Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:14][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[Br:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc2nc(Br)sc2c1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(Br)sc2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-Bromo-6-benzothiazolecarboxylic acid (0.500 g, 1.94 mmol) was suspended in dichloromethane/methanol (12 ml, 6:1) and cooled to 0° C. with an ice-water bath. Then, 2M (trimethylsilyl)diazomethane (2.91 ml, 5.81 mmol) was added dropwise over 5 min. The resulting mixture was warmed to room temperature and stirred at room temperature for 2 hrs. The resulting mixture was concentrated in vacuo to yield methyl 2-bromobenzo[d]thiazole-6-carboxylate.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([C:20](=[O:41])[N:21]([CH3:40])[C@@H:22]([C:34]1[O:38][N:37]=[C:36]([CH3:39])[N:35]=1)[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)[CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:7][C@H:8]([CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)[C:20]([N:21]([CH3:40])[C@@H:22]([C:34]1[O:38][N:37]=[C:36]([CH3:39])[N:35]=1)[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)=[O:41]
Reactant: Cc1noc([C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)[C@@H](Cc2ccc3ccccc3c2)NC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1noc([C@@H](Cc2ccc3ccccc3c2)N(C)C(=O)[C@H](N)Cc2ccc3ccccc3c2)n1
Yield: 61 %

Procedure:
{(1R)-1-{N-Methyl-N-[(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)ethyl]carbamoyl}-2-(2-naphthyl)ethyl}carbamic acid tertbutyl ester (2.4 g, 4.2 mmol) was dissolved in a mixture of trifluoroacetic acid (40 ml) and dichioromethane (40 ml) at 20° C. After 10 min the reaction mixture was concentrated in vacuo and coevaporated from dichioromethane (80 ml). The residue was crystallised from ethyl acetate to give 1.19 g of (2R)-2-amino-N-methyl-N-[(1R)-1-(3-methyl-[1,2,4]oxadiazol-5-yl)-2-(2-naphthyl)-ethyl]-3-(2-naphthyl)propionamide, trifluoroacetic acid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[NH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C(N(CC)CC)C>CC(O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[N:3]=1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Reactant: NCCc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)n1cnc2c(NCCc3ccc(O)cc3)nc(Cl)nc21
Reaction time: 4 h

Procedure:
2,6-dichloro-9-isopropyl-9H-purine (500 g) was added in portions to a stirred mixture of tyramine (593 g), triethylamine (262 g), and i-PrOH (5.0 L) at 50° C. The mixture was stirred at that temperature for 4 hr, then the reaction mixture was concentrated. The residue was taken up in isopropyl acetate (6.0 L) and was washed with 20% citric acid solution (2.0 L) and water (2.0 L). The organic layer was concentrated to dryness, then was taken up in ethanol (2.0 L) and again concentrated to dryness. The crude solid was crystallized from ethanol (3.2 L) to provide the title compound as a solid.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[C:17](=[O:18])[C:16]3[C:11]4=[C:12]([C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=5[N:10]4[CH:9]=2)[CH:13]=[CH:14][N:15]=3)[CH:2]=1.[CH:25](=O)C1C=CC=CC=1>>[CH2:7]([C:8]1[C:17](=[O:18])[C:16]2[C:11]3=[C:12]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=4[N:10]3[CH:9]=1)[CH:13]=[CH:14][N:15]=2)[C:3]1[CH:2]=[CH:25][CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1ccccc1
Reactant: O=c1c(Cc2cccnc2)cn2c3ccccc3c3ccnc1c32
Product: O=c1c(Cc2ccccc2)cn2c3ccccc3c3ccnc1c32
Yield: 58.2 %

Procedure:
According to Example 1<step 4>, the compound (200 mg) produced in Example 26<step 2> was reacted with benzaldehyde (153 mg) to obtain the title compound (116 mg; 42%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11](O)[CH2:10][C@@H:9]1[CH3:19])=[O:7].[Cl:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH2:31][CH2:30][CH2:29]2>>[Cl:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[N:32]([CH:11]1[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([C:6](=[O:7])[C:5]3[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]([CH3:19])[CH2:10]1)[CH2:31][CH2:30][CH2:29]2
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](O)C[C@@H]2C)cc1OC
Reactant: Clc1ccc2c(c1)CCCN2
Product: COc1ccc(C(=O)N2c3ccccc3C(N3CCCc4cc(Cl)ccc43)CC2C)cc1OC
Yield: 37.1 %

