Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[CH:18][C:17]4=[CH:20][CH:21]=[C:22]([C:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=5)[N:16]4[N:15]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].[CH3:38][S:39](Cl)(=[O:41])=[O:40]>>[CH3:38][S:39]([N:26]1[CH2:25][CH:24]=[C:23]([C:22]2[N:16]3[C:17]([CH:18]=[N:19][C:14]([NH:13][C:10]4[CH:11]=[CH:12][C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[CH:8][CH:9]=4)=[N:15]3)=[CH:20][CH:21]=2)[CH2:28][CH2:27]1)(=[O:41])=[O:40]
Reactant: CS(=O)(=O)Cl
Reactant: C1=C(c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)N1CC=C(c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)CC1
Reaction time: 0.08 h
Yield: 36.7 %

Procedure:
Into a 8-dram vial, (4-Morpholin-4-yl-phenyl)-[7-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine (0.080 g, 0.21 mmol), Acetonitrile (15 mL, 290 mmol), Potassium carbonate (0.0587 g, 0.425 mmol) were added and stirred for 5 minutes. Methanesulfonyl chloride (0.0256 g, 0.223 mmol) was added. The reaction was stirred at room temperature over night. The solvent was removed under vacuum. The reaction was partitioned with water and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with DCM and methanol as eluant (0 to 10% methanol). The collected fractions afforded [7-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-morpholin-4-yl-phenyl)-amine as a yellow solid (35 mg, 36%). LCMS (E/I+) 455.10 (M+H). MP 238-240° C. NMR 1H (DMSO-d6)-9.18 (s, 1H), 8.90 (s, 1H), 7.56 (d, 2H, J=8.88 Hz), 7.19 (bs, 1H), 6.94 (d, 2H, J=8.88 Hz), 6.83 (d, 1H, J=4.72 Hz), 6.81 (d, 1H, J=4.72 Hz), 4.00 (bs, 2H), 3.75 (t, 4H, J=5.26 Hz), 3.42 (t, 2H, J=5.96 Hz), 3.05 (t, 4H, J=5.26 Hz), 2.97 (s, 3H), 2.72 (bs, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:20])[C:13]([CH3:15])([CH3:14])[O:12][C:11](OC)=[N:10][S:9]2(=[O:19])=[O:18])[CH:5]=[CH:6][CH:7]=1.[Si:21]([O:28][CH2:29][CH2:30][C@H:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:20])[C:13]([CH3:15])([CH3:14])[O:12][C:11]([NH:38][C@H:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:30][CH2:29][O:28][Si:21]([C:24]([CH3:27])([CH3:25])[CH3:26])([CH3:23])[CH3:22])=[N:10][S:9]2(=[O:19])=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: COC1=NS(=O)(=O)C(C)(c2cccc(Br)c2)C(C)(C)O1
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H](N)c1ccccc1
Solvent: ClCCl
Product: CC1(C)OC(N[C@@H](CCO[Si](C)(C)C(C)(C)C)c2ccccc2)=NS(=O)(=O)C1(C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 69 %

Procedure:
A solution of 209 mg of 5-(3-bromophenyl)-2-methoxy-5,6,6-trimethyl-5,6-dihydro-1,4,3-oxathiazine 4,4-dioxide and 181 mg of (S)-3-(tert-butyldimethylsilanyloxy)-1-phenylpropylamine in 5 ml of methylene chloride was stirred at room temperature for 1 hour and the conversion was checked by LCMS. Since no conversion had taken place yet, the solvent was concentrated by rotary evaporation and the residue was stirred at room temperature for 19 hours. The crude product was purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (237 mg) with a molecular weight of 595.7 g/mol (C27H39BrN2O4SSi); MS (ESI): m/e=596 (M+h+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[CH3:12][O-:13].[Na+].O>CO>[F:9][C:8]([F:11])([F:10])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:13][CH3:12])[CH:7]=1
Reactant: C[O-]
Reactant: FC(F)(F)c1ccnc(Cl)c1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(C(F)(F)F)ccn1
Yield: 85.1 %

