Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])=O.[CH3:4][C:5]([CH3:12])=[CH:6][C:7](=[O:11])[C:8]([OH:10])=[O:9].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1.C([O-])=O.[Na+].P(OCC([C@H]([C@@H]([C@@H](COP(O)(O)=O)O)O)O)=O)(O)(O)=O.SC[C@H]([C@@H](CS)O)O.Cl>C(O)C(N)(CO)CO.C(OCC)(=O)C>[OH:11][C@@H:7]([CH:6]=[C:5]([CH3:12])[CH3:4])[C:8]([OH:10])=[O:9]
Reactant: CC(C)=CC(=O)C(=O)O
Agent: Cl
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: NC(CO)(CO)CO
Solvent: CCOC(C)=O
Product: CC(C)=C[C@H](O)C(=O)O
Temperature: -20 °C
Reaction time: 120 h

Procedure:
MVS/GG (6 units (μ moles/minute/30° C.)) and yeast formate dehydrogenase (5 units) were added to a solution of 4-methyl-2-oxo-3-pentenoic acid (1.0 mM) in deoxygenated Tris buffer (5 mM:pH 6.0; 80 ml) containing NADH (0.02 mM), sodium formate (3.1 mM), fructose-1,6-bisphosphate (0.4 mM) and dithiothreitol (0.08 mM). The solution was stirred at room temperature (-20° C.) under nitrogen for 5 days with periodic addition of 0.2 mM HCl to maintain pH in the range of 6.0-6.2. Acidification to pH 2.0 and extractive work-up with ethyl acetate gave (S)-2-hydroxy-4-methyl-3-pentenoic acid in 91% isolated yield. Analysis of the (R)-MTPA derivative and comparison to a racemic standard gave a value of at least 99% for entantiomeric excess.
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])C.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[C:12]=1[NH:18][NH2:19]>CO>[NH2:9][C:8]1[N:18]([C:12]2[C:11]([Br:10])=[CH:16][CH:15]=[CH:14][C:13]=2[Br:17])[N:19]=[CH:4][C:5]=1[C:6]#[N:7]
Reactant: CCOC=C(C#N)C#N
Reactant: NNc1c(Br)cccc1Br
Solvent: CO
Product: N#Cc1cnn(-c2c(Br)cccc2Br)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(Ethoxymethylene)malononitrile (197 mg, 1.62 mmol) was added portionwise to a stirred solution of (2,6-dibromophenyl)hydrazine (CAS no. 14763-29-2) (430 mg, 1.62 mmol) in MeOH (8085 μl), under nitrogen at 5° C. The resulting solution was allowed to stir for a further 1 hour. The reaction mixture was then heated to reflux and was stirred for 3 hours. The reaction mixture was allowed to cool to ambient temperature, then was evaporated to afford crude product which was used without further purification.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9](Cl)([O:11]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][C:29]1[N:34]=[CH:33][C:32]([NH:35][C:36](=[O:40])[C@@H:37]([CH3:39])[NH2:38])=[CH:31][CH:30]=1)[CH3:21]>ClCCl.CN(C)C1C=CN=CC=1>[CH2:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][C:29]1[N:34]=[CH:33][C:32]([N:35]2[C:36](=[O:40])[C@@H:37]([CH3:39])[NH:38][C:9]2=[O:11])=[CH:31][CH:30]=1)[CH3:21]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCc1ccccc1Oc1ccc(NC(=O)[C@@H](C)N)cn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccccc1Oc1ccc(N2C(=O)N[C@H](C)C2=O)cn1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 168.5 %

Procedure:
In a 50 mL round-bottomed flask N1-{6-[(2-ethylphenyl)oxy]-3-pyridinyl}-D-alaninamide (Intermediate 48, 170.0 mg) was dissolved in dichloromethane (5 mL) to give a pale yellow solution. The reaction mixture was cooled at 0° C. N,N-dimethyl-4-pyridinamine (35.7 mg, 0.292 mmol), triethylamine (0.203 mL, 1.460 mmol) and triphosgene (87 mg, 0.292 mmol) were added. The reaction mixture was stirred at 0° C. After 20 min, the reaction mixture was evaporated in vacuo affording yellow solid that was purified by silica gel chromatography (Biotage system, 10 g SNAP column) eluting with a gradient Cyclohexane/EtOAc from 2:1 to 1:3 in 20 CV; then 1:3 for 5 CV. The collected fractions afforded the title compound as a colourless oil (153.2 mg).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([N:13]3[C:17]4[CH:18]=[CH:19][C:20]([CH:22](O)[CH3:23])=[CH:21][C:16]=4[N:15]=[CH:14]3)[CH:10]=[CH:11][CH:12]=2)=[N:4][CH:3]=1.C1(C)C=CC=CC=1.[N:32]12CCCN=C1CCCCC2.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([N:13]3[C:17]4[CH:18]=[CH:19][C:20]([CH:22]([NH2:32])[CH3:23])=[CH:21][C:16]=4[N:15]=[CH:14]3)[CH:10]=[CH:11][CH:12]=2)=[N:4][CH:3]=1
Reactant: CC(O)c1ccc2c(c1)ncn2-c1cccc(-c2ncc(Cl)s2)c1
Reactant: C1CCC2=NCCCN2CC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(N)c1ccc2c(c1)ncn2-c1cccc(-c2ncc(Cl)s2)c1
Temperature: 10 °C
Reaction time: 0.75 h
Yield: 75.5 %

