Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][CH2:9][O:8]2)=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=[N:3]1.B(F)(F)F.[CH3:21]COCC.[CH3:26][Si](C=[N+]=[N-])(C)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]([CH:7]2[O:8][CH2:9][CH2:10][C:11](=[O:13])[CH2:21][CH2:12]2)=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=[N:3]1.[CH3:1][N:2]1[C:6]([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][CH2:9][CH2:26][O:8]2)=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=[N:3]1
Reactant: Cn1ncc([N+](=O)[O-])c1C1CC(=O)CCO1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CCOCC
Agent: FB(F)F
Solvent: ClCCl
Product: Cn1ncc([N+](=O)[O-])c1C1CC(=O)CCCO1
Product: Cn1ncc([N+](=O)[O-])c1C1CCC(=O)CCO1
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(2-methyl-4-nitro-pyrazol-3-yl)tetrahydropyran-4-one (300 mg, 1.33 mmol) in DCM (12 mL) at −70° C. was added boron trifluoride etherate (0.75 mL, 1.73 mmol) dropwise followed by a (trimethylsilyl)diazomethane solution (2 M in hexanes, 0.87 mL, 1.73 mmol). The reaction mixture was stirred at −70° C. for 90 min, quenched with water (10 mL), diluted with DCM (12 mL) and warmed to room temperature. The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-one as a colourless solid (121 mg) and its regioisomer 2-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-one (151 mg). To a solution of 7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-one (121 mg, 0.51 mmol) in MeOH (5 mL) at 0° C. was added portionwise NaBH4 (23 mg, 0.61 mmol). Stirring continued for 1 hr and the reaction mixture was quenched with 1 M HCl (5 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (3×20 mL) and the combined organic layers were washed with brine (30 mL), separated, dried over Na2SO4 and concentrated under reduced pressure to give 7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-ol as a 1:1 mixture of diastereomers as a colourless oil (85 mg, 27% over two steps). The product was used without further purification as a 1/1 mixture of diastereoisomers. 1H NMR (400 MHz, CDCl3) δ 8.02 and 8.01 (s, 1H), 5.61-5.56 and 5.54-5.50 (m, 1H), 4.26-4.14 (m, 1H), 4.07 and 4.04 (s, 3H), 3.90-3.80 and 3.81-3.63 (m, 1H), 2.20-1.80 (m, 8H).
Reaction SMILES: CS(O[C@H:6]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([F:20])[F:19])=[CH:14][CH:13]=2)[C:7]1=[O:21])(=O)=O.Cl.[F:23][C@H:24]1[C@H:29]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[CH2:28][CH2:27][NH:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(#N)C>[F:19][CH:18]([F:20])[C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[CH2:9][CH2:10][CH:6]([N:26]3[CH2:27][CH2:28][C@@H:29]([C:30]4[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=4)[C@H:24]([F:23])[CH2:25]3)[C:7]2=[O:21])=[CH:13][CH:14]=1
Reactant: CS(=O)(=O)O[C@H]1CCN(Cc2ccc(C(F)F)cc2)C1=O
Reactant: Oc1ccc([C@@H]2CCNC[C@H]2F)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1C(N2CC[C@@H](c3ccc(O)cc3)[C@H](F)C2)CCN1Cc1ccc(C(F)F)cc1
Temperature: 85 °C
Reaction time: 16 h
Yield: 35.8 %

Procedure:
