Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[Cl-].[C:3]1([CH3:17])[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[PH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16].[CH3:18][C:19]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:20]=1[C:21](Cl)=[O:22].[OH:30]O>O1CCCC1>[CH3:18][C:19]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:20]=1[C:21]([P:9](=[O:30])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:17])=[O:22]
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: Cc1ccccc1Pc1ccccc1C
Reactant: OO
Agent: [Cl-]
Agent: [Na]
Solvent: C1CCOC1
Product: Cc1cc(C)c(C(=O)P(=O)(c2ccccc2C)c2ccccc2C)c(C)c1

Procedure:
Under argon and with exclusion of moisture, 4.6 g of chopped sodium (0.20 mol) are placed at room temperature in 100 ml of tetrahydrofuran. Stirring slowly, 24.9 g (0.10 mol) of ditolylphosphine chloride (isomeric mixture of di-ortho, di-para and ortho-para) are added dropwise at 20–25° C. After stirring for 12 h, the red solution is filtered via a glass frit (G2 porosity) into a sulfonation flask with exclusion of moisture and using argon as protective gas. With stirring and cooling, 19.0 g (0.105 mol; 5% excess) of 2,4,6-trimethylbenzoyl chloride are added dropwise over 30 minutes at room temperature. After stirring for another 2 hours, the brownish-red reaction suspension is poured on water and extracted with toluene. The organic phase is dried over magnesium sulfate, filtered and concentrated by evaporation in a rotary evaporator (Rotavap). The resulting phosphine has a 23.24 ppm shift in the 31P-NMR spectrum. The residue is taken up in 100 ml of toluene and charged with 11.5 g (0.10 mol) of hydrogen peroxide (30%). The reaction is complete after stirring for 2 hours at a temperature from 50–60° C. The reaction emulsion is poured on water and washed with an aqueous saturated sodium hydrogencarbonate solution and then dried over magnesium sulfate and filtered. The filtrate is concentrated by evaporation in a Rotavap. The residue is purified over silica gel and dried under high vacuum, yielding 33.8 g (90% of theory) of the title compound in the form of a yellow viscous oil. The 31P-NMR shift is 14.54 ppm.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)(=[O:3])[CH3:2].[CH:15]1C2C(=CC=CC=2)C=C[C:16]=1[OH:25].[NH2:26]O.C(OC(=O)C)(=O)C>C(O)(=O)C>[C:16]([NH:26][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:14]=[CH:13]2)(=[O:25])[CH3:15]
Reactant: Oc1ccc2ccccc2c1
Reactant: CC(=O)Oc1ccc2ccccc2c1
Reactant: NO
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2cc(OC(C)=O)ccc2c1

