Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH3:25])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[N:19][C:20](F)=[C:21]([CH3:23])[CH:22]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[CH3:26][C@@H:27]1[CH2:31][O:30][C:29](=[O:32])[NH:28]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([CH3:25])[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([N:28]4[C@H:27]([CH3:26])[CH2:31][O:30][C:29]4=[O:32])=[N:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(N2CCN(C(=O)c3cnc(F)c(C)c3)CC2)c(C)c1
Reactant: C[C@@H]1COC(=O)N1
Product: CCc1cnc(N2CCN(C(=O)c3cnc(N4C(=O)OC[C@H]4C)c(C)c3)CC2)c(C)c1
Yield: 31.8 %

Procedure:
By reaction and treatment in the same manner as in Example 240 and using [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl](6-fluoro-5-methylpyridin-3-yl)methanone (440 mg) described in Preparation Example 149 and (R)-4-methyloxazolidin-2-one (261 mg) described in Preparation Example 25, the title compound (173 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[I:13]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:1][C:2]1[C:3]([F:12])=[C:4]([I:13])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)c(F)cc1O
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: CC(=O)c1cc(Cl)c(F)c(I)c1O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A solution of 1-(5-chloro-4-fluoro-2-hydroxyphenyl)ethanone (23.8 g, 126 mmol) in acetic acid (100 mL) was treated with N-iodosuccinimide (34.1 g, 151 mmol) and stirred at 70° C. for 2 hours. The reaction mixture was concentrated, diluted with EtOAc and quenched with sat. NaHCO3 solution. The organic layer was separated, washed with water, dried over MgSO4 and concentrated under reduced pressure to give the desired product to be used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]([CH3:20])[CH:7]=[C:8]([C:11]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=1[CH3:19])[C:9]#[N:10])[CH3:2]>[O-]CC.[Na+]>[NH2:10][C:9]1[C:8]([C:11]2[C:12]([CH3:19])=[CH:13][C:14]([CH3:18])=[CH:15][C:16]=2[CH3:17])=[CH:7][N:6]([CH3:20])[C:5]=1[C:4]([O:3][CH2:1][CH3:2])=[O:21]
Reactant: CCOC(=O)CN(C)C=C(C#N)c1c(C)cc(C)cc1C
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)c1c(N)c(-c2c(C)cc(C)cc2C)cn1C

