Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[C:6]([N+:19]([O-:21])=[O:20])[C:5]=1[NH2:22].CC1C([N:31]2[C:36]([CH3:37])=[CH:35][C:34](OS(C(F)(F)F)(=O)=O)=[CH:33][C:32]2=O)=NC=CC=1.[C:47](=[O:50])([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([C:6]2[CH:5]=[C:4]([CH3:9])[CH:3]([CH2:37][C:36]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[C:47](=[O:50])[CH:7]=2)[CH:7]=[C:6]([N+:19]([O-:21])=[O:20])[C:5]=1[NH2:22]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cc([N+](=O)[O-])c1N
Reactant: Cc1cccnc1-n1c(C)cc(OS(=O)(=O)C(F)(F)F)cc1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cc(C2=CC(=O)C(Cc3ccccn3)C(C)=C2)cc([N+](=O)[O-])c1N
Yield: 175.4 %

Procedure:
To a solution of 2-amino-3-nitro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (0.163 g, 0.51 mmol) in ethylene glycol dimethylether (5 mL) was added N-(methyl-2-pyridinyl)-6-methyl-4-trifluoromethylsulfonyloxy-2-pyridone (0.136 g, 0.41 mmol), bis(triphenylphoshine)palladium (II) dichloride (0.029 g, 0.04 mmol), and sodium carbonate (0.62 mL, 1.24 mmol of 2M). The resulting mixture was heated at reflux for 3 hours. After cooling and concentration in vacuo the resulting dark solid was purified (SiO2, 50% ethyl acetate/methylene chloride to 3% methanol in 50% ethyl acetate/methylene chloride) to provide the title compound as an orange solid (0.176 g, 89%). 1H NMR (500 MHz, CDCl3) δ 2.41 (s, 3H), 3.39 (s, 3H), 5.5 (s, 2H), 6.28 (s, 1H), 6.68 (s, 1H), 7.3-7.1 (m, 2H), 7.62 (t, 1H), 8.49 (s, 1H), 8.61 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:15]([O-:17])=[O:16])[C:8]([O:13][CH3:14])=[C:9]([CH:12]=1)[CH:10]=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH2:18](O)[CH2:19][OH:20]>C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([N+:15]([O-:17])=[O:16])[C:8]([O:13][CH3:14])=[C:9]([CH:10]2[O:20][CH2:19][CH2:18][O:11]2)[CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCO
Reactant: COc1c(C=O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Solvent: c1ccccc1
Product: COc1c(C2OCCO2)cc(C(C)(C)C)cc1[N+](=O)[O-]

Procedure:
A solution of 1.0 g (4.2 mmol) of 5-tert-Butyl-2-methoxy-3-nitro-benzaldehyde, 1.18 mL of ethylene glycol, and 0.4 g of pTSA hydrate in 50 mL of benzene was refluxed for 24 h under Dean-Stark conditions. The benzene was evaporated and the resultant oil was redissolved in EtOAc. The organic layer was washed with water, sat'd NaHCO3, and brine. The extract was dried over MgSO4, filtered, and concentrated. Chromatography (10% EtOAc in hexanes) provided 1.0 g of 2-(5-tert-Butyl-2-methoxy-3-nitro-phenyl)-[1,3]dioxolane as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Cl[CH2:18][CH2:19][CH2:20][C:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH2:20][C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25][CH2:24]2)=[O:22])[CH2:13][CH2:12]1
Reactant: O=C(CCCCl)N1CCCc2ccccc21
Reactant: Clc1ccc2[nH]cc(C3CCNCC3)c2c1
Product: Cl
Product: O=C(CCCN1CCC(c2c[nH]c3ccc(Cl)cc23)CC1)N1CCCc2ccccc21

Procedure:
from 5-chloro-3-(piperidin-4-yl)-1H-indole and 4-chloro-1-(3,4-dihydro-2H-quinolin-1-yl)butan-1-one. Mp 158-162° C. 1H NMR (DMSO-d6): 1.85-1.95 (m, 2H); 1.95-2.20 (m, 6H); 2.60-2.75 (m, 4H); 2.95-3.15 (m, 5H); 3.55 (d, 2H); 3.70 (t, 2H); 7.05-7.25 (m, 6H); 7.40 (d, 1H); 7.75 (s, 1H); 10.45 (broad s, 1H); 11.15 (s, 1H). MS m/z: 436 (MH+), 303.
