Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:4][P:5](C(OCC)OCC)(=[O:9])[O:6]CC.[CH2:23]([C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CO>[CH2:23]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH:1][CH2:2][CH:3]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:4][PH:5](=[O:9])[OH:6])=[CH:33][CH:32]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCc1ccc(C=O)cc1
Reactant: CCOC(OCC)P(=O)(CC(CN)c1ccccc1)OCC
Solvent: CO
Product: CCCCCCCCc1ccc(CNCC(C[PH](=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.1 %

Procedure:
A mixture of 69.2 mg (0.210 mmol) of ethyl 3-amino-2-phenylpropyl(diethoxymethyl)phosphinate (Tetrahedron, 1989, 3787-3808) and 48.2 mg (0.221 mmol) of 4-octylbenzaldehyde in 1 mL of MeOH at rt was treated with 6.7 mg (0.105 mmol) of Na(CN)BH3. The resulting reaction mixture was stirred at rt for 16 hr. The reaction was quenched with 0.3 mL of 12 N HCl, then heated up to 60° C. for 5 hr. The mixture was cooled and concentrated. HPLC purification (LC-2) afforded 22 mg (26%) of the title compound. 1H NMR (500 MHz) (CD3OD) δ 0.88 (t, J=7.1, 3H), 1.26-1.30 (m, 10H), 1.58-1.61 (m, 2H), 2.01-2.17 (m, 2H), 2.62 (t, J=7.8, 2H), 3.20-3.23 (m, 1H),3.35-3.46 (m, 2H), 4.11 (s, 2H), 6.92 (d, J=535.4, 1H), 7.23-7.37 (m, 9H); LC-1: 3.31 min; ESI-MS 402 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:16][N:17]3[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:20]=4[N:19]([CH:26]4[CH2:28][CH2:27]4)[C:18]3=[O:29])[N:10]([CH2:11][CH2:12][CH2:13][CH:14]=[O:15])[C:5]2=[CH:4][CH:3]=1.[CH3:30][Mg]I>C1COCC1.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:16][N:17]3[C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:20]=4[N:19]([CH:26]4[CH2:28][CH2:27]4)[C:18]3=[O:29])[N:10]([CH2:11][CH2:12][CH2:13][CH:14]([OH:15])[CH3:30])[C:5]2=[CH:4][CH:3]=1
Reactant: C[Mg]I
Reactant: O=CCCCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2nc(Cl)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(O)CCCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2nc(Cl)ccc21
Temperature: -20 °C
Reaction time: 4 h
Yield: 22.8 %

Procedure:
In a 100 mL dry flask, 4-{5-chloro-2-[1-cyclopropyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)methyl]-1H-imidazo[4,5-b]pyridin-1-yl}butanal 67-1 (1.5 g, 3.6 mmol) was dissolved in dry THF (50 mL) and cooled until −20° C. under N2 atmosphere. An excess methylmagnesium iodide (3M in THF) (1.8 mL, 5.5 mmol, 1.5 eq.) was then gently added dropwise to the cooled solution via syringe. The solution was warmed up until ambient temperature and stirred for 4 hours. The solution was diluted with 30 mL NaHCO3 solution and extracted with EtOAC (30 mL). The combined organics were dried (MgSO4) and concentrated in vacuo. The crude was purified on RP SunFire Prep column (C18 OBD-10 μm,30×150 mm), using a 0.25% NH4HCO3 solution in water-MeOH solution to give 350 mg (22%) of 3-{[5-chloro-1-(4-hydroxypentyl)-1H-imidazo[4,5-b]pyridin-2-yl]methyl}-1-1-cyclopropyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (67) as a white solid.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.99-1.05 (m, 2 H) 1.13-1.22 (m, 5 H) 1.43-1.57 (m, 2H) 1.77-1.91 (m, 2 H) 2.11 (br. s, 1 H) 2.89-2.98 (m, 1 H) 3.81-3.90 (m, 1 H) 4.32-4.50 (m, 2 H) 5.40 (s, 2 H) 7.13 (dd, J=5.27, 0.75 Hz, 1 H) 7.23 (d, J=8.53 Hz, 1 H) 7.65 (d, J=8.28 Hz, 1 H) 8.34 (d, J=5.27 Hz, 1 H) 8.75 (s, 1 H); LCMS m/z=427 (M+H)+
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:11]3=[N:12][C:13]=2[N:14]([O:16][CH3:17])[CH:15]=1)=[O:5])C.Cl.C(O)(=O)C>O>[F:22][C:20]1[C:19]([F:23])=[CH:18][C:11]2=[N:12][C:13]3[N:14]([O:16][CH3:17])[CH:15]=[C:6]([C:4]([OH:5])=[O:3])[C:7](=[O:24])[C:8]=3[CH:9]=[C:10]2[CH:21]=1
Reactant: CCOC(=O)c1cn(OC)c2nc3cc(F)c(F)cc3cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Temperature: 100 °C
Yield: 79.7 %