A solution of (S)-1-(4-(difluoromethyl)benzyl)-2-oxopyrrolidin-3-yl methanesulfonate (500 mg, 1.57 mmol, intermediate M) in 5.0 mL of acetonitrile was added dropwise over 1.5 h to a stirred mixture of 4-((3S,4S)-3-fluoropiperidin-4-yl)phenol, hydrochloride (363 mg, 1.57 mmol, intermediate F) and N,N-diisopropylethylamine (1.09 mL, 6.26 mmol) in 5.0 mL of acetonitrile maintained at 85° C. After complete addition, the reaction mixture was stirred at 85° C. for 16 h. The reaction mixture was concentrated in vacuo. The residue was purified using silica gel column chromatography (0-100% EtOAc/hexanes) to afford a diasteromeric mixture (partial epimerization of the lactam stereocenter) of 1-(4-(difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one (235 mg, 35% yield). A sample of the diastereomeric mixture (780 mg) was separated by preparative chiral SFC (column=Lux Cellulose-2 (21×250 mm, 5 μm); isocratic solvent=20% methanol (with 15 mM ammonia)/80% CO2; temp=35° C.; flow rate=60 mL/min; injection volumn=1.0 mL (˜20 mg/mL in MeOH) stacked @ 13 min intervals; λ=210 nM; Peak 1=19.6 min, Peak 2=24.5 min) to afford the titled compounds of example 6 (Peak-1, 389 mg) and (S)-1-(4-(difluoromethyl)benzyl)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one (Peak 2, 242 mg). Data for Example 6: LC-MS m/z 419.3 (M+H); 1H NMR (500 MHz, chloroform-d) δ 7.50 (d, J=7.9 Hz, 2H), 7.34 (d, J=7.9 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 6.91-6.80 (m, 2H), 6.65 (t, J=56.4 Hz, 1H), 4.96 (s, 1H), 4.77-4.43 (m, 3H), 3.68 (t, J=8.8 Hz, 1H), 3.42-3.33 (m, 1H), 3.29-3.14 (m, 2H), 2.85 (d, J=10.4 Hz, 1H), 2.78-2.69 (m, 1H), 2.69-2.57 (m, 1H), 2.48 (td, J=9.9, 4.9 Hz, 1H), 2.21-2.11 (m, 1H), 2.04 (dq, J=13.0, 8.6 Hz, 1H), 1.94-1.82 (m, 2H)). The relative and absolute configuration of Example 114, P-1 was confirmed by single crystal X-ray analysis.
Reaction SMILES: [Cl-].[OH:2][NH3+:3].[OH-].[Na+].[CH3:6][O:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O>C(O)C>[CH3:6][O:7][CH2:8][C:9](=[N:3][OH:2])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COCC(=O)c1ccccc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCC(=NO)c1ccccc1
Reaction time: 1 h
Yield: 64.2 %

Procedure:
A mixture of hydroxylammonium chloride (10.0 g, 144 mmol) and sodium hydroxide (6.0 g, 150 mmol) in absolute ethanol (200 ml) was stirred for 1 h. The precipitated sodium chloride was filtered off and 2-methoxyacetophenone (10.0 g, 67 mmol) was added to the filtrate. The mixture was heated at reflux for 30 min. The precipitated compound was collected and recrystallised from n-heptane/ethanol 9/1 to give 7.1 g 2-methoxyacetophenone oxime.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:20][C:21]([OH:30])([P:26]([OH:29])(=[O:28])[OH:27])P(O)(=O)O)=[N:10][N:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH:12]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+:35]>CN(C)C=O.O>[Na+:35].[Na+:35].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([CH:20]([P:26]([OH:29])(=[O:27])[OH:28])[CH:21]([OH:30])[P:26]([O-:27])(=[O:28])[O-:29])=[N:10][N:11]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)[CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=P(O)(O)C(O)(Cc1nn(-c2ccc(F)cc2)cc1-c1ccc(Cl)cc1)P(=O)(O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=P([O-])([O-])C(O)C(c1nn(-c2ccc(F)cc2)cc1-c1ccc(Cl)cc1)P(=O)(O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 154.2 %

Procedure:
A solution of 1.9 g of 2-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]-1-hydroxyethane-1,1-diphosphonic acid in 5 ml of dimethylformamide is combined with a solution of 0.8 g of sodium bicarbonate in 10 ml of water and stirred for 2 hours at room temperature. Then the thus-precipitated product is vacuum-filtered, washed with a small amount of water, and dried at 110° C., yielding 1.6 g (76%) of 2-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-3-pyrazolyl]-1-hydroxyethanediphosphonic acid disodium salt, mp above 300° C.