Reaction SMILES: N12CCCN=C1CCCCC2.[SH:12][C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1.Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([NH2:30])(=[O:29])=[O:28]>C(#N)C.O>[S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][S:12][C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:28])(=[O:29])[NH2:30]
Reactant: NS(=O)(=O)c1ccccc1CCl
Reactant: Sc1ncccn1
Solvent: CC#N
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: NS(=O)(=O)c1ccccc1CSc1ncccn1
Reaction time: 70 h
Yield: 85.2 %

Procedure:
With cooling, 7.9 g of 97% 1,8-diazabicyclo[5.4.0]undec-7-ene are added to a suspension of 5.7 g of 98% 2-mercaptopyrimidine in 50 ml of acetonitrile. To the yellowish solution so obtained are added 10.3 g of 2-chloromethylbenzenesulfonamide. The reaction solution is stirred for 70 hours at 20°-22° C. and then diluted with 1 liter of water. The precipitate is isolated by filtration and dried, affording 12.0 g (85% of theory) of 2-(2-sulfamoylphenylmethylthio)pyrimidine of m.p. 128°-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Br:24])[C:21]([F:25])=[C:20]([Br:26])[CH:19]=3)([C:14]([F:17])([F:16])[F:15])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[C:47]1(=[O:57])[NH:51][C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]12.[K]>ClCCCl.CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:13][C:12]([C:18]3[CH:23]=[C:22]([Br:24])[C:21]([F:25])=[C:20]([Br:26])[CH:19]=3)([C:14]([F:17])([F:15])[F:16])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:51]1[C:50](=[O:52])[C:49]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:48]2[C:47]1=[O:57]
Reactant: Cc1ccc(C2=NOC(c3cc(Br)c(F)c(Br)c3)(C(F)(F)F)C2)cc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Agent: [K]
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(C2=NOC(c3cc(Br)c(F)c(Br)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3-(3-chloro-4-methylphenyl)-5-(3,5-dibromo-4-fluorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole (1.1 g) in 1,2-dichloroethane (7 mL) was added N-bromosuccinimide (0.38 g) and 2,2′-azobis(2-methylpropionitrile) (0.028 g). The mixture was heated to reflux for 3 hours and then cooled to room temperature. The resulting mixture was diluted with 1,2-dichloroethane (10 mL), washed with water (30 mL) and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a residue. The residue was dissolved in N,N-dimethylformamide (7 mL), and potassium phthalimide (0.40 g) was added. The mixture was stirred at room temperature for 15 hours. The reaction mixture was then poured into water (10 mL) and extracted with ethyl acetate (10 mL×2). The organic extracts were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the crude title compound as a pale yellow resin (0.75 g), which was used in the next step without purification.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[H-].[Na+].Cl[C:13]1[N:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[CH:17][CH:18]=1>C1COCC1>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[N:15]=[N:14][C:13]([O:9][CH:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[CH:18][CH:17]=2)=[CH:24][CH:23]=1
Reactant: OC1CN2CCC1CC2
Reactant: Fc1ccc(-c2ccc(Cl)nn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(-c2ccc(OC3CN4CCC3CC4)nn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (rac.)-3-quinuclidinol (0.007 mole) in dry THF under nitrogen is treated with sodium hydride (60% in mineral oil; 1.1 equiv.). After 1 hr at room temperature, a solution of 3-chloro-6-(4-fluoro-phenyl)pyridazine (1.0 equiv.) in THF (30 ml) is added, and the reaction mixture heated to reflux for 6 hrs. After cooling to rt, the THF is evaporated and the residue dissolved in ethyl acetate (100 ml) and then washed with water (3×20 ml), followed by sodium chloride solution (20 ml). The ethyl acetate is dried over anhydrous magnesium sulfate, filtered and evaporated to dryness, and the residual oil purified by silica gel column chromatography (eluent: ethyl acetate-methanol-triethylamine (50:10:2) to afford (rac.)