Procedure:
A solution having 5.05 g (27.8 mmol) of 2-chloro-4-trifluoromethylpyridine and 3.59 g (66.5 mmol) of sodium methoxide dissolved in 40 ml of methanol was stirred under reflux with heating for 4 hours. Water was added to terminate the reaction, followed by extraction with diethyl ether. The organic layer was dried over anhydrous sodium sulfate and subjected to filtration on the pad of a silica gel cake. The solvent was distilled off under reduced pressure to obtain 4.19 g (yield: 85%) of 4-trifluoromethyl-2-methoxypyridine.
Reaction SMILES: CN(C)C=O.[CH2:6]([C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][O:27][C:21]=3[CH:20]=2)[S:16][C:17]=1Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:28]([C:30]1([OH:38])[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1)#[CH:29].N>C(OCC)(=O)C.C(N(CC)CC)C>[CH2:6]([C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][O:27][C:21]=3[CH:20]=2)[S:16][C:17]=1[C:29]#[C:28][C:30]1([OH:38])[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Brc1sc(-c2ccc3c(c2)OCO3)nc1Cc1ccccc1
Reactant: C#CC1(O)CN2CCC1CC2
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: OC1(C#Cc2sc(-c3ccc4c(c3)OCO4)nc2Cc2ccccc2)CN2CCC1CC2
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 56.5 %

Procedure:
5 ml of N,N-dimethylformamide was added to a mixture of 377 mg of 4-benzyl-5-bromo-2-(3,4-methylenedioxyphenyl)thiazole, 178 mg of 3-ethynyl-3-quinuclidinol, 68 mg of tetrakis (triphenylphosphine)palladium(0), 18 mg of cuprous iodide and 0.5 ml of triethylamine, followed by heating under stirring at 100° C. in an oil bath for 15 minutes in a nitrogen atmosphere. After cooling as it was, ethyl acetate and aqueous ammonia were added thereto, and the mixture was extracted with ethyl acetate. The organic phase was further washed with brine, dried over anhydrous sodium sulfate and the solvent was removed. The resulting crystals were collected by filtration, to give 253 mg of the target compound.
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[C:9]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16])(=[O:11])[CH3:10]>C1(C)C=CC=CC=1>[C:15]([C:14]1[CH:13]=[C:12]([C:9](=[O:11])[CH2:10][C:3]([O:6][CH3:7])=[O:8])[CH:19]=[CH:18][CH:17]=1)#[N:16]
Reactant: CC(=O)c1cccc(C#N)c1
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)CC(=O)c1cccc(C#N)c1
Yield: 95.4 %

Procedure:
Into a three-necked flask equipped with an argon inlet and a condenser were placed sodium hydride (60%, 689.5 mg, 17.23 mmol), dimethyl carbonate (1.55 g, 17.23 mmol) and 15 mL of toluene. The mixture was stirred under reflux and a solution of 3-acetylbenzonitrile (1.0 g, 6.19 mmol) in toluene (15 mL) was added drop wise. The reaction mixture was stirred at 100° C. for 2 h. The reaction mixture was monitored by LCMS and purified by column chromatography on silica gel eluted with 0-10% of ethyl acetate in petroleum ether to give the product (1.2 g, 86%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]([C:8](=[O:32])[C@@H:9]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[CH3:7])[CH3:2].[C:34]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]([C:8](=[O:32])[C@@H:9]([NH:24][C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:10][N:11]([CH3:34])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[CH3:7])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CN(C)C(=O)[C@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])NC(=O)OC(C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)CN(C)C(=O)[C@H](CN(C)S(=O)(=O)c1ccccc1[N+](=O)[O-])NC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
Compound B (8.0 g, 16.3 mmol) was dissolved in DMF (40 mL) and the reaction mixture was cooled to −10° C. To the reaction mixture was added K2CO3 (6.8 g, 49.1 mmol) followed by addition of MeI (5.1 mL, 81.9 mmol) drop wise and stirred at 0° C. for 1 h. The reaction mixture was filtered and washed with EtOAc. Solvents removed in vacuo and the residue was dissolved in EtOAc (250 mL) and poured into water (500 mL), extracted with EtOAc (2×250 mL), and washed with water (250 mL) and brine (100 mL). The organic layer was dried over Na2SO4, filtered, and then concentrated in vacuo, to afford compound C (8.1 g, 98% yield) as a cream solid. LC-MS [M+H] 503.1 (C20H30N4O9S+H, calc: 503.5). Purity >95% (UV/254 nm). Compound C was used without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[S:13]([OH:16])(=[O:15])=[O:14]>ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:13]([OH:16])(=[O:15])=[O:14])=[C:7]([I:11])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(O)Cl
Reactant: CC(C)(C)c1cccc(I)c1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(S(=O)(=O)O)c(I)c1
Yield: 95.1 %

