Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([OH:21])([CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[N:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][N:8]=1)[CH3:3].C(N(CC)CC)C.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH3:3][C:2]1([CH3:1])[O:21][C:30](=[O:32])[N:6]([C:7]2[CH:12]=[N:11][C:10]([C:13]#[C:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:9][N:8]=2)[CH2:5][CH2:4]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(O)CCNc1cnc(C#Cc2ccccc2)cn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)CCN(c2cnc(C#Cc3ccccc3)cn2)C(=O)O1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
A solution of 2-methyl-4-(5-(phenylethynyl)pyrazin-2-ylamino)butan-2-ol (Example 168, step 2) (84 mg, 0.30 mmol) and triethylamine (91 mg, 125 μl, 0.90 mmol, 3 equiv.) in 2 ml of THF was cooled to 0-5° C. and triphosgene (89 mg, 0.30 mmol, 1 equiv.) was added in portions. The mixture was stirred for 1 hr at 0-5° C. and for 2 hours at room temperature. The reaction mixture was quenched with saturated sodium carbonate solution followed by workup with ethyl acetate/water. The organic layers were combined, dried and concentrated. The crude product was chromatographed over a prepacked 20 g Silica column eluting with a heptane to 50% ethyl acetate in heptane gradient to yield the title compound (66.1 mg, 72% yield) as an off-white solid, MS: m/e=308.3 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:24]1[C:28]2([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:27][C:26](=[O:34])[NH:25]1>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:25]3[C:26](=[O:34])[CH2:27][C:28]4([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[CH2:24]3)=[CH:3][CH:4]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Reactant: O=C1CC2(CCCCC2)CN1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC5(CCCCC5)CC4=O)cc3)CC2)c(C)c1
Yield: 14.7 %

Procedure:
Using (4-bromophenyl) [4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (747 mg) described in Preparation Example 170 and 2-azaspiro[4.5]decan-3-one (306 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (131 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][N:23]=[C:22]4[SH:26])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[OH-].[Na+].S(OC)(O[CH3:33])(=O)=O>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[N:24][N:23]=[C:22]4[S:26][CH3:33])=[CH:17][CH:16]=3)[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCN(c3ccc(-n4cnnc4S)cc3)CC2)cc1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(N2CCN(c3ccc(-n4cnnc4SC)cc3)CC2)cc1
Reaction time: 3 h

Procedure:
A mixture of 9 parts of 4-{4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl}-4H-1,2,4-triazole-3-thiol, 2 parts of sodium hydroxide and 160 parts of methanol is stirred and warmed till all solid enters solution. Then there are added 3.3 parts of dimethyl sulfate and stirring is continued for 3 hours at room temperature. The reaction mixture is poured onto water. The precipitated product is filtered off and crystallized from 1-butanol, yielding 5.3 parts of 1-(4-methoxyphenyl)-4-{4-[3-(methylthio)-4H-1,2,4-triazol-4-yl]phenyl}piperazine; mp. 180° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[CH3:11][Mg]Br.[NH4+].[Cl-]>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([OH:10])([CH3:11])[CH3:9]
Reactant: CC(=O)c1ccccc1C
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(C)(C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
Under the protection by nitrogen, ortho-methylphenylethanone (134 g, 1.0 mol) is dissolved in 1000 ml of tetrahydrofuran and then cooled to −5° C., into which 2 M methylmagnesium bromide in tetrahydrofuran (550 ml) is slowly added dropwise at below 0° C. After the addition, the reactant solution is stirred at room temperature for 3 hours under the detection of TLC. When the reaction is complete, 200 ml of saturated NH4Cl solution is slowly added dropwise into the reactant solution and stirred until no bubbling from the solution. The resulted solution is then extracted by dichloromethane (500 ml×3), the extracts are combined, dried by anhydrous sodium sulfate, absorbed by activated carbon, filtered, and then the solvent is distilled out using rotary evaporator to obtain 132 g of 2-ortho-methylphenyl-2-propanol as a light yellow sticky liquid, with a yield of 88%.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5].I[C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[C:11](=[O:17])[NH:12]2>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.CN(C=O)C.CCN(CC)CC>[OH:6][CH:3]([CH2:4][CH3:5])[C:2]#[C:1][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1/[C:10](=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[C:11](=[O:17])[NH:12]2
Reactant: C#CC(O)CC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, 1-pentyn-3-ol (40 mg, 0.48 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (146 mg, 0.4 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and Cul (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h to yield rac-(Z)-1,3-dihydro-4-(3-hydroxy-1-pentynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 78 mg, 60%).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:9]=[N:10][C:11]([S:14][CH3:15])=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1.Cl[CH2:24][C:25]1[CH:34]=[C:33]([O:35][CH3:36])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]=1[O:37][CH3:38]>>[CH3:38][O:37][C:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]([O:35][CH3:36])=[CH:34][C:25]=1[CH2:24][O:1][CH:2]1[CH:7]([C:8]2[CH:9]=[N:10][C:11]([S:14][CH3:15])=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1
Reactant: COc1cc(CCl)c(OC)c2ccccc12
Reactant: CSc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cn1
Product: COc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(SC)nc2)c(OC)c2ccccc12

