Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([C:25]#[C:26][CH2:27][OH:28])[CH:16]=1>C1COCC1>[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17](/[CH:25]=[CH:26]/[CH2:27][OH:28])[CH:16]=1
Reactant: OCC#Cc1cnc2ccccc2c1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC/C=C/c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a dry, jacketed 250-mL three-necked round-bottom flask was charged sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al, 70% wt. solution in toluene, 11.0 g, 38.1 mmol, 1.39 eq) and anhydrous THF (20 mL). To this precooled (0–2° C.) and magnetically stirred solution was added a THF (50 mL) solution of the 3-(3-quinolyl)-2-propyn-1-ol (5.0 g, 27.32 mmol) via pressure equalizing dropping funnel. The temperature was not allowed to rise above 15° C. After the addition was complete (20 minutes) the mixture was allowed to warm up to room temperature and stirred for one hour. The solution was then cooled to 0° C. and quenched by the addition of aqueous 10% sulfuric acid (20 mL) such that the internal temperature did not rise above 15° C. The biphasic reaction mixture was then washed with ethyl acetate (3×100 mL). The pH of the aqueous acidic product solution was then adjusted to pH 9–10 with aq. conc. NH4OH and back extracted into ethyl acetate (2×125 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give exclusively 3-(3-quinolyl) trans-2-propen-1-ol as a solid: 4.1 g, 81%.
Reaction SMILES: [C:1]1([S:7]([NH:10][CH2:11][CH2:12][C:13]2[CH:23]=[CH:22][C:16]([O:17][CH2:18][C:19](Cl)=[O:20])=[CH:15][CH:14]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.[OH:30][CH2:31][CH:32]([NH2:34])[CH3:33]>O>[OH:30][CH2:31][CH:32]([NH:34][C:19](=[O:20])[CH2:18][O:17][C:16]1[CH:22]=[CH:23][C:13]([CH2:12][CH2:11][NH:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:14][CH:15]=1)[CH3:33]
Reactant: CC(N)CO
Reactant: O=C(Cl)COc1ccc(CCNS(=O)(=O)c2ccccc2)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(CO)NC(=O)COc1ccc(CCNS(=O)(=O)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
A solution of 6.4 g. (18 mMol) 4-[2-(benzenesulphonylamino)-ethyl]-phenoxyacetyl chloride and 25 ml. anhydrous benzene is added dropwise at 0° to 5° C., over the course of 2 hours, to a mixture of 5.4 g. (72 mMol) 1-hydroxy-2-aminopropane and 35 ml. water, a precipitate thereby forming slowly. After standing overnight at 20° C., the precipitate is filtered off with suction and the filter cake is washed with dilute aqueous sodium hydroxide solution and then with water and dried. After recrystallization from ethyl acetate, there are obtained 5.2 g. (74% of theory) of the desired product; m.p. 90°-91° C.
Reaction SMILES: C([O:5]O)(C)(C)C.[Cl:7][C:8]1[CH:13]=[C:12]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:11]=[CH:10][C:9]=1[NH:25][C:26](=[O:34])[C@:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:7][C:8]1[CH:13]=[C:12]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:24])=[O:5])=[CH:19][CH:18]=2)(=[O:15])=[O:16])[CH:11]=[CH:10][C:9]=1[NH:25][C:26](=[O:34])[C@:27]([OH:33])([CH3:32])[C:28]([F:30])([F:31])[F:29]
Reactant: CC(C)(C)OO
Reactant: CSc1ccc(S(=O)(=O)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2)cc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ccc(S(=O)(=O)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
t-Butylhydroperoxide (0.36 ml of a 3M solution in toluene) was added to a solution of (R)-N-{2-chloro-4-[4-(methylsulphanyl)phenylsulphonyl]phenyl}-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 2) (0.247 g) and d-10-camphorsulphonic acid (0.012 g) in chloroform (5 ml) and the mixture was stirred at ambient temperature for 64 hours. The reaction mixture was transferred directly to a silica gel Mega Bond Elut column and eluted with 0-80% ethyl acetate/hexane to give the title compound (0.237 g) as a foam. NMR (CDCl3): 1.74 (s, 3H), 2.74 (s, 3H), 4.2 (brs, 1H), 7.79 (d, 2H), 7.89 (dd, 1H), 8.0 (m, 1H), 8.1 (d, 2H) 8.65 (d, 1H), 9.38 (brs, 1H); MS (ESP−): 468; EA: found: C, 43.3; H, 3.1; N, 2.98%; C17H15ClF3NO5S2 requires: C, 43.3; H, 3.1; N, 2.8%.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:20]=[C:19]([CH:21]([NH2:23])[CH3:22])[O:18][N:17]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].ClC(Cl)(Cl)[C:28]([N:30]=C=O)=[O:29]>ClCCl>[CH:1]([O:4][C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:20]=[C:19]([CH:21]([NH:23][C:28]([NH2:30])=[O:29])[CH3:22])[O:18][N:17]=3)=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)([CH3:2])[CH3:3]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC(C)Oc1ccc(Oc2ccc(-c3cc(C(C)N)on3)cc2)cc1
Solvent: ClCCl
Product: CC(C)Oc1ccc(Oc2ccc(-c3cc(C(C)NC(N)=O)on3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 66.9 %

