Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4][CH2:3]1.Cl[C:29]([O:31][CH3:32])=[O:30]>>[CH3:32][O:31][C:29]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][O:20][C:21]4[CH:25]=[CH:24][O:23][N:22]=4)[O:16][C:15]3=[O:26])=[CH:10][C:9]=2[F:27])[CH2:4][CH2:3]1)=[O:30]
Reactant: COC(=O)Cl
Reactant: NC1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Product: COC(=O)NC1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Yield: 43.6 %

Procedure:
Using essentially the technique of Example 94, starting with 3-(4-(4-aminopiperidin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one (249 mg, 0.66 mmol) and methyl chloroformate (70 mg, 0.74 mmol) in place of methanesulfonyl choride, gave the desired product (125 mg) after chromatography.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:33])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27]OS(C)(=O)=O)[O:24][CH2:23]2)[CH:17]([CH:34]([OH:36])[CH3:35])[C:16]3=[O:37])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[I-:38].[Na+]>CC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:33])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][I:38])[O:24][CH2:23]2)[CH:17]([CH:34]([OH:36])[CH3:35])[C:16]3=[O:37])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: [I-]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(COS(C)(=O)=O)C3)C(C)C12
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CI)C3)C(C)C12
Yield: 55.8 %

Procedure:
A mixture of 0.80 g of product from Example 57, 0.431 g of sodium iodide and 20 ml of acetone is heated at reflux temperature for 5 days. The reaction is concentrated in vacuo and the residue purified by chromatography (silica Gel: 80% ethyl acetate/hexane) to give 0.472 g of the desired product.
Reaction SMILES: O1CC[O:3][CH:2]1[C:6]1[S:10][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[CH:8][C:7]=1[CH3:16].C([O:20][CH2:21][C:22]([N:24]=[C:25]([N:28]([CH3:37])[N:29]=CC1C=CC=CC=1)SC)=O)(=O)C.Cl>C1(C)C=CC=CC=1>[OH:20][CH2:21][C:22]1[N:24]=[C:25]([NH:15][CH2:14][CH2:13][CH2:12][CH2:11][C:9]2[S:10][C:6]([CH:2]=[O:3])=[C:7]([CH3:16])[CH:8]=2)[N:28]([CH3:37])[N:29]=1
Reactant: Cc1cc(CCCCN)sc1C1OCCO1
Reactant: CSC(=NC(=O)COC(C)=O)N(C)N=Cc1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1cc(CCCCNc2nc(CO)nn2C)sc1C=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.7 %

Procedure:
A mixture of 4-[5-(1,3-dioxolan-2-yl)-4-methyl-2-thienyl]-butanamine (2.73 g) and methyl N-[2-(acetoxy)acetyl]-1-methyl-2-(phenylmethylene)-hydrazinecarboximidothioate (3.38 g) was heated to 60° for 2 h. Toluene (20 ml) and 5N hydrochloric acid (12 ml) were added and the mixture stirred at room temperature for 18 h. The mixture was basified to pH 8, washed with toluene, basified to pH 10 and extracted with ethyl acetate. The extract was evaporated to give an oil which was purified by column chromatography on silica using 3:1 ethyl acetate:methanol as eluent to give the title compound as a pale yellow solid (0.6 g) m.p. 118°-121° (softens).
Reaction SMILES: [CH2:1]([C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][N:6]=1)[CH2:2][CH:3]=C.[O:14]1CCOCC1.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O.C(OCC)(=O)C>[O:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:5]([CH2:1][CH2:2][CH:3]=[O:14])=[N:6]1
Reactant: C=CCCc1noc2ccccc12
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=CCCc1noc2ccccc12
Reaction time: 1 h

Procedure:
Compound 26 (549 mg, 3.2 mmol), water (5 mL), 1,4-dioxane (15 mL) and osmium tetroxide (15 mg, 0.06 mmol) were stirred for 5 min. in a small flask. Sodium metaperiodate (1.56 g, 7.3 mmol) was added over 30 min. and the suspension was then stirred for 1 hour. Ethyl acetate and water were added. The phases were separated and the aqueous phase was extracted with ethyl acetate and dichloromethane. The combined organic phases were dried over magnesium sulphate and evaporated to dryness to produce 784 mg of crude 27, which was used directly without further purification in the synthesis compound 28.
Reaction SMILES: [Li].[CH3:2][O:3][C:4]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O>CCOCC>[CH3:2][O:3][C:4]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][CH2:6][CH2:5][CH2:4][OH:3]
Reactant: COc1cccc(C=O)c1OC
Agent: [Li]
Solvent: CCOCC
Product: COc1cccc(CCCCO)c1OC
Reaction time: 1 h
Yield: 157.5 %