Procedure:
In accordance with this invention, N,O-diacetyl-6-amino-2-naphthol (NODAN) is produced from 2-naphthyl acetate, or 2-naphthol and an acetylating agent such as acetic acid or anhydride, by means of an integrated process including the steps of converting the 2-naphthyl acetate, or 2-naphthol and acetylating agent, to 6-hydroxy-2-acetonaphthone (6,2-HAN) by a Fries rearrangement or Friedel-Crafts acetylation respectively, and converting the 6,2-HAN or its acetate esters, i.e., 6-acetoxy-2-acetonaphthone (6,2-AAN) to 6,2-HAN oxime with a hydroxylamine salt. The oxime is then subjected to a Beckmann rearrangement and accompanying acetylation by contacting the oxime with acetic anhydride and a Beckmann rearrangement catalyst to form NODAN.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([CH2:9][O:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]O)([O:7][CH3:8])=[O:6]>CCOCC>[C:5]([CH2:9][O:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][Cl:3])([O:7][CH3:8])=[O:6]
Reactant: COC(=O)COc1ccccc1CO
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: COC(=O)COc1ccccc1CCl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Thionyl chloride (0.48 mol) is added to an ether solution (1L) containing 2-carbomethoxymethoxybenzyl alcohol (0.4 mol), and a small amount of dimethylformanide (0.5 mL). The reaction is stirred at ambient temperature for 12 h, after which it is evaporated and the residue diluted again with ether (1L). This ether solution is washed with 2% sodium hydrogen carbonate solution (3X's) and then dried (magnesium sulfate). The solvent is removed to give 2-carbomethoxymethoxybenzyl chloride which is used directly in Step E.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.[NH2:21][C:22]1[CH:46]=[CH:45][C:25]([O:26][C:27]2[CH:32]=[C:31]([NH:33][C:34]([N:36]3[CH2:40][CH2:39][C@@H:38]([CH2:41][N:42]([CH3:44])[CH3:43])[CH2:37]3)=[O:35])[N:30]=[CH:29][N:28]=2)=[C:24]([F:47])[CH:23]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)C>[CH3:44][N:42]([CH2:41][C@@H:38]1[CH2:39][CH2:40][N:36]([C:34]([NH:33][C:31]2[CH:32]=[C:27]([O:26][C:25]3[CH:45]=[CH:46][C:22]([NH:21][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[S:13])=[CH:23][C:24]=3[F:47])[N:28]=[CH:29][N:30]=2)=[O:35])[CH2:37]1)[CH3:43]
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: CN(C)C[C@@H]1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ncn2)C1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN(C)C[C@@H]1CCN(C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)C1
Reaction time: 1 h
Yield: 38 %

Procedure:
After adding a 2-(4-fluorophenyl)acetyl isothiocyanate-toluene (0.2 M, 2.2 ml) solution to a solution of 4-(4-amino-2-fluorophenoxy)-6-{[(3S)-3-(dimethylaminomethyl)pyrrolidin-1-yl]carbonylamino}pyrimidine (105 mg) and (+)-10-camphorsulfonic acid (65 mg) in ethanol (2.5 ml) at room temperature, the mixture was stirred for 1 hour. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate:heptane=2:1, then ethyl acetate) to provide the title compound (60.5 mg, 38%) as white powder.
Reaction SMILES: N.[OH-:2].[K+].[C:4]([C:23]#[N:24])([C:7]([C:10]([C:13]([C:16]([C:19]([F:22])([F:21])[F:20])([F:18])[F:17])([F:15])[F:14])([F:12])[F:11])([F:9])[F:8])([F:6])[F:5]>>[F:5][C:4]([F:6])([C:7]([F:9])([F:8])[C:10]([F:12])([F:11])[C:13]([F:15])([F:14])[C:16]([F:17])([F:18])[C:19]([F:20])([F:21])[F:22])[C:23]([NH2:24])=[O:2]
Reactant: N#CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: [OH-]
Agent: N
Agent: [K+]
Product: NC(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 98.5 %

Procedure:
A ten-fold excess, fifty (50) ml, of anhydrous ammonia gas were condensed into a four-neck flask fitted with an agitator, reflux condenser, dropping funnel, thermometer, and a drying tube (filled with solid KOH) which had been cooled in a dry ice/ethanol bath. The ammonia was condensed into the flask via the drying tube. With good agitation and cooling, 60 g of a reaction product (perfluoroheptanonitrile), made in accordance with the technique described in Example 4 for conversion of a perfluoroacid to a nitrile, having the structure C6F13CN was added slowly. After addition was completed, the temperature was allowed to slowly rise to ambient allowing the excess ammonia to evaporate. The resulting white solid product was air dried to yield 62.0 g of perfluoroheptanamide having the following formula (a yield of 98.5% with a m.p. at 75-76° C.).
Reaction SMILES: C1(O)C=CC=CC=1.[CH:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([CH3:10])[CH3:9]>O>[C:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([CH3:10])=[CH2:9]
Reactant: CC(C)c1ccc(O)cc1
Solvent: Oc1ccccc1
Solvent: O
Product: C=C(C)c1ccc(O)cc1
Reaction time: 37 h