Procedure:
To a solution of Example 17F (377 mg, 1.12 mmol) in dichloromethane (10 mL) at 0° C. was added trichloroacetyl isocyanate (145 μL, 1.22 mmol). The mixture was stirred at 0° C. for 10 minutes. The reaction was concentrated and the residue was dissolved in methanol (˜60 mL) and a small amount of Na2CO3 was added. The mixture was stirred at room temperature for 3 hours before being concentrated. The residue was dissolved in dichloromethane, which was washed with water (1×) and concentrated. The residue was purified on silica gel eluting with hexane and ethyl acetate gradient to give the desired product as a white solid (286 mg, 67%), MS (DCI): m/z 382 (M+H); 1H NMR (300 MHz, DMSO-d6) δ ppm 7.78-7.86 (m, 2H), 6.99-7.08 (m, 4H), 6.94-6.99 (m, 2H), 6.75 (s, 1H), 6.61 (d, J=8.46 Hz, 1H), 5.59 (br s, 2H), 4.90-5.02 (m, 1H), 4.53-4.63 (m, 1H), 1.41 (d, J=6.99 Hz, 3H), 1.27 (d, J=5.88 Hz, 6H).
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:10]([C:20]([N:22]2[CH2:26][CH2:25][CH2:24][CH:23]2[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:21])[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH2:27]([CH:23]1[CH2:24][CH2:25][CH2:26][N:22]1[C:20]([C@H:10]1[C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH2:12][NH:8][CH2:9]1)=[O:21])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1ccccc1C1CN(Cc2ccccc2)CC1C(=O)N1CCCC1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1[C@@H]1CNC[C@H]1C(=O)N1CCCC1Cc1ccccc1
Reaction time: 2 h

Procedure:
To 1-Benzyl-3-[(2-benzylpyrrolidin-1-yl)carbonyl]-4-(2-methylphenyl)pyrrolidine (0.1 g, 0.228 mmol) in MeOH (10 ml) was added Pearlman's Catalyst (0.05 g, 0.071 mmol) and hydrogenated with a balloon for 2 hours. Filter through celite, concentrate, and purify on reverse phase HPLC. LRMS (M+H)=349.13
Reaction SMILES: [CH2:1]([N:4]1[C:8]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:7][N:6]([CH2:15][CH2:16][CH2:17][CH2:18]Cl)[C:5]1=[O:20])[CH:2]=[CH2:3].Cl.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].C1(C)C=CC=CC=1>[CH2:1]([N:4]1[C:8]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:7][N:6]([CH2:15][CH2:16][CH2:17][CH2:18][N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH3:22])[CH2:35][CH2:34]2)[C:5]1=[O:20])[CH:2]=[CH2:3]
Reactant: C=CCn1c(-c2cccnc2)nn(CCCCCl)c1=O
Reactant: COc1ccccc1N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: Cc1ccccc1
Product: C=CCn1c(-c2cccnc2)nn(CCCCN2CCN(c3ccccc3OC)CC2)c1=O
Temperature: 92.5 °C
Reaction time: 85 h
Yield: 22.2 %