Reaction SMILES: [F:1][C:2]([F:36])([CH:8](O)[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=3)[CH2:18][O:17][N:16]=2)=[C:11]([CH3:34])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].ClC(=O)C(OC)=O>CN(C)C1C=CN=CC=1.C(Cl)Cl.CCOC(C)=O>[F:36][C:2]([F:1])([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:28])[CH3:29])=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:21]=3)[CH2:18][O:17][N:16]=2)=[C:11]([CH3:34])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(F)(F)C(O)c1ccc(C2=NOCN2c2ccc(OC(C)C)c(C(F)(F)F)c2)c(C)c1
Agent: CN(C)c1ccncc1
Agent: COC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)Cc1ccc(C2=NOCN2c2ccc(OC(C)C)c(C(F)(F)F)c2)c(C)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 29 mg (0.06 mmol) of ethyl 2,2-difluoro-3-hydroxy-3-(4-(4-(4-(isopropoxy)-3-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)propanoate (from EXAMPLE 75, Step D) and 21 mg (0.17 mmol) of 4-dimethylaminopyridine in 5.0 mL of CH2Cl2 at ° C. was added 10 μL (0.11 mmol) of methyl chlorooxoacetate. After stirring at 0° C. for 10 min and rt for 20 min, the reaction mixture was diluted with 20 mL of EtOAc and washed with diluted HCl (10 mL), saturated NaHCO3 (10 mL), and brine (10 mL). The organic layer was dried over MgSO4 and concentrated to give the crude ester product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([S:15]([CH3:18])(=O)=O)[N:3]=1.[CH2:19](S)C.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([S:15][CH2:18][CH3:19])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: CCS
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CCSc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, ethanethiol and DBU in DME. EI-MS m/e (%): 246 (M+, 49), 245 ([M—H]+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:5]2.[CH2:17]([S:33](Cl)(=[O:35])=[O:34])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].O>N1C=CC=CC=1>[CH2:17]([S:33]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:5]2)(=[O:35])=[O:34])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: Nc1ccc2[nH]c(-c3ccccc3)cc2c1
Reactant: CCCCCCCCCCCCCCCCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCCCCCS(=O)(=O)Nc1ccc2[nH]c(-c3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
20.8 g of 5-amino-2-phenylindole are dissolved in 200 ml of pyridine, and 32.45 g of hexadecylsulfonyl chloride are added. After stirring for 2 hours at room temperature, a precipitate is obtained by the addition of water. The precipitate is suction filtered and washed with water. It is then stirred into methanol in the cold, suction filtered and recrystallized from ethanol with the addition of a saturated aqueous sodium dithionite solution. The precipitate is suction filtered, washed with water and a little methanol and dried. 47.4 g of the above mentioned compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[NH:15])=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.O=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]1[C:31](OC)=[O:32].[O-]CC.[Na+]>C(O)C>[OH:32][C:31]1[C:19]2[CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23][C:18]=2[N:15]=[C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([N:3]3[CH:4]=[CH:5][N:6]=[C:2]3[CH3:1])=[CH:12][CH:11]=2)[N:16]=1
Reactant: Cc1nccn1-c1ccc(NC(=N)N)cc1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nccn1-c1ccc(Nc2nc(O)c3c(n2)CCN(C(=O)OC(C)(C)C)C3)cc1
Temperature: 110 °C
Yield: 55.8 %

Procedure:
