Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)(C)(C)C.[CH3:28][N:29]([CH3:38])[C:30]1[CH:35]=[CH:34][C:33]([C:36]#[CH:37])=[CH:32][CH:31]=1>>[CH3:28][N:29]([CH3:38])[C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][C:13]2[CH:12]=[C:11]3[C:16]([C:7](=[N:6][OH:5])[CH:8]=[C:9]([C:18]4[N:19]=[CH:20][C:21]5[C:26]([CH:27]=4)=[CH:25][CH:24]=[CH:23][CH:22]=5)[O:10]3)=[CH:15][CH:14]=2)=[CH:32][CH:31]=1
Reactant: C#Cc1ccc(N(C)C)cc1
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Product: CN(C)c1ccc(C#Cc2ccc3c(=NO)cc(-c4cc5ccccc5cn4)oc3c2)cc1

Procedure:
7-(4-dimethylaminophenyl)ethynyl-2-isoquinolin-3-yl-chromen-4-one oxime was prepared in 8% overall yield using the method described in example 24, starting from 7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (example 2B) and 4-dimethylaminophenylacetylene. The title compound was isolated as an orange solid and as a 95/5 mixture of Z/E oxime isomers.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:29][CH:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH2:27]3)=[O:25])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([C:24]([N:26]3[CH2:27][CH:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH2:29]3)=[O:25])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CC(N3CCOCC3)C2)no1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CC(N3CCOCC3)C2)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-butyl (3R)-6-cyclohexyl-3-(3-{[3-(4-morpholinyl)-1-azetidinyl]carbonyl)-1,2,4-oxadiazol-5-yl)hexanoate (Preparation 27) (1.32 g, 2.70 mmol) in dichloromethane (15 ml) was cooled to 0° C. and treated with trifluoroacetic acid (5 ml). The resulting mixture was stirred for 3 hours being allowed to warm to room temperature over this time. The solvent was removed under reduced pressure and the residue azeotroped from toluene (×3) then dichloromethane to afford the title compound as a white foam (1.31 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][Si](C)(C)C)[CH:10]=2)[NH:5][CH2:4][CH2:3]1.[OH-].[K+]>C(O)(C)C>[CH3:1][C:2]1([CH3:18])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[NH:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCNc2ccc(C#C[Si](C)(C)C)cc21
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: C#Cc1ccc2c(c1)C(C)(C)CCN2
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of 569 mg (2.21 mmol) of 4,4-dimethyl-6-trimethylsilylethynyl-1,2,3,4-tetrahydroquinoline (Compound 95) in 3 ml of isopropanol was added, under argon, 1 ml of 1N aqueous KOH solution. The reaction mixture was stirred at room temperature for 36 h and the isopropanol was removed under vacuum. The residue was extracted with ether and the ether extract was washed successively with water and saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue was purified by flash chromatography (silica; 10% ethyl acetate in hexanes) to give the title as a brown oil. PMR (CDCl3): & 1.26 (6H, s), 1.65-1.72 (2H, m), 2.96 (1H, s), 3.27-3.34 (2H, m), 6.34 (1H, d, J~8.3 Hz), 7.08 (1H, dd, J~8.3 Hz, 1.6 Hz), 7.33 (1H, d, J~1.6 Hz).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].Cl.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29](Cl)=[O:30])[CH2:25][CH2:24]1>O1CCCC1>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]([NH:9][CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])=[O:30])[CH2:25][CH2:24]1
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: NCC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CCN(C(=O)NCC(=O)OCc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 43.5 %

Procedure:
4.2 cm3 of triethylamine and 3.02 g of benzyl glycinate hydrochloride are added, at 20° C., to 3 g of 4-methylpiperazin-1-ylcarbonyl chloride hydrochloride in solution in 150 cm3 of tetrahydrofuran. After stirring for 16 hours at 60° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is taken up in 70 cm3 of dichloromethane. The organic phase is successively washed with twice 100 cm3 of a saturated aqueous sodium bicarbonate solution and 70 cm3 of water, and then dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 1.9 g of benzyl N-(4-methylpiperazin-1-ylcarbonyl)-glycinate in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.[Br:22][CH2:23][C:24](=O)[CH2:25][Br:26]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:24]([CH2:25][Br:26])[CH2:23][Br:22])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1
Reactant: O=C(CBr)CBr
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1
Solvent: C1CCOC1
Product: Fc1ccccc1C1=NCC(NN=C(CBr)CBr)=Nc2ccc(Cl)cc21