Procedure:
A stirred suspension of 1-{1-[3-(5-chloro-thiazol-2-yl)-phenyl]-1H-benzoimidazol-5-yl}-ethanol (1.0 g, 2.80 mmol) in a mixture anhydrous toluene (60 ml) and THF (10 ml) was cooled to 10° C. and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.5 ml, 3.36 mmol) and di-phenylphosphoryl azide (0.95 g, 3.36 mmol) were added, successively. Stirring was continued for 45 min at 10° C., whereafter the temperature was raised and the mixture was stirred at reflux for two days. The cooled mixture was concentrated in vacuo and the concentrate was partitioned between ethyl acetate and saturated, aqueous sodium carbonate. The organic extract was dried over magnesium sulphate, concentrated under reduced pressure and eluted through silica gel with a mixture of dichloro-methane, methanol and aqueous ammonia (9:1:0.1 v/v/v) to afford the desired product (0.75 g, 70%). LC-ESI-HRMS of [M+H]+ shows 355.079 Da. Calc. 355.07842 Da. dev. 1.6 ppm.
Reaction SMILES: C(O)(C(F)(F)F)=O.CC(C)(S([NH:13][C:14]1([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]3[N:30]=[C:29]([CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[CH2:39][C:40]([NH2:42])=[O:41])[C:28]([CH3:43])=[CH:27][N:26]=3)=[CH:20][CH:19]=2)[CH2:17][O:16][CH2:15]1)=O)C>C(Cl)Cl>[NH2:13][C:14]1([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]3[N:30]=[C:29]([CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[CH2:39][C:40]([NH2:42])=[O:41])[C:28]([CH3:43])=[CH:27][N:26]=3)=[CH:20][CH:19]=2)[CH2:15][O:16][CH2:17]1
Reactant: Cc1cnc(Nc2ccc(C3(NS(=O)C(C)(C)C)COC3)cc2)nc1CCc1ccccc1CC(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(Nc2ccc(C3(N)COC3)cc2)nc1CCc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.6 %

Procedure:
TFA (0.5 mL) was added to a solution of 2-(2-(2-(2-(4-(3-(1,1-dimethylethylsulfinamido)oxetan-3-yl)phenylamino)-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide (A122) (30 mg, 0.058 mmol) in DCM (3.0 mL) under a nitrogen atmosphere and the resulting mixture stirred at room temperature for 30 minutes, then at 35° C. overnight. The volatiles were evaporated under reduced pressure, keeping the temperature below 30° C. The resulting oil was purified by semi preparative HPLC, to give the title compound 31 (5.0 mg, 21%); 1H NMR (300 MHz, d4-MeOH) δ 8.24 (br s, 1H), 8.15 (s, 1H), 7.85 (d, J=8.8 Hz, 2H), 7.38 (d, J=8.8 Hz, 2H), 7.22 (m, 4H), 5.13 (d, J=7.7 Hz, 2H), 4.97 (d, J=7.7 Hz, 2H), 3.67 (s, 2H), 3.16 (m, 2H), 3.00 (m, 2H), 2.13 (s, 3H). LCMS: rt 4.72 min; m/z 418.2 [M+H]+.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][O:5][C:6]([C:8]12[CH2:13][CH:12]1[CH2:11][CH2:10][C:9]2=[O:14])=[O:7]>CN(C)C=O>[CH3:4][O:5][C:6]([CH:8]1[CH:12]([CH2:13][C:1]#[N:2])[CH2:11][CH2:10][C:9]1=[O:14])=[O:7]
Reactant: COC(=O)C12CC1CCC2=O
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1C(=O)CCC1CC#N
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.4 %