Procedure:
In this example, the procedure employed in Example 1 was repeated by passage of the mixture of air, phenol, water, and para-isopropylphenol over the pretreated catalyst, this time at a temperature of about 400°-480° C. for 37 hours. A total of 23 cuts were taken yielding a total volume of about 330 ml product whose conversions to the para-isopropenylphenol were between about 25-30%.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:28][C:29]([CH3:35])([CH3:34])[CH2:30][C:31](Cl)=[O:32].C(N(CC)CC)C>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[N:13]=[CH:14][N:15]=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:31](=[O:32])[CH2:30][C:29]([CH3:35])([CH3:34])[CH3:28])[CH2:24][CH2:23]3)[C:17]=2[N+:18]([O-:20])=[O:19])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)CC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Yield: 78 %

Procedure:
Compound A2 (0.12 mmol, 50 mg), 3,3-dimethyl-butyryl chloride (0.18 mmol, 24 mg) and triethylamine (0.63 mmol, 88 μL) were dissolved in DMF and microwaved at 80° C. for 5 minutes. The reaction mixture was quenched with water and extracted with ethyl acetate. Removal of organic solvents in vacuo provided Compound A3 as a yellow solid (46 mg, 78%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.98 (s, 1H), 8.20 (s, 1H), 7.77 (d, 2H), 7.64 (d, 2H), 5.44 (heptet, 1H), 3.71 (m, 1H), 3.48 (m, 3H), 2.75 (s, 3H), 2.11 (quartet, 2H), 1.76 (m, 4H), 0.85 (s, 9H). LCMS (ESI), m/z 492.4 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[H-].[Na+].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl.O>CN(C=O)C>[Cl:1][C:2]1[N:6]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Clc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-1H-benzimidazole (3.8 g) in DMF (25 ml) was added sodium hydride (60% in oil, 1.1 g) at 0° C. in several portions. The reaction mixture was stirred at 0° C. for 30 min, 2-(trimethylsilyl)ethoxymethyl chloride (4.7 ml) was added dropwise, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) to give the title compound (6.3 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:6][C:5]=1[OH:19].Br[CH2:22][CH2:23][CH2:24][CH:25]=[CH2:26].C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:6][C:5]=1[O:19][CH2:26][CH2:25][CH2:24][CH:23]=[CH2:22]
Reactant: C=CCCCBr
Reactant: CCCCCCCCOc1ccc(C(=O)OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCCCOc1cc(OCCCCCCCC)ccc1C(=O)OC

Procedure:
A mixture of 66.1 g (0.234 mol) of 2-Hydroxy-4-octyloxy benzoic acid methyl ester obtained in Step 1, 44.7 g (0.30 mol) of 5-Bromopent-1-ene, 207 g (1.5 mol) of K2CO3 and 700 mL of dry butanone is refluxed for 24 h, then allowed to return to room temperature. The reaction mixture is filtered and the butanone is distilled off under reduced pressure. After drying the residue under vacuum a slightly yellow oil (77.5 g, 95%) is obtained, which can be used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C@H:12]1[C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[CH2:31]([NH2:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9]([N:11]1[C@H:12]([C:17](=[O:19])[NH:39][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:13][CH2:14][C:15]1=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Reactant: NCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NCCc1ccccc1)[C@@H]1CCC(=O)N1C(=O)OCc1ccccc1
Temperature: 2.5 °C

