Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1([O:17][CH3:18])[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH:4]1[OH:16].CN(C)C=O.[H-].[Na+].Cl[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O>[CH3:1][O:2][C:3]1([O:17][CH3:18])[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:5][CH:4]1[O:16][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: ClCc1ccccc1
Reactant: COC1(OC)CCN(Cc2ccccc2)CC1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1(OC)CCN(Cc2ccccc2)CC1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a stirred mixture of 37.8 parts of 4,4-dimethoxy-1-(phenylmethyl)-3-piperidinol and 135 parts of N,N-dimethylformamide were added portionwise 4.8 parts of sodium hydride dispersion 78%. The whole was heated to 60°-70° C. and stirring was continued for 30 minutes at 50° C. After cooling to room temperature, there were added dropwise 18.9 parts of (chloromethyl)benzene (exothermic reaction: temperature roses to 37° C. ). Upon completion, stirring was continued fo 2 hours at room temperature. The reaction mixture was poured onto 500 parts of water and the product was extracted twice with 1,1'-oxybisethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was distilled, yielding 33.1 parts (64.6%) of 4,4-dimethoxy-3-(phenylmethoxy)-1-(phenylmethyl)piperidine; bp. 180°-185° C. at 0.3 mm. pressure (intermediate 43).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][N:3]=1.S(Cl)([Cl:12])=O.CN(C)C=O.O>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][Cl:12])[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccnc(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: ClCc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 11.3 g of 2-chloro-4-hydroxymethylpyridine obtained in stage a) below in 200 mL of dichloromethane are added dropwise 6.896 mL of thionyl chloride, followed by 2.1 mL of dimethylformamide, the reaction mixture is stirred for 3 hours at room temperature and 50 mL of water are then added dropwise. The phases are separated and the organic phase is washed with water, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give 12.8 g of 2-chloro-4-chloromethylpyridine in the form of an amber-coloured liquid, which is used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:19]=[O:20])=[C:9]([O:11]S(C(F)(F)F)(=O)=O)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=CC(C=O)=C(O)C=1)(C)(C)C.[BH4-].[Na+]>CO.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:19][OH:20])=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C=O)c(OS(=O)(=O)C(F)(F)F)c1
Agent: CC(C)(C)c1ccc(C=O)c(O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(CO)c(O)c1
Reaction time: 1 h

Procedure:
A stirred, cooled (ice-bath) solution of a 1:1 mixture of trifluoro-methanesulfonic acid 5-tert-butyl-2-formyl-phenyl ester and 4-tert-butyl-2-hydroxy-benzaldehyde (Intermediate 105, 0.47 g) in methanol (8 mL) was treated with sodium borohydride (0.1 g, 2.64 mmol). After 1 h, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue that was subjected to flash column chromatography on silica gel (230–400 mesh) to afford the title product (0.3 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.Br[C:36]1[N:41]([CH3:42])[C:40](=[O:43])[CH:39]=[CH:38][CH:37]=1>>[OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([C:36]3[N:41]([CH3:42])[C:40](=[O:43])[CH:39]=[CH:38][CH:37]=3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1
Reactant: Cn1c(Br)cccc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cccc(=O)n2C)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 6-bromo-1-methylpyridin-2(1H)-one following a procedure analogous to that described in Example 30 Step 2. LC-MS Method 2 tR=1.088 min, m/z=447; 1H NMR (CDCl3) 1.38 (m, 1H), 1.56 (d, 3H), 1.70 (m, 1H), 1.95-2.08 (m, 2H), 2.23 (m, 1H), 2.37 (s, 2H), 3.05 (m, 1H), 3.33 (s, 3H), 3.58 (m, 2H), 5.73 (m, 1H), 6.29 (d, 1H), 6.89 (d, 1H), 7.01-7.09 (m, 4H), 7.21-7.39 (m, 5H), 7.53 (t, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][C:13]1([CH3:22])[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][CH:15](O)[CH2:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH:15]2[CH2:16][C:17]([CH3:20])([CH3:19])[CH2:18][C:13]([CH3:22])([CH3:12])[CH2:14]2)=[O:10])=[CH:6][CH:7]=1
Reactant: CC1(C)CC(O)CC(C)(C)C1
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)CC(OC(=O)Cc2ccc(O)cc2)CC(C)(C)C1
Yield: 106.1 %