Procedure:
In argon atmosphere, potassium cyanide (260 mg, 4 mmol) and 2-oxo-bicyclo [3.1.0] hexane-1-carboxylic acid methyl ester (462 mg, 3 mmol) were added to dimethylformamide (3 ml). The mixture was stirred at the room temperature for 24 hours and was treated in accordance with the process of Preparation 4 to obtain 290 mg of 5-cyanomethyl-2-oxo-cyclopentanecarboxylic acid methyl ester. Yield: 53%.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[NH2:8][C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1>>[N:4]1[CH:3]=[C:2]([C:13]2[CH:14]=[C:9]([CH:10]=[CH:11][CH:12]=2)[NH2:8])[CH:7]=[N:6][CH:5]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Brc1cncnc1
Product: Nc1cccc(-c2cncnc2)c1
Yield: 84 %

Procedure:
This was prepared from 5-bromopyrimidine and 3-aminophenyl boronic acid in 84% yield by the same method as for Description 12.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:13])[O:4][C:5]2[C:10]([C:11]=1[OH:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[O:22]1[CH2:27][CH2:26][N:25]([CH:28](Cl)[CH3:29])[CH2:24][CH2:23]1.C(=O)(O)[O-].[Na+]>C(C(C)=O)C(C)C>[CH3:1][C:2]1[C:3](=[O:13])[O:4][C:5]2[C:10]([C:11]=1[O:12][CH2:29][CH2:28][N:25]1[CH2:26][CH2:27][O:22][CH2:23][CH2:24]1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Cc1c(O)c2ccccc2oc1=O
Reactant: CC(Cl)N1CCOCC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(=O)CC(C)C
Product: Cc1c(OCCN2CCOCC2)c2ccccc2oc1=O
Reaction time: 1 h
Yield: 67 %

Procedure:
8.8 g. (0.05 mol) of 3-methyl-4-hydroxy-coumarin are solubilised in 200 ml. of methyl isobutyl ketone at 80° C., and then, at this temperature, there are added 8.3 g. (0.06 mol) of anhydrous potassium carbonate and 0.5 g. of potassium iodide. The mixture is left for 1 hour at 80° C. while stirring. In 1 hour, there is added a solution of 9.8 g. (0.065 mol) of 2-morpholino-2-chlorethane in 50 ml. of methyl isobutyl ketone. The substance is then refluxed for 8 hours, filtered while hot and evaporated under vacuum. The oil which is obtained is taken up under heat in 200 ml. of a 5% solution of sodium bicarbonate, whereafter it is cooled, and extracted with 3×100 ml of ether. It is dried over NaSO4 and then the ether is evaporated under vacuum. A brown oil is obtained which cannot be crystallised. Weight 10 g.; yield 67% (theoretical yield 14.9 g.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH3:16][C:17]1[C:18](=[O:24])[NH:19][C:20](=S)[NH:21][CH:22]=1>C(O)C>[CH3:16][C:17]1[C:18](=[O:24])[N:19]=[C:20]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][CH:3]=2)[NH:21][CH:22]=1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: Cc1c[nH]c(=S)[nH]c1=O
Solvent: CCO
Product: Cc1c[nH]c(Nc2ccc(C3=NNC(=O)CC3C)cc2)nc1=O
Temperature: 180 °C
Yield: 14.7 %

Procedure:
A stirred mixture of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone (3.25 g) and 5-methylthiouracil (2.5 g) was heated at 180° C. for 11/2 hours. The residual gum was dissolved in hot aqueous ethanol and the solution was evaporated. Trituration of the residue with chloroform:methanol (10:1) gave the crude product as a solid (0.78 g), m.p. 260°-270° C. The filtrate was evaporated and the residue was heated at 180° C. for one hour. Purification of the residue by column chromatography (silica gel, chloroform:methanol, 25:1) gave a further amount of product (0.73 g).
Reaction SMILES: C[Mg]Br.[CH2:4](OCC)C.[CH:9]([C:11]1[N:12]2[CH:18]=[N:17][CH:16]=[C:13]2[S:14][CH:15]=1)=[O:10].[Cl-].[NH4+]>C1COCC1>[OH:10][CH:9]([C:11]1[N:12]2[CH:18]=[N:17][CH:16]=[C:13]2[S:14][CH:15]=1)[CH3:4]
Reactant: CCOCC
Reactant: O=Cc1csc2cncn12
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1csc2cncn12
Reaction time: 3.5 h