Procedure:
(S)-5-Oxo-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (14.9 g, 57 mmol) is suspended in dichloromethane (100 mL) and added DMAP (7.1 g, 58 mmol) while cooling on ice (0-5° C.). The suspension immediately clarified. EDCI (11.1 g, 58 mmol) is added resulting in precipitation which quickly clarified again. Phenethylamine (6.8 mL, 54 mmol) is added slowly via syringe. The reaction is complete in one half hour. The dichloromethane layer is washed with aqueous 10% citric acid, water and saturated bicarb, then dried over anhydrous sodium sulfate, filtered and concentrated to a white solid. LCMS characterization ES+367.1 (m+1).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:8][CH:9]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Br)=[C:17]([CH2:23]Br)[CH:16]=1>CN(C)C(=O)C.CCOCC>[Br:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:19][CH:20]=1)[CH2:21][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=1)(=[O:12])=[O:11])[CH2:23]2
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: BrCc1ccc(Br)cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N2Cc3ccc(Br)cc3C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (440 mg, 60% dispersion in mineral oil, 11 mmol) in N,N-dimethylacetamide (24 mL) was added, dropwise, a solution of p-toluenesulfonamide (1.45 g, 8.5 mmol) in N,N-dimethylacetamide (8 mL) over about 5 min. The frothy solution was stirred for 1 hr at room temperature then heated to 60° C. and stirred at this temperature for 0.5 hr. To this mixture was added, dropwise a solution of 4-bromo-1,2-bis(bromomethyl)benzene (2.9 g 8.4 mmol) in N,N-dimethylacetamide (6 mL). The resulting mixture was stirred for 1 hr then cooled to room temperature and stirred for 17 hr. The mixture was then diluted with ether, washed with water (2×) then brine, dried over sodium sulfate and concentrated. The residue was triturated with ethyl acetate and filtered to give the title compound as a white solid.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[OH:8][CH2:9][N:10]1[CH2:15][CH2:14]C[CH2:12][CH2:11]1.O.[C:17](=O)([O-])[O-].[K+].[K+]>C(O)C>[C:9]([N:10]1[CH2:15][CH2:14][CH:6]([CH2:5][OH:7])[CH2:12][CH2:11]1)(=[O:8])[CH3:17]
Reactant: OCN1CCCCC1
Reactant: CC(=O)OC(C)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(=O)N1CCC(CO)CC1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
1-Acetyl-4-hydroxymethylpiperidine may be obtained in the following manner: acetic anhydride (20.5 cc) is added in the course of 15 minutes to a solution of hydroxymethylpiperidine (23.8 g) in ethanol (100 cc) at a temperature in the region of 10° C., and the mixture is stirred for 18 hours at a temperature in the region of 20° C. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa); the residue obtained is taken up with water (50 cc) and potassium carbonate (50 g), and the solution is extracted with methylene chloride (3×150 cc); the organic extracts are combined, dried and concentrated to dryness under reduced pressure (2.7 kPa). 1-Acetyl-4-hydroxymethylpiperidine (33.6 g) is thereby obtained in the form of an oil, which is employed in the crude state in the subsequent syntheses.
Reaction SMILES: C(O[C:6]([C@H:8]([C@@H:18]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:19]([NH:21][NH:22][C:23](=[O:26])[CH2:24][NH2:25])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])(C)(C)C.[CH2:31]([O:38][NH2:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[O:40]1CCCC[CH:41]1ON>>[CH2:31]([O:38][NH:39][C:6]([C@H:8]([C@@H:18]([CH2:27][CH:28]([CH3:29])[CH3:30])[C:19]([NH:21][N:22]1[C:23](=[O:26])[CH2:24][NH:25][C:41]1=[O:40])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:7])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NOC1CCCCO1
Reactant: CC(C)C[C@@H](C(=O)NNC(=O)CN)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Reactant: NOCc1ccccc1
Product: CC(C)C[C@@H](C(=O)NN1C(=O)CNC1=O)[C@H](CCCc1ccccc1)C(=O)NOCc1ccccc1