Procedure:
A mixture of 4-hydroxyphenylacetic acid (6.08 g), 3,3,5,5-tetramethylcyclohexyl alcohol (6.24 g) , p-toluenesulfonic acid (1 g) and benzene (300 mL) was refluxed for 8 hours with continuous water separation. The mixture was cooled and washed with 10% Na2CO3, then with water. Drying over MgSO4 and evaporation in vacuo yielded 12.3 g of 3,3,5,5-tetramethylcyclohexyl 4-hydroxyphenylacetate. That product, which can be represented by the structural formula ##STR26## is characterized by the following NMR (CDCl3, TMS, ppm): 7,00(d, J=8 Hz, 2H), 6,60(d, J=8 Hz, 2H), 5.00(broad, 1H), 3,40(s, 2H) and 1.8-0.80(m, 18H),
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]([CH2:16][CH2:17][CH:18]3[O:22]CC[O:19]3)[C:5]=2[CH:4]=1.OS(O)(=O)=O.CCOC(C)=O>CC(C)=O.O.CCCCCC>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]([CH2:16][CH2:17][C:18]([OH:22])=[O:19])[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C(CCC1OCCO1)c1ccccc1-2
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc2c(c1)C(CCC(=O)O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
A solution of 2-[(2-methoxyfluoren-9-yl)ethyl]-1,3-dioxolane (3.1 g, 10.0 mmol) in acetone (100 mL) at 0° C. was charged with Jone's reagent (90 mL) (the reagent was made by dissolving 16 g of CrO and 16 ml of H2SO4 (conc.) in 100 ml of water). The reaction mixture was stirred overnight at room temperature. The reaction was monitored by TLC (silica, 25% EtOAc in hexane). The acetone was evaporated, the residue was diluted with water (100 mL). The product was extracted into EtOAc and the organic layer was washed thoroughly with water (x6), until aqueous washings were clear, then the product was extracted into 1N NaOH solution (3×50 mL), the water was washed again with ethyl acetate (1×30 mL) and acidified to pH=1. The oil formed was extracted with ethyl acetate. The ethyl acetate solution was washed with water, brine, dried over magnesium sulfate and evaporated. The residue was dissolved in 25% ethyl acetate/hexane mixture and the solution was filtered through a layer of a coarse silica gel. Evaporation of the filtrate afforded 1.8 g (67.0%) of the 3-(2-methoxyfluoren-9-yl)propionic acid.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])O[C:2]2=O.[CH2:13](Br)CCCCC>>[NH:6]1[C:7]2[C:1](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:2]=[CH:13][C:5]1=[O:12]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: CCCCCCBr
Product: O=c1ccc2ccccc2[nH]1

Procedure:
Following the procedure set forth in Steps (2) to (4) of Preparation A, isatoic anhydride was reacted with hexyl bromide to give 1-hexyl-4-hydroxy-(2(1H)-quinolinone. That the expected product was obtained was confirmed by the spectral data: MS: role 245 (M·+); NMR (DMSO): δ0.9 (t, 3H, CH3 --CH2 --), 4.06 (t, 2H, N--OH2), 6.18 (s, 1H, =CH), 11.87 (br, 1H, OH) ppm.
Reaction SMILES: C[Zn]C.[CH2:4]([Mg]Br)[CH:5]([CH3:7])[CH3:6].[F:10][C:11]([F:33])([F:32])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[CH:22][C:21](/[CH:24]=[N:25]/[S@:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])=[CH:20][N:19]=2)=[CH:14][CH:13]=1>>[CH3:6][CH:5]([CH3:7])[CH2:4][C@H:24]([NH:25][S@:26]([C:28]([CH3:31])([CH3:30])[CH3:29])=[O:27])[C:21]1[CH:22]=[N:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:11]([F:33])([F:32])[F:10])=[CH:13][CH:14]=2)=[N:19][CH:20]=1
Reactant: CC(C)(C)[S@](=O)/N=C/c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Reactant: CC(C)C[Mg]Br
Agent: C[Zn]C
Product: CC(C)C[C@H](N[S@@](=O)C(C)(C)C)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: -78 °C
Reaction time: 1.25 h
Yield: 68.3 %