Procedure:
Synthesized as described for 1 using 1-tert-butyl-3-iodobenzene (9.65 g; 37.09 mmol), chlorosulfonic acid (3.20 mL; 48.22 mmol), and anhydrous dichloromethane (140 mL). Trituration of the crude product from hexanes yielded the title compound as a brown oil (12.0 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]([C@H:14]([OH:16])[CH3:15])[CH2:12][OH:13])=[C:8]([C:17]([NH2:19])=[O:18])[CH:7]=[N:6][N:5]2[CH:20]=1.[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][C:27](B(O)O)=[CH:28][CH:29]=2)[CH:24]=[CH:23]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(N(C)C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[OH:13][CH2:12][C@@H:11]([NH:10][C:9]1[C:4]2[N:5]([CH:20]=[C:2]([C:27]3[CH:26]=[C:25]4[C:30](=[CH:29][CH:28]=3)[N:22]([CH3:21])[CH:23]=[CH:24]4)[CH:3]=2)[N:6]=[CH:7][C:8]=1[C:17]([NH2:19])=[O:18])[C@H:14]([OH:16])[CH3:15]
Reactant: C[C@@H](O)[C@@H](CO)Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: Cn1ccc2cc(B(O)O)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: C[C@@H](O)[C@@H](CO)Nc1c(C(N)=O)cnn2cc(-c3ccc4c(ccn4C)c3)cc12
Temperature: 95 °C
Reaction time: 0.42 h
Yield: 85.7 %

Procedure:
A mixture of 6-bromo-4-(((2R,3R)-1,3-dihydroxybutan-2-yl)amino) pyrrolo[1,2-b]pyridazine-3-carboxamide (25 mg, 0.073 mmol), (1-methyl-1H-indol-5-yl)boronic acid (38.2 mg, 0.219 mmol), PdCl2(dppf)-CH2Cl2 adduct (11.90 mg, 0.015 mmol) and potassium phosphate, tribasic, 2M (0.182 mL, 0.364 mmol) in DMA (0.5 mL) was heated to 95° C. for 45 minutes. After cooling to rt, the reaction mixture was filtered and the filtrate was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 0-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation. 1H NMR (500 MHz, DMSO-d6) δ 10.65 (d, J=8.4 Hz, 1H), 8.17 (s, 1H), 8.10 (d, J=1.5 Hz, 1H), 7.93 (d, J=1.0 Hz, 1H), 7.57 (dd, J=8.4, 1.5 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 7.31 (dd, J=6.7, 2.2 Hz, 2H), 6.43 (d, J=3.0 Hz, 1H), 5.13-4.89 (m, 2H), 4.27-4.08 (m, 2H), 3.80 (s, 3H), 3.73-3.61 (m, 2H), 1.13 (d, J=6.4 Hz, 3H). to afford the title compound (24.6 mg, 85% yield). MS (ES+) m/z: 394.1 (M+H); LC retention time: 1.27 min (analytical HPLC Method P).
Reaction SMILES: CC1C=C(C(O)=O)C=CC=1C1C=CC=CC=1C(F)(F)F.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][C:32]=1[C:33]1[C:37]([CH3:38])=[CH:36][S:35][CH:34]=1)[C:26]([O:28]C)=[O:27]>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][C:32]=1[C:33]1[C:37]([CH3:38])=[CH:36][S:35][CH:34]=1)[C:26]([OH:28])=[O:27]
Reactant: COC(=O)c1ccc(-c2cscc2C)c(OC)c1
Agent: Cc1cc(C(=O)O)ccc1-c1ccccc1C(F)(F)F
Product: COc1cc(C(=O)O)ccc1-c1cscc1C
Yield: 83.1 %

