Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[CH3:34][N:35]([CH3:41])[CH:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH2:40][CH:36]([N:35]([CH3:41])[CH3:34])[CH2:37]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1
Reactant: CN(C)C1CCNC1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(N4CCC(N(C)C)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and 3-dimethylamino-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.16 (s, 1H), 4.00 (t, 2H), 3.80 (t, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.22 (s, 6H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27 (t, 1H), 1.07 (t, 1H), 0.83 (d, 3H). m/z: 446 [M+H]
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[NH2:10].C(O[CH:14]=[C:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C>>[CH2:19]([O:18][C:16](=[O:17])[C:15](=[CH:14][NH:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[Br:1])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:20]
Reactant: COc1ccc(Br)c(N)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1cc(OC)ccc1Br)C(=O)OCC
Temperature: 100 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
A mixture of 2-bromo-5-methoxy-phenylamine (540 mg, 2.64 mmol) and diethyl 2-(ethoxymethylene)malonate (600 mg, 2.7 mmol) was stirred at 100° C. for 2 h. After cooling, the reaction mixture was recrystallized from methanol (10 mL) to give 2-[(2-bromo-5-methoxy-phenylamino)-methylene]-malonic acid diethyl ester as a yellow solid (0.8 g, 81%).
Reaction SMILES: [C:1]([S:5][CH2:6][C:7]1[N:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].B.C1COCC1>C1COCC1>[NH2:14][CH2:13][C:10]1[CH:11]=[N:12][C:7]([CH2:6][S:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:8][CH:9]=1
Reactant: CC(C)(C)SCc1ccc(C#N)cn1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)SCc1ccc(CN)cn1
Temperature: 0 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
Dissolve 6-(tert-butylthio)methyl-pyridine-3-carbonitrile (4.9 g, 23.8 mmol) in anhydrous THF (20 mL) under nitrogen and cool the mixture at 0° C. Add borane-THF complex (71.3 mL, 71.3 mmol, 1M solution in THF). Stir the reaction mixture at room temperature overnight. Pour slowly the reaction mixture into ice-cold 2N aqueous HCl (200 mL) and stir the resulting solution for 4 h. Concentrate in vacuo, take up the resulting solid with a minimum amount of methanol and filter through SCX-2 column eluting with methanol followed by 3N ammonia in methanol to obtain the title compound as a yellow oil (3.8 g, 77%). MS (ES+) m/z: 211 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:11]([CH:12]([OH:27])[C:13]3[C:14]([F:26])=[C:15]([NH:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1)#[N:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]2[C:11]([C:12]([C:13]3[C:14]([F:26])=[C:15]([NH:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:21])=[O:22])[CH:16]=[CH:17][CH:18]=3)=[O:27])=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1)#[N:2]