1-(4-(2-Methyl-1H-imidazol-1-yl)phenyl)guanidine (1.8 g, 8.36 mmol, example 9e), 1-tert-butyl 3-methyl 4-oxopiperidine-1,3-dicarboxylate (2.151 g, 8.36 mmol) and sodium ethoxide (0.569 g, 8.36 mmol) in ethanol (10 mL) were charged in a thick glass vial, which was sealed and heated under microwave irradiation at 110° C. for 2 h. The reaction mixture was allowed to reach room temperature and the solvent was evaporated under reduced pressure. The crude was dissolved in ethyl acetate and washed with water. The organic phase was dried under MgSO4 and concentrated under reduced pressure yielding tert-butyl 4-hydroxy-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (1.970 g, 55.8%). The product was used as such in the subsequent step. MS (ES+) m/z 423.3 (M+H)+
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22]1>>[CH2:19]([O:18][C:16]([N:6]1[CH:7]([C:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:21][CH:22]=2)[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)=[O:17])[CH3:20]
Reactant: CCOC(=O)Cl
Reactant: c1ccc2[nH]ccc2c1
Reactant: c1ccc2c(c1)cnc1ccccc12
Product: CCOC(=O)N1c2ccccc2-c2ccccc2C1c1c[nH]c2ccccc12

Procedure:
6-(1H-Indol-3-yl)-6H-phenanthridine-5-carboxylic acid ethyl ester was prepared from phenanthridine, ethyl chloroformate, and indole according to GP 2. Yield, 50%. (+)-ESI-MS: m/z=369 [M+H]+, 252 [M-indole+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:43](=[O:49])[O:44][C:45](Cl)(Cl)Cl)Cl.[F:51][C:52]1[CH:62]=[CH:61][CH:60]=[CH:59][C:53]=1[O:54][CH2:55][CH2:56]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:43](=[O:49])[O:44][CH2:45][CH2:56][CH2:55][O:54][C:53]2[CH:59]=[CH:60][CH:61]=[CH:62][C:52]=2[F:51])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCCOc1ccccc1F
Reactant: COc1cc2ncnc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCCCOc4ccccc4F)c(C)c3C)c2cc1OC
Temperature: 25 °C
Yield: 49.9 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2,3-dimethylaniline (65 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (90 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-(2-fluorophenoxy)-1-propanol (51 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (52 mg, yield 46%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4]([CH:6]([CH3:15])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])[CH3:5].[Br:16]Br>C(O)(=O)C>[CH3:1][CH2:2][CH2:3][CH:4]([C:6]([Br:16])([CH3:15])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])[CH3:5]
Reactant: CCCC(C)C(C)C(=O)c1ccccc1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCCC(C)C(C)(Br)C(=O)c1ccccc1
Temperature: 0 °C
Yield: 70.6 %

Procedure:
To a solution of the ketone 3 (5.03 g, 0.025 mol) in 15 ml of glacial acetic acid, Br2 (3.94 g, 0.025 mol) was added dropwise, with stirring at 0° C. After the addition was complete the ice bath was removed and the solution was stirred for 2 h at 23° C. The reaction mixture was quenched by the addition of water and after cooling it was extracted with ether. After drying and concentration under vacuum, the residue was purified by flash chromatography, eluting with hexanes, to afford 5.0 g (72%) of compound 4. 1H NMR (100 MHz, CDCl3) δ 0.8 (t, 3H), 1.4 (m, 6H), 1.8 (d, J=6.5 Hz, 3H), 2.7 (t, J=6.4 Hz, 2H), 5.25 (q, 1H), 7.25 (d, J=8.0 Hz, 2H), 7.9 (d, J=8.2 Hz, 2H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.CS(Cl)(=O)=O.[Br:28][C:29]1[N:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CN(C=O)C>[Br:28][C:29]1[N:34]=[CH:33][C:32]([O:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Oc1ccc(Br)nc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(Br)nc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