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino-5-(o-fluorophenyl)-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1,3-dibromopropanone under nitrogen to give 7-chloro-2-[[2-bromo-1-(bromomethyl)ethylidene]hydrazino]-5-(o-fluorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [C:1](#[N:4])[CH2:2][CH3:3].BrC1[CH:11]=[C:10](C)[C:9](/[CH:13]=[CH:14]/[CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)=[C:8]([CH3:28])[CH:7]=1.[C-]#N.[Na+]>[Cu](I)I.O>[C:1]([C:2]1[CH:7]=[C:8]([CH3:28])[C:9](/[CH:13]=[CH:14]/[CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)=[C:10]([CH3:11])[CH:3]=1)#[N:4]
Reactant: Cc1cc(Br)cc(C)c1/C=C/C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCC#N
Agent: I[Cu]I
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: Cc1cc(C#N)cc(C)c1/C=C/C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Under argon atmosphere, 3 ml of propionitrile was added to a mixture of 339 mg of tert-butyl 4-[(E)-2-(4-bromo-2,6-dimethylphenyl)vinyl]piperidine-1-carboxylate, 89 mg of sodium cyanide, 53 mg of tetrakistriphenylphosphine palladium and 17 mg of copper iodide, followed by heating under reflux for 7 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 299 mg of tert-butyl 4-[(E)-2-(4-cyano-2,6-dimethylphenyl)vinyl]piperidine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:24]=[C:23]([CH3:25])[O:22][N:21]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>ClCCl>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][N:12]([C:35](=[O:37])[CH3:36])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:15][CH2:16][C@H:17]([C:20]2[CH:24]=[C:23]([CH3:25])[O:22][N:21]=2)[CH2:18][CH2:19]1
Reactant: CC(=O)Cl
Reactant: Cc1cc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CNC4)CC2)no1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3cc(C)on3)CC2)C1
Reaction time: 0.75 h

Procedure:
To a solution of trans-8-chloro-1-[4-(5-methyl-isoxazol-3-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (50 mg, 0.13 mmol) and triethylamine (0.036 ml, 0.26 mmol) in dichloromethane (1.3 ml) was added acetyl chloride (0.019 ml, 0.26 mmol) at room temperature. Stirring for 45 minutes was followed by quenching with methanol (0.5 ml). The mixture was concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the title compound (24 mg, 43%) as white solid. MS m/e: 426 ([M+H]+).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[CH2:16][OH:17])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)(O)[O-].[Na+]>C(#N)C>[OH:17][CH2:16][C@H:11]1[CH2:12][CH2:13][CH2:14][CH2:15][C@@H:10]1[N:9]([C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CBr
Reactant: C[C@H](N[C@H]1CCCC[C@@H]1CO)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CN([C@@H](C)c1ccccc1)[C@H]1CCCC[C@@H]1CO
Yield: 102.4 %