Reactant: CCCS(=O)(=O)Nc1cccc(C(O)c2c[nH]c3ncc(C#N)cc23)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1cccc(C(=O)c2c[nH]c3ncc(C#N)cc23)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To propane-1-sulfonic acid {3-[(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2-fluoro-phenyl}-amide (23, 77 mg, 0.20 mmol) dissolved in 1 mL of tetrahydrofuran, Dess-Martin periodinane (92.5 mg, 0.218 mmol) was added as a solid. The reaction was stirred at room temperature for 1 hour, then quenched with water. The aqueous layer was separated and extracted with ethyl acetate, and the organice layers combined, washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum and the resulting residue was purified by silica gel column chromatography eluting with ethyl acetate and hexanes to provide the desired compound (P-0003, 67 mg). MS(ESI) [M−H+]−=385.4.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.[N:35]1([C:41]2[CH:51]=[CH:50][C:44]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:43][N:42]=2)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(#N)CC.CCO.O>[O:17]=[C:7]1[NH:6][C:5]2[CH:4]=[C:3]([CH2:2][N:38]3[CH2:39][CH2:40][N:35]([C:41]4[CH:51]=[CH:50][C:44]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:43][N:42]=4)[CH2:36][CH2:37]3)[CH:12]=[N:11][C:10]=2[N:9]2[CH2:13][CH2:14][CH2:15][CH2:16][C@@H:8]12
Reactant: CCOC(=O)c1ccc(N2CCNCC2)nc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 88.9 %

Procedure:
(S)-3-(hydroxymethyl)-7,8,9,10-tetrahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-6(6aH)-one (330 mg, 1.415 mmol) was suspended in propionitrile (3.5 mL) and (cyanomethyl)trimethylphosphonium iodide (413.0 mg, 1.70 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (741 ul, 4.2 mmol). To the stirred mixture was then added ethyl 6-(piperazin-1-yl)nicotinate (366 mg, 1.56 mmol). The reaction was heated to 90° C. with stirring for 16 h. The reaction was then cooled to room temperature, diluted with EtOH (8 ml) and water (1 mL), then filtered. The precipitate was filtered off and dried in vacuum to afford the title compound (567 mg, 89%) as a brown solid. 1H NMR (DMSO-d6) δ (ppm): 10.48 (s, 1H), 8.63 (d, J=2.0 Hz, 1H), 7.93 (dd, J=9.1, 2.3 Hz, 1H), 7.65 (d, J=1.8 Hz, 1H), 6.97 (d, J=2.0 Hz, 1H), 6.85 (d, J=9.1 Hz, 1H), 4.44-4.56 (m, 1H), 4.24 (q, J=7.1 Hz, 2H), 3.84 (dd, J=11.4, 2.8 Hz, 1H), 3.53-3.73 (m, 4H), 3.35 (s, 2H), 2.60 (td, J=12.6, 2.5 Hz, 1H), 2.41 (t, J=4.8 Hz, 4H), 2.05 (br. s., 1H), 1.85 (d, J=12.4 Hz, 1H), 1.64 (d, J=12.4 Hz, 1H), 1.34-1.57 (m, 3H), 1.28 (t, 3H) [M+H] calc'd for C24H30N6O3, 451; found, 451.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C@H:6]1[C:11](=[O:12])[NH:10][C:9]2[CH:13]=[C:14]([CH2:17][C@H:18]([NH:24][C:25]([O:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:15]=[CH:16][C:8]=2[O:7]1)(O)=[O:2].[NH2:33][C:34]1[NH:35][CH:36]=[CH:37][N:38]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:32][C:29]([CH3:30])([CH3:31])[CH2:28][O:27][C:25]([NH:24][C@@H:18]([CH2:17][C:14]1[CH:15]=[CH:16][C:8]2[O:7][C@@H:6]([CH2:5][CH2:4][C:1](=[O:2])[NH:33][C:34]3[NH:35][CH:36]=[CH:37][N:38]=3)[C:11](=[O:12])[NH:10][C:9]=2[CH:13]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:26]
Reactant: CCOC(=O)[C@H](Cc1ccc2c(c1)NC(=O)[C@H](CCC(=O)O)O2)NC(=O)OCC(C)(C)C
Reactant: Nc1ncc[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](Cc1ccc2c(c1)NC(=O)[C@H](CCC(=O)Nc1ncc[nH]1)O2)NC(=O)OCC(C)(C)C

Procedure:
3.2 g of 14 are reacted with 1.88 g of 2-aminoimidazole, 2.96 g of TBTU, 0.29 g of HOBt and 2.95 g of potassium carbonate in 40 ml of DMF analogously to the preparation of 5. Conventional work-up gives 15.