Procedure:
A solution of N-Methyl-N-[2-(2,4,6-trimethylphenyl)-2-cyanovinyl]-glycine ethyl ester (6.8 g, 24 mmol) in 0.28M ethanolic sodium ethoxide (100 mL) was heated at 70° C. for 6 h. The reaction was cooled and evaporated in vacuo. The residue was treated with water and neutralized with acetic acid and the product was extracted with ethyl acetate. After drying the solvent was removed in vacuo to afford 3-Amino-2-ethoxycarbonyl-1-methyl-4-(2,4,6-trimethylphenyl)-1H-pyrrole as a yellow oil.
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH2:25][N:24]([C:34]([O:36][C:37]2[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[CH:39][CH:38]=2)=[O:35])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:46].O1CCOCC1>>[ClH:46].[C:11]1([C@H:9]([NH:8][CH2:21][CH:22]2[CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][CH2:25][N:24]([C:34]([O:36][C:37]3[CH:38]=[CH:39][C:40]([C:41]([OH:43])=[O:42])=[CH:44][CH:45]=3)=[O:35])[CH2:23]2)[CH3:10])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CN(C(=O)Oc2ccc(C(=O)O)cc2)CCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](NCC1CN(C(=O)Oc2ccc(C(=O)O)cc2)CCC1c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 255 mg of 4-({[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidin-1-yl]carbonyl}oxy)benzoic acid was added 3.0 mL of a 4 M hydrogen chloride/1,4-dioxane solution, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was then dissolved in THF. Diisopropylether was added dropwise thereto, and the precipitate was isolated by filtration. This was dried under reduced pressure at 50° C. to obtain 159 mg of 4-({[3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidin-1-yl]carbonyl}oxy)benzoic acid hydrochloride as a white solid.
Reaction SMILES: [S:1]([CH2:4][S:5][C:6]1[S:7][C:8](=[CH2:13])[C:9]([CH3:12])([CH3:11])[N:10]=1)[C:2]#[N:3].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]Cl)=[CH:17][CH:16]=1>ClCCl>[S:1]([CH2:4][S:5][C:6]1[S:7][C:8](=[CH:13][S:21][C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)[C:9]([CH3:11])([CH3:12])[N:10]=1)[C:2]#[N:3]
Reactant: C=C1SC(SCSC#N)=NC1(C)C
Reactant: ClSc1ccc(Cl)cc1
Solvent: ClCCl
Product: CC1(C)N=C(SCSC#N)SC1=CSc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-Thiocyanomethylthio-4,4-dimethyl-5-methylenethiazoline, 4.0 gm (prepared in a manner consistent with Examples 1 and 2) was added to 100 ml of dichloromethane. 3.11 gm of 4-chlorophenylthiochloride was added to the system. The system was stirred at room temperature for 48 hours. The product precipitated from solution. The product was filtered and air-dried to give 4.7 gm of the 2-thiocyanomethylthio-4,4-dimethyl-5-(4-chlorophenylthio)methylenethiazoline as an off-white solid, m.p. 122°-131° C. Listed as compound number 1 in Table I.
Reaction SMILES: [OH:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:8]=2)[CH:3]1[N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C@@H:16]1[CH3:28].[H-].[Na+].[CH3:31]I>C1COCC1>[CH3:31][O:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([F:14])([F:12])[F:13])[CH:8]=2)[CH:3]1[N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C@@H:16]1[CH3:28]
Reactant: CI
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C1c2ccc(C(F)(F)F)cc2CC1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC1Cc2cc(C(F)(F)F)ccc2C1N1CCN(C(=O)OC(C)(C)C)C[C@@H]1C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl (3S)-4-[2-hydroxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazine-1-carboxylate (isomer 1 from step C in Example 9) (50 mg, 0.1 mmol) in THF (2 mL) at 0° C. was added NaH (8 mg, 60% in oil, 0.2 mmol). After being stirred for 10 min, MeI (28 mg, 0.2 mmol) was added. The mixture was stirred at ambient temperature for 1 h and quenched with aqueous NH4Cl. The resulting solution was extracted with EtOAc twice. The extracts were washed with brine, dried (MgSO4), filtered and concentrated to give the crude product. LC/MS calculated for C21H29F3N2O3: (M+H)+ 415; found 415.2.
Reaction SMILES: C(Br)C.[Mg].[CH3:5][CH:6]([CH3:11])[CH2:7][CH2:8][C:9]#[CH:10].[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:15])[CH:13]=[O:14].[Cl-].[NH4+]>CCOCC>[OH:14][CH:13]([C:10]#[C:9][CH2:8][CH2:7][CH:6]([CH3:11])[CH3:5])[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15]
Reactant: CCCCOC(=O)C=O
Reactant: C#CCCC(C)C
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCBr
Product: CCCCOC(=O)C(O)C#CCCC(C)C
Temperature: 25 °C
Yield: 45.5 %