-3-[6-(4-fluorophenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane as a colourless solid. 1H-NMR (400 MHz, CDCl3): δ=8.00 (m, 2H), 7.75 (d, 1H), 7.17 (m, 2H), 7.1 (d, 1H), 5.35 (m, 1H), 3.5 (m, 1H), 2.99-2.83 (m, 5H), 2.32 (m, 1H), 1.98 (m, 1H), 1.76-1.68 (m, 2H), 1.46 (m, 1H).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].C(N(CC)CC)C.[Br:15][C:16]([CH3:21])([CH3:20])[C:17](Br)=[O:18]>O1CCCC1>[Br:15][C:16]([CH3:21])([CH3:20])[C:17]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6])=[O:18]
Reactant: CC(C)(Br)C(=O)Br
Reactant: C=CCCCCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCCCCOC(=O)C(C)(C)Br
Temperature: 4 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
5-Hexen-1-ol (42.6 g), triethylamine (45.8 g), and tetrahydrofuran (0.8 L) were mixed. After ice cooling, 2-bromoisobutyryl bromide (100 g) was dropped. The reaction liquid was stirred at 4° C. for 3 hours, and then at room temperature for 15 hours. The reaction liquid was then filtered, concentrated with an evaporator, and dissolved in diethyl ether (300 mL). The solution was washed with a 1N hydrochloric acid solution (2×300 mL), a saturated sodium bicarbonate solution (2×300 mL), and distilled water (2×300 mL), in this order. After that, the organic layer was dried over sodium sulfate, filtered, and concentrated with an evaporator. The product was then purified through a silica gel column (developing solvent: hexane/ethyl acetate=15/1), and concentrated to give 74.2 g of 5-hexenyl 2-bromo-2-methylpropanate of the following chemical formula (compound 1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH2:6][C:5]2=O.[C:19](=[N:25][Si](C)(C)C)=[N:20][Si](C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH2:6][C:5]2=[N:25][C:19]#[N:20]
Reactant: O=C1CC(c2ccccn2)Oc2ccc(Br)cc21
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1CC(c2ccccn2)Oc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a solution of 6-bromo-2-pyridin-2-yl-chroman-4-one (303 mg, 1 mmol) in DCM (10 mL) was added TiCl4 (4 mL, 1 M in CH2Cl2) dropwise within 15 minutes at room temperature. After stirring for 1 h, N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (0.5 mL, 2.2 mmol) was added dropwise. The mixture was stirred at room temperature overnight and poured into ice-water (50 g). The aqueous layer was extracted with CHCl2, which was combined with the organic layer. The organic layer was dried and concentrated to give crude 6-bromo-2-pyridin-2-yl-chroman-4-ylidene-cyanamide (300 mg, 92%).
Reaction SMILES: [Na].[CH3:2][NH:3][C:4]([NH2:6])=[S:5].[C:7]([CH:9]([CH2:15][CH:16](OCC)OCC)[C:10](OCC)=[O:11])#[N:8]>C(O)C>[CH3:2][N:3]1[C:7]2[NH:8][CH:16]=[CH:15][C:9]=2[C:10](=[O:11])[N:6]=[C:4]1[SH:5]
Reactant: CCOC(=O)C(C#N)CC(OCC)OCC
Reactant: CNC(N)=S
Agent: [Na]
Solvent: CCO
Product: Cn1c(S)nc(=O)c2cc[nH]c21
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
Sodium metal (1.21 g) was dissolved in anhydrous ethanol (50 ml) followed by addition of N-methylthiourea (4.96 g), and the mixture was stirred for dissolution at 50° C. for 30 minutes. Then, a solution of ethyl 2-cyano-4,4-diethoxybutyrate (11.47 g) in ethanol (10 ml) was added and the mixture was refluxed at 100° C. for 5 hours. The solvent was then distilled off under reduced pressure and the residue was-dissolved by adding water (20 ml). Then, 10% hydrochloric acid (75 ml) was added and the mixture was stirred overnight. The resulting precipitate was collected by filtration, washed serially with water, ethanol and ether, and dried to provide the title compound (6.8 g). 1H-NMR (DMSO-d6) δ: 3.82(3H,s), 6.41-6.44(1H,m), 6.92-6.95(1H,s), 12.02(1H,s), 12.06(1H,s).