Procedure:
A mixture of 4-allyl-2-(4-chlorobutyl)-5-(3-pyridyl)-1,2,4-triazol-3(2H,4H)-one (3 g), 1-(2-methoxyphenyl)piperazine monohydrochloride (2.3 g), potassium carbonate (2.76 g), potassium iodide (10 mg) and toluene (100 ml) was stirred at 90-95° C. under nitrogen for 85 hours. During this time, three further portions of 1-(2-methoxyphenyl)piperazine monohydrochloride (3×1.92 g) were added at 17 hourly intervals. The solvent was removed in vacuo, the residue was diluted with water (100 ml), and the product was extracted into ethyl acetate (3×50 ml). The extracts were dried (MgSO4) and the solvent removed in vacuo to leave an oil which was purified by flash chromatography over silica using a 1:1 mixture of ether and methanol as eluant. Appropriate fractions were combined and the solvents removed in vacuo. The residue was triturated with ether, undissolved solid was removed by filtration, and the solvent was removed in vacuo. The residue was triturated with petroleum ether (b.p. 40-60° C.) and the resulting solid was collected by filtration and dried in vacuo at ambient temperature to give 4-allyl-2-{4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl}-5-(3-pyridyl)-1,2,4-triazol-3(2H,4H)-one as an off-white solid (1 g), m.p. 71-75° C.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8]1)(=O)=O.[CH3:14][C:15]1([CH3:27])[C:19]([CH3:21])([CH3:20])[O:18][B:17]([C:22]2[CH:23]=[N:24][NH:25][CH:26]=2)[O:16]1.[H-].[Na+]>CN(C)C=O>[CH3:13][C:9]1([CH3:12])[O:8][C@@H:7]([CH2:6][N:25]2[CH:26]=[C:22]([B:17]3[O:16][C:15]([CH3:27])([CH3:14])[C:19]([CH3:21])([CH3:20])[O:18]3)[CH:23]=[N:24]2)[CH2:11][O:10]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC1(C)OC[C@H](COS(C)(=O)=O)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)O1
Temperature: 90 °C

Procedure:
A mixture of (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl methanesulfonate (1.08, 5.15 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 g, 5.15 mmol) and NaH (262 mg, 10.9 mmol) in N,N-dimethylformamide (25 mL) was heated at 90° C. for 3 hours, then allowed to cool to room temperature., quenched with water and extracted with ethyl acetate (3×). The combined organics were washed with brine, concentrated and the residue was purified by chromatography on an Analogix® Intelliflash™ purification system using a SF25-25 g column at a flow rate of 80 mL/minute, eluting with 0% to 30% ethyl acetate:hexanes over 30 minutes to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[CH:12]=[C:13]([C:15]([O:17]CC)=[O:16])[N:14]=[C:4]2[CH:3]=1.[OH-].[Na+].Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[N:14]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)c1cn2c(cc(Cl)c3ccccc32)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cn2c(cc(Cl)c3ccccc32)n1
Temperature: 25 °C

Procedure:
820 mg of ethyl 5-chloroimidazo-[1,2-a]-quinoline-2-carboxylate were dissolved in 50 ml of ethanol and 6.6 ml of 0.5 N sodium hydroxide solution were added to the solution obtained. The resultant mixture was refluxed for 1 hour, then was cooled to room temperature and acidified to a pH of ~1 by addition of concentrated hydrochloric acid. The solvent was removed under vacuum and the residue was dissolved in methanol. The solution formed was filtered and the filtrate was reduced in volume under vacuum and then was cooled to obtain off-white crystals of 5-chloroimidazo-[1,2-a]-quinoline-2-carboxylic acid hydrochloride melting at 263°-265° C. (decomposition).
Reaction SMILES: [C:1]([NH:16][C:17]1[CH:27]=[C:26]2[C:20]([C:21]([Cl:37])=[C:22]([O:28][CH2:29][CH2:30][C:31]3C=CC=CC=3)[O:23][C:24]2=[O:25])=[CH:19][CH:18]=1)(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[C@@H:14]2[C@@H:9]([NH:10][C:11]([NH:13]2)=[O:12])[CH2:8][S:7]1.NC1C=C2C(C(Cl)=C(OCCC)OC2=O)=CC=1>O>[C:1]([NH:16][C:17]1[CH:27]=[C:26]2[C:20]([C:21]([Cl:37])=[C:22]([O:28][CH2:29][CH2:30][CH3:31])[O:23][C:24]2=[O:25])=[CH:19][CH:18]=1)(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[C@@H:14]2[C@@H:9]([NH:10][C:11]([NH:13]2)=[O:12])[CH2:8][S:7]1
Reactant: O=C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)Nc1ccc2c(Cl)c(OCCc3ccccc3)oc(=O)c2c1
Agent: CCCOc1oc(=O)c2cc(N)ccc2c1Cl
Solvent: O
Product: CCCOc1oc(=O)c2cc(NC(=O)CCCC[C@@H]3SC[C@@H]4NC(=O)N[C@@H]43)ccc2c1Cl
Yield: 20 %

