Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[Br:13][C:14]1[CH:15]=[C:16]([C:20]2([CH3:27])[NH:24][C:23](=[O:25])[NH:22][C:21]2=[O:26])[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][CH:12]=[C:3]([CH2:2][N:22]2[C:21](=[O:26])[C:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([Br:13])[CH:15]=3)([CH3:27])[NH:24][C:23]2=[O:25])[CH:4]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CC1(c2cccc(Br)c2)NC(=O)NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN2C(=O)NC(C)(c3cccc(Br)c3)C2=O)c1
Reaction time: 18 h
Yield: 107.2 %

Procedure:
In analogy to the literature (Moloney et al., J. Med. Chem. 1997, 40, 2347-2362), methyl 3-bromomethylbenzoate (4.75 g, 20.7 mmol) was added to a suspension of hydantoin 1 (5.0 g, 18.6 mmol) and potassium carbonate (3.1 g, 22.5 mmol) in DMF (75 mL) at 23° C. After 18 h, the reaction mixture was partitioned between water and EtOAc, and the aqueous layer extracted with EtOAc. The combined organic layers were washed with water (1×), NaHCO3 (1×), water (1×), brine (1×), then dried over MgSO4. After filtration, concentration in vacuo gave an oil, which was subjected to silica gel chromatography (20→50% EtOAc/hexanes) to yield the desired material as a white sticky foam (8.32 g, 100%). 1H NMR (400 MHz, CDCl3) δ 7.92 (m, 2H), 7.58 (m, 1H), 7.34-7.46 (m, 4H), 7.20 (m, 2H), 4.66 (s, 2H), 3.84 (s, 3H), 1.76 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1.[CH3:18][Mg+].[Br-]>C1COCC1>[OH:1][C:2]1([CH3:18])[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:3]1
Reactant: C[Mg+]
Reactant: O=C1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC1(O)CCCN(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 53 %

Procedure:
To a solution of benzyl 3-oxopiperidine-1-carboxylate (2.33 g, 10 mmol) in dry THF (50 mL) at −78° C. was added MeMgBr (3.6 mL, 3M solution in THF, 11 mmol) slowly. The reaction was allowed to stir at −78° C. for 10 min then slowly warmed to r.t. The reaction was quenched with NH4Cl and dissolved in EtOAc (300 mL) and washed with saturated NH4Cl and brine, dried and filtered, and concentrated to give the crude. The crude material was further purified by silica gel chromatography to yield benzyl 3-hydroxy-3-methylpiperidine-1-carboxylate. (53% yield). LCMS (m/z): 250.1 (MH+); LC Rt=2.98 min.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[F:12][C:13]([F:35])([F:34])[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21]/[N:22]=[CH:23]/[C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=2)=[CH:17][CH:16]=1>C(Cl)Cl>[Cl:1][C:23](=[N:22][NH:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][C:13]([F:34])([F:35])[F:12])=[CH:16][CH:17]=1)[C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc(/C=N/Nc2ccc(OC(F)(F)F)cc2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CSC
Product: COC(=O)c1ccc(C(Cl)=NNc2ccc(OC(F)(F)F)cc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a magnetically stirred solution of N-chlorosuccinimide (0.59 g, 4.43 mmoL) in CH2Cl2 (8 mL) at 0° C. was added dimethyl sulfide (0.85 mL, 8.87 mmoL) and the reaction mixture was stirred for 15 minutes (min) and then cooled to −78° C. To this solution was added (E)-methyl 4-((2-(4-(trifluoromethoxy)-phenyl)hydrazono) methyl)benzoate dissolved in 8 mL of CH2Cl2 and the reaction mixture was stirred at this temperature for 1 hour (h), warmed to room temperature and stirred for 2 h. The solution was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (15 mL) and added to a silica gel (SiO2) loading cartridge and purified via flash column chromatography (Gradient EtOAc/hexanes). The title compound was obtained as a yellow solid as a mixture of E and Z isomers: mp 159-162° C.; 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 8.07 (d, J=8.8 Hz, 2H), 7.98 (d, J=8.8 Hz, 2H), 7.20 (s, 4H), 3.95 (s, 3H); 19F NMR (376 MHz, CDCl3) δ−58.32; ESIMS m/z 372 ([M+H])+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[C:27]4[CH2:26][CH2:25][CH2:24][C:23]([C:28]([O:30]C)=[O:29])=[CH:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:12][CH2:13][CH:14]([C:17]3[C:27]4[CH2:26][CH2:25][CH2:24][C:23]([C:28]([OH:30])=[O:29])=[CH:22][C:21]=4[CH:20]=[CH:19][CH:18]=3)[CH2:15][CH2:16]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC(=O)C1=Cc2cccc(C3CCN(S(=O)(=O)c4ccc(C)cc4)CC3)c2CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N2CCC(c3cccc4c3CCCC(C(=O)O)=C4)CC2)cc1
Reaction time: 13 h
Yield: 58.4 %