Procedure:
Dimethyl zinc (117 mL, 2.0 M in toluene, 234 mmol) was added to an oven-dried and nitrogen-purged 500 mL round bottom flask with stir bar. Isobutylmagnesium bromide (103 mL, 2.0 M in ether, 206 mmol) was added over 5 min with stirring and the solution was allowed to stir at room temperature for 30 minutes. (S)-2-Methyl-propane-2-sulfinic acid 1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-meth-(E)-ylideneamide (48.83 g, 137.4 mmol) was placed in an oven dried nitrogen-purged 2 L 3-necked flask with addition funnel, overhead stirring, and internal temperature. The solid was dissolved in anhydrous THF (690 mL) and cooled to −78° C. where it was a white suspension. The zincate solution was cannulated into the addition funnel and then added dropwise over 75 min to the sulfinyl imine, maintaining an internal temperature of less than −72° C. The reaction was then allowed to stir at −78° C. as a yellow solution. At 75 min, the reaction was quenched with saturated NH4Cl, adding 100 mL over 45 min, keeping the internal temperature below −70° C. A second 400 mL was then added more quickly (˜20 min), keeping the internal temperature below −47° C. Gas evolution was observed at these higher temperatures indicating perhaps a latency period. Upon adding a final 100 mL, no gas evolution was observed indicating the reaction was quenched. The cold bath was removed, another 300 mL of water was added and the reaction allowed to warm to 5° C. at which point the contents were added to an addition funnel, along with ethyl acetate and some additional water. The layers were separated and the aqueous layer extracted with three additional portions of ethyl acetate. The combined organics were dried over MgSO4. Purification was done on half the material in two batches by silica gel flash chromatography (ethyl acetate/heptane) to give (S)-2-methyl-propane-2-sulfinic acid {(S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butyl}-amide (38.83 g, 68%) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.82 (s, 2H) 8.57 (d, J=8.2 Hz, 2H) 7.75 (d, J=8.4 Hz, 2H) 4.49 (q, J=7.2 Hz, 1H) 3.44 (d, J=5.7 Hz, 1H) 1.99 (dt, J=13.9, 7.3 Hz, 1H) 1.51-1.77 (m, 2H) 1.24 (s, 9H) 0.99 (d, J=6.6 Hz, 3H) 0.95 (d, J=6.4 Hz, 3H); MS (M+1): 414.3.
Reaction SMILES: [OH:1][C@H:2]([CH2:12][O:13]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][N:4]1[CH:11]=[N:10][C:8]([NH2:9])=[N:7][C:5]1=[O:6].S(O[CH2:44][P:45](=[O:54])([O:50]C(C)C)[O:46]C(C)C)(C1C=CC(C)=CC=1)(=O)=O.[H-].[Na+].Br[Si](C)(C)C>CN(C=O)C.C(O)(=O)C>[OH:13][CH2:12][C@@H:2]([O:1][CH2:44][P:45]([OH:54])([OH:50])=[O:46])[CH2:3][N:4]1[CH:11]=[N:10][C:8]([NH2:9])=[N:7][C:5]1=[O:6]
Reactant: Cc1ccc(S(=O)(=O)OCP(=O)(OC(C)C)OC(C)C)cc1
Reactant: Nc1ncn(C[C@H](O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)n1
Agent: C[Si](C)(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Nc1ncn(C[C@@H](CO)OCP(=O)(O)O)c(=O)n1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
A solution of 1-[(2S)-2-hydroxy-3-(triphenylmethoxy)propyl]-5-azacytosine (934 mg, 2.18 mmol) and diisopropyl tosyloxymethylphosphonate (1.05 g, 3 mmol) in DMF (30 ml) was cooled to −20° C. and 60% oil dispersion of NaH (240 mg, 6 mmol) was added. The mixture was stirred at −20° C. for 15 min, then the temperature was let to rise to approx. 25° C. (room temperature) and the stirring continued for additional 15 h. Acetic acid was added drop wise to pH 7, the mixture evaporated and the residue coevaporated with toluene (2×50 ml). Acetonitrile (30 ml) was added, followed by bromotrimethylsilane (2.7 ml, 20 mmol), the resulting suspension stirred in dark at room temperature for 48 h and evaporated. The residue was coevaporated with acetonitrile (3×50 ml). 90% Aqueous solution of methanol (50 ml) was added and the solution neutralized to pH 7.0 with 0.2 M triethylammonium hydrogencarbonate. The solution was concentrated to minimal volume (approx. 5 ml) and partitioned between water (100 ml) and ether (100 ml). An aqueous layer was concentrated to a volume 5 ml and applied onto a column of Dowex 1 (AcO− form, 60 ml). Elution was performed with water (300 ml), then with a linear gradient of acetic acid (0.5-1 M, 1 l) and lastly, the pure product was eluted with 1 M formic acid. UV absorbing fractions were taken down in vacuo and the residue coevaporated several times with water till a complete removal of acid. The residue was crystallized from aqueous ethanol, crystals collected by suction, washed with ethanol and ether and dried in vacuo. Yield: 200 mg (33%) of pure HPMP-5-azaC.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8]C=O)[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1>C(O)C.Cl>[NH2:8][C:6]1[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][C:3]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[C:2]([Cl:1])[N:7]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)c(Cl)nc1NC=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2)c(Cl)nc1N