Procedure:
The title compound was prepared following procedure described for Intermediate 5, step 2, but starting from methyl 3-methoxy-4-(4-methyl-3-thienyl)benzoate (2.30 g; 8.77 mmol; 1 eq.), affording the title compound as a brown solid (1.81 g, 83%). 1H NMR: (DMSO-d6, 300 MHz) δ 13.05 (s, 1H), 7.62-7.59 (m, 2H), 7.40-7.39 (d, J=3.23 Hz, 1H), 7.32-7.29 (d, J=7.48 Hz, 1H), 7.25-7.23 (m, 1H), 3.82 (s, 3H), 2.99 (s, 3H). LC/MS (Method A): 248.8 (M+H)+; 246.9 (M−H)−. HPLC (Method A) Rt 3.99 min (Purity: 97.4%).
Reaction SMILES: C([O:8][CH2:9][CH:10]=[O:11])C1C=CC=CC=1.P([O-])([O-])([O-])=O.[OH:17][CH2:18][C:19](=[O:21])[CH3:20].C(OCC1C=CC=CC=1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2].C(#N)C>[CH3:20][C:19]([C@@H:18]([C@H:9]([CH2:10][OH:11])[OH:8])[OH:17])=[O:21]
Reactant: CC(=O)CO
Reactant: O=CCOCc1ccccc1
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Agent: [OH-]
Solvent: c1ccc(COCc2ccccc2)cc1
Solvent: CO
Solvent: CC#N
Product: CC(=O)[C@H](O)[C@@H](O)CO
Reaction time: 48 h
Yield: 81 %