Procedure:
A suspension of 3-ethoxycarbonyl-7,8-difluoro-1-methoxy-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine (2.78 g) in 17.5% strength hydrochloric acid (30 cc) and acetic acid (30 cc) is heated to a temperature in the region of 100° C. for 1 hour. After cooling to approximately 20° C., the reaction mixture is poured into water (100 cc). The precipitate formed is drained and washed with water (3×+cc) and ethanol (2×5cc). After 1 recrystallization in dimethylformamide (100 cc) containing ethanol (20%), 7,8-difluoro-1-methoxy-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid (2.03 g) is obtained in the form of a yellow solid, m.p. 325°-327° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.[CH3:11][N:12](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:10][C:4]1[N:3]=[C:2]([Cl:1])[C:7]([C:11]#[N:12])=[C:6]([CH3:9])[N:5]=1
Reactant: CN(C)C=O
Reactant: Cc1nc(N)nc(Cl)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1nc(N)nc(Cl)c1C#N
Temperature: 140 °C
Yield: 5 %

Procedure:
A mixture of 4-chloro-5-iodo-6-methylpyrimidin-2-ylamine (1.35 g, 5.0 mmol), zinc cyanide (288 mg, 2.45 mmol) and tetrakis(triphenylphosphine)palladium (290 mg, 5 mol %) in DMF (20 mL) was purged with argon gas and heated at 140° C., for 15 min, by microwave irradiation. After cooling to RT, the residue was partitioned between EtOAc and water. The aqueous phase was further extracted with EtOAc and the combined organic fractions washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-30% EtOAc in DCM) followed by further column chromatography (Si—PCC, gradient 0-7% MeOH in DCM) to afford the title compound (40 mg, 5%) as a pale yellow solid. LCMS (Method C): RT 2.23 min [M+H]+ 169.00. 1H NMR (DMSO-d6, 400 MHz): δ 8.11 (2H, br s), 2.42 (3H, s)
Reaction SMILES: [CH3:1][C@H:2]([C:15]([OH:17])=[O:16])[C:3]1[CH:4]=[CH:5][C:6]2[CH:7]=[C:8]([O:13]C)[CH:9]=[CH:10][C:11]=2[CH:12]=1>Br>[OH:13][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[CH:12]=[C:3]([CH:2]([CH3:1])[C:15]([OH:17])=[O:16])[CH:4]=[CH:5]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: Br
Product: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
A mixture of Naproxen (500 grams) and 48% HBr solution (1500 ml) was refluxed for 10 Hours, poured onto ice water (3000 ml), and stirred for 30 minutes. Crude 2-(6-hydroxy-naphthalen-2-yl)-propionic acid was filtered, dried and recrystallised from a mixture of ethyl acetate and hexane to give pure 2-(6-hydroxy-naphthalen-2-yl)-propionic acid (380 grams, 81%) as a white powder with a melting point of 186-188° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=1>O1CCCC1>[CH:18]1([CH2:17][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=3)=[CH:7][CH:6]=2)[C:9](=[O:10])[NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (prepared in Example 3, 63.0 mg, 0.20 mmol) in tetrahydrofuran (10 mL) was treated with N,N-diisopropylethylamine (0.082 mL, 0.48 mmol) and nicotinoyl chloride hydrochloride (35.6 mg, 0.20 mmol). The reaction mixture was stirred at 25° C. for 24 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 ethyl acetate/methanol) afforded N-{4-[2-cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl]-phenyl}-nicotinamide (58.9 mg, 70%) as a white solid: mp 240-242° C.; EI-HRMS m/e calcd for C23H24N4O2S (M+) 420.1619, found 420.1625.
Reaction SMILES: CS[C:3]1[CH2:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O)(=O)C>C(Cl)(Cl)Cl>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:3]2[CH2:4][C:5]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[N:9]=2)[CH2:23][CH2:22]1
Reactant: CSC1=Nc2ccccc2N=C(c2ccccc2)C1
Reactant: CN1CCNCC1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CN1CCN(C2=Nc3ccccc3N=C(c3ccccc3)C2)CC1