Procedure:
This compound was prepared similarly as 7-biotinylamino-4-chloro-3-(2-phenylethoxy)isocoumarin from biotin acid chloride and 7-amino-4-chloro-3-propyloxyisocoumarin, yield 20%, mp 127°-131° C., NMR was consistent with the assigned structure, mass spectra (FAB+) m/e=502 (M+Na+1). Anal. Calc. for C22H26N3O5ClS.H2O: C, 53.06; H, 5.67; N, 8.44; Cl, 7.12. Found: C, 53.30; H, 5.67; N, 8.49; Cl, 7.03.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Li]CCCC.[Br:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]([Cl:22])[N:16]=1.CN([CH:26]=[O:27])C>C1COCC1>[Br:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]([Cl:22])[N:16]=1.[Cl:1][C:2]1[N:3]=[C:4]([CH:26]=[O:27])[C:5]([CH3:8])=[CH:6][CH:7]=1
Reactant: Cc1ccc(Cl)nc1
Reactant: CN(C)C=O
Agent: Cc1ccc(Cl)nc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(Cl)nc1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
2-Bromo-6-chloro-3-methyl-pyridine was prepared from 2-chloro-5-methylpyridine by by the method of Gros P. and Fort Y. (J. Org. Chem., 2005, 8220). A solution of n-BuLi (1.6M in hexanes) (2.0 ml, 3.30 mmol) in dry THF (6 ml) at −78° C. under argon was treated dropwise with a solution of 2-bromo-6-chloro-3-methyl-pyridine (642 mg, 3.10 mmol) in dry THF (4 ml) and stirred at this temperature for 30 minutes. A solution of DMF (385 μl, 4.70 mmol) in dry THF (1 ml) was added dropwise and stirred at −78° C. for a further 45 minutes before warming to ambient temperature. The reaction was quenched with MeOH (3 ml), treated with water and extracted with EtOAc. The combined organics were dried over MgSO4, filtered and evaporated under reduced pressure before purification by column chromatography on SiO2, eluting with 2% EtOH in DCM to afford 6-chloro-3-methyl-pyridine-2-carbaldehyde as a yellow solid (217 mg, 45%). 1H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 7.60 (d, J=7.7 Hz, 1H), 7.42 (d, J=7.7 Hz, 1H), 2.64 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][NH:6][C:7]1[C:12]([C:13]([OH:15])=O)=[C:11]([O:16][CH3:17])[N:10]=[C:9]([S:18][CH3:19])[N:8]=1.[NH2:25][CH2:26][C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1.O.ON1C2C=CC=CC=2N=N1.CN(C)C=O>C(=O)([O-])O.[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:5][NH:6][C:7]1[C:12]([C:13](=[O:15])[NH:25][CH2:26][C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[C:11]([O:16][CH3:17])[N:10]=[C:9]([S:18][CH3:19])[N:8]=1
Reactant: COc1ccc(CNc2nc(SC)nc(OC)c2C(=O)O)cc1Cl
Reactant: NCc1ncccn1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nc(SC)nc(OC)c2C(=O)NCc2ncccn2)cc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a mixture of 4-(3-chloro-4-methoxybenzylamino)-5-carboxy-6-methoxy-2-methylthiopyrimidine (prepared in the above (2)) 183 mg, 2-aminomethylpyrimidine 70 mg, 1-hydroxybenzotriazole hydrate 67 mg and dimethylformamide 4 ml is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimido hydrochloride 114 mg on an ice bath, and the mixture is stirred for 14 hours at room temperature. The reaction mixture is diluted with an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The ethyl acetate layer is washed, dried and concentrated in vacuo. The residue is separated with silica gel chromatography (solvent; chloroform:ethyl acetate=20:1→10:1) to give 4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]-6-methoxy-2-methylthiopyrimidine as a colorless crystalline powder 208 mg. mp 171-172° C.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([C:24]([O:26]CC)=[O:25])[CH:18]=3)[CH2:12]2)=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].CO>O>[F:31][C:2]([F:1])([F:32])[C:3]1[CH:30]=[CH:29][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([C:24]([OH:26])=[O:25])[CH:18]=3)[CH2:12]2)=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cc([C@H]2CCCN(C(=O)OCc3ccc(C(F)(F)F)cc3)C2)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc([C@H]2CCCN(C(=O)OCc3ccc(C(F)(F)F)cc3)C2)cc1C(=O)O
Temperature: 25 °C
Yield: 99.5 %