Procedure:
Benzyloxyacetaldehyde (80 mg, 0.53 mmol) in) in) 0.5 mL of acetonitrile, was added to 9 mL of a solution of antibody 38C2 (35 mg, 0.23 mmol) in PBS (phosphate buffer saline, 100 mM), followed by the addition of of hydroxyacetone. (0.5 mL, 6.3 mmol). After 48 hr at room temperature the reaction reached 56% conversion and the mixture was freeze dried. The remaining residue was extracted with methylene chloride. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel, ethyl acetate/hexane, 1/1) to give pure 2111α (39 mg, 0.17 mmol, 32%) in 97% ee. Benzyl ether 2111α (39 mg, 0.17 mmol) was dissolved in 1 mL of methanol and hydrogenated with a catalytic amount of palladium hydroxide on carbon. After two hr, the mixture was filtered through celite and the solvent was removed under reduced pressure to give pure 1-deoxy-L-xylulose 1111 (19 mg, 0.14 mmol, 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[N:15]=[C:16]([NH2:18])[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:26]([C:29](Cl)=[O:30])([CH3:28])[CH3:27]>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[N:15]=[C:16]([NH:18][C:29](=[O:30])[CH:26]([CH3:28])[CH3:27])[N:17]=[C:13]3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cccc3nc(N)nn23)cc1
Reactant: CC(C)C(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cccc3nc(NC(=O)C(C)C)nn23)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of the 5-(4-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.07 g, 0.291 mmol) in dry acetonitrile (2 mL) was added triethylamine (0.12 mL, 0.874 mmol) followed by isopropanecarbonyl chloride (0.046 mL, 0.437 mmol). The reaction mixture was then allowed to warm to ambient temperature overnight. Further triethylamine (1.5 eq) and acid chloride (1.2 eq) were added to ensure complete reaction. The solvent was then removed and 3 mL of methanol-ammonia 7M was added to the crude and the mixture was stirred 6 h. The solution was concentrated under reduced pressure and the crude was purified by preparatory HPLC. LCMS method: 2, RT: 4.33 min, MI: 311 [M+1]. NMR 1H (DMSO): 1.05 (d, 6H), 2.65-2.75 (m, 1H), 3.86 (s, 3H), 7.06 (d, 2H), 7.19 (d, 1H), 7.57-7.69 (m, 2H), 7.95 (d, 2H), 10.68 (brs, 1H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([CH2:8][C:9]#[N:10])=[O:7])=[CH:4][CH:3]=1.CO[C:15](OC)([N:17]([CH3:19])[CH3:18])[CH3:16]>C(Cl)(Cl)Cl>[CH3:19][N:17]([CH3:18])/[C:15](/[CH3:16])=[C:8](/[C:6](=[O:7])[C:5]1[CH:11]=[CH:12][C:2]([F:1])=[CH:3][CH:4]=1)\[C:9]#[N:10]
Reactant: N#CCC(=O)c1ccc(F)cc1
Reactant: COC(C)(OC)N(C)C
Solvent: ClC(Cl)Cl
Product: C/C(=C(/C#N)C(=O)c1ccc(F)cc1)N(C)C
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a solution of 1.6 g. of p-fluorobenzoylacetonitrile [Pihl et al., Reakts. Sposobnost Org. Soedin. Tartu. Gos. Univ., 5 (1), 27, (1968)] in 30 ml. of chloroform, cooled to -10° C., is added 1.4 g. of N,N-dimethylacetamide dimethylacetal. The reaction mixture is stirred at -10° C. for 2 hours and then evaporated in vacuo to an oil. This oil is dissolved in 150 ml. of benzene and filtered through Magnesol®. The filtrate is evaporated to 50 ml. and petroleum ether is added to effect crystallization. The product is collected by filtration and then recrystallized from benzene-petroleum ether with charcoal treatment giving the desired product.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][C:48]1[CH:49]=[C:50]([CH:53]=[C:54]([CH3:56])[CH:55]=1)[CH2:51][NH2:52]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([NH:52][CH2:51][C:50]4[CH:53]=[C:54]([CH3:56])[CH:55]=[C:48]([CH3:47])[CH:49]=4)=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc(C)cc(CN)c1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCc2cc(C)cc(C)c2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 3,5-dimethylbenzylamine (Trans World chemicals) to give the title product. LC-MS (ES+) 782 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=O)[CH2:9][CH2:10][C:11](=O)[CH:12]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH:29]3[CH2:31][CH2:30]3)(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[N:6][CH:7]=1.C([O-])(=O)C.[NH4+:38]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:38][C:11]([CH:12]([C:20]3[CH:21]=[CH:22][C:23]([S:26]([CH:29]4[CH2:31][CH2:30]4)(=[O:27])=[O:28])=[CH:24][CH:25]=3)[CH2:13][CH:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: O=C(CCC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)c1ccc(Br)cn1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(Br)cn3)[nH]2)cc1)C1CC1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 90 %

Procedure:
To a solution (10 mL) of 1-(5-bromopyridin-2-yl)-5-[4-(cyclopropylsulfonyl)phenyl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (1.29 g) in acetic acid (10 mL) was added ammonium acetate (3.00 g), and the mixture was stirred at 110° C. for 45 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (1.12 g, yield 96%) was obtained as a white amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 517 (MH+).
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:18]([OH:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.Cl.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1>N1C=CC=CC=1>[C:22]([O:20][C:9]1[CH:8]=[CH:7][C:6]2[C@@H:5]3[C@H:14]([C@H:15]4[C@@:2]([CH2:3][CH2:4]3)([CH3:1])[C@@H:18]([O:19][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=3)[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: Cl
Solvent: c1ccncc1
Product: C[C@]12CC[C@@H]3c4ccc(OC(=O)c5cccnc5)cc4CC[C@H]3[C@@H]1CC[C@@H]2OC(=O)c1cccnc1
Temperature: 0 °C
Yield: 90 %