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH:10][C:11]([NH:13][C:14]1[N:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[N:15]=1)=[S:12])(=[O:9])=[O:8].[Na].[CH3:29]I.O>C(#N)C.C(O)C>[C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH:10][C:11](=[N:13][C:14]1[N:15]=[C:16]([CH3:21])[CH:17]=[C:18]([CH3:20])[N:19]=1)[S:12][CH3:29])(=[O:9])=[O:8]
Reactant: CI
Reactant: Cc1cc(C)nc(NC(=S)NS(=O)(=O)c2ccccc2-c2ccccc2)n1
Agent: [Na]
Solvent: CC#N
Solvent: CCO
Solvent: O
Product: CSC(=Nc1nc(C)cc(C)n1)NS(=O)(=O)c1ccccc1-c1ccccc1
Yield: 38.8 %

Procedure:
3.98 g of 1-(2-biphenylylsulfonyl)3-(4,6-dimethylpyrimidin-2-yl)thiourea was suspended in 50 ml of dry acetonitrile, and a solution of 0.3 g of metallic sodium in 10 ml of ethanol was added, and the mixture was heated under reflux for 30 minutes. After cooling, 1.85 g of methyl iodide was added, and the mixture was heated under reflux for 5 hours. The reaction mixture was cooled, and then poured into 100 ml of water. The product was extracted with methylene chloride. Methylene chloride was evaporated under reduced pressure, and the residue was recrystallized from ethanol to give 1.6 g of the desired 1-(2-biphenylylsulfonyl)3-(4,6-dimethylpyrimidin-2-yl)2-methylisothiourea (compound No. II-1) which was the same as obtained in Example 1. mp. 154°-157° C.
Reaction SMILES: [H-].[Na+].[CH:3]([C@@H:6]1[C:11](=[O:12])[NH:10][CH2:9][CH2:8][N:7]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:5])[CH3:4].[F:20][C:21]1[CH:30]=[C:29](F)[C:28]([N+:32]([O-:34])=[O:33])=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24]>CN(C=O)C>[F:20][C:21]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:27][C:28]([N+:32]([O-:34])=[O:33])=[C:29]([N:10]2[CH2:9][CH2:8][N:7]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[C@H:6]([CH:3]([CH3:5])[CH3:4])[C:11]2=[O:12])[CH:30]=1
Reactant: CC(C)[C@@H]1C(=O)NCCN1C(=O)OC(C)(C)C
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])c(N2CCN(C(=O)OC(C)(C)C)[C@H](C(C)C)C2=O)cc1F
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
Under N2 atmosphere, NaH (8.8 g, 0.22 mol, 60% in mineral oil, 1.1 eq.) was added in portions at −10° C. to a 1 L three-neck flask containing (R)-tert-butyl 2-isopropyl-3-oxopiperazine-1-carboxylate (26.66 g, 0.11 mol) in DMF (300 mL). The mixture was stirred at −10° C. for 30 min. Then the mixture was added dropwise to a 1 L three-neck flask containing methyl 2,4-difluoro-5-nitrobenzoate (26.3 g, 0.121 mol, 1.1 eq.) in DMF (200 mL) at −20° C. over 10 min After addition, the resulting mixture was stirred between −20° C. and −30° C. for another 10 min. The reaction was quenched with sat. aq. NH4Cl (200 mL) and then water (800 mL). The aqueous layer was extracted with EtOAc (3×1 L). The combined organic layers were washed with water (3×1 L) and brine, and dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was evaporated under vacuum. The residue was purified by column chromatography on silica gel eluting with petroleum ether: EtOAc 8:1˜4:1 to give (R)-tert-butyl 4-(5-fluoro-4-(methoxycarbonyl)-2-nitrophenyl)-2-isopropyl-3-oxopiperazine-1-carboxylate (32 g, 66.3% yield) as a yellow solid. LC-MS MS (ESI) m/z 384.1 [M−56+H]+, 462.1 [M+Na]+. 1H NMR (CDCl3 300 MHz): δ 8.63 (d, J=6.9 Hz, 1H), 7.16 (d, J=10.2 Hz, 1H), 4.61-4.30 (m, 2H), 3.97-3.89 (m, 4H), 3.62-3.48 (m, 2H), 2.40-2.34 (m, 1H), 1.49 (s, 9H), 1.08 (d, J=6.9 Hz, 3H), 1.01 (d, J=6.9 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]2[NH:6][C:7]([SH:9])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].[N+]([C:18]1[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=1)([O-])=O>O1CCCC1>[Cl:12][C:11]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([S:9][C:18]3[O:22][C:21]([CH:23]=[O:24])=[CH:20][CH:19]=3)=[N:6][C:5]=2[CH:10]=1
