Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:29](O)=[O:30])[CH2:20][CH2:19][N:18]([C:21]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:32][N:33]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.NO>CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:29]([NH:33][OH:32])=[O:30])[CH2:16][CH2:17][N:18]([C:21]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])[CH2:19][CH2:20]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C(=O)c3cccnc3)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)NO)CCN(C(=O)c3cccnc3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(3-pyridinylcarbonyl)-4-piperidinecarboxamide was prepared following the procedure Example 64 (step 6). Starting from 4-(4-But-2-ynyloxybenzenesulfonyl)-1-(3-pyridinylcarbonyl)-4-piperidinecarboxylic acid (195 mg, 0.44 mmol) in dimethylformamide (4 ml), 1-hydroxybenzotriazole (72 mg, 0.53 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (119 mg, 0.62 mmol), N-methylmorpholine (0.072 ml, 0.66 mmol), and hydroxylamine (0.135 ml, 2.2 mmol), 65 mg (32%) of the product was isolated as a solid. HR-MS: m/z Calculated for C22H23N3O6S 458.1380; Found 458.1373.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:21][C:22]([NH:24][C@H:25]([C:29](O)=[O:30])[CH:26]([CH3:28])[CH3:27])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][C:29](=[O:30])[C@H:25]([CH:26]([CH3:27])[CH3:28])[NH:24][C:22]([O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(CO)NC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a cooled solution of 2-(N-(tert.-butyloxycarbonyl)-amino)-2-methylpropan-1-ol (J. Am. Chem. Soc 113 (1991) p 8883) (4.73 g, 25 mmole), 4-dimethylamino-pyridine (0.61 g, 5 mmole) and N-benzyloxycarbonyl-L-valine (6.28 g, 25 mmole) in dichloromethane (70 ml) was added dicyclohexyl-carbodiimide (6.19 g, 30 mmole) and the mixture was stirred 2 days at room temperature. The mixture was cooled, the urethane was filtered and the solution evaporated under reduced pressure. Ethyl acetate (200 ml) was added and the organic phase was washed twice with 5% acetic acid, 5% sodium hydrogencarbonate and water. The organic phase was dried with, sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with hexane/ethyl acetate. Yield: 10.2 g=96%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].[H-].[Na+].Br[CH2:17][C:18]([CH3:29])=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=1.O>CN(C)C=O>[CH:26]([C:23]1[CH:22]=[CH:21][C:20]([CH:19]=[C:18]([CH3:29])[CH2:17][O:1][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=2[CH3:13])=[CH:25][CH:24]=1)([CH3:28])[CH3:27]
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Reactant: CC(=Cc1ccc(C(C)C)cc1)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=Cc1ccc(C(C)C)cc1)COc1cc(C)c(NC=O)c(C)c1C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a solution of N-(4-hydroxy-2,3,6-trimethylphenyl)formamide (3.00 g, 16.7 mmol) in N,N-dimethylformamide (30 ml) was added at 0° C. under a nitrogen atmosphere sodium hydride (a 60% dispersion in liquid paraffin, 0.74 g, 18.4 mmol) and the resulting mixture was stirred at the same temperature for 10 minutes. To the reaction solution was added 1-(3-bromo-2-methyl-1-propenyl)-4-isopropylbenzene (4.66 g, 18.4 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. Water was added into the reaction solution and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried on magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was crystallized from ethyl acetate-hexane to obtain 3.70 g (63% yield) of the title compound. Melting point: 153-155° C.
Reaction SMILES: N[C:2]1C=CC=C2[C:3]=1C(=O)N(C1CCC(=O)NC1=O)C(C)=N2.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[C:24]=1[C:25]([OH:27])=[O:26]>C(O)(=O)C>[CH3:2][C:3]1[O:26][C:25](=[O:27])[C:24]2[C:28]([N+:32]([O-:34])=[O:33])=[CH:29][CH:30]=[CH:31][C:23]=2[N:22]=1
Reactant: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: Nc1cccc([N+](=O)[O-])c1C(=O)O
Solvent: CC(=O)O
Product: Cc1nc2cccc([N+](=O)[O-])c2c(=O)o1