Procedure:
A solution of 13.3 parts of 2-methylthio-4-phenyl-3H-1,5-benzodiazepine, 26 parts by volume of 1-methylpiperazine and 1.5 part of glacial acetic acid in 150 parts by volume of chloroform is stirred at reflux temperature overnight. The solvent is then removed under reduced pressure and the residue partititoned between water and benzene. The benzene portion is washed with water and then extracted with 10% acetic acid. The acidic extract is washed with benzene and then made alkaline with concentrated ammonia. The alkaline mixture is extracted with benzene, the benzene extract washed with water and then dried over anhydrous magnesium sulfate. After the solvent is removed a crude yellow solid is obtained. The crude solid is recrystallized from a mixture of chloroform and n-hexane to yield 4-(4-methyl-1-piperazinyl)-2-phenyl-3H-1,5-benzodiazepine, melting at about 155°-157° C. This compound has the following formula ##STR16##
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][CH3:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].S(O[CH2:23][CH2:24][S:25][C@H:26]1[CH2:43][CH2:42][C@@:41]2([CH3:44])[C@H:28]([CH2:29][CH2:30][C@@H:31]3[C@@H:40]2[CH2:39][CH2:38][C@@:36]2([CH3:37])[C@:32]3([OH:50])[CH2:33][CH2:34][C@@H:35]2[C:45]2[CH:49]=[CH:48][O:47][CH:46]=2)[CH2:27]1)(C1C=CC(C)=CC=1)(=O)=O.O>CN(C)C=O>[N:1]1([CH2:6][CH2:7][N:8]([CH3:9])[CH2:23][CH2:24][S:25][C@H:26]2[CH2:43][CH2:42][C@@:41]3([CH3:44])[C@H:28]([CH2:29][CH2:30][C@@H:31]4[C@@H:40]3[CH2:39][CH2:38][C@@:36]3([CH3:37])[C@:32]4([OH:50])[CH2:33][CH2:34][C@@H:35]3[C:45]3[CH:49]=[CH:48][O:47][CH:46]=3)[CH2:27]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)OCCS[C@H]2CC[C@@]3(C)[C@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](c5ccoc5)CC[C@]43O)C2)cc1
Reactant: CNCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCS[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccoc4)CC[C@]32O)C1)CCN1CCCC1
Temperature: 25 °C
Yield: 60.7 %

Procedure:
To a solution of 0.34 g of N-(2-(1-pyrrolidinyl)ethyl) methylamine in 5 ml of dimethylformamide, 0.045 g of NaH (60% dispersion in mineral oil) were added under nitrogen and the mixture was stirred at room temperature for half an hr; a solution of 0.50 g of 3β-(2-tosyloxyethylthio)-17β-(3-furyl)-5β-androstan-14β-ol, prepared as described in Ex. 51, in 2 ml of dimethylformamide was added, the mixture was stirred for another 4 hrs and then 7 ml of water were poured in. The residue was extracted with ethyl acetate, the organic solution was washed with water to neutral pH, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using methylene chloride/methanol 95/5 as eluant to give 0.28 g of the title compound (I-ca)as an amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: BrCCCCBr
Reactant: CC1(C)CC(=O)Nc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(=O)Nc2cc(OCCCCBr)ccc21
Temperature: 60 °C
Reaction time: 6 h

Procedure:
To a solution (20 ml) of 7-hydroxy-4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (0.4 g) in DMF were added 1,4-dibromobutane (0.75 ml) and potassium carbonate (0.35 g) and the mixture was stirred at 60° C. for 6 hr. After cooling to room temperature, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=100:1→50:1) to give the title compound (0.6 g) as a colorless solid.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3Cl)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>ClC1C=CC=CC=1Cl>[OH:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][NH:19][C:2]2[C:15]3[C:14](=[O:16])[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][C:12]=4[NH:19][CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=4)[C:7](=[O:18])[C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:23][CH:24]=1
Reactant: NCCc1ccc(O)cc1
Reactant: O=C1c2cccc(Cl)c2C(=O)c2c(Cl)cccc21
Solvent: Clc1ccccc1Cl
Product: O=C1c2cccc(NCCc3ccc(O)cc3)c2C(=O)c2c(NCCc3ccc(O)cc3)cccc21
Temperature: 160 °C
Yield: 60.6 %