Reaction SMILES: [C:1]1([C:7]([SH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=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.[H-].[Na+].[C:23]([CH:27]([O:37][SiH:38]([CH3:40])[CH3:39])[C@@H:28]1[C@@H:31](S(C)(=O)=O)[NH:30][C:29]1=[O:36])([CH3:26])([CH3:25])[CH3:24]>CO.CC(C)=O.O>[C:23]([CH:27]([O:37][SiH:38]([CH3:40])[CH3:39])[C@@H:28]1[C@@H:31]([S:20][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:30][C:29]1=[O:36])([CH3:26])([CH3:24])[CH3:25]
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[SiH](C)OC([C@H]1C(=O)N[C@@H]1S(C)(=O)=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(C)=O
Product: C[SiH](C)OC([C@H]1C(=O)N[C@@H]1SC(c1ccccc1)(c1ccccc1)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At 0°, 12.5 g of triphenylmethyl mercaptan are suspended in 70 ml of methanol and there is added in portions, over a period of 10 minutes, a total of 2.2 g of a 55% sodium hydride suspension in oil. There is then added dropwise, over a period of 30 minutes, an emulsion of 11.1 g of (3S,4R)-3-(tert.-butyldimethylsilyloxymethyl)-4-methylsulphonylazetidin-2-one (European Patent Application No. 82113) in 70 ml of acetone and 70 ml of water. After being stirred for 30 minutes at 0° and for 1 hour at room temperature, the reaction mixture is concentrated in a rotary evaporator, methylene chloride is added thereto, and the aqueous phase is separated off. The organic solution is washed with brine and dried over sodium sulphate. After concentration, the crude title compound is purified by chromatography over silica gel (eluant toluene/ethyl acetate 19:1). TLC (toluene/ethyl acetate 19:1): Rf =0.64; IR (methylene chloride): 3390, 1760, 1117, 835 cm-1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)(=[O:4])=[O:3].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([O:27][C:28]2[CH:33]=[CH:32][C:31](Br)=[CH:30][CH:29]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH2:23][CH:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([N:10]3[C:11]4[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:13][CH:12]=4)[CH:8]=[CH:9]3)=[CH:30][CH:29]=2)[CH2:25][CH2:26]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CS(=O)(=O)c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(S(C)(=O)=O)ccc43)cc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 by using 5-(methylsulfonyl)-1H-indole (intermediate-21) and tert-butyl-4-(4-bromophenoxy)piperidine-1-carboxylate (intermediate-77) (0.130 g, 24%).
Reaction SMILES: [Cl:1][C:2]([Cl:12])([Cl:11])[C:3]([C:5]1[N:6]([CH3:10])[CH:7]=[CH:8][N:9]=1)=[O:4].C1C(=O)N([Br:20])C(=O)C1>C1COCC1>[Br:20][C:8]1[N:9]=[C:5]([C:3](=[O:4])[C:2]([Cl:1])([Cl:11])[Cl:12])[N:6]([CH3:10])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1ccnc1C(=O)C(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: Cn1cc(Br)nc1C(=O)C(Cl)(Cl)Cl
Temperature: -10 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
To the solution of 2,2,2-trichloro-1-(1-methyl-1H-imidazol-2-yl)ethanone (1.5 g, 6.6 mmol) in 26 mL of anhydrous THF was added 2.35 g of NBS at −10° C. The resulting mixture was stirred at −10° C. for 2 h, then 25° C. for 16 h. The solution was evaporated and the residue was purified by silica gel column (DCM as eluent) to give 1-(-4-bromo-1-methyl-1H-imidazol-2-yl)-2,2,2-trichloroethanone (1.18 g, yield 58%). 1H NMR (300 MHz, CDCl3) δ 7.15 (s, 1H), 4.05 (s, 3H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[C:27]([Br:28])=[CH:26][C:10]2[C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[O:13][C:9]=2[CH:8]=1.N1C=CC=CC=1>ClCCl.O>[Br:28][C:27]1[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:10]=2[CH:26]=1
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(Br)cc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
MsCl (31.7 g, 277.5 mmol) was added to a solution of ethyl 6-amino-5-bromo-2-(4-fluorophenyl)benzofuran-3-carboxylate (35 g, 92.5 mmol) and pyridine (60 mL) in dichloromethane (300 mL) at 0° C. After stirred overnight at room temperature, the mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo, the resulting residue was purified using crystallized with EtOAc to provide the pure product of ethyl 5-bromo-2-(4-fluorophenyl)-6-(methylsulfonamido)benzofuran-3-carboxylate (35 g, yield: 82%). 1H-NMR (CDCl3, 400 MHz) δ 8.27 (s, 1H), 8.01˜8.05 (m, 2H), 7.87 (s, 1H), 7.15˜7.19 (m, 2H), 6.87 (s, 1H), 4.38˜4.43 (m, 2H), 3.00 (s, 3H), 1.40 (t, J=40 Hz, 3H). MS (M+H)+: 456/458.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([NH:20][CH2:21][CH2:22][N:23]([CH3:34])[C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][CH:14]=2)=[CH:4][CH:3]=1.C([CH:37]([C:41](Cl)=[O:42])[C:38](Cl)=[O:39])C.[CH3:44][CH2:45][OH:46]>ClCCCl>[CH2:45]([O:46][C:41](=[O:42])[CH2:37][C:38]([N:20]([CH2:21][CH2:22][N:23]([CH3:34])[C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[C:11]1[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][CH:14]=[C:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:10]=1)=[O:39])[CH3:44]