Procedure:
To 0.8 g (0.12 g-atoms) of lithium ribbon cut in small pieces in 50 mL of anhydrous ether stirred at room temperature under an argon atmosphere was added 12 g (0.06 mol) of 3-bromo-propan-1-ol 1-ethoxy ethyl ether [P. E. Eaton, G. F. Cooper, R. C. Johnston, and R. H. Mueller, J. Org. Chem. 37, 1947 (1972)]. After about 1 mL was added, the reaction mixture was cooled in an ice-salt bath and the rest of the bromo compound was added dropwise over 35 minutes. Stirring was continued with cooling for 1.5 hours and then 7.5 g (0.045 mol) of 2,3-dimethoxybenzaldehyde in 45 mL of anhydrous ether was added dropwise over 30 minutes. After 1 hour, the cooling bath was removed and stirring was continued at room temperature for 1 hour. The reaction mixture was poured into half-saturated ammonium sulfate solution. The ether layer was separated, dried (Na2SO4) and concentrated to an oil (13.9 g). Ethanol (25 mL), water (25 mL) and 2 mL of concentrated hydrochloric acid were added and the solution was left at room temperature for 35 minutes. Potassium carbonate was added with stirring until the mixture was basic. The ethanol was removed under reduced pressure and the product was extracted with ethyl acetate. The dried extract was concentrated to an oil (12.0 g). This was dissolved in 150 mL of ethanol, 1 g of 10% palladium on carbon was added and the mixture was shaken on a Parr hydrogenator under an initial hydrogen pressure of 55 psi for 5 hours. The reaction mixture was filtered through Celite and the filtrate was concentrated to an oil. Purification by HPLC using 30% ethylacetate-hexane gave 7.45 g (79% yield) of 4-(2,3-dimethoxyphenyl)butan-1-ol.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].F[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]([C:12]2[CH:17]=[N:16][CH:15]=[N:14][CH:13]=2)[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(Nc2cncnc2)cc1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Product: CS(=O)(=O)c1ccc(N(c2ccc(S(C)(=O)=O)cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-methylsulfonylphenyl)-amino]pyrimidine and 4-fluoro-methanesulfonylbenzene
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[N:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.C([O-])(=O)C.[NH4+].[N+:24]([CH3:27])([O-:26])=[O:25]>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[N:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:27][N+:24]([O-:26])=[O:25]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(-n2ccc(C(F)(F)F)n2)cc1Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1ccc(-n2ccc(C(F)(F)F)n2)cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-chloro-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]benzaldehyde (i.e. the product of Step A; 6.0 g, 0.025 mol) in acetic acid (24 mL) was added ammonium acetate (5.6 g, 73 mmol), and the resulting mixture was stirred for 15 min at 0° C. Nitromethane (12.5 g, 204 mmol) was then added, and the mixture was stirred at 80° C. for 2 h. The reaction mixture was poured into ice water and extracted with ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (2×250 mL), and the combined organic layers were washed with brine (200 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluted with 30% ethyl acetate in hexanes to afford the title compound (7.1 g).
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24](O)=[O:25])[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:59][O:60][CH:61]1[CH2:66][CH2:65][N:64]([CH2:67][C:68]2[CH:73]=[CH:72][C:71]([CH2:74][NH:75][CH3:76])=[CH:70][CH:69]=2)[CH2:63][CH2:62]1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([N:75]([CH2:74][C:71]3[CH:70]=[CH:69][C:68]([CH2:67][N:64]4[CH2:65][CH2:66][CH:61]([O:60][CH3:59])[CH2:62][CH2:63]4)=[CH:73][CH:72]=3)[CH3:76])=[O:25])[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: CNCc1ccc(CN2CCC(OC)CC2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)O)co2)C2CC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)N(C)Cc3ccc(CN4CCC(OC)CC4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)furan-3-carboxylic acid (40 mg, 0.105 mmol), EDCI (28 mg, 0.158 mmol), HOBt (21 mg, 0.16 mmol), DIPEA (0.04 mL, 0.21 mmol), 1-{4-[(4-methoxypiperidin-1-yl)methyl]phenyl}-N-methylmethanamine dihydrochloride (36 mg, 0.13 mmol) and DCM (10 mL).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[C:6]#[N:7].[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29]>>[C:6]([C:5]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:3][CH2:2][N:22]([CH3:21])[CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29])#[N:7]
Reactant: CNCCc1cccc(C(=O)OC)c1
Reactant: COc1ccc(C(C#N)(CCCBr)C(C)C)cc1OC
Product: COC(=O)c1cccc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)c1