Reactant: Sc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(Sc2nc3cc(Cl)c(Cl)cc3[nH]2)o1
Temperature: 25 °C
Yield: 65.1 %

Procedure:
5,6-Dichloro-1H-benzimidazole-2-thiol (1.0 g, 4.56 mmol) is suspended into 50 mL of tetrahydrofuran under argon. Then, 0.33 g (6.85 mmol) of sodium hydride is added. The reaction mixture is stirred at room temperature until gas evolution has ceased. 5-Nitro-2-furaldehyde (0.64 g, 4.57 mmol) is then added and the reaction mixture is stirred at room temperature for 1 h, upon which it is poured on ice and extracted 3 times with ethyl acetate. The organic extracts are combined, washed with brine, dried on magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a prepacked 200 g 15-40 μm silica gel cartridge (eluting solvent: ethyl acetate/cyclohexane 50/50 v/v; rate: 50 mL/min). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. The residue is triturated in diisopropyl ether, filtered and dried under reduced pressure. 0.93 g of 5-(5,6-dichloro-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde is obtained as a yellow powder. mp: 170° C.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][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][CH2:17][CH3:18].C([O-])(=O)C.[Zn+2:25].C([O-])(=O)C.[OH-].[Mg+2].[OH-]>>[C:1]([O-:20])(=[O:19])[CH2:2][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][CH2:17][CH3:18].[Zn+2:25].[C:1]([O-:20])(=[O:19])[CH2:2][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][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CC(=O)[O-]
Agent: [Mg+2]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]

Procedure:
32.5 grams of a formulated Sulfo-EPT composition, 17.5 grams of HDPE, and 8.1 grams of stearic acid were blended in a Brabender mixing head for 13 minutes at 160° C and 50 rpm. This blend was placed in a rubber mill and 2.6 grams of zinc acetate were added over a one minute time period while milling at 160° C. After the zinc acetate was completely added, the total blend was milled for an additional 31/2 minutes at 160° C. The Sulfo-EPT composition used in this experiment contained 30 milliequivalents of acid groups, and had been neutralized with 3 equivalents of magnesium hydroxide prior to blending. The amount of zinc acetate and stearic acid was sufficient to yield 3 equivalents of the preferential plasticizer zinc stearate.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]#[CH:5].C[O:7][C:8]([C:10]1[C:15]([Cl:16])=[CH:14][C:13](Br)=[CH:12][N:11]=1)=[O:9].O>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:16][C:15]1[C:10]([C:8]([OH:9])=[O:7])=[N:11][CH:12]=[C:13]([C:5]#[C:4][CH2:3][O:2][CH3:1])[CH:14]=1
Reactant: COC(=O)c1ncc(Br)cc1Cl
Reactant: C#CCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: C1CCOC1
Product: COCC#Cc1cnc(C(=O)O)c(Cl)c1
Temperature: 80 °C

Procedure:
To a solution of 3-methoxy-propyne (421 mg, 6 mmol), bis(triphenylphosphine)palladium(II) chloride (84 mg, 0.12 mmol), copper(I) iodide (23 mg, 0.12 mmol) and N Eta (1.17 ml, 8.4 mmol) in THF (10 ml) under Argon was added 3-chloro-5-bromo-pyridine-2-carboxylic acid methyl ester (284 mg, 1.2 mmol) and the mixture was heated to 80° C. for 5 h. At 0° C. water (12 ml) was added and the mixture was extracted with EtOAc. The aq. Phase was acidified to pH 1 by addition of 1N HCl, extracted with DCM. The combined DCM extracts were washed with half-saturated aq. sodium chloride, dried with Na2SO4 and evaporated to provide the title compound as an off-white solid, which was used for coupling reactions without further purification.
