-amino-2-fluoropyridin-3-yl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (6a) and 4,7-dichloropyrido[3,2-d]pyrimidine (intermediate 9). MS m/z=456.0 [M+H]+. Calculated for C18H14ClF4N7O: 455.8
Reaction SMILES: [CH2:1]([C:5]([C:18]1N=C[C:21]([N+:24]([O-:26])=[O:25])=[CH:20][N:19]=1)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]#[CH:4]>[N+](C1C=CC=CC=1)([O-])=O>[N+:24]([C:21]1[CH:4]=[C:3]2[CH2:2][CH2:1][C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])[C:18]2=[N:19][CH:20]=1)([O-:26])=[O:25]
Reactant: C#CCCC(C(=O)OCC)(C(=O)OC(C)(C)C)c1ncc([N+](=O)[O-])cn1
Solvent: O=[N+]([O-])c1ccccc1
Product: CCOC(=O)C1(C(=O)OC(C)(C)C)CCc2cc([N+](=O)[O-])cnc21

Procedure:
A solution of tert-butyl ethyl but-3-yn-1-yl(5-nitropyrimidin-2-yl)propanedioate (10.2 g, 28.1 mmol) in 100 mL of nitrobenzene was heated to 150° C. for 4 hours. Nitrobenzene was removed by vacuum and the residue was purified by column chromatography (Petroleum ether:EtOAc=10:1) to afford the title compound; MS m/z 337 (M+1)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:9]=[C:10]=[O:11])[CH3:8].[CH:12]1([C:15]2[NH:19][N:18]=[C:17]([O:20][C:21]3[C:26]([Cl:27])=[CH:25][C:24]([C:28]([F:31])([F:30])[F:29])=[CH:23][C:22]=3[Cl:32])[CH:16]=2)[CH2:14][CH2:13]1.Cl>C(OCC)(=O)C>[CH2:7]([NH:9][C:10]([N:19]1[C:15]([CH:12]2[CH2:13][CH2:14]2)=[CH:16][C:17]([O:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([C:28]([F:31])([F:29])[F:30])=[CH:23][C:22]=2[Cl:32])=[N:18]1)=[O:11])[CH3:8]
Reactant: FC(F)(F)c1cc(Cl)c(Oc2cc(C3CC3)[nH]n2)c(Cl)c1
Reactant: CCN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
Potassium carbonate (0.23 g, 1.7 mmol) and ethyl isocyanate (0.11 g, 1.5 mmol) were added to a solution of 5-cyclopropyl-3-(2,6-dichloro-4-trifluoromethylphenyloxy)pyrazole (0.51 g, 1.5 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a colorless viscous substance of N-ethyl-5-cyclopropyl-3-(2,6-dichloro-4-trifluoromethylpheyloxy)pyrazole-1-carboxamide (0.54 g, yield: 88.2%). 1H-NMR (CDCl3, TMS, ppm): δ 0.70 (m, 2H), 1.07 (m, 2H), 1.20 (t, J=7.3 Hz, 3H), 2.81 (m, 1H), 3.36 (dq, J=6.0 and 7.3 Hz, 2H), 5.45 (s, 1H), 6.60-6.85 (m, 1H), 7.66 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9](I)[O:10][C:3]=12.[CH:12]1(B(O)O)[CH2:14][CH2:13]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH:12]3[CH2:14][CH2:13]3)[O:10][C:3]=12
Reactant: Clc1ccnc2cc(I)oc12
Reactant: OB(O)C1CC1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1ccnc2cc(C3CC3)oc12
Temperature: 100 °C
Reaction time: 48 h