Procedure:
To a solution of methyl 4-[1-(4-methylphenylsulfonyl)piperidin-4-yl]-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (1.0 g) in ethanol/THF (20/40 ml) was added at room temperature 1N sodium hydroxide solution (2.7 ml), and the mixture was stirred for 13 hours. Under reduced pressure, the mixture was concentrated. To the mixture was added water, and the mixture was washed with ethyl acetate. To the aqueous layer was added 1N hydrochloric acid (5 ml), and the mixture was extracted with ethyl acetate/THF. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated, and the resulting colorless crystals were collected by filtration, which were washed with hexane to give colorless crystals of 4-[1-(4-methylphenylsulfonyl)piperidin-4-yl]-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (565.4 mg).
Reaction SMILES: Cl.Cl[C:3]1[S:4][C:5]2[C:6]([N:11]=1)=[N:7][CH:8]=[CH:9][CH:10]=2.[Br:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)C>CC#N>[Br:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:3]2[S:4][C:5]3[C:6]([N:11]=2)=[N:7][CH:8]=[CH:9][CH:10]=3)=[CH:18][CH:17]=1
Reactant: Clc1nc2ncccc2s1
Reactant: Oc1ccc(OCCBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CC#N
Product: BrCCOc1ccc(Oc2nc3ncccc3s2)cc1
Yield: 87.4 %