Procedure:
6-Chloro-5-(4-chlorophenyl)-2-formamido-3-pyridinecarboxylic acid, ethyl ester (0.5 gram) was partially dissolved in 50 ml ethanol and treated with about 5-6 drops concentrated HCl. The reaction mixture was refluxed for approximately 3 hours, and upon cooling, a solid precipitate was collected, yield 350 mg, m.p. 195°-198° C.
Reaction SMILES: CO.O.C(=O)([O-])[O-].[K+].[K+].[Cl:10][C:11]1[CH:12]=[C:13]2[C:19]3([CH2:23][CH2:22][N:21]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]3)[CH2:18][N:17](C(=O)C(F)(F)F)[C:14]2=[CH:15][CH:16]=1>C(OCC)(=O)C>[Cl:10][C:11]1[CH:12]=[C:13]2[C:19]3([CH2:23][CH2:22][N:21]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]3)[CH2:18][NH:17][C:14]2=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)CN1CCC2(C1)CN(C(=O)C(F)(F)F)c1ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)CN1CCC2(CNc3ccc(Cl)cc32)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 101.8 %

Procedure:
Methanol (10.7 mL), water (3.6 mL), and potassium carbonate (0.4 g, 2.86 mmol) were added to t-butyl 2-(5-chloro-1-(2,2,2-trifluoroacetyl)spiro[indoline-3,3′-pyrrolidin]-1′-yl)acetate (0.6 g, 1.43 mmol), and the obtained mixture was then stirred at room temperature for 1.5 hours. Thereafter, the reaction solution was diluted with ethyl acetate, and was then washed with water and brine. The organic layer was concentrated in vacuo to obtain t-butyl 2-(5-chlorospiro[indoline-3,3′-pyrrolidin]-1′-yl)acetate (0.47 g, >100%) in the form of a light brown oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])/[C:16]/3=[CH:23]\[C:24]2[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=2[CH3:33])(=[O:12])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:34]1([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38][CH2:37][CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[C:4]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])/[C:16]/3=[CH:23]\[C:24]2[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:42]3[CH2:43][CH2:44][CH:39]([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)[CH2:40][CH2:41]3)=[O:32])[C:25]=2[CH3:33])(=[O:11])=[O:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)cc(Cl)c4)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)cc(Cl)c4)cc32)c(C)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
5-[5-(3,5-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.24 mmol) was coupled with 4-pyrrolidin-1-yl-piperidine (45 mg, 1.2 eq.) using HOBt (1.2 eq.), EDAC.HCl (1.2 eq.) and TEA (3 eq.) in DMF (25 mL) to give the titled compound. MS m/z 639 [M−1].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]3[NH:15][CH:16]=[C:17]([CH3:18])[C:13]=3[C:12]([C:19]([OH:21])=O)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)C.N1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]=[CH:11][C:12]([C:19]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:21])=[C:13]3[C:17]([CH3:18])=[CH:16][NH:15][C:14]=23)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c[nH]c2c(Nc3cccc(Cl)c3)ncc(C(=O)O)c12
Reactant: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1COCCN1
Solvent: CN(C)C=O
Product: Cc1c[nH]c2c(Nc3cccc(Cl)c3)ncc(C(=O)N3CCOCC3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-(3-chloro-phenylamino)-3-methyl-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid (34 mg) in dimethylformamide (2 ml) was added 4-ethylmorpholine (57 μl), morpholine (19 μl), 1-hydroxybenzotriazole hydrate (24 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg) and the solution stirred at room temperature overnight. The dimethylformamide was evaporated and the residue triturated with 5% sodium bicarbonate to give an off white solid. The solid was filtered, washed thoroughly with water, and dried over sodium hydroxide at 50° C. to afford 1-[7-(3-chloro-phenylamino)-3-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl]-1-morpholin-4-yl-methanone (22 mg).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)#[N:2].O[CH2:12][CH:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:14]([OH:16])[CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]2[O:16][CH:14]([CH3:15])[CH:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][O:8]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCCCCC(CO)C(C)O
Reactant: N#Cc1ccc(C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCCCC1COC(c2ccc(C#N)cc2)OC1C