Procedure:
Estradiol (2 g, 0.0073 mol) was added to nicotinoyl chloride hydrochloride (5.3 g, 0.029 mol) in dry pyridine (30 ml) at 0° C. The mixture was refluxed for 1 hour and then poured over 100 ml of ice water, filtered and dried over P2O5 under vacuum. Yield 90% (3.18 g), m.p. 148°-150° C. NMR (CDCl3) δ 9.2-9.0 (br s, 2H, C2 pyridinium protons), 8.7-8.3 (m, 2H, C6 pyridinium protons), 8.4-8.0 (m, 2H, C4 pyridinium protons), 7.5-7.1 (m, 3H, C5 pyridinium protons+C1 estradiol proton), 6.9-6.7 (m, 2H, C2,4 estradiol protons), 5.0-4.7 (m, 1H, C17α estradiol proton), 3.2-1.3 (estradiol skeletal protons, 15), 1.0-0.9 (s, 3 H, C18 estradiol protons). IR (KBr) 1750, 1725 cm-1 (2 C=O stretching). Anal. calculated for C30H31N2O4 : C, 74.50; H, 6.47; N, 5.79. Found: C, 74.40; H, 6.32; N, 5.75. The product has the formula: ##STR1471##
Reaction SMILES: [C:1](O)(=[O:6])[CH:2]=[CH:3][CH2:4][CH3:5].C(N(CC)CC)C.CC(C)(C)C(Cl)=O.[C:22]1([C@H:28]2[CH2:32][O:31][C:30](=[O:33])[NH:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([Li])CCC>O1CCCC1>[C:1]([N:29]1[C@@H:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:32][O:31][C:30]1=[O:33])(=[O:6])/[CH:2]=[CH:3]/[CH2:4][CH3:5]
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Reactant: CCC=CC(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC/C=C/C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a solution of 2-pentenoic acid (5.44 g, 54 mmol) and triethylamine (6 g, 60 mmol) in anhydrous tetrahydrofuran (120 mL) under nitrogen at −78° C. was added trimethylacetyl chloride (7.36 mL, 60 mmol). The reaction mixture was stirred at −78° C. for 10 minutes, 0° C. for 1 hour, then re-cooled to −78° C. At the same time, in a seperate flask charged with a solution of (S)-(+)-4-phenyl-2-oxazolidinone (8.86 g, 54 mmol) in anhydrous tetrahydrofuran (130 mL) under nitrogen at −78° C. was added dropwise a solution of n-butyl lithium (22 mL, 54 mmol, 2.5 M in hexanes). The mixture was stirred at −78° C. for 20 minutes and then transferred via a cannula into the reaction flask containing the mixed anhydride at −78° C. The reaction mixture was stirred at 0° C. for 1 hour, then warmed to room temperature and stirred for 18 hours. The mixture was quenched with saturated aqueous ammonium chloride solution (200 mL), concentrated to about half of its original volume under reduced pressure to remove tetrahydrofuran. The remaining mixture was extracted with ethyl acetate (2×250 mL). The organic layer was separated, combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography over silica gel eluted with 2:1 ethyl acetate/hexanes to give (S)-3-((E)-pent-2-enoyl)-4-phenyl-oxazolidin-2-one as a white foam (9.9 g, 75%).
Reaction SMILES: [ClH:1].[CH3:2][O:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([CH2:13][O:14][CH3:15])[CH:12]=1)[C:8]#[N:9].[CH2:16]([OH:18])[CH3:17]>>[ClH:1].[CH3:2][O:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([CH2:13][O:14][CH3:15])[CH:12]=1)[C:8](=[NH:9])[O:18][CH2:16][CH3:17]
Reactant: CCO
Reactant: COCc1cc(C#N)cc(COC)c1
Agent: Cl
Product: CCOC(=N)c1cc(COC)cc(COC)c1
Reaction time: 5.5 h
Yield: 46 %

Procedure:
Hydrogen chloride gas was passed through a solution of 3,5-bis-methoxymethyl-benzonitrile (1 g, 5.2 mmol) in anhydrous ethanol (150 mL) at room temperature. After 5.5 h, hydrogen chloride gas was stopped. The solvent was evaporated in vacuo and the residue was triturated in diethyl ether to afford ethyl 3,5-bis-methoxymethyl-benzimidate hydrochloride (658 mg, 46%). It was used without further purification.