Procedure:
Reaction of 1f with 2d produced 3o. MS found M+H=453. The oxalate salt of 3o was recrystallized from ethyl acetate; mp 135-136° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:20]=[C:7]3[N:8]=[CH:9][CH:10]=[C:11]([S:12][C:13]4[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=4)[N:6]3[N:5]=2)[CH2:3][CH2:2]1.Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)=[N:24][N:23]=1>CC(O)(C)C.C(Cl)Cl>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:22]([NH:19][C:16]3[CH:15]=[CH:14][C:13]([S:12][C:11]4[N:6]5[N:5]=[C:4]([CH:1]6[CH2:3][CH2:2]6)[CH:20]=[C:7]5[N:8]=[CH:9][CH:10]=4)=[CH:18][CH:17]=3)=[N:23][N:24]=2)=[CH:37][CH:36]=1
Reactant: Nc1ccc(Sc2ccnc3cc(C4CC4)nn23)cc1
Reactant: Clc1ccc(-c2nnc(Cl)c3ccccc23)cc1
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: Clc1ccc(-c2nnc(Nc3ccc(Sc4ccnc5cc(C6CC6)nn45)cc3)c3ccccc23)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A resealable tube charged with a mixture of 4-(2-cyclopropylpyrazolo[1,5-a]pyrimidin-7-ylthio)benzenamine (100 mg, 0.354 mmol) and 1-chloro-4-(4-chlorophenyl)phthalazine (97 mg, 0.354 mmol) in tBuOH (2 mL) was heated to 100° C. After 3 hrs, the mixture was cooled to RT, diluted with CH2Cl2, and washed with water and brine. After drying the organic fraction with sodium sulfate, the solvent was removed in vacuo. The residue was purified by silica gel chromatography using 20-90% Hexanes:EtOAc to afford 4-(4-chlorophenyl)-N-(4-(2-cyclopropylpyrazolo[1,5-a]pyrimidin-7-ylthio)phenyl)phthalazin-1-amine. MS: Found M+H+=521.2.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[C:9]([S:13][C:14]2[C:15]([F:34])=[CH:16][C:17]([N+:31]([O-])=O)=[C:18]([CH:20]=[C:21]([CH2:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:22]#[N:23])[CH:19]=2)[CH:10]=[CH:11][CH:12]=1.[NH4+].[Cl-].CO>[Zn].C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[CH:8]=[C:9]([S:13][C:14]2[CH:19]=[C:18]3[C:17](=[CH:16][C:15]=2[F:34])[N:31]=[C:22]([NH2:23])[C:21]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:20]3)[CH:10]=[CH:11][CH:12]=1
Reactant: N#CC(=Cc1cc(Sc2cccc(C3OCCCO3)c2)c(F)cc1[N+](=O)[O-])CC1CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc2cc(F)c(Sc3cccc(C4OCCCO4)c3)cc2cc1CC1CCOCC1

Procedure:
In three μwave tubes 3-[5-(3-[1,3]dioxan-2-yl-phenylsulfanyl)-4-fluoro-2-nitro-phenyl]-2-(tetrahydro-pyran-4-ylmethyl)-acrylonitrile (0.25 g, 0.52 mmol, each tube), Zn (3 g, 0.046 mol, each tube), NH4Cl (0.98 g, 0.018 mol, each tube), CH3OH (3 mL, in each tube), and THF (1 mL, in each tube) were reacted via μwave @ 300W, 130° C. for 12 min. The resulting mixtures were combined, filtered through Celite®, and the solvent removed to yield a residue, which was purified by silica column chromatography (50% EtOAc/heptanes) to yield a solid.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][NH:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.C(#N)C.C(N(CC)CC)C.FC(F)(F)S(O[CH2:45][C:46]([F:52])([F:51])[C:47]([F:50])([F:49])[F:48])(=O)=O>>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][N:21]([CH2:45][C:46]([F:52])([F:51])[C:47]([F:50])([F:49])[F:48])[CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(CC(F)(F)C(F)(F)F)C4)c3)n2)cn1
Temperature: 45 °C
Yield: 5.9 %