Procedure:
7-Chloro-2-iodofuro[3,2-b]pyridine (0.130 g, 0.47 mmol), cyclopropylboronic acid (0.080 g, 0.93 mmol), and tricyclohexylphosphine (0.026 g, 0.093 mmol) were dissolved in 3 mL toluene and 1 mL water. Potassium phosphate (0.30 g, 1.4 mmol) was added followed by PdOAc2 (0.010 g, 0.047 mmol), the reaction was flushed with argon, and the reaction stirred at 100° C. for 48 h. The reaction was cooled to RT and partitioned between DCM and water. The layers were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried with sodium sulfate, filtered, and concentrated. The crude material was purified via column chromatography (gradient elution 0-50% EtOAc:Hex) to afford 7-chloro-2-cyclopropylfuro[3,2-b]pyridine as an orange oil. MS: M+H+=194.4.
Reaction SMILES: O=[Cr](=O)=O.C1C=CC=CN=1.C1C=CC=CN=1.N1C=CC=CC=1.[OH:23][CH:24]([C:45]([F:50])([F:49])[CH2:46][CH2:47][CH3:48])[CH2:25][CH2:26][CH2:27][C@H:28]1[C@H:32]([CH3:33])[CH2:31][C:30](=[O:34])[C@@H:29]1[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42]>C(Cl)Cl>[F:49][C:45]([F:50])([CH2:46][CH2:47][CH3:48])[C:24](=[O:23])[CH2:25][CH2:26][CH2:27][C@H:28]1[C@H:32]([CH3:33])[CH2:31][C:30](=[O:34])[C@@H:29]1[CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42]
Reactant: CCCC(F)(F)C(O)CCC[C@H]1[C@H](C)CC(=O)[C@@H]1C/C=C\CCCC(=O)OC
Agent: O=[Cr](=O)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC(F)(F)C(=O)CCC[C@H]1[C@H](C)CC(=O)[C@@H]1C/C=C\CCCC(=O)OC
Yield: 81 %

Procedure:
Celite (5 g) was added to Collins reagent prepared from chromic anhydride (1.2 g) and pyridine in methylene chloride (20 ml), followed by addition of a solution of the alcohol (31) (0.138 g) in methylene chloride (10 ml). The resultant mixture was stirred at room temperature for 30 minutes, followed by the usual work-up. The obtained crude product was subjected to silicagel column chromatography to give the titled compound (32).
Reaction SMILES: Cl[C:2]1[CH:22]=[N:21][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[CH:11][C:10]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:9][CH:8]=3.CC(C)([O-])C.[Na+].[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([NH2:37])[CH:32]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(O)(C)(C)C>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([NH:37][C:2]2[CH:22]=[N:21][C:5]3[NH:6][C:7]4[C:12]([C:4]=3[CH:3]=2)=[CH:11][C:10]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][CH:8]=4)[CH:34]=[CH:35][CH:36]=1
Reactant: Clc1cnc2[nH]c3ccc(CCc4ccccc4)cc3c2c1
Reactant: COc1cccc(N)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Product: COc1cccc(Nc2cnc3[nH]c4ccc(CCc5ccccc5)cc4c3c2)c1
Reaction time: 8 h
Yield: 28.7 %

Procedure:
3-chloro-6-(2′-phenylethyl)-9H-pyrido[2,3-b]indole (50 mg, 0.16 mmol, 1 equiv.), Pd2 dba3 (8.2 mg, 0.008 mmol, 0.05 equiv.), 2-Dicyclohexyl phosphino-2′,4′,6′-Triisopropylbiphenyl (L2)(8.1 mg, 0.016 mmol, 0.1 equiv.), sodium tert-butoxide (36 mg, 0.37 mmol, 2.2 equiv.) are introduced in a schlenk tube and flushed with N2. tert-butanol (0.255 ml) and m-Anisidine (25 mg, 0.20 mmol, 1.2 equiv.) are then added. The reaction is carried out at 100° C. overnight and then filtered over celite and evaporated under reduced pressure. The crude product (yellow oil) is purified over silica gel chromatography (eluant AcOEt/PE 4:6, 6:4) to afford the product as a green solid (18 mg, 0.046 mmol) in 29% yield. mp=161-165; IR 3359, 3145, 3022, 1595, 1494, 1467, 1383, 1218, 1151, 1038, 968, 891, 809, 771, 685 cm−1; 1H NMR (300 MHz, CDCl3) 9.94 (br s, 1H, H9), 8.18 (s, 1H, H2), 7.78 (s, 1H, H4), 7.41 (d, 1H, J=8.3 Hz, H8), 7.32-7.14 (m, 71-1, CHPh+CHAn), 6.52 (d, 1H, J=8.1 Hz, H7), 6.47-6.44 (m, 2H, H5+CHPh or CHAn), (br s, 1H, NHAn), 3.77 (s, 3H, OCH3), 3.12-2.97 (m, 4H, 2CH2); MS (+ESI) [M+H+]=394.3
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1>CO>[CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([O:12][C:13]3[CH:14]=[CH:15][C:16]([NH2:19])=[CH:17][CH:18]=3)[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])c1ccc(OC2CCN(C3CCCC3)CC2)cc1
Solvent: CO
Product: Nc1ccc(OC2CCN(C3CCCC3)CC2)cc1
Yield: 943.6 %

