Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:17]1([N:23]=[C:24]=[S:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C)C=CC=CC=1>C(OCC)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:7]2[C:2]([NH:1][C:24]([NH:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[S:25])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:11][CH:12]=1
Reactant: S=C=Nc1ccccc1
Reactant: Nc1ncccc1OCc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: S=C(Nc1ccccc1)Nc1ncccc1OCc1ccc(Cl)cc1

Procedure:
A mixture of 2-amino-3-(4-chlorobenzyloxy)pyridine (3.37 g, 0,014 mol), phenyl isothiocyanate (2.33 g, 0,017 mol) and toluene (10 ml) was refluxed for 3.5 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 4.36 g (82%), m.p. 162°-164 ° C.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][C:27]=1CO>C(Cl)Cl>[Br:5][CH2:1][C:27]1[CH:28]=[C:29]([C:32]([F:34])([F:35])[F:33])[CH:30]=[CH:31][C:26]=1[I:25]
Reactant: BrC(Br)(Br)Br
Reactant: OCc1cc(C(F)(F)F)ccc1I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(I)c(CBr)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Carbon tetrabromide (1.86 g; 5.6 mmol) and triphenylphosphine (1.47 g; 5.6 mmol) were added successively to a stirred solution of [2-iodo-5-(trifluoromethyl)phenyl]methanol (Intermediate 10, 1.13 g; 3.74 mmol) in CH2Cl2 (25 mL) at 0° C. under N2. The reaction was stirred at room temperature for 48 h. A second equivalent of carbon tetrabromide (1.2 g; 3.74 mmol) and triphenylphosphine (0.98 g; 3.74 mmol) was added and the reaction was stirred an additional 14 h. The solvent was removed in vacuo and the residue was purified by flash chromatography on silica gel (0-25% EtOAc/hexanes gradient) to afford 2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene as a clear oil. 1H NMR (CDCl3, 500 MHz): δ 8.02 (d, J=8.2 Hz, 1H), 7.73 (d, J=1.8 Hz, 1H), 7.26 (dd, J=8.3, 1.8 Hz, 1H), 4.64 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[C:15]([CH3:24])=[C:16]([S:20]([NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:6]=2)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Nc1nc(-c2ccccc2)cs1
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1nc(-c2ccccc2)cs1

Procedure:
The title compound was prepared from 2-amino-4-phenylthiazole and 3-chloro-2-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (51.8 mg) with purity >90%. MS (pos) m/z 365.1.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)(=[O:4])=[O:3].[Cl:18][C:19]1[N:24]=[C:23](Cl)[CH:22]=[CH:21][N:20]=1.C1C=CC2N(O)N=NC=2C=1.C([O-])([O-])=O.[K+].[K+]>CC(O)C.CC(N(C)C)=O>[Cl:18][C:19]1[N:24]=[C:23]([N:13]2[C:14]3[C:10](=[C:9]([O:8][CH2:7][CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12]2)[CH:22]=[CH:21][N:20]=1
Reactant: CS(=O)(=O)CCCOc1cccc2[nH]ccc12
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CC(C)O
Product: CS(=O)(=O)CCCOc1cccc2c1ccn2-c1ccnc(Cl)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 94 %

Procedure:
4-(3-Methanesulfonyl-propoxy)-1H-indole (188.1 g), 2,4-dichloropyrimidine (221.25 g), HOBT (20.08 g), K2CO3 (143.68 g) and DMA (1.6 L) were heated to 85° C. for 20 h. IPA (5 was then added and the mixture was stirred for 20 min, then cooled to 0° C. for 3 h and filtered. The collected solid was rinsed with IPA and water, and the solid was dried in vacuo at 55° C. for 4 days to yield 1-(2-chloro-pyrimidin-4-yl)-4-(3-methanesulfonyl-propoxy)-1H-indole (94%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:10][C:9]=2[O:23][CH3:24])[CH:5]=[CH:4][CH:3]=1.[CH3:25]OC1C=C(C2OC3C=CC=CC=3N=2)C=CC=1B1OC(C)(C)C(C)(C)O1.BrC1C(C)=CC=CN=1>>[CH3:24][O:23][C:9]1[CH:10]=[C:11]([C:14]2[O:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[CH:4][C:3]([CH3:25])=[CH:2][N:7]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1-c1cccc(Br)n1
Agent: Cc1cccnc1Br
Product: COc1cc(-c2nc3ccccc3o2)ccc1-c1ccc(C)cn1