Procedure:
In a manner analagous to that described in Example 1, parts (vi)-(viii), but using 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-2′-glycinyl-4-methylvalerohydrazide and O-benzylhydroxylamine in place of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-2′-glycinyl-4-methylvalerohydrazide and O-(tetrahydro-2H-pyran-2(RS)-yl)hydroxylamine respectively there was obtained 2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenylbutyl]-4-methyl-N-(2,5-dioxo-1-imidazolidinyl)valeramide in the form of a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C@H:13]([C@@H:16]([OH:18])[CH3:17])[C@@H:12]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=1>CN(C=O)C>[CH2:3]([N:10]1[CH2:15][CH2:14][C@H:13]([C@H:16]([O:18][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=2)[CH3:17])[C@@H:12]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: C[C@H](O)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](Oc1ccc(Cl)cn1)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 20 h

Procedure:
A mixture of 69 mg (1.7 mmol) NaH (55% suspension in mineral oil), 359 mg (1.08 mmol) (S)-1-[(3S,4S)-1-benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanol and 225 mg (1.52 mmol) 2,5-dichloropyridine in 2 mL DMF was stirred for 20 h at 40° C. Further 0.2 eq. 2,5-dichloropyridine was added and stirring was continued for 20 h at 60° C. After evaporation the residue was purified by column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane to afford after evaporation of the product containing fractions 205 mg (43%) of the title compound as colorless viscous oil. MS (m/e): 441.1 [(M+H)+]
Reaction SMILES: CN(P(N(C)C)N(C)C)C.[C:11]([O:14][CH:15]([C:24](=[O:26])[CH3:25])[CH2:16][CH:17]1[C:19]([CH3:21])([CH3:20])[CH:18]1[CH:22]=O)(=[O:13])[CH3:12].[C:27](Cl)(Cl)([Cl:29])[Cl:28].O>C(OCC)C>[C:11]([O:14][CH:15]([C:24](=[O:26])[CH3:25])[CH2:16][C@H:17]1[C:19]([CH3:21])([CH3:20])[C@H:18]1[CH:22]=[C:27]([Cl:29])[Cl:28])(=[O:13])[CH3:12]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(=O)OC(CC1C(C=O)C1(C)C)C(C)=O
Agent: CN(C)P(N(C)C)N(C)C
Solvent: CCOCC
Solvent: O
Product: CC(=O)OC(C[C@@H]1[C@H](C=C(Cl)Cl)C1(C)C)C(C)=O
Reaction time: 0.08 h
Yield: 52.8 %

Procedure:
Tri(dimethylamino)phosphine (40 mmol) was added with stirring at -20° C. to a solution of 1-(2-formyl-3,3-dimethylcyclopropyl)-3-oxo-2-butyl acetate (14.2 mmol) and carbon tetrachloride (40 mmol) in diethyl ether (160 ml) kept under nitrogen. Then, the temperature of the mixture was allowed to rise to 20° C. Water (50 ml) was added, the mixture was stirred for 5 minutes and, after settling, the organic phase was isolated. The organic phase was washed with two 50-ml portions of water. The washed organic phase was dried over anhydrous magnesium sulphate and the solvent was evaporated from the dried solution to leave a residue (2.2 g) containing 1-[2-(2,2-dichlorovinyl)-3,3-dimethylcyclopropyl]-3-oxo-2-butyl acetate (100% (1R,cis), yield 54%).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[CH3:21][S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.CO.C(Cl)Cl>CCCCCC>[OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[S:22][CH3:21])[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Reactant: CSc1ccccc1B(O)O
Solvent: CO
Solvent: ClCCl
Solvent: CCCCCC
Product: CSc1ccccc1-c1cc2[nH]c3ccc(O)cc3c2c2c1C(=O)NC2=O
Yield: 72 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 2-(methylthio)benzeneboronic acid according to the procedure described in example 8 gave 9-hydroxy-4-[2-(methylsulfanyl)phenyl]pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (508) (I; Ar=2-(methylsulfanyl)phenyl) in a 72% yield, mp (MeOH/CH2Cl2)/hexane) 208–216° C. 1H NMR [(CD3)2SO] δ 11.76 (br s, 1H), 10.95 (br s, 1H), 9.25 (br s, 1H), 8.31 (d, J=2.5 Hz, 1H), 7.47 (s, 1H), 7.44 (d, J=8.6 Hz, 1H), 7.43 (td, J=7.3, 2.2 Hz, 1H), 7.38 (br d, J=7.5 Hz, 1H), 7.27 (dd, J=7.8, 2.2 Hz, 1H), 7.24 (td, J=7.3, 1.3 Hz, 1H), 7.07 (dd, J=8.7, 2.5 Hz, 1H), 2.32 (s, 3H). Found: C, 66.55; H, 3.88; N, 7.38. C21H14N2O3S.1/4H2O requires C, 66.57; H, 3.86; N, 7.39.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[Br:15].[C:17](Cl)(=[O:19])[CH3:18]>>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[Br:15])[C:17](=[O:19])[CH3:18]
Reactant: CN(C)CCNc1ccc([N+](=O)[O-])cc1Br
Reactant: CC(=O)Cl
Product: CC(=O)N(CCN(C)C)c1ccc([N+](=O)[O-])cc1Br