A mixture of N-Boc-4-piperidinemethanol (5.0 g, 23.22 mmol), Et3N (4.85 mL, 34.83 mmol) in CH2Cl2 (100 mL) at 0° C. was treated dropwise with methanesulfonyl chloride (2.16 mL, 27.86 mmol). The reaction mixture was stirred at 0° C. for 0.5 h, diluted with CH2Cl2 and washed with water and brine. The CH2Cl2 layer was dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was mixed with 6-bromo-3-pyridinol (6.06 g, 34.83 mmol) and K2CO3 (6.41 g, 46.44 mmol) in DMF. The resulting mixture was heated at 65° C. overnight, cooled to ambient temperature and partitioned between water and EtOAc. The organic layer was separated and washed with 2N NaOH, water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product, which was purified by chromatography on a silica gel column to give 5.88 g (68%) of 1,1-dimethylethyl 4-{[(6-bromo-3-pyridinyl)oxy]methyl}-1-piperidinecarboxylate. 1H NMR (400 MHz, CDCl3): δ 8.00 (1H, d, J=3.1 Hz), 7.32 (d, 1H, J=8.6 Hz), 7.05 (dd, 1H, Ja=8.7 Hz, Jb=3.2 Hz), 4.13 (bs, 2H), 3.79 (d, 2H, J=6.5 Hz), 2.80-2.65 (m, 2H), 2.00-1.85 (m, 1H), 1.80-1.70 (m, 2H), 1.43 (s, 9H), 1.30-1.15 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH3:25][N:26]([C:34]1[N:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:36][N:35]=1)C(=O)OC(C)(C)C>>[CH3:25][NH:26][C:34]1[N:39]=[CH:38][C:37]([C:2]2[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]4)[S:8][C:6]=3[N:7]=2)=[CH:36][N:35]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: OC1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: CNc1ncc(-c2nc(N3CCOCC3)c3cc(CN4CCC(O)CC4)sc3n2)cn1
Yield: 24 %

Procedure:
1-((2-chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperidin-4-ol (187 mg, 0.5 mmol) was utilized in a Suzuki coupling with tert-butyl methyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)carbamate (238 mg, 0.7 mmol) according to General Procedure Suzuki to provide 381 (53 mg) after reverse phase HPLC purification. MS (Q1) 442 (M)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12](N)=[O:13])[C:5](=[CH:10][CH:11]=1)[C:6]([NH:8][CH3:9])=[O:7].[Cl:15][CH2:16][CH:17]1[O:19][CH2:18]1>FC(F)(F)CO>[Cl:15][CH2:16][CH:17]([OH:19])[CH2:18][NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[N:8]([CH3:9])[C:6](=[O:7])[C:5]2=[CH:10][CH:11]=1
Reactant: CNC(=O)c1ccc(N)cc1C(N)=O
Reactant: ClCC1CO1
Solvent: OCC(F)(F)F
Product: CN1C(=O)c2ccc(NCC(O)CCl)cc2C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.3 %

Procedure:
Twenty-five grams (0.142 mole) 4-amino-N-methylphthalamide, prepared according to the method described in J. Chem. Soc. 26: (1937), and 20.7 g (0.21 mole) 1-chloro-2,3-epoxypropane were added to 150 ml 2,2,2-trifluoroethanol and the reaction mixture was heated to reflux with stirring for 48 hrs. Seventy to eighty ml of 2,2,2-trifluoroethanol was removed by distillation and a heavy yellow precipitate formed when the remaining solution cooled to room temperature. This precipitate was triturated with ethyl acetate, collected by filtration and dried to give 29.5 g (77% yield) of the desired intermediate m.p. 136°-138.5° C. Calculated for C12H13ClN2O3 ; C, 53.64; H, 4.88; N, 10.45. Found: C, 53.87; H, 4.85; N, 10.81.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=2)=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[H-].[Na+].[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>N1C=CC=CC=1.CN(C=O)C>[N+:1]([C:4]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:16]=2)=[CH:7][C:5]=1[NH:6][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1ccc(-c2ccc([N+](=O)[O-])c(N)c2)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-c2ccc([N+](=O)[O-])c(NC(=O)c3ccc(OC)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.3 %

Procedure:
A suspension of 102 (599 mg, 2.20 mmol), NaH 60% (141 mg, 3.52 mmol) and 4-methoxybenzoyl chloride (450 mg, 2.64 mmol) in pyridine (5 ml) and DMF (12 ml) was stirred at room temperature during 48 h. The solid was filtered out and rinsed with MeOH to give 584 mg (82%) of the title compound 103 as a yellow solid. 1H NMR: (400 MHz, DMSO) δ (ppm): 10.72 (s, 1H), 8.13-8.08 (m, 3H), 7.96 (d, J=8.8 Hz, 2H), 7.90 (d, J=8.6 Hz, 2H), 7.74 (dd, J=8.6, 2.2 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H).