Procedure:
1-cyclopentyl-4-(4-nitrophenoxy)piperidine (1.30 g) was dissolved in methanol, and the target compound (11.0 g, 86%) was obtained as a light brown solid by catalytic reduction using a palladium charcoal catalyst.
Reaction SMILES: C(OC(=O)C1C=CC(NC2CCCCC2)=C(NC(C2C=C3C(=CC=2)N=[C:26]([C:31]2[C:36]([C:37]4[CH:42]=[CH:41][C:40](Cl)=[CH:39][CH:38]=4)=[CH:35][CH:34]=[C:33](C(N4CCCC4)=O)[CH:32]=2)C=C3)=O)C=1)C.ClC1C=CC(C2C([C:63]3[CH:72]=[CH:71][C:70]4[C:65](=[CH:66][CH:67]=[C:68]([C:73]5[N:77]([CH:78]6[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]6)[C:76]6[CH:84]=[CH:85][C:86]([C:88]([OH:90])=[O:89])=[CH:87][C:75]=6[N:74]=5)[CH:69]=4)[N:64]=3)=CC(C(N3CCCC3)=O)=CC=2)=CC=1.C1(C(C2C=CC=CC=2)C(C)=O)C=CC=CC=1.C(C1C=CC=CC=1)(=O)C>>[CH:36]([C:63]1[CH:72]=[CH:71][C:70]2[C:65](=[CH:66][CH:67]=[C:68]([C:73]3[N:77]([CH:78]4[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]4)[C:76]4[CH:84]=[CH:85][C:86]([C:88]([OH:90])=[O:89])=[CH:87][C:75]=4[N:74]=3)[CH:69]=2)[N:64]=1)([C:31]1[CH:26]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CCOC(=O)c1ccc(NC2CCCCC2)c(NC(=O)c2ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(Cl)cc4)ccc3c2)c1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Agent: CC(=O)C(c1ccccc1)c1ccccc1
Solvent: CC(=O)c1ccccc1
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(C(c4ccccc4)c4ccccc4)ccc3c1)n2C1CCCCC1

Procedure:
The title compound was synthesized in four steps as described for Compound 13, Compound 25, Compound 27, Q=ethyl and Compound 204, respectively, except 1,1-diphenylacetone was used in the first step, instead of acetophenone.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.Cl.[NH2:10][NH:11][C:12](N)=[O:13]>Cl.C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:4]([C:12](=[O:13])[NH:11][N:10]=2)[N:3]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: NNC(N)=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc2ccc(Cl)nn12

Procedure:
To a stirring solution of 3 g (20 mmol) of 3,6-dichloropyridazine and 4.5 g (40 mmol) semicarbazide hydrochloride in 100 mL of a 3:1 mixture of ethanol/water was added 5 drops of concentrated hydrochloric acid. The resulting solution was heated to reflux for 24 h under nitrogen then evaporated in vacuo and the resulting solid was recrystallized from ethanol to yield the title compound as a yellow crystalline solid. A similar route to this compound is described in the literature (P. Francavilla, et. al. J. Heterocyclic Chem., 1971, 8, 415-419). LC/MS 171.2 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2([C:14]([O:16]CC)=[O:15])[CH2:13][CH2:12][CH2:11]2)=[O:8])[CH:4]=[N:3][CH:2]=1.[OH-].[Na+]>C1COCC1.O>[N:1]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11]2)=[O:8])[CH:4]=[N:3][CH:2]=1
Reactant: CCOC(=O)C1(NC(=O)c2cncnc2)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1(C(=O)O)CCC1)c1cncnc1
Temperature: 25 °C
Reaction time: 64 h
Yield: 90.7 %