Procedure:
A mixture of (R)-3-(3-ethoxycarbonyl-4-methyl-phenyl)-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester (2.12 g, 4.72 mmol), potassium carbonate (1.30 g, 9.43 mmol), methanol (25 mL) and water (6 mL) was heated at reflux for 3 h, cooled to room temperature and concentrated under reduced pressure. The resulting residue was taken up in water (150 mL), acidified with 1N aqueous hydrochloric acid and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to yield 1.98 g (99%) (R)-3-(3-carboxy-4-methyl-phenyl)-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][O:9][C:10]1[C:15](B(O)O)=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[N:11]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:8][O:9][C:10]1[C:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[N:11]=1
Reactant: COc1ccc(B(O)O)c(OC)n1
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccn2)c(OC)n1
Temperature: 90 °C
Reaction time: 20 h

Procedure:
2-Bromopyridine (0.475 mL, 0.78 g, 4.9 mmol) and 2,6-dimethoxy-3-pyridineboronic acid (1.09 g, 6.0 mmol, excess) were dissolved in THF (25 mL) at RT. Aqueous solution of K2CO3 (1.65 g in 10 mL of water, 12 mmol, excess) was added, followed by Pd(PPh3)4 (295 mg, 0.25 mmol). The mixture was stirred at 90° C. for 20 h under argon to give yellow solution. Organic solvent was removed under reduced pressure and the residue was extracted with dichloromethane and water. Evaporation of organic phase provided red oil that was purified by chromatography on silica gel eluting with CH2Cl2/MeOH 0 to 0.2%. The fractions containing pure product were collected, while those containing impurities were again purified by chromatography using the same conditions. After three chromatographic purifications the total yield was 965 mg (4.39 mmol; 90%) of yellow oil that crystallized as yellow solid on standing. Anal. Calcd for C12H12N2O2.0.2H2O (MW 219.84): C, 65.56; H, 5.69; N, 12.74. Found: C, 65.74; H, 5.63; N, 12.53. 1H NMR (400 MHz, CD2Cl2): 8.64 (d, J 4.0, 1H), 8.32 (d, J 8.0, 1H), 8.03 (d, J 8.0, 1H), 7.74 (t, J 8.0, 1H), 7.19 (m, 1H), 6.47 (d, J 8.0, 1H), 4.06 (s, 3H), 4.00 (s, 3H). 13C NMR (100 MHz, CD2Cl2): 163.24, 160.16, 154.36, 149.44, 142.44, 136.01, 123.97, 121.38, 114.30, 102.02, 53.75, 53.52.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][C:21](=[O:26])[C:22]([O:24]C)=[O:23])[CH:9]=1)(=[O:3])[CH3:2]>C1COCC1>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][C:21](=[O:26])[C:22]([OH:24])=[O:23])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(=O)Nc1cc(NCCNC(C)=O)nc(-c2ccccc2)n1
Solvent: C1CCOC1
Product: CC(=O)NCCNc1cc(NC(=O)C(=O)O)nc(-c2ccccc2)n1