Procedure:
Prepared from 4-[N-(2-dimethylamino-ethyl)-amino]-3-bromo-nitrobenzene and acetyl chloride
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][C@@H:8]1[CH2:13][N:12]2[CH2:14][CH2:15][CH2:16][C@H:11]2[C:10](=[O:17])[NH:9]1)([CH3:4])[CH3:3].[H-].[Na+].I[CH3:23]>CN(C)C=O>[CH3:4][C:2]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][C@@H:8]1[CH2:13][N:12]2[CH2:14][CH2:15][CH2:16][C@H:11]2[C:10](=[O:17])[N:9]1[CH3:23])([CH3:1])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CN2CCC[C@H]2C(=O)N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)[C@@H]2CCCN2C[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.9 %

Procedure:
(3S,8aS)-3-({[(1,1-Dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrrolo[1,2-a]pyrazin-1 (2H)-one (1.51 g, 5.32 mmol) in dimethylformamide (8 mL) was added to an ice-cooled suspension of sodium hydride (60 wt. % dispersion in oil; 213 mg, 5.32 mmol) in dimethylformamide (8 mL). The mixture was stirred at 0° C. for 0.25 h and then iodomethane (0.332 mL, 5.32 mmol) was added dropwise. The mixture was stirred at room temperature for 0.5 h and then was stirred at 70° C. for 2 h. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate. The combined organic portion was dried over sodium sulfate, filtered and concentrated in vacuo to afford (3S,8aS)-3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-methylhexahydropyrrolo[1,2-a]pyrazin-1(2H)-one as a yellow oil (1.552 g, 5.21 mmol) which was dissolved in tetrahydrofuran (20 mL) and treated with tetrabutylammonium fluoride (1.0M solution in tetrahydrofuran; 10.4 mL, 10.4 mmol) for 2 h at room temperature. The mixture was concentrated in vacuo and purified by column chromatography (10% methanol in dichloromethane) to afford (3S,8aS)-3-(hydroxymethyl)-2-methylhexahydropyrrolo[1,2-a]pyrazin-1(2H)-one as a yellow oil (496 mg, 2.70 mmol, 51% yield from (3S,8aS)-3-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one). 1H NMR (400 MHz, CDCl3): 3.98-3.93 (m, 1H), 3.86 (dd, 1H), 3.61-3.55 (m, 1H), 3.29-3.25 (m, 1H), 3.09-3.03 (m, 1H), 3.03-2.97 (m, 1H), 3.02 (s, 3H), 2.93 (dd, 1H), 2.87-2.79 (m, 1H), 2.32-2.21 (m, 1H), 2.00-1.86 (m, 2H), 1.83-1.64 (m, 1H); MS (EI) for C9H16N2O2: 185 (MH+).