Procedure:
A Grignard reagent was prepared under dry nitrogen by the addition, over a 1 hour period, of a solution comprising 10.9 grams (g) (0.10 mole) of ethyl bromide is 15 milliliters (ml) of anhydrous ether to a stirred suspension of 2.4 g (0.10 g atom) of clean magnesium metal turnings in 70 ml of dry ether. Stirring at 25° C. was continued for an additional hour and then a solution of 9.6 g (0.10 mole) of 5-methyl-1-hexyne in 15 ml of dry ether was added during 30 minutes with stirring. The resulting greyish solution was then heated at reflux for 2 hours and cooled to room temperature. The solution was transferred under dry nitrogen to a 200 ml addition funnel, followed by flushing with two 15 ml portions of dry ether. This solution was then added over a 45 minute period to a stirred solution of 13.0 g (0.10 mole) of n-butyl glyoxalate in 70 ml of dry ether cooled to -20° C. The mixture was stirred at -20° C. for 2 hours and allowed to warm to room temperature overnight. The resulting yellow-orange solution was cautiously treated with 75 ml of saturated ammonium chloride solution and after stirring for 5 minutes, the two phases which formed were separated. The aqueous phase was extracted twice with 60 ml portions of ether and the combined organic phases were washed with three 75 ml portions of brine and dried over MgSO4. After filtration and concentration at the stripper, the residual reddish-orange oil (18.0 g.), was fractionated through a 15 cm Vigreux column to afford, after a small forerun, a single volatile fraction, boiling point (b.p.) 107.0°-117.0° C./0.20 millimeter (mm). Redistillation of this cut provided 10.3 g (41% yield) of n-butyl 2-hydroxy-7-methyl-3-octynoate as a light yellow, sweet smelling, mobile oil, b.p. 112.0°-115.0° C./0.20 mm.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][NH:5][CH2:6][C:7]1[NH:8][C:9](=[O:17])[C:10]2[CH2:16][O:15][CH2:14][CH2:13][C:11]=2[N:12]=1.[F:22][C:23]1[CH:40]=[CH:39][C:26]([C:27]([CH:29]2[CH2:34][CH2:33][N:32]([CH2:35][C:36](O)=[O:37])[CH2:31][CH2:30]2)=[O:28])=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([CH:29]2[CH2:30][CH2:31][N:32]([CH2:35][C:36]([N:5]([CH2:4][C:3]3[CH:18]=[CH:19][CH:20]=[CH:21][C:2]=3[F:1])[CH2:6][C:7]3[NH:8][C:9](=[O:17])[C:10]4[CH2:16][O:15][CH2:14][CH2:13][C:11]=4[N:12]=3)=[O:37])[CH2:33][CH2:34]2)=[O:28])=[CH:39][CH:40]=1
Reactant: O=c1[nH]c(CNCc2ccccc2F)nc2c1COCC2
Reactant: O=C(O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Product: O=C(c1ccc(F)cc1)C1CCN(CC(=O)N(Cc2nc3c(c(=O)[nH]2)COCC3)Cc2ccccc2F)CC1

Procedure:
Following general procedure of Example 4, the title compound was prepared (52 mg) from 2-((2-fluorobenzylamino)methyl)-7,8-dihydro-3H-pyrano[4,3-d]pyrimidin-4(5H)-one and 2-(4-(4-fluorobenzoyl)piperidin-1-yl)acetic acid. Exact mass calculated for C29H30F2N4O4 536.6. found 537.4 (ESI, M+H); 1H NMR (400 MHz, dichloromethane-d2) δ ppm 7.87-8.12 (m, 2H) 7.16-7.45 (m, 5H) 7.04-7.14 (m, 1H) 4.69 (br. s., 1H) 4.61 (d, J=11.62 Hz, 3H) 4.48 (d, J=4.55 Hz, 3H) 4.31 (br. s., 1H) 3.84-4.08 (m, 7H) 3.39 (br. s., 1H) 3.28 (br. s., 1H) 2.63-2.79 (m, 2H) 2.28 (br. s., 2H) 1.97-2.20 (m, 2H).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[C:6]([O:10][C:11](=[O:25])[NH:12][C:13]([CH3:24])([CH3:23])[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])([CH3:9])([CH3:8])[CH3:7].C(=O)(O)[O-].[Na+]>CN(C)C(=O)C>[C:6]([O:10][C:11](=[O:25])[NH:12][C:13]([CH3:24])([CH3:23])[CH2:14][N:15]([C:3](=[O:4])[CH2:2][Br:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(CNc1ccccc1Cl)NC(=O)OC(C)(C)C
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(CN(C(=O)CBr)c1ccccc1Cl)NC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 95.3 %