Reaction SMILES: C([C:3]([CH2:16][CH3:17])(P(=O)([O-])[O-])/[C:4](/[CH3:11])=[CH:5]/[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C([Li])CCC.[CH3:23][C:24]1([CH3:46])[CH2:33][CH:32]=[C:31]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[C:30]2[CH:29]=[C:28](/[C:41](/C)=[CH:42]/C=O)[CH:27]=[CH:26][C:25]1=2>C1COCC1.CCOCC>[CH3:11]/[C:4](/[CH:3]=[CH:16]/[CH:17]=[C:41](/[C:28]1[CH:27]=[CH:26][C:25]2[C:24]([CH3:23])([CH3:46])[CH2:33][CH:32]=[C:31]([C:34]3[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=3)[C:30]=2[CH:29]=1)\[CH3:42])=[CH:5]\[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)/C=C(\C)C(CC)(CC)P(=O)([O-])[O-]
Reactant: C/C(=C\C=O)c1ccc2c(c1)C(c1ccc(C)cc1)=CCC2(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(C)/C=C/C=C(\C)c1ccc2c(c1)C(c1ccc(C)cc1)=CCC2(C)C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of diethyl-(E)-3-ethoxycarbonyl-2-methylallylphosphonate [prepared in accordance with J. Org. Chem. 39: 821 (1974)] 264.0 mg, (1.00 mmol) in THF (2 ml) was added 26.0 mg (0.41 mmol, 0.65 ml)of n-butyllithium in hexanes (1.6 M solution) followed immediately by the addition of (E)-3-(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalen-yl)-2-butenal (Compound X) 82.0 mg, 0.26 mmol) in THF (3 ml). After 1 hour, the reaction mixture was diluted with ether (60 ml), washed with water (5 ml), saturated aqueous NaCl (5 ml) and dried over MgSO4. After removal of the solvents under reduced pressure, the title compound was isolated as an oil by column chromatography (5% EtOAc/hexanes, followed by HPLC using 1% EtOAc/hexanes). 1H NMR (acetone-d6): δ7.36-7.43 (2H, m), 7.18-7.27 (4H, m), 7.17 (1H, d, J=1.7 Hz), 7.08 (1H, dd, J=11.2, 15.2 Hz), 6.46 (1H, d, J=11.2 Hz), 6.38 (1H, d, J=15.2 Hz), 5.98 (1H, t, J=4.7 Hz), 5.78 (1H, s), 4.10 (2H, q, J=7.1 Hz), 2.35 (3H, s), 2.33 (3H, s), 2.32 (2H, d, J=4.7 Hz), 2.12 (3H, s), 1.31 (6H, s), 1.22 (3H, t, J=7.1 Hz).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[SH:10][C:11]1[S:12][CH2:13][CH2:14][N:15]=1.Cl[O-].[Na+]>O>[CH:1]1([NH:7][S:10][C:11]2[S:12][CH2:13][CH2:14][N:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: SC1=NCCS1
Agent: [Na+]
Agent: [O-]Cl
Agent: [OH-]
Solvent: O
Product: C1CCC(NSC2=NCCS2)CC1
Yield: 86.7 %

Procedure:
A mixture of 12.3 g (124 mmole) of cyclohexylamine and 30 ml of water was thoroughly stirred in an ice bath, and 30 ml of a 1N sodium hydroxide aqueous solution having dissolved therein 3.57 g (30 mmole) of 2-mercaptothiazoline and 22.3 ml (30 mmole) of a 10% sodium hypochlorite aqueous solution were simultaneously added thereto dropwise. After allowing the mixture to react at room temperature for 1 hour, the reaction mixture was filtered with suction. The resulting solid was washed with water and dried under reduced pressure to obtain 5.61 g (26 mmole) of the titled compound in a percent yield of 87%.