Procedure:
In an analogous manner to that described in Example 125 (g), from tert-butyl (3'RS,4'RS)-3'-hydroxy-6-methylsulphanyl-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridine-1'-carboxylate by alkylation with 2-chloromethyl-1,4-dimethoxy-naphthalene [J. Amer. Chem. Soc. 64, 2657 (1942)] there was obtained tert-butyl (3'RS,4'RS)-3'-(1,4-dimethoxy-naphthalen-2-ylmethoxy)-6-methylsulphanyl-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridine-1'-carboxylate in the form of a colourless solid; MS: 526 (M+H)+.
Reaction SMILES: C([O:4][C:5](=[O:20])[C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=1[O:16][CH2:17][CH2:18][CH3:19])CC>[Li+].[OH-]>[CH2:17]([O:16][C:7]1[CH:8]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:10]=[CH:11][C:6]=1[C:5]([OH:20])=[O:4])[CH2:18][CH3:19]
Reactant: CCCOC(=O)c1ccc(C(F)(F)F)cc1OCCC
Agent: [Li+]
Agent: [OH-]
Product: CCCOc1cc(C(F)(F)F)ccc1C(=O)O

Procedure:
2-Propoxy-4-trifluoromethyl-benzoic acid propyl ester (957 mg, 3.44 mmol) was reacted with 1N LiOH (10 ml) at room temperature for 4 hrs. The reaction solvent was removed in vacuo. Water (30 ml) was added to the resulting residue, which was neutralized with 1 N aqueous HCl solution. The aqueous mixture was extracted with ethylacetate (30 ml×3). A combined organic layer was dried over MgSO4, and concentrated in vacuo to yield quantitatively title compound.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:29])([CH3:28])[O:6][CH:7]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:8]1=O)([CH3:4])[CH3:3].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]([Si:5]([CH3:29])([CH3:28])[O:6][CH:7]1[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:8]1=[S:39])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(S(=O)(=O)c2ccc(N3CCCCC3)cc2)C1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OC1CCN(S(=O)(=O)c2ccc(N3CCCCC3)cc2)C1=S
Yield: 133.1 %

Procedure:
A mixture of 2.7 g of the product obtained in Stage A above with 1.55 g of Lawesson reagent in 25 cm3 of toluene is taken to reflux for 3 hours 15 minutes. After cooling, the solvent is eliminated and the residue is chromatographed on silica (eluant: ethyl acetate - n-hexane (3-7)). 2.32 g of the desired product is obtained. M.p.=152.5-153° C. after dissolution in ethyl acetate and precipitation with hexane.
Reaction SMILES: [CH2:1]([OH:6])[C:2]#[C:3][CH2:4][OH:5].[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1>CCOCC>[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:5][CH2:4][C:3]#[C:2][CH2:1][OH:6]
Reactant: C1=COCCC1
Reactant: OCC#CCO
Solvent: CCOCC
Product: OCC#CCOC1CCCCO1
Yield: 68.8 %

Procedure:
To a mixture of 5.0 g of 2-butyne-1,4-diol and 10 milligrams of p-toluenesulfonic add and 150 ml of dry ether there was added dropwise with stirring at room temperature 4.9 g of 3,4-dihydro-2H-pyran. After stirring overnight at ambient temperature the ether was evaporated and the residue was poured into 200 ml of water. The aqueous solution was extracted with hexane (2×100 ml) and then re-extracted with ether (3×100 ml). The combined ether extracts were washed with 100 ml of brine, dried over magnesium sulfate and evaporated to yield 6.8 g of 4-tetrahydropyranoxy-2-butyn-1-ol.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][CH3:13])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)[NH2:18]>CN1CCCC1=O.C(=O)([O-])O.[Na+]>[Cl:14][C:15]1[CH:16]=[C:17]([NH:18][C:2]2[C:3]3[N:10]([CH2:11][CH2:12][CH3:13])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: CCCn1ccc2ncnc(Cl)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCCn1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21
Temperature: 120 °C
Reaction time: 2 h
Yield: 57.1 %