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([SH:18])=[N:16][N:17]=3)[N:14]=2)[CH:6]=[N:5]1.Br[C:20]1[C:21]([N+:30]([O-:32])=[O:31])=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[CH:25][CH:24]=[CH:23]2>C(O)C.CO.ClCCl>[CH3:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([S:18][C:20]4[C:21]([N+:30]([O-:32])=[O:31])=[C:22]5[C:27](=[CH:28][CH:29]=4)[N:26]=[CH:25][CH:24]=[CH:23]5)=[N:16][N:17]=3)[N:14]=2)[CH:6]=[N:5]1
Reactant: Cn1cc(-c2ccc3nnc(S)n3n2)cn1
Reactant: O=[N+]([O-])c1c(Br)ccc2ncccc12
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: Cn1cc(-c2ccc3nnc(Sc4ccc5ncccc5c4[N+](=O)[O-])n3n2)cn1
Temperature: 70 °C
Reaction time: 4 h
Yield: 75.8 %

Procedure:
A solution of KOH (146 mg, 2.6 mmol) in ethanol (10 mL) was degassed by bubbling in nitrogen for 15 min. To the solution was added 6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol (500 mg, 2.15 mmol) and 6-bromo-5-nitro-quinoline (600 mg, 2.36 mmol). The reaction mixture was stirred at 70° C. for 4 h, then cooled to room temperature, diluted with 10% methanol/dichloromethane and adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-7% methanol/dichloromethane afforded 659 mg of 6-[6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl]-5-nitro-quinoline as a dark yellow solid (76% yield).
Reaction SMILES: C[O:2]C(=O)NC(C(N1CCCC1C1NC(C2C=CC3C4C(=C5C=CC(C6NC(C7CCCN7C(=O)C(NC(OC)=O)C(C)C)=NC=6)=CC5=CC=4)OCC=3C=2)=CN=1)=O)C(C)C.[F:61][C:62]([F:94])([F:93])[S:63]([O:66][C:67]1C=C[C:70]2[C:71]([CH:92]=1)=[CH:72]C=[C:74]1[C:79]=2[O:78][CH2:77][C:76]2[CH:80]=[C:81]([O:84][S:85]([C:88]([F:91])([F:90])[F:89])(=[O:87])=[O:86])[CH:82]=[CH:83][C:75]1=2)(=[O:65])=[O:64]>>[F:94][C:62]([F:93])([F:61])[S:63]([O:66][C:67]1[CH:74]=[C:79]2[O:78][CH2:77][C:76]3[C:75]4[C:70]2=[C:71]([CH2:72][O:2][C:83]=4[CH:82]=[C:81]([O:84][S:85]([C:88]([F:90])([F:91])[F:89])(=[O:86])=[O:87])[CH:80]=3)[CH:92]=1)(=[O:65])=[O:64]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3c(c2)COc2c-3ccc3cc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)ccc23)[nH]1)C(C)C
Reactant: O=S(=O)(Oc1ccc2c(c1)COc1c-2ccc2cc(OS(=O)(=O)C(F)(F)F)ccc12)C(F)(F)F
Product: O=S(=O)(Oc1cc2c3c(c1)OCc1cc(OS(=O)(=O)C(F)(F)F)cc(c1-3)OC2)C(F)(F)F

Procedure:
(1-{2-{[5-(7-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-5,10-dihydro-chromeno [5,4,3-cde]chromen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: Title compound was prepared according to the method employed to prepare (1-{2-[5-(2-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-6-H-dibenzo[c,h]chromen-8-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester, substituting trifluoro-methanesulfonic acid 7-trifluoromethane sulfonyloxy-5,10-dihydro-chromeno[5,4,3-cde]chromen-2-yl ester for trifluoro-methanesulfonic acid 2-trifluoromethanesulfonyloxy-6-H-dibenzo[c,h]chromen-8-yl ester.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([C:19]1[N:23]3[CH:24]=[CH:25][C:26]([O:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:27][C:22]3=[N:21][CH:20]=1)[CH:15]=[CH:14]2)C1C=CC=CC=1.C([O-])=O.[NH4+].C(O)=O>CO.[OH-].[OH-].[Pd+2]>[CH3:32][O:31][CH2:30][CH2:29][O:28][C:26]1[CH:25]=[CH:24][N:23]2[C:19]([C:16]3[CH:15]=[CH:14][C:13]4[C:18](=[C:9]([OH:8])[CH:10]=[CH:11][CH:12]=4)[N:17]=3)=[CH:20][N:21]=[C:22]2[CH:27]=1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(OCc5ccccc5)c4n3)cnc2c1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O=CO
Product: COCCOc1ccn2c(-c3ccc4cccc(O)c4n3)cnc2c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