Procedure:
Utilizing the general procedure outlined in the synthesis of 2-[4-(6-bromopyridin-2-yl)-3-methoxyphenyl]-1,3-benzoxazole, 2-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazole (200 mg, 0.57 mmol) was reacted with 2-bromo-3-methylpyridine (63 μL, 0.57 mmol) to afford the desired 2-[3-methoxy-4-(5-methylpyridin-2-yl)phenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.55–8.53 (d, 1H), 7.98–7.95 (m, 1H), 7.88 (s, 1H), 7.81–7.78 (m, 1H), 7.61–7.56 (m, 2H), 7.46–7.44 (d, 1H), 7.39–7.35 (m, 2H), 7.23–7.19 (m, 1H), 3.91 (s, 3H), 2.19 (s, 3H). MS (ESI) 317 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([CH2:12][C:13]([OH:15])=[O:14])[CH2:5]2.C([O-])([O-])=O.[K+].[K+].[NH:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>N1C=CC=CC=1>[N:22]1([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[CH:6]([CH2:12][C:13]([OH:15])=[O:14])[CH2:5]3)[CH:26]=[CH:25][N:24]=[CH:23]1
Reactant: c1c[nH]cn1
Reactant: O=C(O)CC1Cc2cc(F)ccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=C(O)CC1Cc2cc(-n3ccnc3)ccc2C1=O
Yield: 39.4 %

Procedure:
A mixture of 3.3 g of 5-fluoro-2,3-dihydro-1-oxo-1H-indene-2-acetic acid [prepared by following the procedure of G. Cignarella, M. Loriga, G. A. Pinna, M. A. Pirisi, P. Schaitti, and D. Selva, Il Farmaco, Ed. Sci. 37(2), 133-40 (1981)], 2.2 g of anhydrous K2CO3, 1.65 g of imidazole, and 0.15 g of CuO in 15 ml of pyridine is heated to reflux for 24 hours. The reaction mixture is filtered, the filtrate is diluted with water, and the pH of the solution is adjusted to 5. The solid is filtered, washed with water, and crystallized from ethanol to yield 1.6 g of the product, 2,3-dihydro-5-(1H-imidazol-1-yl)-1-oxo-1H-indene-2 acetic acid, mp 224°-226° dec.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)=[C:4]([O:18][CH3:19])[CH:3]=1.C([Li])CCC.CCCCCC.[C:31]([N:38]1[CH2:41][C:40](=[O:42])[CH2:39]1)([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].O>O1CCCC1>[CH2:16]([C:13]1[CH:14]=[CH:15][C:10]([CH2:9][O:8][C:5]2[CH:6]=[CH:7][C:2]([C:40]3([OH:42])[CH2:39][N:38]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:41]3)=[CH:3][C:4]=2[O:18][CH3:19])=[CH:11][CH:12]=1)[CH3:17]
Reactant: CCc1ccc(COc2ccc(Br)cc2OC)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc(COc2ccc(C3(O)CN(C(=O)OC(C)(C)C)C3)cc2OC)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
To a solution of 4-bromo-1-(4-ethylbenzyloxy)-2-methoxybenzene (1.2 g) prepared in (1) in THF (6.0 mL) was added dropwise 1.6 N n-butyllithium/hexane (2.8 mL) at −78° C. under argon atmosphere. The mixture was stirred at −78° C. for 30 min. A solution of 1-Boc-azetidin-3-one (0.64 g) in THF (6.0 mL) was added dropwise over 10 min to the mixture at −78° C. The reaction mixture was allowed to warm to RT and then stirred for 14 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Developing solvent: hexane/ethyl acetate=3/1 to 1/1) to give the title compound (0.88 g, 57%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([CH3:15])[N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:26]([O:28][CH3:29])=[O:27].Cl.[OH2:31]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([C:8]1[C:13]([NH2:14])=[C:12]([C:26]([O:28][CH3:29])=[O:27])[CH:11]=[C:10]([CH3:15])[N+:9]=1[O-:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)Cl
Reactant: Cc1ccc(N)c(C(=O)OC(C)(C)C)n1
Reactant: O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(C)[n+]([O-])c(C(=O)OC(C)(C)C)c1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
2 mL of a chloroform solution containing 0.24 g (1 mmol) of 2-t-butoxycarbonyl amino-6-methylpyridine and 0.26 g (2 mmol) of diisopropylethylamine was prepared, and was cooled in ice water. The above mixed solution was added dropwise at 0° C. to 0.3 mL of a chloroform solution containing 0.11 g (1.2 mmol) of methyl chloroformate. After stirring further for 20 minutes, the temperature was raised to room temperature. After stirring further for 5 hours at room temperature, 5 mL of water and 1 mL of 3N hydrochloric acid were added thereto, followed by liquid separation. The organic layer obtained by liquid separation was dried with magnesium sulfate, followed by filtration, and the resulting solution was concentrated under reduced pressure to obtain 0.27 g of 2-t-butoxycarbonyl-methoxycarbonyl amino-6-methyl pyridine-N-oxide (yield: 96%) as a pale yellow oily liquid which was the target product.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]2[C:17](O)=[O:18])=[CH:5][CH:4]=1.[Cl:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([NH2:32])[CH:30]=2)[NH:25][N:24]=1.N=C=N>CN(C=O)C>[Cl:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([NH:32][C:17]([C:10]3[CH:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:20])([F:21])[F:1])=[CH:8][CH:7]=4)[CH2:14][C:13](=[O:15])[NH:12][C:11]=3[CH3:16])=[O:18])[CH:30]=2)[NH:25][N:24]=1
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Reactant: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2)CC(=O)N1
Agent: N=C=N
Solvent: CN(C)C=O
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Cl)c3c2)C(c2ccc(C(F)(F)F)cc2)CC(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.4 %