Procedure:
A mixture of 2-chloro[1,3]thiazolo[4,5-b]pyridine hydrochloride (863 mg, 4.17 mmol), 4-(2-bromo-ethoxy)-phenol (905 mg, 4.17 mmol), and Cs2CO3 (5.88 g, 16.67 mmol) was stirred in CH3CN (42 mL) for 16 h. After filtration through diatomaceous earth, the organic filtrate was partitioned with 1 M NaOH (3×10 mL) and satd. aq. NaCl (1×10 mL). The organic layer was dried and concentrated to yield a red oil. Additional desiccation under high vacuum yielded a brown solid in red oil. Diethyl ether was added, and the mixture was sonicated for 20 min to give a homogenous suspension. The pink solid was filtered and discarded, and the ether solution was concentrated to yield the title compound as a yellow solid (1.28 g, 87%). 1H NMR (500 MHz, CDCl3): 8.58 (dd, J=4.8, 1.7, 1H), 8.02 (dd, J=7.9, 1.67 1H), 7.38-7.34 (m, 2H), 7.21 (dd, J=7.9, 4.8, 1H), 7.01-6.97 (m, 2H), 4.33 (t, J=6.2, 2H), 3.68 (t, J=6.2, 2H). MS (ESI): mass calcd. for C14H11BrN2O2S, 349.97; m/z found, 351.0 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[C:10]([NH2:12])=[NH:11])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].[Cl:22][C:23]([SH:26])(Cl)Cl>ClCCl>[Cl:22][C:23]1[S:26][N:12]=[C:10]([CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=2)[O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)[N:11]=1
Reactant: N=C(N)C(OC1CCCCO1)c1cccc(Cl)c1
Reactant: SC(Cl)(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Clc1cccc(C(OC2CCCCO2)c2nsc(Cl)n2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To an ice-cooled solution of 2-(3-chlorophenyl)-2-(tetrahydropyran-2-yloxy)acetamidine hydrochloride (12.0 g, 39.51 mmol) in dichloromethane (20 mL) and sodium hydroxide (9.49 g, 0.237 mol, dissolved in 60 mL water) was added a solution of perchloromethyl mercaptan (9.18 g, 49.46 mmol) in dichloromethane (50 mL) over a period of 35 min. The reaction mixture was stirred at ice-cold temperature for a further 1 h and the organic layer was collected, dried (sodium sulfate), filtered and concentrated in vacuo. Purification by column chromatography on silica gel using a mixture of hexane and ethyl acetate (94/6) afforded the title compound as a light yellow oil (8.4 g, 61.5%). 1H-NMR (CDCl3) δ7.56 (d, J=6.9 Hz, 1H, Ar--H), 7.39-7.44 (m, 1H, Ar--H), 7.28-7.32 (m, 2H, Ar--H),6.08 and 6.03 (s, 0.5H each, α-H), 4.84 and 4.72 (t, J=3.1Hz, 0.5H each, OCHO), 3.49-3.92 (m, 2H, OCH2), 1.55-1.94 (m, 6H, 3CH2).
Reaction SMILES: [C:1](=[N:14][NH:15]C1C=CC(S(NCCN2CCOCC2)(=O)=O)=C(C)C=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:36]1[CH:37]=[C:38]([S:42]([NH:45][CH2:46][CH2:47][O:48][CH3:49])(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=1>>[C:1](=[N:14][NH:15][C:36]1[CH:37]=[C:38]([S:42]([NH:45][CH2:46][CH2:47][O:48][CH3:49])(=[O:43])=[O:44])[CH:39]=[CH:40][CH:41]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCNS(=O)(=O)c1cccc(Br)c1
Reactant: Cc1cc(NN=C(c2ccccc2)c2ccccc2)ccc1S(=O)(=O)NCCN1CCOCC1
Product: COCCNS(=O)(=O)c1cccc(NN=C(c2ccccc2)c2ccccc2)c1

Procedure:
The compound was prepared in the same manner as described for 4-(N′-benzhydrylidenehydrazino)-2-methyl-N-(2-morpholin-4-yl-ethyl)benzene sulfonamide, replacing 4-bromo-2-methyl-N-(2-morpholin-4-yl-ethyl)benzene sulfonamide with 3-bromo-N-(2-methoxyethyl)benzene sulfonamide. 1H-NMR (DMSO-d6) δ 9.32 (s, 1H), 7.67 (t, J=2.1 Hz, 1H), 7.63 to 7.48 (m, 4H), 7.46 to 7.41 (m, 3H), 7.39 to 7.26 (m, 6H), 7.15 to 7.12 (m, 1H), 3.29 (t, 5.7 Hz, 2H), 3.15 (s, 3H), 2.87 (q, J=5.7 Hz, 2H); MS LC-MS [M+H]+=410, RT=3.50 min.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C1(OC2C=CC=CC=2)C=CC=CC=1.[O-]CC.[Na+].C([O:31][C:32](=O)[CH:33]=[C:34]([NH2:36])[CH3:35])C>C(O)C>[CH2:6]([O:5][C:3]([C:2]1[C:1](=[O:9])[NH:36][C:34]([CH3:35])=[CH:33][C:32]=1[OH:31])=[O:4])[CH3:7]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC(=O)C=C(C)N
Agent: CC[O-]
Agent: [Na+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1c(O)cc(C)[nH]c1=O
Temperature: 160 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
In a 22 L vessel fitted with a mechanical stirrer and distillation head was charged 2.5 L (16.47 mol) diethyl malonate followed by 4.0 L diphenyl ether. Agitation was started and 1.12 Kg (16.47 mol, 1 eq) of sodium ethoxide was added via a powder funnel. The mixture was gradually, heated to 160° C. and the liberated ethanol was removed via distillation, approximately 950 mL. After 30 min, ethanol distillation ceased and 2.127 Kg (16.47 mol, 1 eq) of 3-amino-but-2-enoic acid ethyl ester was added, and the resulting ethanol formed removed via distillation. After 30 minutes the mechanical stirrer could no longer stir the foamy mass. At this point, external heating was ceased and the mixture allowed to cool to ambient temperature. To the mixture was charged 4 L of methyl-tert-butyl ether (MTBE) and the granular solid broken up with a spatula. The solid was filtered and washed with MTBE. To the solid was then added 100 mL of conc. HCl and 2 L of chloroform to solublize the mixture. The mixture was then taken up three times in 4 L chloroform, and decanted into a 20 L bucket. The combined organic phases were dried over sodium sulfate. The mixture was concentrated in vacuo to afford an orange gummy mass, which was triturated with MTBE and filtered, washing the filter cake with MTBE. The resulting solid was recrystallized from ethanol to afford the desired product as pinkish needles.
Reaction SMILES: [C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28][N:18]2[CH2:19][CH2:20][CH2:21][C@H:16]([C:3]([C:1]#[N:2])([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:17]2)=[CH:25][CH:24]=1
Reactant: Clc1ccc(CCBr)cc1
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCN(CCc2ccc(Cl)cc2)C1