Procedure:
A mixture of 27.7 grams (0.1 mole) of 1,8-dichloroanthraquinone, 30 grams (0.22 mole) of p-(2-aminoethyl)phenol in 200 milliliters of o-dichlorobenzene was heated to 160° C. for 18 hours. The mixture was cooled to room temperature, and the product was collected by filtration. Thereafter, the aforementioned product was recrystallized from isopropanol to yield 29 grams (62 percent) of 1,8-bis[2-(p-hydroxyphenyl)ethylamino]anthraquinone as a red powder, m.p. 181° to 182° C.; vis (DMF), λmax 520 nm (ε 12,000); ms 478 (M+); Analysis Calculated for C30H26N2O4 : C, 75.29; H, 5.48; N, 5.86; O, 13.38. Found: C, 74.94; H, 5.30; N, 5.63; O, 13.17.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:11]([S:14][CH2:15][CH:16]([CH3:20])[C:17](Cl)=[O:18])(=[O:13])[CH3:12]>>[C:11]([S:14][CH2:15][CH:16]([CH3:20])[C:17]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:18])(=[O:13])[CH3:12]
Reactant: CC(=O)SCC(C)C(=O)Cl
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Product: CC(=O)SCC(C)C(=O)N[C@@H](CCC(=O)O)C(=O)O

Procedure:
Following the procedure of Example 16, L-glutamic acid is reacted with 3-acetylthio-2-methylpropanoyl chloride to give (±)-N-[3-(acetylthio)-2-methyl -1-oxopropyl]-L-glutamic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:11][OH:12])=[CH:4][CH:3]=1.[CH3:26][S:27]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28]>>[CH3:26][S:27]([C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[CH:4][C:5]([CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[CH2:9][C:10]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:11][OH:12])=[CH:6][CH:7]=2)[CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28]
Reactant: Cc1ccccc1C(CC(=NO)c1ccncc1)c1ccc(Br)cc1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1ccccc1C(CC(=NO)c1ccncc1)c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1

Procedure:
In analogy to example 22, from 3-(4-bromo-phenyl)-1-pyridin-4-yl-3-o-tolyl-propan-1-one oxime (example 31) and (3-methylsulfonylphenyl)boronic acid was prepared the title compound as a mixture of E and Z isomers (2:1) as a white foam, MS (ESI+): m/z=471.1 ([M+H]+).
Reaction SMILES: Br[C:2]1[C:3]([C:31]#[N:32])=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[C:11]([CH3:16])([CH3:15])[C:10]3[CH:17]=[C:18]([O:21][CH2:22][C@H:23]4[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]4)[CH:19]=[CH:20][C:9]=3[C:8](=[O:30])[C:7]2=1.[Cu][C:34]#[N:35].O>CC(N(C)C)=O>[CH3:29][C:25]1([CH3:28])[O:24][C@@H:23]([CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:9]3[C:8](=[O:30])[C:7]4[C:6]5[C:14](=[C:2]([C:34]#[N:35])[C:3]([C:31]#[N:32])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:15])([CH3:16])[C:10]=3[CH:17]=2)[CH2:27][O:26]1
Reactant: CC1(C)OC[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4c(Br)c(C#N)ccc4c2C3=O)O1
Reactant: N#C[Cu]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC1(C)OC[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4c(C#N)c(C#N)ccc4c2C3=O)O1
Temperature: 200 °C
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere, 4-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound U6, 20.0 mg, 40.37 μmol) was dissolved in DMA (0.35 mL), added with copper (I) cyanide (18.1 mg, 201.9 μmol), and stirred at 200° C. for 1 hr under irradiation with microwave. The reaction solution was poured into water, extracted with ethyl acetate, washed with water and saturated brine, dried over sodium sulfate, and then filtered. The residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound as a crude product.
Reaction SMILES: C([Li])(C)(C)C.[CH:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[CH:20]([CH:22]=[CH2:23])=[O:21]>C1COCC1>[CH:22]([CH:20]([C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=2)=[CH:14][CH:15]=1)[OH:21])=[CH2:23]
Reactant: Brc1ccc(Oc2ccccc2)cc1
Reactant: C=CC=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C=CC(O)c1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
tert-Butyllithium (24.5 mL, 1.7M in pentane, 42.2 mmol) was added dropwise over 30 min to a solution of 4-bromodiphenyl ether (5.00 g, 20.1 mmol) in THF (50 mL) at -78° C. under argon. The cooling bath was removed and the bright yellow reaction mixture was warmed to 0° C. over 20 min. The reaction was stirred at 0° C. for 30 min, at which time a tan-colored solution developed. Freshly distilled acrolein (1.6 mL, 24 mmol) was added dropwise over 5 min. The colorless reaction mixture was stirred at 0° C. for 15 min, then quenched by addition of saturated NH4Cl (10 mL). The mixture was diluted with diethyl ether (200 mL) and the organic layer was washed with water (20 mL) and brine (50 mL), then dried over MgSO4. Evaporation gave a crude oil which was purified by flash chromatography on silica gel (400 g) eluted with a step gradient of 10:90 EtOAc/hexane to 15:85 EtOAc/hexane to 20:80 EtOAc/hexane to provide title compound (3.31 g, 73%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br:14]Br>C1C=CC=CC=1>[Br:14][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: BrBr
Solvent: c1ccccc1
Product: O=C(CBr)c1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
In a 500 mL round-bottomed flask was added 1-(4-chloro-3-nitrophenyl)ethanone (11.98 g, 60 mmol) in benzene (75 mL) to give a white suspension. Bromine (9.59 g, 60.0 mmol) was added dropwise over 5 minutes to give a deep red solution. The mixture was stirred for 1 hour to give a yellow solution that was concentrated in vacuo to a yellow solid. Recrystallized from 9:1 hexane/ethyl acetate gave 2-bromo-1-(4-chloro-3-nitrophenyl)ethanone as yellow needles.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([CH3:8])=[N:3]1.C([N:17]=[C:18]=[S:19])(=O)C1C=CC=CC=1>>[CH3:1][N:2]1[C:6]([NH:7][C:18]([NH2:17])=[S:19])=[CH:5][C:4]([CH3:8])=[N:3]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cc1cc(N)n(C)n1
Product: Cc1cc(NC(N)=S)n(C)n1