Procedure:
A solution of (1S,2S)-2-[(S)-1-phenylethylamino]cyclohexyl)methanol (11, 120.9 g, 0.524 mol, 1.0 equiv. based on HCl salt 10) dissolved in acetonitrile (610 mL) was charged to a 2 L reactor, which is equipped with mechanical stirrer and thermocouple under nitrogen atmosphere. To this solution, ethyl bromoacetate (12, 104.9 g, 0.628 mol, 1.2 equiv.) and anhydrous sodium bicarbonate (57.2 g, 0.681 mol, 1.3 equiv.) were added sequentially with agitation. The contents were heated to reflux temperature for NLT 18 h with vigorous agitation under nitrogen atmosphere. Acetonitrile was distilled out under vacuum to about 300 mL volume and the mixture was cooled to less than 30° C. temperature and diluted with 327 ml, of heptanes and 423 mL of water. The contents were mixed for NLT 15 min and allowed settle to form two layers. The bottom aqueous layer was separated and further extracted with 2×327 mL of heptanes. The two heptanes extracts were combined with the organic layer in the reactor and washed sequentially with 1×327 mL of water and 1×327 mL 3.5 M aqueous sodium chloride solution. The heptanes solution was dried using anhydrous magnesium sulfate (13.5 g), filtered and concentrated under vacuum at NMT 60° C. temperature. The crude product was further dried under vacuum to afford 171.4 g of ethyl 2-(((1S,2S)-2-(hydroxymethyl)cyclohexyl)((S)-1-phenylethyl)amino) acetate (13) as viscous oil, which was carried to the next step without further purification. Analytical HPLC (Daicel Chiralpack AD-RH column, Size: 150×4.6 mm); 0.02 M Ammonium acetate buffer (pH: 7.7-7.8): Acetonitrile/50:50, 0.3 mL/min, Wave length: 220 nm, Column oven temperature: 55° C., Rt: 23.62 min; LC-MS (m/z): 320.2 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:27])[CH2:23][CH2:24][S:25][CH3:26])=[CH:17][CH:16]=3)[C:11]=2[CH2:12][CH2:13][CH3:14])=[O:6])[CH2:3][CH2:2]1.[OH:28]OS([O-])=O.[K+]>CO>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:27])[CH2:23][CH2:24][S:25]([CH3:26])=[O:28])=[CH:19][CH:20]=3)[C:11]=2[CH2:12][CH2:13][CH3:14])=[O:6])[CH2:2][CH2:3]1
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)CCSC)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(NC(=O)CCS(C)=O)cc1
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a solution of N-cyclopropyl-1-(4-{[3-(methylthio)propanoyl]amino}phenyl)-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.10 g) obtained in Example 10 in methanol (6 ml) was added an aqueous solution (2 ml) of Oxone (0.10 g) at room temperature, and the mixture was stirred for 1 hr. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol-diethyl ether to give the title compound as a white powder (0.09 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH:14]([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]([O:12][CH:14]([CH3:16])[CH3:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(C)Br
Reactant: COC(=O)c1ccc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC(C)C)cc1Cl
Temperature: 25 °C
Yield: 61.2 %

Procedure:
Methyl 2-chloro-4-hydroxybenzoate (Acros Organics; 0.2 g, 1.072 mmol) was stirred with 2-bromopropane (0.201 ml, 2.144 mmol) and potassium carbonate (296 mg, 2.144 mmol) in DMF (2 ml) at 100° C. for 1.5 hr. The mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated under vacuum and the residue was purified by Mass-Directed Auto-Preparative HPLC (formic acid modifier) to give the title compound as a yellow oil (150 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.FC(F)(F)S([C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)(=O)=O>O>[N:1]1([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: C1COCCN1
Solvent: O
Product: N#Cc1ccc(N2CCOCC2)cc1
Temperature: 120 °C
Yield: 52 %

Procedure:
A mixture of morpholine (3 g, 34 mmol) and the freshly prepared 4-[(trifluoromethyl)sulfonyl] benzonitrile (1.2 g, 5.1 mmol, Ref.: A. M. Echavarren and J. K. Stille, J. Am. Chem. Soc. 1987, 109, 5478-5486.), is heated at 120° C. The conversion of the 4-[(trifluoromethyl)sulfonyl]benzonitrile is complete after 20 hours. Water (10 ml) is than added into the reaction mixture. The precipitate is filtered off, washed with water and dried under vacuum (30° C.). Recrystallisation (50% aqueous ethanol) of the dried crude product gives 0.5 g of the title-compound. Yield: 52%, m.p. 82-83° C.; MS 188 (100, M+); H1 NMR (CDCl3): δ 7.46 (dd, 2H), 6.81 (dd, 2H), 3.79 (t, 4H), 3.22 (t, 4H); C13 NMR (CDCl3): δ 153.69, 133.71, 120.07, 114.26, 101.16, 66.65, 47.49.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:17](Cl)[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)C.C1(C)C=CC=CC=1>[CH2:17]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCCCC1
Reactant: ClCOCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: c1ccc(COCc2ccccc2)cc1
Temperature: -78 °C