Procedure:
In another embodiment, provided herein is a method for preparing 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof; comprising the steps of (a) reacting 2-amino-6-nitrobenzoic acid with an activated acetic acid in a solvent to form 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one; (b) reacting 2-methyl-5-nitro-4H-benzo[d][1,3]oxazin-4-one with 3-aminopiperidine-2,6-dione or a salt thereof in a solvent to form 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione; (c) reducing 3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione in a solvent in the presence of formic acid to form N-(3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolin-5-yl)formamide; and (d) hydrolyzing N-(3-(2,6-dioxopiperidin-3-yl)-2-methyl-4-oxo-3,4-dihydroquinazolin-5-yl)formamide in a solvent to form 3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione, or an enantiomer or a mixture of enantiomers thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof; wherein steps (a), (b), (c), and (d) are each as described herein elsewhere.
Reaction SMILES: C([O:4][CH:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:6][CH2:7][CH:8]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])[C:11](=[O:23])[CH2:10][S:9]1)(=O)C.C([O-])(=O)CCCCCC>>[OH:4][C@@H:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:6][CH2:7][CH:8]1[N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:11](=[O:23])[CH2:10][S:9]1
Reactant: CCCCCC(CCC1SCC(=O)N1CCCCCCC(=O)OC)OC(C)=O
Agent: CCCCCCC(=O)[O-]
Product: CCCCC[C@H](O)CCC1SCC(=O)N1CCCCCCC(=O)O

Procedure:
This compound is prepared exactly by the same method as described in Example 1, Step B, except that the methyl 7-[2-(3-acetyloxyoctyl)-4-oxo-3-thiazolidinyl]-heptanoate is replaced by methyl 7-[2-3(S)-acetyloxyoctyl)-4-oxo-3-thiazolidinyl]heptanoate. Purification of the product resulting from this method by column chromatography on silica gel affords the pure title compound as a pale yellow oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(C)=O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f49) and commercially available acetylchloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[CH3:9].Br[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:42][C:43]([OH:45])=[O:44]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]([NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[CH2:42][C:43]([OH:45])=[O:44])=[CH:22][CH:23]=1)=[O:34])[CH3:9]
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Reactant: O=C(O)Cc1ccccc1Br
Product: Cc1noc(-c2ccc(-c3ccccc3CC(=O)O)cc2)c1NC(=O)OC(C)c1ccccc1Cl

Procedure:
Prepared according to the procedure described in Example 19, Step 1 using {3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-carbamic acid 1-(2-chloro-phenyl)-ethyl ester and 2-bromophenylacetic acid.
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.[NH2:13][CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([NH:13][CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])=[O:5]
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NCC(=O)OCc1ccccc1

Procedure:
A 10-20% excess of BOC-Gly-OH is coupled to the H-Gly-O-Bzl with DCC in dichloromethane for one hour. The solution is filtered and the solvent is removed on a rotary evaporator. The residue is taken up in ethyl acetate and washed successively with 1M KHSO4, water, saturated NaHCO3 solution, and water. The ethyl acetate solution is dried over MgSO4, filtered, and the solvent is removed on a rotary evaporator to form BOC-Gly-Gly-O-Bzl as a semisolid oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH3:21])[C:17]([C:18]([NH2:20])=[O:19])=[C:13]2[N:12]=[CH:11][CH:10]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]1[N:14]2[N:15]=[C:16]([CH3:21])[C:17]([C:18]([NH2:20])=[O:19])=[C:13]2[NH:12][CH2:11][CH:10]=1
Reactant: Cc1nn2c(-c3cc(Cl)ccc3Cl)ccnc2c1C(N)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nn2c(c1C(N)=O)NCC=C2c1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 3.21 g portion of 7-(2,5-dichlorophenyl)-2methylpyrazolo(1,5-a)pyrimidine-3-carboxamide (Example 2) is suspended in 150 ml of glacial acetic acid and stirred under nitrogen at room temperature. Then 1.5 g of sodium cyanoborohydride is added in portions and stirring is continued for 3 hours. The reaction mixture is evaporated to dryness in vacuo and when water is added to the residue a white precipitate forms. This solid is collected and dissolved in dichloromethane, and this solution is washed with an aqueous saturated solution of sodium bicarbonate. Then the organic phase is dried over anhydrous sodium sulfate and filtered. The filtrate is evaporated in vacuo and gives 2.95 g of the product of this example as a white solid, mp 93-96° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.S1C2C=CC=CC=2N=C1NC(C1C=CC=C2C=1CN(C1SC(CCCI)=C(C(OCC)=O)N=1)CC2)=O.[CH3:44][N:45]1[CH2:50][CH2:49][CH:48]([NH:51][C:52]2[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][CH:53]=2)[CH2:47][CH2:46]1.[S:59]1[C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][C:62]=2[N:61]=[C:60]1[NH:68][C:69]([C:71]1[CH:72]=[CH:73][CH:74]=[C:75]2[C:80]=1[CH2:79][N:78]([C:81]1[N:86]=[C:85]([C:87]([O:89][C:90]([CH3:93])([CH3:92])[CH3:91])=[O:88])[C:84]([CH2:94][CH2:95][CH2:96]I)=[CH:83][CH:82]=1)[CH2:77][CH2:76]2)=[O:70]>>[S:59]1[C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][C:62]=2[N:61]=[C:60]1[NH:68][C:69]([C:71]1[CH:72]=[CH:73][CH:74]=[C:75]2[C:80]=1[CH2:79][N:78]([C:81]1[N:86]=[C:85]([C:87]([O:89][C:90]([CH3:92])([CH3:91])[CH3:93])=[O:88])[C:84]([CH2:94][CH2:95][CH2:96][O:58][C:55]3[CH:56]=[CH:57][C:52]([NH:51][CH:48]4[CH2:47][CH2:46][N:45]([CH3:44])[CH2:50][CH2:49]4)=[CH:53][CH:54]=3)=[CH:83][CH:82]=1)[CH2:77][CH2:76]2)=[O:70]
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1CCCI
Reactant: CN1CCC(Nc2ccc(O)cc2)CC1
Agent: CCOC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)sc1CCCI
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(Nc2ccc(OCCCc3ccc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)OC(C)(C)C)cc2)CC1