Procedure:
Starting with cis-1-(3,4-dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (400 mg, 1.22 mmol) prepared in Reference Example 1 and 6-chloro-1,2,3,4-tetrahydroquinoline (614 mg, 3.66 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (216 mg, yield: 37%) as a colorless oil. (cis:trans=3.4:1)
Reaction SMILES: [CH:1]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]2[C:2]=1[CH:3]1[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH:4]1[CH2:5][O:6]2.[H-].[Na+].[CH2:21](Br)[CH:22]=[CH2:23].Cl>CN(C=O)C.O>[CH2:23]([O:11][C:9]1[CH:8]=[C:7]2[C:2]([CH:3]3[O:14][C:13]4[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=4[CH:4]3[CH2:5][O:6]2)=[CH:1][CH:10]=1)[CH:22]=[CH2:21]
Reactant: Oc1ccc2c(c1)OCC1c3ccccc3OC21
Reactant: C=CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc2c(c1)OCC1c3ccccc3OC21
Yield: 49.3 %

Procedure:
Compound 6a,11a-Dihydro-6H-benzo[4,5]furo[3,2-c]chromen-3-ol (100 mg, 0.42 mmol) was dissolved in DMF (5 ml) and NaH (10 mg, 0.42 mmol) was added to the solution at room temperature, followed by allyl bromide (0.07 ml, 0.84 mmol). The reaction mixture was stirred at room temperature to 6 hours and poured into iced water and neutralized with 10% HCl to get the white precipitate. Precipitate were washed with water and purified by silica gel column chromatography using hexane-chloroform as the eluent to give 3-(allyloxy)-6a,11a-dihydro-6H-benzofuro[3,2-c]chromene (58 mg, 50%) as white solid.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:11]2[N:12]([CH3:16])[C:13](=O)[NH:14][C:10]=2[C:9]([CH3:17])=[CH:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:13]1[N:12]([CH3:16])[C:11]2[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:7][CH:8]=[C:9]([CH3:17])[C:10]=2[N:14]=1
Reactant: CCC(CC)c1ccc(C)c2[nH]c(=O)n(C)c12
Reactant: O=P(Cl)(Cl)Cl
Product: CCC(CC)c1ccc(C)c2nc(Cl)n(C)c12
Temperature: 110 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A mixture of 7-(1-ethylpropyl)-1,4-dimethyl-1,3-dihydro-2H-benzimidazol-2-one (105 mg, 0.452 mmol) in phosphorous oxychloride (1.23 mL) was stirred at 110° C. for 3 h. The reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=10:1-1:1) and crystallized from ethyl acetate/n-hexane to afford the title compound as colorless crystals (100 mg, 88%).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[C@H:18]([CH2:19][CH2:20][C:21](=[O:25])[CH:22]=2)[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:26])[CH2:11][CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].C(Cl)(Cl)(Cl)[Cl:51]>C(#N)C.ClCCl>[Cl:51][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[C@H:18]([CH2:19][CH2:20][C:21](=[O:25])[CH:22]=2)[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:26])[CH2:11][CH2:10]1
Reactant: ClC(Cl)(Cl)Cl
Reactant: C[C@]12CC[C@H]3[C@@H]([C@H](CCCCCO)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: O=C([O-])O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CC#N
Product: C[C@]12CC[C@H]3[C@@H]([C@H](CCCCCCl)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O