Procedure:
Ethyl 1-[(pyrimidin-5-ylcarbonyl)amino]cyclobutanecarboxylate (0.939 g, 3.77 mmol) was dissolved in THF (36.0 mL) prior to addition of aqueous sodium hydroxide (6.03 mL, 1M). The reaction mixture was then allowed to stir over the weekend (ca. 64 h) at ambient temperature. Most of the THF was then removed under reduced pressure to yield an oily aqueous layer, which was diluted with additional water, prior to three-fold extraction with diethyl ether. The aqueous layer was then made neutral by the addition of HCl (6.00 mL, 1H) and then saturated with sodium chloride. Repeated extraction of this aqueous layer with EtOAc (ca. 500 mL total) followed by concentration of the organic layers provided 1-[(pyrimidin-5-ylcarbonyl)-amino]cyclobutanecarboxylic acid (0.756 g) as a white solid giving proton NMR and LC/MS data consistent with theory.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:22]([N:25]=[C:26]=[O:27])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:26]([NH:25][CH:22]([CH3:24])[CH3:23])=[O:27])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: CC(C)N=C=O
Solvent: Cc1ccccc1
Product: CC(C)NC(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
(R)—N2-Indan-1-yl-quinoline-2,6-diamine (0.30 g, 1.09 mmol) was dissolved in toluene (5 mL). Isopropyl isocyanate (0.93 g, 1.09 mmol) was added and the reaction mixture was stirred at 60° C. for 2 h. Upon cooling to room temperature a precipitation formed which was filtered off and washed twice with dichloromethane. After drying the title compound was obtained as a white solid (330 mg, 85%); MS: m/e=276.4 (M+H+).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[Cl:17])=[NH:8])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27]>>[Br:1][C:2]1[S:6][C:5]([C:7]2[N:9]([C:10]3[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=3[Cl:17])[CH2:24][C:25]([C:26]([F:29])([F:28])[F:27])([OH:30])[N:8]=2)=[CH:4][CH:3]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: N=C(Nc1cc(Cl)ccc1Cl)c1ccc(Br)s1
Agent: O=C([O-])O
Agent: [Na+]
Product: OC1(C(F)(F)F)CN(c2cc(Cl)ccc2Cl)C(c2ccc(Br)s2)=N1
Temperature: 50 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To a suspension of 5-bromo-N-(2,5-dichloro-phenyl)-thiophene-2-carboxamidine (634 mg, 1.8 mmol) and sodium bicarbonate (227 mg, 2.7 mmol) in 8 mL 2-proponal was added 3-bromo-1,1,1-trifluoroacetone (520 mg, 2.7 mmol). The reaction mixture was heated at 50° C. for 1.5 hrs, then at 80° C. for 4 hrs. After cooling to room temperature, the residue was filtered out and washed with dichloromethane. The filtrate and washings were combined together and concentrated under vacuum to give a light pink solid that was used directly for the next step (820 mg, 99% yield). 1H-NMR (400 MHz, DMSO-d6): δ 3.09 (d, 1H), 3.95 (dd, 1H), 6.31 (d, 1H), 6.91 (d, 1H), 7.15 (m, 1H), 7.33 (dd, 1H), 7.44 (m, 2H).
Reaction SMILES: [CH2:1]([Li])CCC.[CH2:6]([O:13][C:14]1[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CCCCCC>[CH2:6]([O:13][C:14]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:1])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: [Li]CCCC
Reactant: COC(=O)c1cc(C=O)ccc1OCc1ccccc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=Cc1ccc(OCc2ccccc2)c(C(=O)OC)c1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of methyltriphenylphosphonium bromide (4.1 g) in tetrahydrofuran (40 ml) was added 1.56M n-butyl lithium solution in hexane (7.2 ml) at room temperature, and the mixture was stirred for 1 hour. After the reaction mixture was cooled to −70° C., a solution of methyl 2-benzyloxy-5-formylbenzoate (2.82 g) in tetrahydrofuran (40 ml) was added, and the resulting mixture was stirred for 15 hours with gradually warming up to room temperature. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=4/1) gave methyl 2-benzyloxy-5-vinylbenzoate (2.63 g).