Procedure:
Under an argon atmosphere, 1 ml of a 3.0M methylmagnesium bromide-diethyl ether solution was added dropwise to 15 ml of an anhydrous THF solution containing 304 mg of 3- formylimidazo[5,1-b]thiazole at -78° C., and the mixture was then stirred at the same temperature for 3.5 hours. Further, an aqueous ammonium chloride solution was added to the reaction solution, and the solution was then extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by a silica gel column chromatograph to obtain 296 mg of the title compound as a colorless crystal.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]([C:19]([F:22])([F:21])[F:20])=[N:17][N:16]=[C:15]2[CH3:23])[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:23][C:15]1[N:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:18]([C:19]([F:22])([F:20])[F:21])=[N:17][N:16]=1
Reactant: Cc1nnc(C(F)(F)F)n1C1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1nnc(C(F)(F)F)n1C1CCNCC1

Procedure:
A solution of 1-benzyl-4-[3-methyl-5-(trifluoromethyl)-4H-1,2,4-triazol-4-yl]piperidine (2.97 g) in ethanol (45 ml) was hydrogenated under a hydrogen filled balloon using 20% palladium hydroxide on charcoal as catalyst. The mixture was filtered through celite and evaporated to dryness to give the title compound, yield 2.14 g, LC-MS M+H 235, NMR (CDCl3); 1.90 (2H, d), 2.16 (2H, m), 2.42 (1H, br N—H), 2.66 (3H, s), 2.78 (2H, t), 3.32 (1H, d), 4.26 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[F:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][CH2:20][NH2:21])=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][CH2:20][NH:21][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:13])=[CH:17][CH:16]=1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Reactant: NCCc1ccc(F)cc1
Product: O=C(NCCc1ccc(F)cc1)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 1 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18) and 4-fluorophenethylamine. The product was purified by mass directed purification to give the title compound as an orange solid. δH (CD3OD): 2.93 (2H, t), 3.60 (2H, t), 6.97–7.04 (3H, m), 7.24–7.30 (2H, m), 7.65 (1H, s), 8.56 (1H, s); m/z (ES+)=318 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4](/[C:18](/[CH3:26])=[C:19](/[F:25])\[C:20](OCC)=[O:21])[C:3]=1[O:27][CH:28]([CH3:30])[CH3:29].[H-].C([Al+]CC(C)C)C(C)C>>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([C:14]([CH3:15])([CH3:16])[CH3:17])[C:6]=2[CH:5]=[C:4](/[C:18](/[CH3:26])=[C:19](/[F:25])\[CH2:20][OH:21])[C:3]=1[O:27][CH:28]([CH3:30])[CH3:29]
Reactant: CCOC(=O)/C(F)=C(/C)c1cc2c(c(Br)c1OC(C)C)C(C)(C)CC=C2C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: C/C(=C(\F)CO)c1cc2c(c(Br)c1OC(C)C)C(C)(C)CC=C2C(C)(C)C

Procedure:
Following General Procedure G-1, ethyl (2E)-3-(4-bromo-8-tert-butyl-3-isopropoxy-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-2-fluoro-but-2-enoate (Compound A-131, 115 mg, 0.24 mmol) and diisobutylaluminum hydride (1M in methylene chloride, 0.64 mL, 0.64 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 10% ethyl acetate in hexanes).
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23]C=C[N:20]=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[NH:25]1C(CN)=CC=N1>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[NH:20][N:25]=[CH:23][CH:24]=3)[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: NCc1ccn[nH]1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Agent: Cl
Product: Cc1nc(NCc2ccn[nH]2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the general procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using (1H-pyrazol-5-ylmethyl)amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a light-yellow solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.28-1.37 (m, 5H), 1.60-1.69 (m, 5H), 1.86 (s, 3H), 2.25 (s, 3H), 3.98 (d, J=10.74 Hz, 1H), 4.52 (d, J=4.82 Hz, 2H), 6.12 (s, 1H), 7.59 (s, 1H), 7.98 (s, 1H), 12.15 (bs, 1H); MS (ESI) m/z 301.5 (M+1)+.
Reaction SMILES: [OH:1][C:2]1([CH3:25])[CH2:8][CH:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[O:6][C:4](=[O:5])[CH2:3]1.C(N(CC)CC)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:33]([O:1][C:2]1([CH3:25])[CH2:8][CH:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:13][CH:12]=2)[O:6][C:4](=[O:5])[CH2:3]1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(O)CC(=O)OC(CCc2ccc(OCc3ccccc3)cc2)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1(C)CC(=O)OC(CCc2ccc(OCc3ccccc3)cc2)C1
Temperature: 0 °C