Procedure:
The product of Example 5, Step 2 (0.100 g, 0.330 mmol, 1.00 equiv), 3-chloro-1H-indazol-5-amine (84 mg, 0.502 mmol, 1.50 equiv) and PS-carbodiimide resin (456 mg, 0.502 mmol, 1.00 equiv) were suspended in 2.0 mL DMF and stirred overnight at room temperature. The reaction mixture was concentrated to approximately 1 mL DMF and water was added. The resulting precipitate was collected by filtration and washed with 50% CH2Cl2/hexanes. The product was purified by preparative reverse phase HPLC (19×50 Xterra Prep RP 10-90% CH3CN/5 mM NH4HCO3 over 9 min, 25 ml/min) to provide 5.0 mg (3%) of the title compound as a white solid. MS (ES+) m/e 449 [M+H]+
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:5]=1[C:6](O)=[O:7])#[N:2].C[N:15](C)C=O.C(Cl)(=O)C(Cl)=O>O1CCCC1>[C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:5]=1[C:6]([NH2:15])=[O:7])#[N:2]
Reactant: CN(C)C=O
Reactant: Cc1ccc(CC#N)c(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: Cc1ccc(CC#N)c(C(N)=O)c1

Procedure:
2-Cyanomethyl-5-methylbenzoic acid (16.3 g) and dimethylformamide (0.1 mL) were suspended in tetrahydrofuran (160 mL), and oxalyl dichloride (12.2 mL) was added dropwise under ice-cooling. After cease of foaming, the solvent was evaporated. The obtained residue was dissolved in tetrahydrofuran, and the solution was added dropwise to 28% aqueous ammonia solution under ice-cooling. After the completion of the reaction, the solvent was evaporated, and the precipitated crystals were collected by filtration to give 2-cyanomethyl-5-methylbenzamide (10.9 g).
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)[CH2:3][CH2:4]Cl.[I-].[Na+].[CH2:19]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1.C(=O)([O-])O.[Na+]>C(O)(C)C>[O:1]=[C:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)[CH2:3][CH2:4][N:29]1[CH2:30][CH2:31][CH:26]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:27][CH2:28]1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C1CCc2cc(C(=O)CCCl)ccc2N1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)O
Product: O=C1CCc2cc(C(=O)CCN3CCC(Cc4ccccc4)CC3)ccc2N1
Reaction time: 2 h