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCN(C)C(=O)OCc1ccccc1
Reactant: CCC(C(=O)Cl)C(=O)Cl
Reactant: CCO
Solvent: ClCCCl
Product: CCOC(=O)CC(=O)N(CCN(C)C(=O)OCc1ccccc1)c1cc(Cc2ccc(F)cc2)cnc1C(=O)OCC

Procedure:
A solution of ethyl 5-[(4-fluorophenyl)methyl]-3-{[2-(methyl {[(phenylmethyl)oxy]carbonyl}amino)ethyl]amino}-2-pyridinecarboxylate (1.62 g, 3.5 mmol) and ethyl malonyl chloride (1.24 mL, 8.7 mmol) in DCE (50 mL) was heated under nitrogen at reflux for 2 hrs. An additional 0.5 mL of the ethyl malonyl chloride was added and the reaction was stirred at reflux an additional ½ hour. The mixture was cooled, treated with EtOH (25 mL), and then concentrated in vacuo. The residue was purified on silica gel eluting with a gradient between 0 and 100% EtOAc in CH2Cl2 to provide after combination and concentration in vacuo of pure fractions the product as an yellow viscous oil: 1H NMR (400 MHz, DMSO-d6@90° C.) δ ppm 1.11 (t, J=6.77 Hz, 2 H), 1.28 (t, J=7.14 Hz, 3 H), 2.82 (s, 3 H), 3.03 (s, 3 H), 3.34-3.43 (m, 2 H), 3.96 (d, J=5.85 Hz, 2 H), 4.02-4.07 (m, 4 H), 4.27-4.35 (m, 2 H), 5.02 (s, 2H), 7.08 (t, J=8.87 Hz, 2 H), 7.23-7.34 (m, 7 H), 7.70 (s, 1 H), 8.59 (s, 1 H); ES+ MS: 580 (M+H+).
Reaction SMILES: Br.[NH2:2][CH2:3][CH2:4][Br:5].[C:6](=O)([O-])[O-:7].[K+].[K+].[F:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([O:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][C:14]=1[N:26]1C(=O)[CH:30]2[CH2:33][CH2:34][CH2:35][C:28](=[CH:29]2)[C:27]1=[O:36].Cl>C(#N)C>[F:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([O:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:15][C:14]=1[NH:26][C:27](=[O:36])[C:28]1[CH2:35][CH2:34][CH2:33][CH2:30][C:29]=1[C:6]([NH:2][CH2:3][CH2:4][Br:5])=[O:7]
Reactant: O=C([O-])[O-]
Reactant: O=C1C2=CC(CCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: NCCBr
Agent: Br
Agent: Cl
Agent: [K+]
Solvent: CC#N
Product: O=C(NCCBr)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 165.9 %

Procedure:
2-Aminoethyl bromide hydrobromide (0.280 g, 1.37 mmol) and potassium carbonate (0.110 g, 0.796 mmol) were placed into a round bottom flask (25 cc), followed by stirring at room temperature in an acetonitrile solvent until the generation of gas ceased. Then, N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide (0.500 g, 1.37 mmol) was added thereto, followed by stirring for 30 minutes at room temperature. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (20 ml), and the mixture was extracted with ethyl acetate (30 ml x 3 portions). After drying the organic layer over anhydrous magnesium sulfate, the drying agent was removed, and the solvent was distilled off under reduced pressure. The precipitated crystals were isolated by filtration, washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(2-bromoethyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.644 g, 96.4% yield).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[C:5]([NH:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[N:4][N:3]=1.C(O)(=O)C.CO>C(Cl)Cl.[Pd]>[CH2:22]([N:19]([CH2:20][CH3:21])[CH2:18][CH2:17][CH2:16][NH:15][C:5]1[C:6]2[CH:7]=[C:8]3[N:13]([C:14]=2[C:2]([CH3:1])=[N:3][N:4]=1)[CH2:12][CH2:11][CH2:10][CH2:9]3)[CH3:23]
Reactant: CCN(CC)CCCNc1nnc(C)c2c1cc1ccccn12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)CCCNc1nnc(C)c2c1cc1n2CCCC1

Procedure:
4-(Methyl)-N,N-diethyl-N'-[pyridazino[4,5-b]indolizin-1-yl]-1,3-propanediamine (2.75 g, 8.83 mmoL) was hydrogenated in a Parr appartus with 10% Pd on charcoal (0.54 g) in a 1:1 mixture of acetic acid and methanol at 55 psi and room temperature. Filtration through Solka Floc to remove the catalyst and evaporation of the filtrate gave a crude product which was passed through a pad of alumina eluting with 5% methanol in methylene chloride to give the free base of the title product in quantitative yield. The free base was converted to the monofumarate salt: m.p.171°-172° C.