Procedure:
The carboxylic esters (621A; 3.75 g) were dissolved in anhydrous diethyl ether (50 ml) and cooled to −78° C., under an atmosphere of nitrogen. KHMDS (69 ml of a 0.5M solution in toluene) was added dropwise and the resulting mixture was stirred for a further 15 min., before the addition of BOMCl (1.7 eq.) and the reaction flask was removed from the cooling vessel and allowed to warm slowly to room temperature. Water (approx. 10 ml) was added and the mixture was partitioned between EtOAc and 10% aq. HCl. The organic phase was separated, washed with sat. aq. sodium bicarbonate, water, dried (MgSO4), and the volatiles removed under reduced pressure. The residue was purified by silica gel column chromatography using EtOAc:Hexanes (1:20) as eluent, providing the intermediate benzyl ether (3.01 g), a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[CH:22]([CH3:28])[NH:21][CH2:20][CH2:19]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][C:25]([O:26][CH3:27])=[C:16]([O:15][CH3:14])[CH:17]=4)[CH:22]3[CH3:28])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1cc2c(cc1OC)C(C)NCC2
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: COc1cc2c(cc1OC)C(C)N(C(=O)c1cc3ncc(Br)cn3n1)CC2

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][CH2:31][C:32](O)=[O:33])[C:25]=1[CH3:35])(=[O:12])=[O:11].CCN(C(C)C)C(C)C.[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][CH2:31][C:32]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[O:33])[C:25]=1[CH3:35])(=[O:11])=[O:12]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)O
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-{5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-propionic acid (100 mg, 0.19 mmol), DIPEA (45 mg, 1.9 eq.) and morpholine (82 mg, 5 eq.) in DMF (2 mL) was stirred at rt for 30 mins. To the mixture was added HATU (85 mg, 1.2 eq.) was added and stirring was continued for another 3 hours. The reaction was concentrated, diluted with DCM, washed with sat.NaHCO3 and water, concentrated and triturated with methanol to give the titled compound as a pale orange solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[C:14]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=2)[C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[F:28][C:29]([F:43])([F:42])[C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[N:34][CH:35]=1.Cl>N1C=CC=CC=1>[F:43][C:29]([F:28])([F:42])[C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH2:37][CH2:38][N:39]([C:2]3[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]4[CH:13]=[C:14]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=4)[C:3]=3[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:40][CH2:41]2)=[N:34][CH:35]=1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Reactant: NS(=O)(=O)c1cccc(-c2nc(C(F)(F)F)nc(Cl)c2-c2ccccc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: NS(=O)(=O)c1cccc(-c2nc(C(F)(F)F)nc(N3CCN(c4ccc(C(F)(F)F)cn4)CC3)c2-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-[6-chloro-5-phenyl-2-(trifluoromethyl)pyrimidin-4-yl]benzenesulfonamide (0.1 g, 0.242 mmol) in pyridine (2 ml) was treated with 1-[5-(trifluoromethyl)pyridin-2-yl]piperazine (0.3 g, 0.68 mmol) and the reaction mixture was stirred for 1 hour at room temperature. Subsequently the reaction mixture was poured onto crushed ice containing two drops of concentrated hydrochloric acid, extracted with ethyl acetate (25 ml) and the organic layer was washed with brine and evaporated. The title compound was obtained by column chromatographic purification of the crude material with 30% ethyl acetate in hexane. 1H-NMR (DMSO-d6) δ: 3.33-3.37 (m, 4H), 3.56 (m, 4H), 6.86-6.88 (d, 1H), 7.10-7.12 (d, 2H), 7.22-7.29 (m, 3H), 7.35-7.37 (m, 1H), 7.44-7.48 (m, 1H), 7.74-7.79 (m, 3H), 8.38 (s, 1H); MS m/z: 608.8 (M+).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([OH:10])[C:4]=2[N:3]=[N:2]1.[H-].[Na+].[C:13]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])([CH3:15])[CH3:14]>O1CCCC1>[Si:17]([O:10][C:9]1[C:4]2[N:3]=[N:2][NH:1][C:5]=2[CH:6]=[CH:7][CH:8]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:19])[CH3:18]
Reactant: Oc1cccc2[nH]nnc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc2[nH]nnc12
Reaction time: 0.17 h