Procedure:
Methyl [(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)amino](oxo)acetate (10 mg) was dissolved in anhydrous THF (1.5 ml) and potassium trimethylsilanate (4 mg) added. The reaction was left for 3 hrs after which time a precipitate of the title compound was visible which was filtered (10 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH:7](O)[CH2:8][O:9][CH2:10][CH2:11][N:12]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:19]3[C:14]([N:15]([CH3:30])[C:16](=[O:29])[N:17]([CH3:28])[C:18]3=[O:27])=[CH:13]2)[S:5][CH:6]=1.C(N(CC)CC)C.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([CH:7]2[CH2:8][O:9][CH2:10][CH2:11][N:12]3[C:20]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[C:19]4[C:18](=[O:27])[N:17]([CH3:28])[C:16](=[O:29])[N:15]([CH3:30])[C:14]4=[C:13]23)[S:5][CH:6]=1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCOCC(O)c3nc(Cl)cs3)cc2n(C)c1=O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C(c1nc(Cl)cs1)COCC3
Reaction time: 0.25 h

Procedure:
6-(2-(2-(4-Chlorothiazol-2-yl)-2-hydroxyethoxy)ethyl)-1,3-dimethyl-5-phenyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (300 mg, 0.651 mmol), and triethylamine (0.272 mL, 1.953 mmol) were dissolved in DCM (10 mL) and Tf2O (0.165 mL, 0.976 mmol) was added in a single portion. The mixture was stirred at room temp. for 15 mins and further triethylamine (0.272 mL, 1.953 mmol) and Tf2O (0.165 mL, 0.976 mmol) were added. After 45 mins, further triethylamine (0.272 mL, 1.953 mmol) and Tf2O (0.165 mL, 0.976 mmol) were added. After stirring for a further 45 mins, the reaction was quenched with sat. NaHCO3(aq) and extracted with DCM (3×). The combined organic phases were passed through a hydrophobic frit and evaporated under vacuum. The residue was redissolved in DCM and evaporated onto silica. The silica was deposited onto a 10 g silica cartridge and the system gradient-eluted from 10-80% EtOAc/hexane. The product fractions were combined and evaporated. The resulting residue was triturated with DCM/Et2O/hexane and the precipitate collected by filtration to afford the title compound as a pale yellow solid;
Reaction SMILES: C([O:4][CH:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C:19]1[CH:18]=[CH:17][C:16]([O:23][CH3:24])=[CH:15][C:14]=1[CH2:13][CH:12]3[CH2:25][CH2:26][CH3:27])(=O)C.C([O-])(=O)C.[Na+].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:24][O:23][C:16]1[CH:17]=[CH:18][C:19]2[C@@H:20]3[C@H:11]([C@H:8]4[C@@:6]([CH2:22][CH2:21]3)([CH3:7])[C:5](=[O:4])[CH2:10][CH2:9]4)[C@H:12]([CH2:25][CH2:26][CH3:27])[CH2:13][C:14]=2[CH:15]=1
Reactant: CCCC1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)C(OC(C)=O)CC[C@H]3[C@H]12
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCC[C@@H]1Cc2cc(OC)ccc2[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Reaction time: 1 h

Procedure:
To a solution of 10.4 g of 3-O-methyl, 7α-propylestradiol 4 in 50 ml of methylene chloride were subsequently added 15 g. of powdered sodium acetate, 30 g of silicagel and 32 g of pyridinium chlorochromate. After stirring for 1 hr the oxidation was complete. Excess reagent was destroyed by addition of 1 ml of isopropanol, followed by 150 ml of hexane 10 min. later. All the precipitates were filtered over Celite, and the filtrate was concentrated to dryness. This provided 9.6 g of essentially pure ketone 5; Rf 0.54 (hept./ethyl acetate 7/3).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[C:1]([CH2:3][C:4]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:6])#[N:2]
Reactant: N#CCC(=O)O
Reactant: Nc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: N#CCC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
Cyanoacetic acid (1.0 g, 11.7 mmol) is added to a stirred suspension of PCl5 (2.4 g, 11.7 mmol) in dry dichloromethane (200 ml). The reaction mixture is heated to reflux and kept stirring for 30 min. After cooling to rt, aniline (1.07 ml, 11.7 mmol) is added dropwise and the reaction is stirred at reflux for additional 2 h, then cooled to 0° C. and neutralized by addition of aqueous saturated Na2CO3 solution. The precipitate is filtered off, washed with water and dried under high vacuum to give title compound (1.54 g) as a white solid in 82% yield: tR (LC-2) 1.50 min; ESI-MS(+): m/z 183.33 [M+Na]+ (calcd 160.17 for C9H8N2O).