Procedure:
To a solution of 4-chloro-5-propyl-5H-pyrrolo[3,2-d]pyrimidine (80 mg) in 1-methyl-2-pyrrolidone (0.8 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (193 mg), and the reaction mixture was stirred at 120° C. for 2 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL), and extracted with ethyl acetate (30 mL×3). The organic layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent:ethyl acetate/methanol=100/0→95/5). The object fraction was concentrated under reduced pressure. To the residue was added a mixed solvent of diisopropyl ether and chloroform. The resultant precipitate was collected by filtration and dried under reduced pressure to give the title compound (96 mg) as a pale-purple powder.
Reaction SMILES: C([O:4][CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:15](=[O:17])[CH3:16])[CH:9]=1)[CH3:7])(=O)C.C(=O)(O)[O-].[Na+]>C(O)C.O>[C:15]([C:10]1[CH:9]=[C:8]([CH:6]([CH3:7])[CH2:5][OH:4])[CH:13]=[CH:12][C:11]=1[OH:14])(=[O:17])[CH3:16]
Reactant: CC(=O)OCC(C)c1ccc(O)c(C(C)=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)c1cc(C(C)CO)ccc1O
Yield: 72 %

Procedure:
2-(3-Acetyl-4-hydroxyphenyl)propyl acetate (20.0g; 0.0847 mol) and sodium bicarbonate (25.4g; 0.31 mol) were dissolved in ethanol (200 ml) and water (150 ml), and the mixture was refluxed for 20 hours. Ethanol was removed in vacuo and the residue was extracted with ether (3 × 150 ml). The combined ether extracts were washed with water, saturated sodium bicarbonate solution, brine, and then dried over magnesium sulphate. The product, after removing solvent, was chromatographed on silica gel using ether as eluent to give a pale brown oil (15.0g; 72% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[N:4][N:3]=1.[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1>CC(C)=O.ClCCl>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([O:27][CH2:26][C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)=[N:3][N:4]=2)=[CH:14][CH:15]=1
Reactant: Clc1ccc(Nc2nnc(Cl)c3ccccc23)cc1
Reactant: OCc1ccncc1
Solvent: ClCCl
Solvent: CC(C)=O
Product: Clc1ccc(Nc2nnc(OCc3ccncc3)c3ccccc23)cc1
Yield: 87 %

Procedure:
The general procedure used for the preparation of Example 3 was used in step 1 of the preparation of Example 4 from 1-chloro-4-(4-chlorophenylamino)phthalazine and 4-pyridyl-carbinol; (87% yield). TLC (20% acetone/dichloromethane): Rf=0.26.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].[NH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>>[OH:35][C:6]1[C:5]([C:3]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:4])=[N:14][C:13]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[C:12]2[C:7]=1[CH:8]=[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:10](=[O:28])[N:11]2[CH2:21][CH:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2CC2CCOCC2)c1O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2CC2CCOCC2)c1O
Temperature: 25 °C
Yield: 19.4 %

Procedure:
A mixture of 5-hydroxy-2-oxo-3-phenyl-8-pyridin-3-yl-1-(tetrahydro-pyran-4-ylmethyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (36 mg, 0.076 mmol), β-alanine (545 mg, 6.1 mmol) and NaOMe solution (9 mL, 4.6 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 7.8 mg of the title compound as a pale brown solid. MS: (+) m/z 529.41 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH:13]=[CH:12][C:11]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[CH:10][C:9]=2[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=2.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][C:30]#[N:31]>CC(C)=O>[CH3:1][N:2]1[C:14]2[CH:13]=[CH:12][C:11]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:29][C:30]#[N:31])=[CH:19][CH:20]=3)=[CH:10][C:9]=2[C:8]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=2
Reactant: N#CCBr
Reactant: Cn1c2c(c3cc(-c4ccc(O)cc4)ccc31)CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1c2c(c3cc(-c4ccc(OCC#N)cc4)ccc31)CCCC2