Procedure:
To a solution of 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (Example 62; 30.0 mg, 0.0694 mmol) in acetonitrile (694 μL, 0.0694 mmol) was added triethylamine (38.7 μL, 0.278 mmol) and 2,2,3,3,3-pentafluoropropyl trifluoromethanesulfonate (39.1 mg, 0.139 mmol). The reaction mixture was heated to 45° C. for 2 hours. The crude reaction mixture was purified by reverse phase HPLC to afford 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(2,2,3,3,3-pentafluoropropyl)azetidin-3-yl)acetonitrile (2.0 mg, 5.9% yield). MS (apci) m/z=492.2 (M+H).
Reaction SMILES: CO[CH2:3][N:4]([CH2:12][Si](C)(C)C)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:17]1([O:22][C:23]2[CH:24]=[C:25](/[CH:31]=[CH:32]/[C:33]([O:35][CH3:36])=[O:34])[CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[CH2:21][CH2:20][CH2:19][CH2:18]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:17]1([O:22][C:23]2[CH:24]=[C:25]([C@H:31]3[C@H:32]([C:33]([O:35][CH3:36])=[O:34])[CH2:3][N:4]([CH2:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:12]3)[CH:26]=[CH:27][C:28]=2[O:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COC(=O)/C=C/c1ccc(OC)c(OC2CCCC2)c1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(OC)c(OC2CCCC2)c1
Reaction time: 12 h
Yield: 85.5 %

Procedure:
To a solution of N-methoxymethyl-N-(phenylmethyl)trimethylsilylmethylamine (2.84 g, 12 mmol) and (E)-methyl 3-(3-cyclopentoxy-4-methoxyphenyl)prop-2-enoate (2.76 g, 10 mmol) in 20 mL of CH2Cl2 cooled to 0° C. was added a 1 mL of a 1M solution of trifluoroacetic acid. Stirring was continued for 12 hr, and the solution was partitioned between ether and sat. NaHCO3. The layers were separated and the aqueous layer was extracted ethyl acetate (2×). The combined organic layers were dried (K2CO3), filtered, and concentrated under reduced pressure to a pale yellow oil. Chromatography on silica gel (3:1, hexanes:ethyl acetate) provided trans-3-(3-cyclopentoxy-4-methoxyphenyl)-4-methoxycarbonyl-1-(phenylmethyl)pyrrolidine (3.5 g, 86%) as a colorless oil. 1H-NMR (300 MHz): δ 2.74-3.09 (m, 5), 3.67 (s, 3), 3.81 (s, 3), 4.75 (m, 1).
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@H:17]([CH2:28][OH:29])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C=C1C2[C@](C)(CCC(=[O:49])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1>>[OH:29][CH2:28][C@@H:17]1[CH:18]2[C@:23]([CH3:24])([CH2:22][CH2:21][C:20](=[O:49])[CH2:19]2)[C@@H:25]2[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]2)([CH3:5])[C:3](=[O:2])[CH2:8][CH2:7]3)[CH2:16]1
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Reactant: C[C@]12CCCCC1[C@@H](CO)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCC(=O)CC1[C@@H](CO)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 85 %