Procedure:
The same product is obtained from 8.05 g of 7α-(5-hydroxypentyl)-estr-4-ene-3,17-dione (Example 1b) by a 3.5-hour reaction with 8.66 g of triphenylphosphine in 85 ml of carbon tetrachloride and 30 ml of acetonitrile at room temperature. The reaction mixture is diluted with dichloromethane, shaken out with saturated bicarbonate solution and with saturated common salt solution, dried with sodium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel with dichloromethane and ethyl acetate, whereby 4.08 g of 7α-(5-chloropentyl)-estr-4-ene-3,17-dione is obtained, [α]D22=+68° (c=0.5% in chloroform)
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[CH:14]=[C:13]([S:15]([CH3:18])(=[O:17])=[O:16])[CH:12]=[CH:11][C:10]=2[O:19][CH:20]([CH3:22])[CH3:21])=[O:8])[CH2:3]1.[N+:23]([C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)([O-:25])=[O:24]>>[CH:20]([O:19][C:10]1[CH:11]=[CH:12][C:13]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:14][C:9]=1[C:7]([N:4]1[CH2:5][CH2:6][CH:2]([O:1][C:29]2[CH:30]=[CH:31][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=2)[CH2:3]1)=[O:8])([CH3:22])[CH3:21]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(O)C1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)C1
Yield: 25 %

Procedure:
Prepared in analogy to Example 4 from rac-(3-hydroxy-pyrrolidin-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone (Example 9(a)) and 4-nitrophenol. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 25%). MS (m/e): 449.3 (M+H+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:16][CH3:17])=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=C)=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:19].[Na+].O>O1CCOCC1.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:16][CH3:17])=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=[O:19])=[CH:4][CH:3]=1
Reactant: C=CCn1c(=O)cc(OC)c2ccc(F)cc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(=O)n(CC=O)c2cc(F)ccc12
Reaction time: 5 h
Yield: 93.2 %

Procedure:
A solution of 7-fluoro-4-(methyloxy)-1-(2-propen-1-yl)-2(1H)-quinolinone (0.386 g, 1.66 mmol), sodium periodate (0.83 g, 3.7 mmol) and osmium tetroxide (1.7 ml, 4% in water) in 1,4-dioxane (15 ml) containing water (3 ml) was stirred for 5 h. The mixture was separated between dichloromethane and water. The organics were isolated, dried and concentrated to provide the title compound (0.364 g, 93%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[Mg].[C:10]([P:14](Cl)[C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])([CH3:12])[CH3:11].S(=O)(=O)(O)O>O1CCCC1.[Cu]Cl.C1(C)C=CC=CC=1>[C:10]([P:14]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1ccccc1Br
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Agent: Cl[Cu]
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccccc1P(C(C)(C)C)C(C)(C)C
Reaction time: 4 h
Yield: 91 %