Procedure:
1,3-Dimethyl-5-amino pyrazole (111.0 g.) and benzoyl iso thiocyanate (180.0 g.) were reacted as described in Example IV to give 110.3 g. of the product, mp 221°-224° C.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([NH:8][C:9]([N:11]1[C:15]([CH3:16])=[CH:14][C:13]([O:17][C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[CH:20][N:19]=2)=[N:12]1)=[O:10])[CH3:7]>C(O)(=O)C>[CH2:6]([NH:8][C:9]([N:11]1[C:15]([CH3:16])=[C:14]([Cl:4])[C:13]([O:17][C:18]2[C:23]([Cl:24])=[CH:22][C:21]([C:25]([F:26])([F:27])[F:28])=[CH:20][N:19]=2)=[N:12]1)=[O:10])[CH3:7]
Reactant: CCNC(=O)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)cc1C
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCNC(=O)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
Sulfuryl chloride (0.16 g, 1.2 mmol) was added to a solution of N-ethyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole-1-carboxamide (0.35 g, 1.0 mmol) in acetic acid (5 ml), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant. The solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of N-ethyl-4-chloro-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-methylpyrazole-1-carboxamide (0.35 g, yield: 92.1%). mp: 111-112° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.23 (t, J=7.3 Hz, 3H), 2.66 (s, 3H), 3.41 (dq, J=5.8 and 7.3 Hz, 2H), 6.85-7.10 (m, 1H), 8.03 (d, J=2.0 Hz, 1H), 8.31 (m, 1H).
Reaction SMILES: Cl[CH:2]([CH3:19])[C:3](=[O:18])[C:4](=[N:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[SH:20][CH2:21][CH2:22][OH:23].C(N(CC)CC)C>C(Cl)(Cl)Cl>[OH:23][CH2:22][CH2:21][S:20][CH:2]([CH3:19])[C:3](=[O:18])[C:4](=[N:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: OCCS
Reactant: CCCCCCON=C(C(=O)OCC)C(=O)C(C)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCON=C(C(=O)OCC)C(=O)C(C)SCCO
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99.7 %

Procedure:
Ethyl 4-chloro-3-oxo-2-n-hexyloxyiminovalerate (255.0 g.), 2-mercaptoethanol (86.1 g.), triethylamine (11.13 g.) and chloroform (2.8 l.) were treated in a similar manner to that of Example I-(i) and stirred at room temperature for 3.5 hours. The resultant solution was treated in a similar manner to that of Example I-(i) to give ethyl 4-(2-hydroxyethylthio)-3-oxo-2-n-hexyloxyiminovalerate (290.5 g.).