Procedure:
1.52 ml of bromoacetyl bromide (17.5 mmol) was added to a solution of 3.49 g of [2-(2-chlorophenylamino)-1,1-dimethylethyl]carbamic acid t-butyl ester obtained in Example (1h) (11.7 mmol) in N,N-dimethylacetamide (58 ml) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. Hexane was added to the residue, and the solid was collected by filtration to obtain 4.68 g of the title compound (yield: 95%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[C:19]([CH:24]=[C:25]([Cl:27])[N:26]=3)[C:20]([O:22]C)=[O:21])[CH2:13][CH2:12]2)=[O:9])[NH:5][C:6]=1[CH3:7].[OH-].[Li+].Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[C:19]([CH:24]=[C:25]([Cl:27])[N:26]=3)[C:20]([OH:22])=[O:21])[CH2:13][CH2:12]2)=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: COC(=O)c1cc(Cl)nc(N2CCC(NC(=O)c3cc(Br)c(C)[nH]3)CC2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)cc(Cl)n3)CC2)cc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl 2-(4-{[(4-bromo-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-6-chloroisonicotinate (Example 43, 1.7 g, 3.72 mmol) was dissolved in THF (10 ml). 2 N lithium hydroxide (10 ml) was added and the reaction was stirred at room temperature for 3 h. The mixture was acidified with 1 N HCl and was extracted with EtOAc (3×50 ml), dried over Na2SO4 and concentrated in vacuo.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2([CH2:26][C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[NH:12][C:11](=S)[N:10]([CH2:14][CH:15]3[CH2:20][CH:19]4[CH2:21][CH:17]([C:18]4([CH3:23])[CH3:22])[CH:16]3[CH3:24])[C:9]2=[O:25])=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:43]([C:45]1[CH:54]=[CH:53][C:48]([C:49](=[O:52])[CH2:50]Br)=[CH:47][CH:46]=1)#[N:44]>C1COCC1>[O:25]=[C:9]1[N:10]([CH2:14][CH:15]2[CH2:20][CH:19]3[CH2:21][CH:17]([C:18]3([CH3:23])[CH3:22])[CH:16]2[CH3:24])[C:11](=[CH:50][C:49]([C:48]2[CH:53]=[CH:54][C:45]([C:43]#[N:44])=[CH:46][CH:47]=2)=[O:52])[NH:12][C:8]1([CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)[CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: CC1C(CN2C(=O)C(Cc3ccncc3)(Cc3ccncc3)NC2=S)CC2CC1C2(C)C
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC1C(CN2C(=O)C(Cc3ccncc3)(Cc3ccncc3)NC2=CC(=O)c2ccc(C#N)cc2)CC2CC1C2(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
5,5-Bis-pyridin-4-ylmethyl-2-thioxo-3-(2,6,6-trimethyl-bicyclo[3.1.1]hept-3-ylmethyl)-imidazolidin-4-one (101 mg, 0.225 mmol) was dissolved in anhydrous THF (3.0 ml) under an atmosphere of dry N2. The reaction was then cooled to 0° C. and potassium bis(trimethylsilyl)amide (46.8 mg, 0.235 mmol) was added. After stirring for 15 minutes, 4-cyanophenacyl bromide (51.5 mg, 0.230 mmol) was added to the reaction and the reaction was subsequently stirred for 20 minutes. The mixture was subsequently partitioned between CH2Cl2 and saturated sodium bicarbonate (NaHCO3) solution. The CH2Cl2 layer was dried over Na2SO4, filtered, and concentrated under vacuum to give a yellow oil. The oil was chromatographed on silica gel using 50% ethyl acetate in hexanes to remove unreacted 4-cyanophenacyl bromide and then eluted with 2% methanol in ethyl acetate to give 112 mg (0.189 mmol) of the titled compound as a yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15]>C(O)C.C(OCC)(=O)C>[CH2:18]([O:17][C:13](=[O:16])[CH2:14][CH2:15][NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:19]
Reactant: C=CC(=O)OCC
Reactant: COc1ccc(CN)cc1OC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNCc1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 3,4-dimethoxy-benzylamine (100 g) and ethyl acrylate (65 ml) in ethanol (2L) and cylcohexane (1L) was stirred at room temperature for 20 hours then evaporated to give the title compound as a colourless oil (154 g). MS: 268 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C@H:8]2[CH2:12][CH:11]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH:10]=[CH:9]2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[Li+].CC([N-]C(C)C)C.[C:31]1(=[O:35])[CH2:34][CH2:33][CH2:32]1>C1COCC1>[CH3:7][C:4]1[N:3]([C@H:8]2[CH2:12][C@@:11]([C:31]3([OH:35])[CH2:34][CH2:33][CH2:32]3)([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH:10]=[CH:9]2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: O=C1CCC1
Reactant: Cc1ccc(C)n1[C@@H]1C=CC(C(=O)OCc2ccccc2)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(C)n1[C@@H]1C=C[C@@](C(=O)OCc2ccccc2)(C2(O)CCC2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.7 %