Procedure:
A mixture containing 3-(R)-(+)-(1-cyano-1,1-diphenylmethyl)-piperidine (1 g--see Preparation 1), 4-chlorophenethyl bromide (0.72 g), anhydrous potassium carbonate (1.5 g) and acetonitrile (25 ml) was heated under reflux for 4 hours. The mixture was partitioned between dichloromethane (50 ml) and 10% aqueous potassium carbonate (30 ml), the layers separated, and the aqueous layer extracted with dichloromethane (3×30 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with hexane containing dichloromethane (30% up to 70%) and then dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give an oil which was crystallised form acetonitrile to give the title compound as colourless rhombs, yield 0.85 g, m.p. 129-131° C., [α]D25 +20.3 (c 1.0, CH2Cl2).
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7].[ClH:11]>>[Cl:11][CH2:2][CH2:3][NH:4][C@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7]
Reactant: Cl
Reactant: O=C(O)[C@H](CS)NCCO
Product: O=C(O)[C@H](CS)NCCCl
Yield: 93.8 %

Procedure:
40 g (0.24 mol) 2-hydroxyethyl cysteine was placed in a 1000 ml flask, to which was added 550 ml concentrated hydrochloric acid, followed by reflux for 7 h. After completion of the reflux, the reaction mixture was allowed to stand at room temperature to separate out white crystal, which was filtered and dried obtaining 41.6 g of a white crystal product, yield 93.8%.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([CH3:25])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[CH:24]=[C:23]([CH3:25])[S:22][C:12]=2[N:13]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc2c(Cl)nc(-c3ccccn3)nc2s1
Product: Cc1cc2c(NCc3ccccc3)nc(-c3ccccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyridin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-benzylamino-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:33][C@@H:32]([C:34]4[CH:45]=[CH:44][C:37]5[O:38][C:39]([CH3:43])([CH3:42])[O:40][CH2:41][C:36]=5[CH:35]=4)[O:31][C:30]3=[O:46])[CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[C:48](Cl)(=[O:55])[C:49]1[CH:54]=[CH:53][CH:52]=[N:51][CH:50]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:43][C:39]1([CH3:42])[O:38][C:37]2[CH:44]=[CH:45][C:34]([C@H:32]3[O:31][C:30](=[O:46])[N:29]([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][C:14]4[CH:13]=[C:12]([NH:11][C:9]([NH:8][C:4]5[CH:3]=[C:2]([NH:1][C:48]([C:49]6[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=6)=[O:55])[CH:7]=[CH:6][CH:5]=5)=[O:10])[CH:17]=[CH:16][CH:15]=4)[CH2:33]3)=[CH:35][C:36]=2[CH2:41][O:40]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)Nc5cccc(N)c5)c4)C(=O)O3)ccc2O1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)Nc5cccc(NC(=O)c6cccnc6)c5)c4)C(=O)O3)ccc2O1
Reaction time: 5.5 h
Yield: 89.6 %