Procedure:
1H-benzo[d][1,2,3]triazol-4-ol (2.0 g) in tetrahydrofuran (30 mL) was treated with 60% sodium hydride (0.622 g). After 10 minutes, tert-butylchlorodimethylsilane (2.454 g) was added. The solution was stirred for 16 hours. The solvent was removed, and the residue was purified by flash column chromatography on silica gel using 10-50% ethyl acetate in hexanes as eluent to give the title compound.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].[Br:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH2:32][CH:33]3[CH2:35][O:34]3)[C:23]3[C:28]([C:29]=2[CH:30]=1)=[CH:27][C:26]([Br:31])=[CH:25][CH:24]=3>C1COCC1.CCOC(C)=O>[Br:17][C:18]1[CH:19]=[CH:20][C:21]2[N:22]([CH2:32][CH:33]([OH:34])[CH2:35][O:3][CH2:4][CH2:5][N:6]3[C:10](=[O:11])[C:9]4[C:8](=[CH:15][CH:14]=[CH:13][CH:12]=4)[C:7]3=[O:16])[C:23]3[C:28]([C:29]=2[CH:30]=1)=[CH:27][C:26]([Br:31])=[CH:25][CH:24]=3
Reactant: O=C1c2ccccc2C(=O)N1CCO
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1n2CC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCOCC(O)Cn1c2ccc(Br)cc2c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 44 %

Procedure:
Sodium hydride dispersion (31.6 mg, 0.79 mmol) was added to a solution of N-(2-hydroxyethyl)-phthalimide (153.7 mg, 0.80 mmol) in anhydrous THF (1.2 ml, 0.67 M). The suspension is stirred for 15 minutes before the addition of carbazole epoxide 2-A. The reaction was stirred at room temperature for five minutes and then at 60° C. for 1 hour. The cooled reaction was diluted with EtOAc and washed with water. The aqueous layer was extracted and the combined organics were filtered over a celite pad. The Crude product was used without further purification. Yield=44%
Reaction SMILES: [OH:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:4]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[N:3]1.[CH3:29][N:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:31](Cl)=[O:32]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:5]2[C:4]([C:22]3[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[N:3][N:2]([O:1][C:31](=[O:32])[N:30]([CH3:29])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:6]=2[C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[CH:16][CH:17]=1
Reactant: COc1ccc(-c2c(-c3ccc(F)cc3)c(-c3ccc(C)cc3)nn2O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: COc1ccc(-c2c(-c3ccc(F)cc3)c(-c3ccc(C)cc3)nn2OC(=O)N(C)c2ccccc2)cc1

Procedure:
The title compound was prepared from 1-hydroxy-4-(4-fluorophenyl)-5-(4-methoxyphenyl)-3-(4-methylphenyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (11%, crystals).
Reaction SMILES: [CH:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][C:10]([NH:12][C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([O:18]C)=[O:17])=[O:11])=[CH:6][C:5]=1[CH3:25])([CH3:3])[CH3:2].[I-].[Li+]>N1C=CC=CC=1>[CH:1]([C:4]1[CH:24]=[CH:23][C:7]([O:8][CH2:9][C:10]([NH:12][C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=2)[C:16]([OH:18])=[O:17])=[O:11])=[CH:6][C:5]=1[CH3:25])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cccc(NC(=O)COc2ccc(C(C)C)c(C)c2)c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: Cc1cc(OCC(=O)Nc2cccc(C(=O)O)c2)ccc1C(C)C

Procedure:
A solution of methyl 3-[2-(4-isopropyl-3-methyl-phenoxy)acetylamino]benzoate (948 mg, 2.78 mmol) and lithium iodide (3.72 g, 27.8 mmol) in anhydrous pyridine (15 mL) was heated to reflux for 20 h, then cooled and evaporated. The residue was taken up in water, and extracted twice with ethyl acetate. The extracts were washed with 1 N hydrochloric acid and brine, combined, dried over magnesium sulfate, filtered and evaporated to afford a semisolid mixture. The mixture was fractionally crystallized using ether-hexane to afford the title product as a solid, collected by filtration and dried under vacuum, m.p. 188–189° C. (772 mg, 2.36 mmol, 85%). 1H NMR (300 MHz, CDCl3): δ 8.44 (1H, br s), 8.03–7.96 (2H, m), 7.79 (1H, dt, J=7.7, 1.3 Hz), 7.39 (1H, t, J=7.9 Hz), 7.14 (1H, d, J=8.8 Hz), 6.79–6.73 (2H, m), 4.54 (2H, s), 3.03 (1H, heptet, J=7.0 Hz), 2.28 (3H, s), 1.14 (6H, d, J=7.0 Hz). MS (ESI): m/e 330 (3), 329 (21), 328 (100). Elemental analysis: calc. for C19H21NO4.0.1H2C, 69.33; H, 6.49; N, 4.25. observed C, 69.22; H, 6.53; N, 4.17.