Procedure:
To a cold (−78 C), stirred solution of 6.17 g (20.9 mmol) of benzyl (4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)cyclopent-2-ene-1-carboxylate (Preparation SRT-0233) in 40 mL of dry THF, under Ar, was slowly added 23.3 mL of a commercial 1.8 M solution of LDA. The resulting solution was warmed to 0 C, stirred at that temperature for 10 min, and then recooled to −78 C for the addition of 2.3 mL (31 mmol) of cyclobutanone. This solution was stirred at −78 C for 1 h, then quenched at −78 C by the slow addition of a solution of 4.0 mL of 12 N HCl in 10 mL of THF. Ethyl acetate and excess 1 M citric acid were added and the mixture was allowed to warm to RT. Extractive workup was followed by flash chromatography on silica using 25% ethyl acetate in heptane to provide 5.55 g (73%) of the title compound as a thick amber oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.44-1.56 (m, 1H) 1.88-2.31 (m, 6H) 2.12 (s, 6H) 2.27 (dd, J=14.7, 7.5 Hz, 1H) 2.76 (dd, J=14.5, 9.0 Hz, 1H) 5.18 (s, 2H) 5.26-5.32 (m, 1H) 5.71 (s, 2H) 6.06 (dd, 1H) 6.10 (dd, 1H) 7.30-7.39 (m, 5H). TLC Rf 0.36 (30% ethyl acetate in hexane). LC-MS ES+ 366.2
Reaction SMILES: [NH2:1][CH:2]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:3][C:4](=C)[CH2:5][C:6]([NH:17][CH:18]=[O:19])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].ClC(C)=CC.C(Br)C=C>C(OCC)(=O)C.C(O)C>[NH2:1][CH:2]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:3][CH:4]=[CH:5][C:6]([NH:17][CH:18]=[O:19])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: C=C(CC(N)C(=O)OCC)CC(NC=O)(C(=O)OCC)C(=O)OCC
Agent: CC=C(C)Cl
Solvent: C=CCBr
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(N)CC=CC(NC=O)(C(=O)OCC)C(=O)OCC

Procedure:
Using the procedure for the preparation of triethyl 5-amino-1-(formylamino)-3-methylene-1,1,5-pentanetricarboxylate, chloro-methylpropene replaced the allyl bromide to obtain the expected product in the form of an oil with an Rf=0.4 in ethyl acetate/ethanol 4:1.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][C@@H:9]([O:35][C:36]([O:38][CH3:39])=[O:37])[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2OCC(C)(C)C[O:18]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].C(O[C@H]1[C@@H]2O[C@@H]2[C@@]2(C)C(=C[C@@H](O)[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C2OCC(C)(C)CO2)C)C1)(=O)C>>[C:1]([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][C@@H:9]([O:35][C:36]([O:38][CH3:39])=[O:37])[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]=[O:18])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Agent: CC(=O)O[C@@H]1CC2=C[C@@H](O)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Product: COC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C=O)CC[C@H]3[C@H]12
Yield: 73.8 %