Procedure:
In a 500 ml four-necked flask thoroughly purged with nitrogen, a Grignard reagent solution previously prepared from 20.5 g (0.12 mol) of 2-bromotoluene and 3.1 g (0.13 mol) of metallic magnesium in a mixed solvent of 100 ml of tetrahydrofuran and 40 ml of toluene, and 0.05 g (0.0005 mol (corresponding to 0.5% by mol)) of copper(I) chloride were placed. To the contents of the flask, a solution of 18.1 g (0.10 mol) of di-tert-butylphosphinous chloride in 30 ml of tetrahydrofuran was dropwise added over a period of 1 hour with maintaining the temperature at 25° C. to 30° C. After the dropwise addition was completed, stirring was conducted at 50° C. for 4 hours. After the temperature of the reaction solution was returned to room temperature, disappearance of di-tert-butylphosphinous chloride was confirmed by gas chromatography. Thereafter, 30 ml of a 5% sulfuric acid aqueous solution was added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, followed by further distillation. Then, fractions given by distillation at 112° C. to 114° C. under reduced pressure of 3 Torr were collected. As a result, 21.5 g (purity: 99.0%) of the aimed di-tert-butyl(2-methylphenyl)phosphine was obtained. The yield was 91.0%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]1>CN(C=O)C.CO>[NH2:16][C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[C:10](=[O:15])[CH2:9]2)=[C:2]([F:1])[CH:3]=1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1=O
Solvent: CN(C)C=O
Solvent: CO
Product: CN1CCN(c2ccc(N)cc2F)CC1=O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
3-Fluoro-4-(4-methyl-3-oxopiperazin-1-yl)nitrobenzene (3.33 g) was dissolved in a mixture of DMF (40 ml) and methanol (10 ml), and the solution flushed with argon. Ammonium formate (4.15 g) was added, and the mixture cooled to 5° C. Palladium (10% on carbon, 104 mg) was added, and the temperature allowed to rise to ambient as the mixture was stirred under argon for 2 hours. Solvents were evaporated to give an air sensitive product, 5-amino-2-(4-methyl-3-oxopiperazin-1-yl)fluorobenzene, which was used as such in the next stage.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:19])OC2C=CC=CC=2)[N:7]([CH2:20][CH:21]([CH3:23])[CH3:22])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:33][O:34][C:35]1[CH:36]=[C:37]2[C:42](=[CH:43][C:44]=1[O:45][CH3:46])[N:41]=[CH:40][N:39]=[C:38]2[O:47][C:48]1[CH:49]=[C:50]([CH:52]=[CH:53][CH:54]=1)[NH2:51]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:51][C:50]2[CH:52]=[CH:53][CH:54]=[C:48]([O:47][C:38]3[C:37]4[C:42](=[CH:43][C:44]([O:45][CH3:46])=[C:35]([O:34][CH3:33])[CH:36]=4)[N:41]=[CH:40][N:39]=3)[CH:49]=2)=[O:19])[N:7]([CH2:20][CH:21]([CH3:22])[CH3:23])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)Cn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4CC(C)C)c3)c2cc1OC
Temperature: 25 °C
Yield: 37.3 %

Procedure:
A stirred solution of phenyl 3-tert-butyl-1-isobutyl-1H-pyrazol-5-ylcarbamate (150 mg, 0.47 mmol), N,N-Diisopropylethylamine (80 mg, 0.62 mmol) and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described in Example 113A) (92 mg, 0.31 mmol) in THF (1.0 mL) was heated at 60° C. for 15 h. After cooling to rt, the reaction solution was partitioned between dichloromethane and a saturated aqueous solution of sodium carbonate. The organic phase was separated and concentrated under reduced pressure. The crude product was purified via silica gel column chromatography (eluting with a gradient of 40:1 to 20:1 dichloromethane: methanol) then reverse-phase preparative HPLC to afford 1-(3-tert-butyl-1-isobutyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (60 mg, 38%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ9.09 (s, 1H), 8.57 (s, 1H), 8.49 (s, 1H), 7.61 (m, 1H), 7.57 (m, 1H), 7.37-7.41 (m, 2H), 7.24 (m, 1H), 6.94 (m, 1H), 6.01 (s, 1H), 4.00 (s, 3H), 3.99 (s, 3H), 3.71 (d, J=7.6 Hz, 2H), 2.07 (m, 1H), 1.20 (s, 9H), 0.83 (d, J=6.4 Hz, 6H); LC-MS (ESI) m/z 519 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[CH:21]1(CO)C[CH2:22]1>C[O-].[Na+].C1C=CC=CC=1>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21]3)=[O:14])=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCC1CC1
Reactant: CCOC(=O)c1ccc(OCc2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: O=C(OCC1CC1)c1ccc(OCc2ccccc2)cc1
Reaction time: 4 h
Yield: 100 %

Procedure:
A mixture of 12.8 parts of ethyl 4-(phenylmethoxy)benzoate, 180 parts of benzene and 5 drops of a sodium methoxide solution 30% was stirred and refluxed using a water separator. 10.8 Parts of cyclopropanemethanol in 90 parts of benzene was added dropwise during a period of 1 hour. Upon complete addition, stirring was continued for 4 hours at reflux. After cooling, the whole was washed with water, the organic layer was dried, filtered and evaporated, yielding 14 parts (100%) of (cyclopropylmethyl) 4-(phenylmethoxy)benzoate as a residue (int. 3).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2(O)[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)(O)[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I.[PH2](O)=O>C(O)(=O)C>[C:46]1([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:26]2[C:27]3[C:32]([C:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[C:20]4[C:25]=2[CH:24]=[CH:23][CH:22]=[CH:21]4)=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: OC1(c2ccccc2-c2ccccc2-c2ccccc2)c2ccccc2C(O)(c2ccccc2-c2ccccc2-c2ccccc2)c2ccccc21
Agent: I
Agent: O=[PH2]O
Solvent: CC(=O)O
Product: c1ccc(-c2ccccc2-c2ccccc2-c2c3ccccc3c(-c3ccccc3-c3ccccc3-c3ccccc3)c3ccccc23)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 87.9 %