Procedure:
A solution of N-(3-aminophenyl)-N′-[3-({2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethoxy}methyl)phenyl]-urea (0.20 g) in pyridine (4 ml) was treated under nitrogen at 200 with nicotinoyl chloride hydrochloride (0.118 g) and the mixture stirred for 5.5 h. Sat. sodium bicarbonate solution (25 ml) was added and the product was extracted with dichloromethane (3×20 ml). The combined organic layer was dried (Na2SO4) and the solvent removed in vacuo to give a residue that was purified by SPE. Elution with dichloromethane-EtOAc (1:0, 1:1, then 0:1), then MeOH-EtOAc (1:50), followed by solvent evaporation in vacuo gave the title compound (0.209 g). LCMS RT=3.54 min, ES+ve 738 (MH)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1.CN(C)C=O.Br[CH2:22][CH2:23]Cl.Cl>CCOC(C)=O>[Cl:3][C:4]1[N:9]=[CH:8][C:7]([C:10]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:23][CH2:22]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)Cc1ccc(Cl)nc1
Reactant: ClCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccc(Cl)nc2)CC1
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 0.60 g, 15 mmol) was added to a solution of ethyl (6-chloropyridin-3-yl)acetate (1.0 g, 0.0050 mol) in N,N-dimethylformamide (10 mL, 0.1 mol) at rt under an atmosphere of nitrogen. After 30 minutes, 1-bromo-2-chloro-ethane (0.84 mL, 0.010 mol) was added to the mixture at 0° C. The reaction mixture was stirred at 35° C. for 4 hours and then at room temperature overnight. The mixture was poured into a mixture of ice-water (50 ml) and EtOAc (50 ml) and the resulting mixture was acidified (to pH 2) by slow addition of 6 N HCl. The layers were separated and the organic layer was washed successively with water and brine, dried over MgSO4 and concentrated. The residue was chromatographed by combiflash (ethyl acetate in hexanes: 80%, on silica gel) to afford the desired product. LC/MS: 226.0 and 228.0 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C:16](=[O:32])[NH:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Li+].I[CH3:36]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[C:16]([O:32][CH3:36])=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(n2[nH]c(=O)c(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1nn(C2CCN(C(=O)OC(C)(C)C)CC2)c(-c2ccncc2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 13.4 %

Procedure:
A solution of 4-[4-(4-chlorophenyl)-3-oxo-5-pyridin-4-yl-2,3-dihydro-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.135 g, 0.3 mmol) in dry DMF (2 mL) was cooled to 0° C. and added lithium hydride (0.0035 g, 0.45 mmol). After stirring for 5 minutes, iodomethane (0.037 mL, 0.6 mmol) was added and the reaction was allowed to gradually warmed to room temperature and stirred for 20 hours. The reaction was diluted with ethyl acetate and washed with water; the aqueous layer was back-washed with ethyl acetate. The combined organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo. Flash chromatography with 1%, 3%, and 5% methanol/methylene chloride afforded 18.8 mg (13%) of a monomethylated product. MS (ES+): 469.2 (M+H)+.
Reaction SMILES: [C:1]([O:11]CC)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C-:14]#[N:15].[K+].[Cl-].[NH4+]>CN(C=O)C>[C:14]([CH:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:2][C:1]([OH:11])=[O:10])#[N:15]
Reactant: CCOC(=O)C=Cc1ccccc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: N#CC(CC(=O)O)c1ccccc1
Temperature: 105 °C
Reaction time: 7 h