Procedure:
The title compound II-ad was prepared in 85% yield from 3,3:17,17-bis(ethylendioxy)-6α-hydroxymethylandrostane by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.50 (3H, m), 2.52-0.74 (21H, m), 1.11 (3H, s), 0.88 (3H, s).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][C@H:29]4[C@H:33]([OH:34])[CH2:32][NH:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][C@H:29]4[C@H:33]([OH:34])[CH2:32][N:31]([C:35](=[O:38])[CH2:36][CH3:37])[CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: CCC(=O)Cl
Reactant: COc1cc(-c2ccnc3c(C(=O)N[C@@H]4CNC[C@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: CCC(=O)N1C[C@@H](O)[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ccnc23)C1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3R*,4R*)-4-hydroxypyrrolidin-3-yl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f24) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([O:14][C:15]([C:17]1[CH:22]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[C:21]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:20]([CH3:34])[NH:19][C:18]=1[CH3:35])=[O:16])[CH3:13].C([O-])(=O)C.[Na+]>C(Cl)Cl>[CH2:32]([O:31][C:29]([C:21]1[CH:22]([C:23]2[CH:24]=[N+:25]([O-:9])[CH:26]=[CH:27][CH:28]=2)[C:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])=[C:18]([CH3:35])[NH:19][C:20]=1[CH3:34])=[O:30])[CH3:33]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1cccnc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccc[n+]([O-])c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 2.1 g of 3-chloroperbenzoic acid in 40 ml of methylene chloride is added dropwise to a mixture of 3.3 g of 2,6-dimethyl-4-(3-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and 1.4 g of sodium acetate in 50 ml of methylene chloride. The reaction mixture is stirred at room temperature for 20 hours and extracted with a 2N aqueous sodium carbonate solution and then twice with an aqueous iron(II) sulphate solution. The organic solution is dried and concentrated by evaporation under reduced pressure. The residue is chromatographed over 400 g of silica gel, there being used as liquid phase a 95:5 mixture of chloroform and methanol and the chromatograph being effected by means of thin layer chromatography (silica gel; mobile phase: chloroform/methanol 95:5). The eluate, which contains the main portion of the desired compound, is concentrated by evaporation, and the residue is crystallised from acetonitrile. In this manner, 2,6-dimethyl-4-(1-oxido-3-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is obtained, which melts at 191°-193° and is identical to the product obtainable in accordance with the process of Example 2.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:21])[C:8]([C@H:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:14][OH:15])=[C:9]2[OH:12])=[CH:4][CH:3]=1.N1C=CN=C1.[C:27](Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29].[NH4+].[Cl-]>C(Cl)Cl>[C:27]([O:15][CH2:14][C@H:13]([C:8]1[C:7]([CH3:21])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=2)[C:9]=1[OH:12])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1cc2ccc(Br)cc2c(O)c1[C@@H](CO)OC(C)(C)C
Reactant: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: Cc1cc2ccc(Br)cc2c(O)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of (S)-7-bromo-2-(1-tert-butoxy-2-hydroxyethyl)-3-methylnaphthalen-1-ol (1.84 g, 5.20 mmol) in CH2Cl2 (15 mL) added imidazole (426 mg, 6.25 mmol) and pivalyl chloride (705 μL, 5.7 mmol). The reaction was stirred at room temperature for 36 h. A saturated solution of NH4Cl was added. The layers were separated, and the organic layer was dried, filtered, and concentrated in vacuo. The crude material was purified by column chromatography (EtOAc/hexanes) to give the product. 1H-NMR: 400 MHz, (CDCl3) δ: 8.21 (s, 1H), 7.63 (m, 2H), 7.26 (s, 1H), 5.47 (dd, J=10, 3 Hz, 1H), 4.62 (dd, J=12, 10 Hz, 1H), 4.14 (dd, J=12, 3 Hz, 1H), 2.75 (s, 3H), 1.22 (s, 9H) 1.11 (s, 9H).
Reaction SMILES: COC[O:4][CH2:5][C:6]1[N:7]=[C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:9][C:10]=1[CH2:11][CH2:12][CH3:13].S(=O)(=O)(O)O.O1CCCC1>C(OCC)(=O)C>[C:14]1([C:8]2[O:9][C:10]([CH2:11][CH2:12][CH3:13])=[C:6]([CH2:5][OH:4])[N:7]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCc1oc(-c2ccccc2)nc1COCOC
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1oc(-c2ccccc2)nc1CO
Yield: 95.7 %

Procedure:
A mixture of 4-methoxymethoxymethyl-2-phenyl-5-propyloxazole (2.64 g), 10% sulfuric acid (10 mL) and tetrahydrofuran (100 mL) was heated under reflux for 24 hrs. To the reaction mixture was added ethyl acetate, and the mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give (2-phenyl-5-propyl-4-oxazolyl)methanol as a colorless oil (2.10 g, 96%).
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12]O)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.O=S(Cl)[Cl:22].Cl>>[CH2:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][Cl:22])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@H]1CC[C@H](CCO)CC1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCC[C@H]1CC[C@H](CCCl)CC1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A mixture of 31 g (0.17 mol) of 2-(trans-4'-butylcyclohexyl) ethanol and 14 g (0.18 mol) of anhydrous pyridine was stirred over an ice water bath and 25 g (0.21 mol) of SOCl2 was added drop-wise to the mixture. The resulting reaction product was stirred and heated with a mantle heater at 105° to 110° C. for 3 hours. The reaction product was cooled to room temperature and poured into a beaker containing ice and concentrated hydrochloric acid. The oily layer was separated out and the aqueous layer was extracted with chloroform. The two layer were combined and washed with an aqueous 10% hydrochloric acid solution and water. The chloroform was distilled off. The residual liquid was distilled in a vacuum (b.p. 96° C./3 mmHg) to yield 30 g (0.15 mol) of 2-(trans-4'-butylcyclohexyl)-1-chloroethane.