Procedure:
9,10-bis(2-(2-Phenylphenyl)phenyl)-9,10-dihydroxy-9,10-dihydro-anthracene (2.9 g, 4.3 mmole) was suspended in acetic acid (45 ml). To the resultant suspension, a 57% hydroiodic acid (6 ml, 45 mmole, 10 eq) was added and the obtained mixture was stirred at 100° C. for 6 hours. To the reaction mixture, a 50% aqueous solution of hypophosphorous acid (30 ml) was added. The formed solid was separated by filtration and washed with water, methanol and acetone and a light yellow solid (2.4 g, 88%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH2:15])[CH2:10]2)[CH:5]=[C:4]([I:16])[CH:3]=1.C(N(CC)CC)C.[O:24]=[C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=[O:34])[N:26]1[CH2:35][CH2:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][S:37]([CH2:36][CH2:35][N:26]3[C:25](=[O:24])[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:27]3=[O:34])(=[O:38])=[O:39])[CH2:10]2)[CH:5]=[C:4]([I:16])[CH:3]=1
Reactant: NC1CCCC(Nc2cc(I)cc(Cl)n2)C1
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)NC1CCCC(Nc2cc(I)cc(Cl)n2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 145a (280 mg, 0.8 mmol) in CH2Cl2 (10 mL) was added triethylamine (110 mg, 1 mmol) and followed by 2-(1,3-dioxoisoindolin-2-yl)ethanesulfonyl chloride (262 mg, 0.95 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by flash chromophatography (EtOAc/hexanes=1:4) to give the title compound. Yield: 180 mg (32%). MS (DCI/NH3) m/z 589 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([O:35][CH3:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([O:35][CH3:36])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: COc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1c[nH]c3ncccc13)C2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(c1CN1CCNCC1)O/C(=C\c1c[nH]c3ncccc13)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0645 g, 0.131 mmol) in methylene chloride (1 mL) was added with trifluoroacetic acid (1 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and then added with saturated aqueous sodium hydrogencarbonate (6 mL), and the mixture was extracted five times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated to obtain the objective (Z)-2-[(1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-methoxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0500 g, 97%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12](O)=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:21])=O.CN(C)C=O>ClCCl.C(=O)(O)[O-].[Na+]>[C:1]1([S:7]([N:10]2[CH2:17][CH2:16][CH2:15][CH:11]2[C:12]([Cl:21])=[O:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1CCCN1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.9 %

Procedure:
To a solution of the N-phenylsulfonyl proline (1.5 g, 5.8 mmol) in anhydrous dichloromethane (20 mL), were added oxalyl chloride (2.0 M in dichloromethane, 5.9 mL, 11.8 mmol) and a catalytic amount of dimethylformamide. The solution was stirred for 1 hour at room temperature. The reaction mixture was then condensed and diluted with a saturated aqueous solution of sodium bicarbonate (10 mL) and extracted with dichloromethane (20 ml). The organic layers were dried over magnesium sulfate (MgSO4) and filtered and concentrated under reduced pressure to yield 1-benzenesulfonyl-pyrrolidine-2-carbonyl chloride (220 mg) as a yellow solid used without any further purification.
Reaction SMILES: C(OC1N=NC(C#CC2C=CC(C(F)(F)F)=CN=2)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[CH:58])=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Cl:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=1I>>[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[C:58][C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=2[Cl:59])=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: Clc1ccccc1I
Agent: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)nc1
Product: Clc1ccccc1C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Yield: 59 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 1-chloro-2-iodobenzene in 59% yield.