Procedure:
2.4 Grams of 6-(1-oxo-3-chloropropyl)-3,4-dihydrocarbostyril and 1.6 g of sodium iodide were mixed in 60 ml of isopropanol and stirred at 40°-50° C. for 2 hours. Then 2.2 g of 4-benzylpiperidine and 3.0 g of DBU were added to the reaction mixture and refluxed by heating for 6 hours. The reaction mixture was poured into 100 ml of 5%-sodium hydrogen-carbonate aqueous solution and stirred at a room temperature for 1 hour. The insoluble matters fromed were collected by filtration washed with water and dried, then recrystallized from ethanol to obtain 1.8 g of 6-[1-oxo-3-(4-benzyl-1-piperidyl)propyl]-3,4-dihydrocarbostyril in light yellow plate-like crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]4[NH:19][C:20]([C:22]5[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]([CH3:31])[CH3:30])[CH:23]=5)=[CH:21][C:14]=34)=[CH:11][N:10]([CH2:32][CH3:33])[N:9]=2)=[CH:4][CH:3]=1.[CH3:34][NH:35][CH3:36].[O:37]1[CH2:41]CCC1>>[CH3:31][N:29]([CH2:28][C:24]1[CH:23]=[C:22]([C:20]2[NH:19][C:15]3=[N:16][CH:17]=[CH:18][C:13]([C:12]4[C:8]([C:5]5[CH:4]=[CH:3][C:2]([NH:1][C:41](=[O:37])[N:35]([CH3:36])[CH3:34])=[CH:7][CH:6]=5)=[N:9][N:10]([CH2:32][CH3:33])[CH:11]=4)=[C:14]3[CH:21]=2)[CH:27]=[CH:26][CH:25]=1)[CH3:30]
Reactant: C1CCOC1
Reactant: CNC
Reactant: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(N)cc2)n1
Product: CCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a stirred solution of 4-[3-(4-aminophenyl)-1-ethyl-1H-pyrazol-4-yl]-2-[3-(dimethylaminomethyl)phenyl]-1H-pyrrolo[2,3-b]pyridine (1.0 mmol) in tetrahydrofuran (15 mL) was added p-nitrophenylchloroformate (1.1 mmol). After stirring for 1 h at room temperature a solution of 2.0 M dimethylamine in tetrahydrofuran (14 mmol) was added. The reaction was stirred an additional 1 h at room temperature then concentrated under vacuum. The residue which remained was triturated with aqueous sodium hydroxide, filtered, washed with cold water, and dried under vacuum. Purification by Gilson reverse phase HPLC afforded title compound as an off-white solid (46%). ESMS (M+H)+: 508.4
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)[CH3:2].O=[C:16]([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:17]([OH:19])=[O:18]>C1C=CC=CC=1.O1CCOCC1>[C:17]([C:16]1([CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C:7]2[NH:8][C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=2[CH2:5][CH2:4][N:3]1[CH2:1][CH3:2])([OH:19])=[O:18]
Reactant: O=C(O)CCCC(=O)C(=O)O
Reactant: CCNCCc1c[nH]c2ccccc12
Solvent: c1ccccc1
Solvent: C1COCCO1
Product: CCN1CCc2c([nH]c3ccccc23)C1(CCCC(=O)O)C(=O)O
Yield: 40 %