8-(Benzyloxy)-2-(7-(2-methoxyethoxy)-imidazo[1,2-a]pyridin-3-yl)quinoline (5.0 g, 11.75 mmol) was slurried in MeOH (117.5 ml). Ammonium formate (7.410 g, 117.5 mmol) and Pd(OH)2/C (0.8252 g, 0.5876 mmol) were added. The reaction mixture was heated to reflux for 2 hours, then cooled to 20° C. Formic acid was added to the slurry until solids went into solution. The mixture was filtered and the filter paper was washed with 10% formic acid in methanol. The filtrate was concentrated to an oil. To the oil was added an excess of NH3 in methanol and resulting the solids were concentrated to dryness. Water was added to the solids and the slurry was stirred for 1 hour (pH was 6.5-7.0 by pH paper). The solids were collected by filtration and then taken up in toluene and concentrated to dryness under vacuum dry for 12 hours to obtain 3.8 g (96% yield) of the desired product.
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[CH:11][N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[CH:17][CH:16]=3)[CH:13]=[C:9]2[C:8](=[O:27])[N:7]([CH3:28])[C:6]1=[O:29])[CH:2]([CH3:4])[CH3:3].Cl[N:31]1[C:35](=[O:36])[CH2:34][CH2:33][C:32]1=[O:37]>C(Cl)(Cl)(Cl)Cl.CN(C=O)C>[O:37]=[C:32]1[CH2:33][CH2:34][C:35](=[O:36])[N:31]1[C:11]1[N:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:13]=[C:9]2[C:8](=[O:27])[N:7]([CH3:28])[C:6](=[O:29])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:10]=12
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3ccc(-c4ccccn4)cc3)cc21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3ccc(-c4ccccn4)cc3)c(N3C(=O)CCC3=O)c21
Temperature: 100 °C
Yield: 17.2 %

Procedure:
1-isobutyl-3-methyl-6-(4-(pyridin-2-yl)benzyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (186 mg, 0.48 mmol) is dissolved in a mixture of CCl4 and DMF (3/1, v/v), and then N-chlorosuccinimide (67 mg, 0.51 mmol) is added. The reaction mixture is heated in a Biotage microwave at 100° C. for 30 min. Solvents are removed under vacuum, and the residue is purified by a semi-preparative HPLC to give pure product as white solids (40 mg, yield 20%). MS (ESI) m/z 486.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH:29]=O)=[N:21]1.N1CCCCC1>CO>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](/[CH:29]=[C:8]2\[O:9][C:5]3[C:4]([CH2:13][N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:21]1
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: COc1ccc2c(c1CN1CCOCC1)OCC2=O
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1CN1CCOCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 12.2 %

Procedure:
A solution of 6-methoxy-7-(morpholinomethyl)benzofuran-3(2H)-one (0.131 g, 0.500 mmol) in methanol (2 mL) was added with 1H-indazole-3-carboxaldehyde (0.0877 g, 0.600 mmol) and piperidine (0.00425 g, 0.0500 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was subjected to silica gel column chromatography (chloroform/methanol), and the resulting crude product was crystallized from ethyl acetate. The precipitated solid was collected by filtration, and then suspended in acetonitrile and thereby washed to obtain the objective (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-(morpholinomethyl)benzofuran-3(2H)-one (0.0238 g). Further, the filtrate was concentrated, and the resulting residue was purified again by silica gel column chromatography (chloroform/methanol) to obtain the objective (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-(morpholinomethyl)benzofuran-3(2H)-one (0.0254 g) (0.0492 g, 25% in total).