Procedure:
A mixture of 0.1 mol of p-cyanobenzaldehyde, 0.1 mol of 3-hydroxymethyl-2-octanol, 200 ml of benzene and 150 mg of p-toluenesulfonic acid is boiled under a water separator until the reaction is complete. Usual working-up gives 2-p-cyanophenyl-5-n-pentyl-4-methyl-1,3-dioxane.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10](=[O:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:13][C:14]1[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=1[CH:16]=[CH:17][CH2:18]Br>C(COC)OC>[C:3]1([CH:9]([CH2:18][CH:17]=[CH:16][C:15]2[CH:20]=[CH:21][CH:22]=[CH:23][C:14]=2[CH3:13])[C:10](=[O:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)Cc1ccccc1
Reactant: Cc1ccccc1C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)C(CC=Cc1ccccc1C)c1ccccc1
Temperature: 25 °C

Procedure:
Sodium hydride (11.76 g., 0.28 mole, oil dispersion) is suspended in glyme (400 ml.) and phenyl acetone (37.57 g., 0.28 mole) in glyme (50 ml.) is added dropwise with stirring. After complete addition, the mixture is heated to reflux for one hour. The mixture is cooled to room temperature and a solution of crude o-methylcinnamyl bromide (59.10 g., 0.28 mole) in glyme (50 ml.) is added dropwise. When addition is complete, the mixture is heated on a steam bath for 24 hours then allowed to cool. After filtration of inorganic salts and removal of solvent from filtrate, a dark viscous residue is obtained. Trituration of this residue with petroleum ether (30°-60°C., 100ml.) produces tan solid, yield 26.5 g., m.p. 72°-75°C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12](=[S:20])OC2C=CC=CC=2)[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([CH3:28])[CH:27]=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:32]2[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[C:26]([CH3:28])[CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:30][CH2:31]2)=[S:20])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: COc1nc(C)c(C)nc1NC(=S)Oc1ccccc1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Product: COc1nc(C)c(C)nc1NC(=S)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 68.4 %

Procedure:
Phenyl N-(5,6-dimethyl-2-methoxypyrazin-3-yl)thiocarbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 28 to obtain the titled compound.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[C:2]1([C:8]2([C:14]#[N:15])[CH2:9][CH2:10][N:11]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:13]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC1(c2ccccc2)CCN(Cc2ccccc2)CC1

Procedure:
4-Phenyl-4-cyano-piperidine hydrochloride (10 g, 44.9 mmol), Benzyl bromide (5.4 mL, 45.4 mmol), and potassium carbonate (25.2 g, 182.3 mmol) were combined in THF/water (80 mL/20 mL). After 18 hours the reaction mixture was partitioned between water and dichloromethane. The organic layer was separated and extracted with water, dried over MgSO4, filtered and evaporated in vacuo to give a residue. The residue was recrystallized from hexane to give 4-phenyl -4-cyano-1-benzyl-piperidine as a solid: mp=73°-74° C.
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:34]([O:41][C:42]1[C:49]([F:50])=[CH:48][C:45]([CH:46]=O)=[CH:44][C:43]=1[F:51])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O>C1COCC1>[CH2:34]([O:41][C:42]1[C:49]([F:50])=[CH:48][C:45]([CH2:46][CH:2]=[O:3])=[CH:44][C:43]=1[F:51])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=Cc1cc(F)c(OCc2ccccc2)c(F)c1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=CCc1cc(F)c(OCc2ccccc2)c(F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 20.3 %

Procedure:
After methoxymethyl triphenyl phosphonium chloride (1.04 g, 3.02 mmol) was dissolved in anhydrous THF (9 mL), LiHMDS 1.0M THF solution (3 mL, 3.02 mmol) was added thereto at 0° C., and the mixture was stirred for 15 minutes. 4-Benzyloxy-3,5-difluoro-benzaldehyde (0.50 g, 2.01 mmol) obtained in Step B of Preparation Example 2 was dissolved in anhydrous THF (6 mL), and the solution was added thereto. The mixture was stirred at room temperature for 3 hours. After the termination of the reaction, the reactant was added with water, and then extracted with EtOAc. The organic layer was separated, dried with MgSO4, concentrated under reduced pressure, and then purified by column chromatography (eluent, EtOAc/Hex=1/5). After the obtained product was dissolved in THF (7.68 mL), 2N HCl (3.84 mL) was added thereto, and the mixture was stirred at 70° C. for 5 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure, added with water, and then extracted with EtOAc. The organic layer was separated, dried with MgSO4, concentrated under reduced pressure, and the purified by column chromatography (eluent, EtOAc/Hex=1/5) to obtain the title compound (0.107 g, 20%).