Procedure:
5 g of N-ethyl-tryptamine (i.e., 3-(2-ethylaminoethyl)-indole) were dissolved in 100 ml of absolute benzene, and a solution of 4.70 g of α-keto-adipic acid in 50 ml of absolute dioxane was added thereto at room temperature. The mixture was refluxed for 20 hours. After the reaction was completed, the mixture was evaporated to remove solvent. The residue thus obtained was recrystallized from ethanol, whereby 3.51 g of 1,2,3,4-tetrahydro-1-carboxy-1-(3-carboxypropyl)-2-ethyl-β-carboline were obtained. Yield: 38.0%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][NH:11][C:10](=[O:14])[C:9]=2[C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[Br:23]Br.Cl[CH2:26][C:27]1[C:28]([CH3:37])=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=1>CO.O.CCOC(C)=O>[Br:23][C:13]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[C:9]([C:15]2[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=2)[C:10](=[O:14])[N:11]([CH2:26][C:27]2[C:28]([CH3:37])=[N:29][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:32]=2)[N:12]=1
Reactant: Cc1nc(C(F)(F)F)ccc1CCl
Reactant: BrBr
Reactant: N#Cc1ccc(-c2c(-c3ccc(Cl)cc3)cn[nH]c2=O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc(Br)c(-c2ccc(Cl)cc2)c(-c2ccc(C#N)cc2)c1=O
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 81.1 %

Procedure:
To a suspension of 4-(5-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile (2.21 gm, 7.2 mmol) in 30 ml of methanol at rt was added LiOH monohydrate (0.45, 10.8 mmol). The resulting mixture was heated to 70° C. and stirred at this temperature for 15 min. Br2 (2.3 g, 14.4 mmol) was then carefully added dropwise to the reaction mixture. After addition was complete, the color of Br2 disappeared after 2 minutes. HPLC indicated that the reaction had proceeded to 40% completion. Additional Br2 (˜0.8 g, 5 mmol) was then added followed by additional LiOH monohydrate (0.21 g, 5 mmol). The Br2 was consumed within 2 minutes after addition. The reaction was then cooled to rt and the solvent was removed under reduced pressure. The resulting residue was reconcentrated from acetone (2×20 ml). To the resulting light brown residue was added 20 mL DMF, followed by addition of LiOH monohydrate (0.612 g, 14.40 mmol) and 3-(chloromethyl)-2-methyl-6-(trifluoromethyl)pyridine (1.65 gm, 7.91 mmol) at rt under Ar. The reaction mixture was heated to 70° C. and stirred at this temperature for 1 hr. After this time, the solution was cooled to rt and diluted with water (50 ml) and EtOAc (50 ml) and stirred for 10 minutes. The layers were separated and organic phase was washed with saturated aqueous NaCl (100 mL). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the crude product. The crude product was purified using an automated column chromatography system (ISCO, 120 gm silica gel) eluting with a gradient of 20%-80% EtOAc/Hex to give product as off-white solid (3.27 gm, 81% yield). HPLC retention time (method B) 3.91 min; LCMS (M+H)=561.0.
Reaction SMILES: [FH:1].[Br:2]N1C(=O)CCC1=O.[N+](=[C:12]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:13]([O:15][CH3:16])=[O:14])=[N-]>N1C=CC=CC=1.CCOCC>[Br:2][C:12]([F:1])([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:13]([O:15][CH3:16])=[O:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)CCC(=[N+]=[N-])C(=O)OC
Reactant: F
Solvent: CCOCC
Solvent: c1ccncc1
Product: COC(=O)CCC(F)(Br)C(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Part B. To a cold solution of 5 mL of 70% hydrogen fluoride in pyridine and 1.2 g (6.7 mmol) N-bromosuccinimide in 10 mL of ether is added a solution of dimethyl 2-diazopentane-1,5-dioate (1.1 g, 5.9 mmol) in ether (10 mL) at 0° C. The mixture is stirred at 0° C. for 30 minutes The solution is washed with water (20 mL), brine (20 mL) and dried over sodium sulfate. The solvent is removed in vacuo to yield dimethyl 2-bromo-2-fluoropentane-1,5-dioate which can be further purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:27])=[CH:5][C:6]=1[CH:7]1[CH2:12][C:11]([NH:13][NH:14]S(C2C=CC(OC)=CC=2)(=O)=O)=[CH:10][C:9](=[O:26])[CH2:8]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36](=O)[CH2:37][CH3:38]>CO>[Cl:1][C:2]1[S:3][C:4]([Cl:27])=[CH:5][C:6]=1[CH:7]1[CH2:12][C:11]2[N:13]=[N:14][CH:35]=[C:36]([CH2:37][CH3:38])[C:10]=2[C:9](=[O:26])[CH2:8]1
Reactant: COc1ccc(S(=O)(=O)NNC2=CC(=O)CC(c3cc(Cl)sc3Cl)C2)cc1
Reactant: CCC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCc1cnnc2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.9 %