Procedure:
The procedure of Example 41 was repeated except that 5.5 mg (0.01 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-methoxycarbonyloxypregn-5-en-3β-yl acetate was used in lieu of 4.9 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-hydroxypregna-5-en-3β-yl acetate to give 3.4 mg of 3β-acetoxy-1α,2α-epoxy-7α-methoxycarbonyloxypregn-5-ene-20-carbaldehyde (yield: 74%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[SH:15][C:16]1[S:17][CH:18]=[CH:19][CH:20]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:15][C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Sc1cccs1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: CC(C)(C)OC(=O)N1CCC(Sc2cccs2)CC1

Procedure:
By a similar manner to Reference Example 35, 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.01 g, 5.0 mmol) was reacted with 2-mercaptothiophene (0.70 g, 6.0 mmol) to give the titled compound as pale yellow oily substance (987 mg, 66%).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].C([O-])([O-])=O.[K+].[K+].F[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=1[F:26]>CN(C=O)C>[F:26][C:18]1[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:17]=1[CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)CC(=O)OC
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Temperature: 50 °C
Reaction time: 5 h
Yield: 76.3 %

Procedure:
To a stirred solution of dimethyl malonate (6.22 g, 47.1 mmol, 1.5 eq) in DMF (30 mL) was added K2CO3 (8.70 g, 63 mmol, 2.0 eq) and heated to 50° C. for 30 min when 1,2-difluoro-4-nitrobenzene (5.0 g, 31.4 mmol, 1.0 eq) was added and the reaction mixture was stirred for 5 h at 50° C. The reaction mixture was cooled to RT, filtered to remove K2CO3, and the DMF was evaporated under vacuum. The residue was diluted with EtOAc (100 mL), washed with water, brine, dried over Na2SO4 and evaporated to get dimethyl 2-(2-fluoro-4-nitrophenyl)malonate (6.5 g, 76%) as a solid (TLC system: EtOAc/PE (3:7), Rf: 0.50).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])=[CH:17][C:16]=2[O:27][CH2:28][C:29]([O:31]CC)=[O:30])=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[CH:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]=[C:24]([CH3:25])[CH3:26])=[CH:17][C:16]=2[O:27][CH2:28][C:29]([OH:31])=[O:30])=[O:14])=[CH:9][CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)COc1cc(OCC=C(C)C)ccc1C(=O)C=Cc1ccc(C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)=CCOc1ccc(C(=O)C=Cc2ccc(C(C)(C)C)cc2)c(OCC(=O)O)c1
Temperature: 45 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
To a solution of 47.3 g of 4-t-butyl-2'-ethoxycarbonylmethoxy-4'-(3-methyl-2-butenyloxy)chalcone in 600 ml of ethanol was added a solution of 29.0 g of potassium carbonate in 100 ml of water, the mixture was stirred at 45° C. for 8 hours. After neutralization with dilute sulfuric acid, the precipitated solid was collected by filtration, washed with water, dried and recrystallized from ethanol to give 29.9 g of 4-t-butyl-2'-carboxymethoxy-4'-(3-methyl-2-butenyloxy)chalcone as pale yellow needles.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[CH:25](N(CC)C(C)C)(C)C>C(#N)C.C(OCC)(=O)C>[CH3:25][O:15][C:14]([C:11]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)=[O:16]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Solvent: CC#N
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)C1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Yield: 97.6 %

Procedure:
1-tert-Butyloxycarbonyl-4-phenyl-piperidine-4-carboxylic acid (0.9162 g, 3 mmol) was allowed to react with methyl iodide (1.87 mL, 30 mmol, 10 eq.) in the presence of N,N-diisopropylethylamine (2.61 mL, 15 mmol, 5 eq.) in acetonitrile (30 mL) at 20° C. for 16 hours. The solution was diluted with ethyl acetate and washed with 1N HCl, saturated sodium bicarbonate and saturated sodium chloride. The organic phase was dried over magnesium sulfate and the solvent was concentrated in vacuo to give 0.935 g (98%) of the title compound.