Reaction SMILES: [Li+].[OH-].[OH:3][CH2:4][CH2:5][CH2:6][C:7]#[C:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=1.CCOC(C)=O>O.C1COCC1>[OH:3][CH2:4][CH2:5][CH2:6][C:7]#[C:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(C#CCCCO)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C#CCCCO)cc1
Temperature: 42 °C
Reaction time: 4 h
Yield: 93.1 %

Procedure:
LiOH (2 g, 83 mmol) in H2O (30 mL) was added dropwise to a stirring solution of Intermediate 20 (2 g, 9.2 mmol) in THF (30 mL). The resulting mixture was stirred at 42° C. for 4 h. After cooling, water (100 mL) and EtOAc (200 mL) were added. The mixture was extracted with EtOAc. The organic layer and the H2O layer were independently neutralized with 1N HCl. The aqueous layer was extracted with EtOAc and the combined organic layers dried over MgSO4 (s). The material was concentrated by rotary evaporation and the crude solid was purified by trituration with EtOAc and hexanes to give the title compound as a white powder (1.75 g, 93%). 1H NMR (400 MHz, DMSO-d6) δ 13.05 (brs, 1H), 7.88 (dd, 2H, J=8.5, 1.5 Hz), 7.47 (dd, 2H, J=8.5, 1.5 Hz), 4.55 (brs, 1H), 3.50 (t, 2H, J=5.5 Hz), 2.50 (m, 2H), 1.68 (m, 2H); ES/MS calcd. for C12H1O3+205.1. found m/z=205 (M+H)+.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[CH3:7][C:8]1([CH3:22])[CH2:13][CH2:12][C:11](=O)[CH:10]2[C:15]([CH3:21])([CH3:20])[CH:16]3[CH2:19][C:9]12[CH2:18][CH2:17]3>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1CCCCC1>[CH:1](=[C:11]1[CH:10]2[C:15]([CH3:20])([CH3:21])[CH:16]3[CH2:19][C:9]2([CH2:18][CH2:17]3)[C:8]([CH3:22])([CH3:7])[CH2:13][CH2:12]1)[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CC1(C)C2CCC3(C2)C1C(=O)CCC3(C)C
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCCCC1
Product: CC=C1CCC(C)(C)C23CCC(C2)C(C)(C)C13
Temperature: 25 °C
Reaction time: 78 h
Yield: 61.9 %

Procedure:
Potassium tert-butoxide (13.0 g, 0.116 mol) and ethyltriphenylphosphonium bromide (41.6 g, 0.112 mol) were added to a solution of 2,2,7,7-tetramethyltricyclo[6.2.1.01,6]undecan-5-one (1, 20.0 g, 0.091 mol) in cyclohexane (200 ml), the reaction mixture was stirred at room temperature for 78 h and filtered through Celite®. The filtrate was concentrated and distilled under reduced pressure to give (at 95° C./0.1 mbar) 5-ethylidene-2,2,7,7-tetramethyltricyclo[6.2.1.01,6]undecane (2b, 13.1 g, 62% yield, colourless liquid).