Procedure:
The compound 104B was prepared as a TFA salt in a similar manner to the synthesis of step 2 of Example 51 by substituting compound 51A and compound 2C with compound 104A and compound 96D, respectively: APCI (+)/LC/MS: 733 (M+H)−.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([Li])CCC.[CH:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[C:23]1([CH:22]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:7][NH:8]3)=[CH:4][CH:3]=2)[OH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Brc1ccc2c(-c3ccccc3)n[nH]c2c1
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1ccc2c(-c3ccccc3)n[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a stirred solution of 6-bromo-3-phenyl-1H-indazole (109 mg, 0.40 mmol) in anhydrous THF (3 mL) was added n-butyl lithium solution (2M in hexanes, 0.47 mL, 0.94 mmol) dropwise at −78° C. under argon. The reaction mixture was stirred at −78° C. for 30 min and at −40° C. for 6 min before benzaldehyde (0.1 mL, 1 mmol) was added at −40° C. The reaction mixture was then stirred at rt for 1 hr. quenched with saturated aqueous ammonium chloride solution (5 mL) and extracted with ethyl acetate (10 mL). The ethyl acetate extract was dried (Na2SO4) and concentrated. Silica gel flash chromatography gave phenyl(3-phenyl-1H-indazol-6-yl)methanol (71 mg, 0.24 mmol, 59% yield) as a solid.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>CO>[NH2:1][C:4]1[C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)Cc1ncccc1[N+](=O)[O-]
Solvent: CO
Product: COC(=O)Cc1ncccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-(3-nitropyridin-2-yl)acetate (1 g, 5 mmol) was dissolved in MeOH and stirred under the atmosphere of H2 at room temperature overnight. LC-MS find the desired product. It was filtered through a pad of Celite and evaporated to get the desired product. It was directly used for the next step. LC-MS: m/z (M+H)=167.1
Reaction SMILES: O.[CH3:2][C@@:3]12[C:11](=[O:12])[CH2:10][CH2:9][C@H:8]1[C@@H:7]1[CH2:13][CH2:14][C:15]3[C@@H:21]([C@H:6]1[CH2:5][CH2:4]2)[CH2:20][CH2:19][C:17](=[O:18])[CH:16]=3.Cl[CH2:23][CH2:24]Cl>>[CH3:2][C@@:3]12[C@:11]([OH:12])([C:23]#[CH:24])[CH2:10][CH2:9][C@H:8]1[C@@H:7]1[CH2:13][CH2:14][C:15]3[C@@H:21]([C@H:6]1[CH2:5][CH2:4]2)[CH2:20][CH2:19][C:17](=[O:18])[CH:16]=3
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reactant: ClCCCl
Solvent: O
Product: C#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C

Procedure:
A water-jacketed glass column of 2.7 cm inner diameter is packed with a suspension of 50.0 g of basic alumina (sold by Shokubai Kasei Kogyo Co. Ltd. under trade name of ACBR-3, calcined at a temperature above 500° C. and pulverized to about 50 mesh) in 100 ml of 1,2-dichloroethane (to a depth of 13.0 cm) and water is passed through the jacket so as to set the temperature at 20° C. In 1400 ml of 1,2-dichloroethane, 20.00 g of crude 19-norethisterone of 91.8% purity which results from ethynylation of 19-norandrost-4-ene-3,17-dione and which contains 1.7% ethynylestradiol in addition to other impurities is dissolved at 20° C. and the resulting solution is introduced on the top of the column at a linear velocity of 2 m/hr using a feed pump. The 1,2-dichloroethane solution passed through the alumina is received in an Erlenmeyer flask. After the solution of 19-norethisterone in 1,2-dichloroethan has been passed, 500 ml of 1,2-dichloroethane is further passed through the alumina to wash it. The two liquids are combined and concentrated to dryness at reduced pressure with 1,2-dichloroethane being distilled off.
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)[C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].C([O-])(=O)C.[NH2+]1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[C:27]2[S:23][C:24](=[O:29])[NH:25][C:26]2=[O:28])=[CH:17][CH:16]=1)[C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: O=C1CSC(=O)N1
Reactant: CN(CCOc1ccc(C=O)cc1)c1nc2ccccc2s1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CN(CCOc1ccc(C=C2SC(=O)NC2=O)cc1)c1nc2ccccc2s1