Procedure:
The desired product was prepared using a procedure similar to step 5 of example 3. Thus, 4-(9-methyl-6,7,8,9-tetrahydro-5H-carbazol-3-yl)-phenol (0.194 g, 0.699 mmol) was reacted with K2CO3 (0.116 g, 0.839 mmol) and bromoacetonitrile (0.101 g, 0.839 mmol) in acetone (8 ml) to give the product (0.153 g, 0.484 mmol, 69%) as a white solid, mp 204-206° C. 1H NMR (DMSO-d6) δ 1.77-1.82 (m, 2H), 1.84-1.90 (m, 2H), 2.67 (t, J=5.8 Hz, 2H), 2.72 (t, J=5.8 Hz, 2H), 3.61 (s, 3H), 5.19 (s, 2H), 7.12 (d, J=8.7 Hz, 2H), 7.33 (dd, J=1.4, 8.4 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.59 (s, 1H), 7.65 (d, J=8.6 Hz, 2H); [ESI(+)], m/z 317 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([NH2:18])[C:14]([NH2:17])=[CH:15][CH:16]=2)[CH2:4][CH2:3]1.O.[N:20]#[C:21]Br>C(O)(=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]3[NH:17][C:21]([NH2:20])=[N:18][C:13]=3[CH:12]=2)[CH2:4][CH2:3]1
Reactant: N#CBr
Reactant: CN1CCN(CCOc2ccc(N)c(N)c2)CC1
Solvent: CC(=O)O
Solvent: O
Product: CN1CCN(CCOc2ccc3[nH]c(N)nc3c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 149.4 %

Procedure:
A 100 mL flasked was charged with 4-(2-(4-methylpiperazin-1-yl)ethoxy)benzene-1,2-diamine (4.35 mmol), water (50 mL) and acetic acid (2 mL) and stirred at room temperature for 15 minutes. The reaction mixture was placed in an ice bath and then charged with cyanogen bromide (0.526 g, 5 mmol). The reaction mixture was allowed to warm to room temperature and stirred over night. The reaction mixture was concentrated under reduced pressure and redissolved in acetone, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give 1.79 g of 5-(2-(4-methylpiperazin-1-yl)ethoxy)-1H-benzo[d]imidazol-2-amine. This material was used without any further purification. MS (EI): 276 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[CH:12][N:13]([CH2:15][CH2:16][C:17]([NH:20][CH2:21][CH:22]([C:24]3[CH:25]=[C:26]([NH:30][S:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)(=[O:33])=[O:32])[CH:27]=[CH:28][CH:29]=3)[OH:23])([CH3:19])[CH3:18])[CH:14]=2)=[CH:6][CH:5]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[CH:12][N:13]([CH2:15][CH2:16][C:17]([NH:20][CH2:21][CH:22]([C:24]3[CH:25]=[C:26]([NH:30][S:31]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)(=[O:33])=[O:32])[CH:27]=[CH:28][CH:29]=3)[OH:23])([CH3:18])[CH3:19])[CH:14]=2)=[CH:8][CH:9]=1
Reactant: CC(C)(CCn1cnc(-c2ccc([N+](=O)[O-])cc2)c1)NCC(O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(CCn1cnc(-c2ccc(N)cc2)c1)NCC(O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Yield: 99.3 %