Procedure:
One hundred milligrams of 3-hydroxy-3-methyl-7-(p-benzyloxyphenyl)-5-heptanolide was dissolved in 0.1 ml of methylene chloride and 0.63 ml of acetic anhydride, 0.50 ml of triethylamine and 1.5 mg of N,N-dimethyl-4-pyridineamine were added thereto under cooling at 0° C. After allowing to stand under ice-cooling for 4 hours, the reaction mixture was poured into ice-water and the crystals thus precipitated were recrystallized from a mixture of ethyl acetate and n-hexane (1:10) affording 68 mg of the desired compound melting at 98°-101° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[O:16])=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][C:15]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])=[O:16])=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)NCc1ccccc1F
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)NCc4ccccc4F)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-3-(2-fluoro-benzyl)-urea and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [OH:1][CH:2]1[C:15]([CH:16]=[CH:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:4](=[O:25])[CH2:3]1.C(O)C.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C(N(CC)CC)C>[OH:1][CH:2]1[C:15]([CH:16]=[CH:17][CH:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:4](=[O:25])[CH2:3]1
Reactant: CCCCCC(=O)C=CC1=C(CCCCCCC(=O)O)C(=O)CC1O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCC(O)C=CC1=C(CCCCCCC(=O)O)C(=O)CC1O
Reaction time: 0.42 h

Procedure:
To a solution of 12 parts of 11-hydroxy-9,15-dioxoprosta-8(12),13-dienoic acid in 28 parts of ethanol, cooled to 0°-5°, is added dropwise a solution of 3 parts of triethylamine in 275 parts of water. To that mixture is added dropwise with cooling and stirring a solution of 0.32 part of sodium borohydride in 32 parts of water. Stirring at approximately 10° is continued for about 25 minutes, at the end of which time the reaction mixture is poured carefully into excess aqueous citric acid. Extraction with ether affords an organic solution, which is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 11,15-dihydroxy-9-oxoprosta-8(12),13-dienoic acid. This mixture of epimeric 11-hydroxy compounds is separated by chromatography on silica gel. Elution with 30% ethyl acetate in chloroform affords epimer A, characterized by an ultraviolet absorption maximum at about 277 millimicrons with a molecular extinction coefficient of about 24,400. Further elution of the column with 50% ethyl acetate in chloroform yields epimer B, characterized by an ultraviolet absorption maximum at about 277.5 millimicrons with a molecular extinction coefficient of about 23,400.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[CH2:12].C(=O)(O)[O-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N+:8]([C:4]1[CH:3]=[C:2](/[CH:12]=[CH:11]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: C=Cc1ccccn1
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(/C=C/c2ccccn2)c1
Temperature: 110 °C
Reaction time: 5 h
Yield: 49.7 %

Procedure:
A mixture of 1-iodo-3-nitrobenzene (7.47 g), 2-vinylpyridine (4.73 g), palladium(II) acetate (0.20 g), tetrabutylammonium chloride (8.34 g) and sodium bicarbonate (6.3 g) in N,N-dimethylformamide (50 ml) was stirred at 110° C. for 5 hours. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 2-[(E)-2-(3-nitrophenyl)vinyl]pyridine (3.37 g).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16].Cl.C(O)(=O)C.[NH3:26]>[Cu]I>[NH2:26][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16]
Reactant: N
Reactant: Cc1cc(Br)c2cnn(-c3cccc(C(=O)O)c3)c2c1
Agent: [Cu]I
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(N)c2cnn(-c3cccc(C(=O)O)c3)c2c1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
A suspension of 3-(4-bromo-6-methyl-1H-indazol-1-yl)benzoic acid (1450.5 g, 4.38 mol) and copper (I) iodide (42.47 g, 0.22 mol, 5 mol %) in aqueous ammonia (0.88 sg, 13.5 L) was heated in a sealed pressure vessel until a pressure of 7 Bar±0.3 Bar was generated (contents temperature ˜78° C.). Stirring was continued for a period of ca. 2 days. The reaction mixture was cooled to 20° C. and then charged in to a Controlled Lab Reactor fitted with a 5M HCl scrubber. The solution was heated at reflux to remove excess ammonia by gradually raising the contents temperature to >90° C.—end point pH 7.87. The reaction mixture was then cooled to 60±3° C. and acetic acid (725 mL, 12.7 mol) was added slowly to form a precipitate—end point pH=5.68. The batch was cooled to 5±3° C. and stirred for 825 minutes. The slurry was filtered and washed with water (3×4.5 L). The solid was dried in vacuo at 50° C. to afford the title compound (1112.3 g).