Procedure:
Ethyl cinnamate (85.3 g, 0.484 mol), potassium cyanide (64.2 g, 0.986 mol) and ammonium chloride (38.9 g, 0.726 mol) were mixed with aqueous DMF (90%, 360 mL). The mixture was stirred at 105° C. for 7 hours. The somewhat cooled mixture was filtered and most of the DMF was evaporated. The residue was taken up in diethyl ether and 1 M HCl. The aqueous phase was extracted twice with diethyl ether. The combined diethyl ether phases were evaporated and the black oil was suspended in EtOH (200 mL) and 2 M NaOH (250 mL) and stirred at ambient temperature for 2 hours. The mixture was diluted with brine (200 mL) and water (400 mL) and washed twice with diethyl ether. After acidification (12 M HCl) the aqueous phase was extracted three times with diethyl ether. The pooled organic phases were dried (Na2SO4) and the solvent evaporated affording the title compound as a black oil, 74 g (87%): 1H NMR (CDCl3) δ1.05 (d, 3H), 1.17 (d, 3H), 1.22 (d, 6H), 2.68 (dd, 1H), 3.16 (dd, 1H), 3.4 (br, 1H), 3.76 (m, 1H) 4.19 (dd, 1H), 7.31 (m, 5H), 8.9 (br, 1H).
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[NH:8]1[CH:12]=[CH:11][N:10]=[CH:9]1>C(O)C>[NH:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]1[OH:7]
Reactant: c1c[nH]cn1
Reactant: C1CCC2OC2C1
Solvent: CCO
Product: OC1CCCCC1c1ncc[nH]1
Yield: 76.4 %

Procedure:
A mixture of cyclohexene oxide (Va) (9.81 g), ethanol (25 ml) and imidazole (13.6 g) was refluxed under heating for 70 hours and the ethanol is removed by evaporation. After addition of a small amount of water, the residue was extracted with chloroform. The extract was washed with a saturated aqueous solution of sodium chloride, dried and evaporated to give 2-imidazolylcyclohexanol (IVa) (12.7 g) as crystaline residue (yield 76%). Mp. 133°-134° C. NMR: δ (CDCl3) 1.3-2.2m8H, 3.6m2H, 4.86s1H, 6.83s1H, 6.89s1H, 7.30s1H ppm.
Reaction SMILES: C1(C2C=CC=CC=2)C=CC([C:7]2[C:16]3[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=3)[C:10]([OH:19])=[CH:9][C:8]=2[C:20](O)([CH3:22])[CH3:21])=CC=1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33](S(O)(=O)=O)=[CH:32][CH:31]=1>C(OC)(C)(C)C>[CH3:18][O:17][C:12]1[C:11]2[C:10]([OH:19])=[CH:9][C:8]3[C:20]([CH3:22])([CH3:21])[C:32]4[CH:31]=[C:30]([C:40]5[CH:15]=[CH:16][CH:7]=[CH:8][CH:9]=5)[CH:35]=[CH:34][C:33]=4[C:7]=3[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1cccc2c(-c3ccc(-c4ccccc4)cc3)c(C(C)(C)O)cc(O)c12
Solvent: COC(C)(C)C
Product: COc1cccc2c3c(cc(O)c12)C(C)(C)c1cc(-c2ccccc2)ccc1-3
Temperature: 25 °C
Yield: 569.6 %

Procedure:
In an oven-dried flask placed under a nitrogen atmosphere and equipped with a Dean-Stark trap, the product of Step 5 (20 g) was stirred in xylenes (300 mL). To this was added p-toluenesulfonic acid (990 mg). The reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. It was transferred to a separatory funnel and washed with saturated aqueous solution of sodium bicarbonate (300 mL), dried over sodium sulfate and then concentrated by rotary evaporation to yield a solid. The solid was slurried in a minimal amount of methyl tert-butyl ether and collected by vacuum filtration yielding 12 g of 4-methoxy-7,7-dimethyl-9-phenyl-7H-benzo[C]fluoren-5-ol.