Procedure:
1.69 g (3.07 mmol) N-[3-(2-{3-[4-(4-nitro-phenyl)-imidazol-1-yl]-1,1-dimethyl-propylamino}-1-hydroxyethyl)-phenyl]-benzenesulphonamide, 0.10 g palladium on activated charcoal, and 30 mL methanol were shaken in an autoclave at ambient temperature under a hydrogen atmosphere of 1 bar for 3 h. The reaction mixture was filtered and the filtrate was freed from solvent using the rotary evaporator. 1.59 g (3.05 mmol, 99%) N-[3-(2-{3-[4-(4-amino-phenyl)-imidazol-1-yl]-1,1-dimethyl-propylamino}-1-hydroxyethyl)-phenyl]-benzenesulphonamide were obtained as a colourless solid.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][N:17]=[N:16][CH:15]=2)[CH2:8][C:9]([O:11]CC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][N:17]=[N:16][CH:15]=2)[CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(c1ccccc1)c1ccnnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CC(c1ccccc1)c1ccnnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
To a solution of ethyl 3-phenyl-3-(pyridazin-4-yl)propanoate (1.0 g, 3.9 mmol) in MeOH (20 mL) was added 2N NaOH (6 mL, 11.7 mmol), the resulting mixture was stirred at room temperature overnight. MeOH was removed under reduced pressure and pH adjusted to 4-5 by aq. HCl (2N), extracted with AcOEt (6×100 ml), the combined organic layer was washed with brine, dried over Na2SO4 and concentrated to get the 3-phenyl-3-(pyridazin-4-yl)propanoic acid (750 mg, yield: 84%). 1H NMR (CDCl3 400 MHz): δ9.27 (d, J=1.2 Hz, 1H), 9.09 (dd, J=4.0, 1.2 Hz, 1H), 7.67 (dd, J=5.6, 2.4 Hz, 1H), 7.41-7.36 (m, 2H), 7.34-7.27 (m, 2H), 7.24-7.18 (m, 1H), 4.48 (t, J=8.0 Hz, 1H), 3.27-3.15 (m, 1H), 3.10-3.00 (m, 1H).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[C:16]1([S:22]([N:25]2[C:29]3[CH:30]=[N:31][C:32]([C:35]#[N:36])=[C:33](O)[C:28]=3[C:27]3[CH:37]=[CH:38][CH:39]=[N:40][C:26]2=3)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1.Cl>C(Cl)Cl>[C:16]1([S:22]([N:25]2[C:29]3[CH:30]=[N:31][C:32]([C:35]#[N:36])=[C:33]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[C:28]=3[C:27]3[CH:37]=[CH:38][CH:39]=[N:40][C:26]2=3)(=[O:24])=[O:23])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: N#Cc1ncc2c(c1O)c1cccnc1n2S(=O)(=O)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ncc2c(c1OS(=O)(=O)C(F)(F)F)c1cccnc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
Trifluoromethanesulfonic anhydride (0.91 g, 0.54 mL, 3.22 mmol) was added dropwise to a suspension of 9-benzenesulfonyl-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (1.03 g, 2.93 mmol) in pyridine (1.2 mL, 14.7 mmol) and dry DCM (20 mL) at 0° C. The reaction mixture was then allowed to warm to ambient temperature and stirred for 2 h. The reaction mixture was treated with 1N hydrochloric acid (10 mL) and the phases were separated. The aqueous phase was extracted with DCM (2×10 mL), the combined organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by chromatography (silica, 5 g column, Si-SPE, DCM) to afford the title compound as a white solid (855 mg, 60%). LCMS (Method B): RT=4.22 min, M+H+=483.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH:4]=[C:5]1[CH2:10][N:9](C(OCC2C=CC=CC=2)=O)[C@H:8]([C:21]([O:23]CC2C=CC=CC=2)=[O:22])[C@@H:7]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:6]1.[H][H]>CO.[Pd]>[C:34]([O:33][C:31]([C@H:7]1[CH2:6][CH:5]([CH2:4][C:3]([O:2][CH3:1])=[O:38])[CH2:10][NH:9][C@@H:8]1[C:21]([OH:23])=[O:22])=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: [H][H]
Reactant: COC(=O)C=C1C[C@H](C(=O)OC(C)(C)C)[C@@H](C(=O)OCc2ccccc2)N(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC1CN[C@H](C(=O)O)[C@@H](C(=O)OC(C)(C)C)C1
Yield: 88.6 %

Procedure:
A solution of 1,2-dibenzyl 3-tert-butyl(2S,3S)-5-(2-methoxy-2-oxoethylidene)piperidine-1,2,3-tricarboxylate (98 mg, 0.188) in methanol (5 mL) was hydrogenated in the presence of 10% palladium on carbon (100 mg, 0.094), under balloon pressure of hydrogen, overnight. The resulting reaction mixture was filtered through a pad of celite and the precipitate was washed with methanol (2×5 mL). The volatiles were removed in-vacuo to afford 50 mg (88%) of (2S,3S)-3-(tert-butoxycarbonyl)-5-(2-methoxy-2-oxoethyl)piperidine-2-carboxylic acid as a sticky amorphous solid, which was used directly in the following coupling without further purification. LCMS (ESI): 246 (M-t-Bu+H+), 302 (M+H+).