Procedure:
A solution of 4-[2-(N-methyl-N-(2-benzothiazolyl)amino)ethoxy]benzaldehyde (1.9 g) and 2,4-thiazolidinedione (0.8 g) in toluene (100 ml) containing a catalytic quantity of piperidinium acetate was boiled under reflux in a Dean and Stark apparatus for 2 hours. The mixture was cooled and filtered and the filtered solid was dried to give the title compound (mp 219° C.).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[C:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])[CH3:29].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:28]([C:31]1[CH:36]=[C:35]([N:8]2[C:9](=[O:26])[C:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]2[CH3:27])[CH:34]=[CH:33][CH:32]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCCc1nc(C)n(-c2cccc(C(C)=O)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (5.0 g), (3-acetylphenyl)boronic acid (5.0 g), triethylamine (10.0 mL), pyridine (5.0 mL) and molecular sieves 4 A (10.0 g) in methylene chloride (100 mL) was added copper(II) acetate (5.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (2.20 g, 33%).
Reaction SMILES: C[Mg]Cl.CON(C)[C:7]([C@@H:9]1[CH2:13][S:12][C:11](=[O:14])[N:10]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:8].[C:25](O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[C:7]([C@@H:9]1[CH2:13][S:12][C:11](=[O:14])[N:10]1[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)(=[O:8])[CH3:25]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: COc1ccc(CN2C(=O)SC[C@H]2C(=O)N(C)OC)cc1
Agent: C[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2C(=O)SC[C@H]2C(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A dry three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with a solution of methylmagnesium chloride in THF (0.805 L, 3 M). The solution was purged with nitrogen and cooled to 0° C. In a separate flask, the title compound from Example 4 (250.0 g, 0.805 mol) was dissolved in dry THF (1.0 L). This solution was added to the solution of methylmagnesium chloride at a rate that maintained an internal reaction temperature less than 5° C. The reaction was monitored by HPLC and was complete upon the disappearance of the starting material (approx. 20 minutes after completing the addition). The reaction mixture was slowly added into a 10% citric acid solution (1 L) at a rate that maintained a temperature of less than 25° C. The mixture was diluted with water, and the THF was removed by distillation at 70° C. (80° C. external) and 1 atm. The product was extracted with ethyl acetate, and the organic phase was separated and concentrated by distillation at 76° C. (95° C. external) and 1 atm to a final volume of ˜800 mL. The solution was allowed to cool to room temperature, and n-heptane was added to give a precipitate. The suspension was stirred for 30 minutes, and the solid was isolated by filtration and dried in a vacuum oven at 40° C. overnight to afford the title compound (170 g, 80%).
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C@H:16]3[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[H-].[Na+].Br[CH2:26][CH:27]=[CH:28][CH3:29]>CN(C=O)C>[CH2:26]([O:22][C@H:19]1[CH2:18][CH2:17][C@H:16]([C@H:13]2[CH2:14][CH2:15][C@H:10]([C@H:7]3[CH2:6][CH2:5][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:8]3)[CH2:11][CH2:12]2)[CH2:21][CH2:20]1)[CH:27]=[CH:28][CH3:29]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H]([C@H]3CC[C@H](O)CC3)CC2)CC1
Reactant: CC=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC=CCO[C@H]1CC[C@H]([C@H]2CC[C@H]([C@H]3CC[C@H](CCC)CC3)CC2)CC1
Temperature: 25 °C

Procedure:
To a solution of 10.0 g (33.1 mmol) of trans-4-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)cyclohexanol in 100 ml of DMF was added dropwise, while stirring the solution at room temperature, a suspension of 1.19 g (49.6 mmol) of NaH in 10 ml of DMF. After completion of the dropwise addition, the reaction mixture was stirred for 2 hours and then the temperature of the reaction mixture was gradually allowed to rise up to about 80° C. and a solution of 5.35 g (39.7 mmol) of 1-bromo-2-butene in 20 ml of DMF was added dropwise. After completion of the dropwise addition, the mixture was heated under reflux at the same temperature for 5 hours. After the reaction solution was allowed to cool down to room temperature, the reaction product was poured into an ice-water and extracted with 500 ml of toluene. The organic layer was washed three times with water, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. A silica gel column chromatography (developing solvent: toluene) of the residue gave 5.96 g of crude 1-(2-butenyloxy)-trans-4-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)cyclohexane.