Procedure:
To a mixture of 5-(2,5-dichlorothiophen-3-yl)-1-[2-(4-methoxyphenylsulfonyl)hydrazino]cyclohexen-3-one (1.79 g), anhydrous potassium carbonate (0.718 g) and methanol (30 ml) was added under ice-cooling 1-bromobutan-2-one (0.785 g), and the mixture was stirred at room temperature for 2 hours. To the mixture was added anhydrous potassium carbonate (1.2 g), and the mixture was stirred for 2 hours. Under reduced pressure, the solvent was evaporated, and the residue was extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified with silica gel column chromatography to give 7-(2,5-dichlorothiophen-3-yl)-4-ethyl-5,6,7,8-tetrahydrocinnolin-5-one (0.26 g) as oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:29][C:28](=O)[CH:27]=[C:26]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N:37]3[CH:41]=[N:40][CH:39]=[N:38]3)[CH:32]=2)[O:25]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:28](=[O:29])[CH2:27][C:26](=[O:25])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[N:40][CH:39]=[N:38]2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3cncn3)c2)O1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-n2cncn2)c1

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) and 2,2-dimethyl-6-(3-[1,2,4]triazol-1-yl-phenyl)-[1,3]dioxin-4-one (Example J13) according to the general procedure K. Obtained as an orange foam (233 mg).
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH:16]=O)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[NH2:18][C:19]([CH3:24])([CH2:22][OH:23])[CH2:20][OH:21]>>[ClH:1].[Cl:1][C:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:9]([CH2:16][NH:18][C:19]([CH3:24])([CH2:22][OH:23])[CH2:20][OH:21])=[C:10]2[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]2
Reactant: O=Cc1c2ccccc2c(Cl)c2ccccc12
Reactant: CC(N)(CO)CO
Product: CC(CO)(CO)NCc1c2ccccc2c(Cl)c2ccccc12
Product: Cl

Procedure:
Using the reductive amination procedure outlined in 1, 10-chloroanthracene-9-carbaldehyde (Aldrich) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave 2-(((10-chloro-9-anthracenyl)methyl)amino)-2-methyl-1,3-propanediol hydrochloride mp 268°-269° (dec), (CH3OH/Et2O), (C, H, Cl, N).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:11][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]([CH2:15][CH:16]=[CH2:17])[CH3:14].C(N(CC)CC)C.C(#N)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:11][N:12]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH:13]([CH2:15]/[CH:16]=[CH:17]/[C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1)[CH3:14]
Reactant: C=CCC(C)N(C)C(=O)OC(C)(C)C
Reactant: Brc1ccc2c(c1)OCO2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C/C=C/c1ccc2c(c1)OCO2)N(C)C(=O)OC(C)(C)C
Temperature: 82.5 °C
Yield: 111.7 %

Procedure:
Under a nitrogen atmosphere, a mixture of 4-bromo-1,2-(methylenedioxy)benzene (1.20 g, 5.97 mmol), N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine (1.19 g, 5.97 mmol), palladium(II) acetate (13.5 mg, 0.06 mmol), tri-o-tolylphosphine (73.1 mg, 0.24 mmol), triethylamine (1.7 mL, 11.9 mmol) and anhydrous acetonitrile (3.4 mL) was stirred and heated under reflux at 80-85° C. (oil bath temperature) for 22 h. The resulting mixture, containing brown solids, was cooled to ambient temperature, diluted with water (25 mL), and extracted with CHCl3 (3×25 mL). The combined CHCl3 extracts were dried (Na2SO4), filtered, concentrated by rotary evaporation and dried under high vacuum to produce an orange-yellow oil (2.13 g). The crude product was purified by column chromatography on silica gel (100 g), eluting with ethyl acetate-hexane (15:85, v/v). Selected fractions containing the product (Rf 0.33) were combined, concentrated by rotary evaporation and the residue was vacuum dried to give 1.08 g (56.6%) of a light-yellow oil.