Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:7]=2[O:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:38]N1C(=O)CCC1=O>CCCCCC>[Br:38][CH2:2][CH2:3][C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:7]=2[O:6][CH:5]=1
Reactant: COC(=O)COc1cccc2c(CCO)coc12
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Product: COC(=O)COc1cccc2c(CCBr)coc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
Methyl (3-(2-hydroxyethyl)benzofuran-7-yloxy)acetate (1.30 g) was dissolved in THE (15 ml) and the solution was cooled to 0° C. To this solution, triphenylphosphine (2.05 g) and N-bromosuccinimide (NBS, 1.39 g) were added and the resulting solution was stirred for 1 hour. Hexane (10 ml) was added to the reaction solution and the reaction solution was filtered through Celite. The filtrate was poured into water layer (50 ml) and extracted twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying the resultant over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=3/1) using silica gel to obtain the desired compound (1.39 g, yield: 85%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:20])([CH2:15][O:16]C(=O)C)[CH2:10][O:11]C(=O)C.[OH-].[K+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:20])([CH2:15][OH:16])[CH2:10][OH:11]
Reactant: CC(=O)OCC(O)(COC(C)=O)c1ccc(F)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: OCC(O)(CO)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.8 %

Procedure:
In a 200 ml reaction vessel, 10 g of 2-(2,4-difluorophenyl)-1,3-diacetoxy-2-propanol was dissolved in 30 ml of toluene and thereto was added 30 ml of 30% aqueous KOH solution The resulting liquid was stirred at room temperature for 24 hours and more. Then a toluene-layer and an aqueous layer were separated from each other and the aqueous layer was extracted twice with 50 ml of ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The solvent was removed therefrom and the residue was purified in the same manner as in Example 32 to give 6.5 g of 2-(2,4-difluorophenyl)-1,2,3-propanetriol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][NH:11][CH:12]=2)[CH:7]=1.Br[CH2:25][C:26]([CH3:28])=[CH2:27].C(=O)([O-])[O-].[Cs+].[Cs+].CC(N(C)C)=O>CCOC(C)=O>[CH3:1][C:2]1[CH:3]=[C:4]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:21])([F:23])[F:22])[CH:17]=[CH:16][N:15]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH2:27][C:26]([CH3:28])=[CH2:25])[CH:12]=2)[CH:7]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cn[nH]c2)c1
Reactant: C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: C=C(C)Cn1cc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)cn1
Temperature: 100 °C
Reaction time: 1.25 h

Procedure:
N-(3-Methyl-5-(1H-pyrazol-4-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amine (34 mg, 0.11 mmol), 3-bromo-2-methylprop-1-ene (11 μl, 0.11 mmol), cesium carbonate (69 mg, 0.21 mmol) and DMA (210 μL) were combined in a vial and stirred at 100° C. for 1.25 hours. The reaction mixture was diluted with EtOAc, washed with aqueous sodium bicarbonate, then brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude N-(3-methyl-5-(1-(2-methylallyl)-1H-pyrazol-4-yl)phenyl)-4-(trifluoromethyl)pyrimidin-2-amine as a yellow oil. MS ESI calcd. for C19H19F3N5 [M+H]+ 374. found 374.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[N:20]1[CH:24]=[C:23]([CH2:25][CH2:26][NH2:27])[NH:22][CH:21]=1.CCN(C(C)C)C(C)C>>[N:20]1[CH:24]=[C:23]([CH2:25][CH2:26][NH:27][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[NH:22][CH:21]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: NCCc1cnc[nH]1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCCc2cnc[nH]2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-(3H-imidazol-4-yl)-ethylamine and DIEA to give 2-[2-(3H-imidazol-4-yl)-ethylamino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 350 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1I>>[Br:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[S:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Cl:1]
Reactant: Fc1ccc(I)c(Br)c1
Reactant: Fc1ccc(S)c(Cl)c1
Product: Fc1ccc(Sc2ccc(F)cc2Br)c(Cl)c1

Procedure:
Prepared from 2-chloro-4-fluoro-benzenethiol and 2-bromo-4-fluoro-1-iodo-benzene.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:25][C:2]([F:1])([F:24])[O:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OC(F)(F)F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(OC2CCNCC2)cc1
Reaction time: 8 h
Yield: 82.7 %

Procedure:
Tert-butyl 4-(4-trifluoromethoxyphenoxy)-piperidine-1-carboxylate (92 g, 254.59 mmol) prepared in Reference Example 189 was dissolved in methylene chloride (100 ml). Trifluoroacetic acid (200 ml) was added dropwise to this solution at room temperature, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, and the residue was then dissolved in methylene chloride, which was neutralized with a sodium hydroxide aqueous solution. The mixture was extracted with methylene chloride. The extract was washed with brine, dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (methylene chloride/methanol=5/1) to afford 4-(4-trifluoromethoxyphenoxy)piperidine (55 g, yield 83%) as a white powder.
Reaction SMILES: [C:1](=O)([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[O:2]CC1C=CC=C(Br)C=1.BrC1C=C(CO)C=CC=1.[OH:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:1]([O:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:2])=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: O=C(OCc1cccc(Br)c1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CO
Agent: OCc1cccc(Br)c1
Product: CCOC(=O)COC(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
The title compound was prepared using a procedure analogous to 3-bromobenzyl 4-nitrophenyl carbonate except that (3-bromophenyl)methanol was replaced with ethyl 2-hydroxyacetate. LCMS, [M+Na]+=292.0. 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J=9.2 Hz, 2H), 7.37 (d, J=9.2 Hz, 2H), 4.72 (s, 2H), 4.25 (q, J=7.2 Hz, 2H), 1.28 (t, J=7.1 Hz, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:12]=[CH:11][C:10]=1[OH:29])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S([O-])(=O)(=O)C.[CH3:35][C:36]1([CH3:43])[O:40][CH:39]([CH2:41]O)[CH2:38][O:37]1>CN(C)C=O>[CH2:3]([C:9]1[CH:14]=[C:13]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:12]=[CH:11][C:10]=1[O:29][CH2:41][CH:39]1[CH2:38][O:37][C:36]([CH3:43])([CH3:35])[O:40]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCCCCCCCc1ccc(O)c(CCCCCC)c1
Reactant: CC1(C)OCC(CO)O1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCc1ccc(OCC2COC(C)(C)O2)c(CCCCCC)c1

Procedure:
To a suspension of 2.27 g of prewashed 50% sodium hydride in 65 ml of dimethylformamide was added dropwise a solution of 11.78 g of 2-hexyl-4-tetradecylphenol in 65 ml of dimethylformamide. This mixture was heated for 1/2 hour, then 8.61 g of the mesylate of solketal was added. The mixture was heated at reflux for 3 hours, cooled, quenched carefully with water and extracted several times with ether. The ether extracts were combined, dried and the solvent evaporated, giving 15 g of the desired compound.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.O[CH:13]([C:20]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=1[O:28][CH3:29])[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1>FC(F)(F)C(O)=O>[CH3:29][O:28][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH3:27])[C:20]=1[CH:13]([S:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: COC(=O)c1ccc(S)cc1
Reactant: COc1cccc(OC)c1C(O)Cn1ccnc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(SC(Cn2ccnc2)c2c(OC)cccc2OC)cc1
Reaction time: 2 h
Yield: 92.5 %

Procedure:
20 ml of trifluoroacetic acid were added, whilst ice-cooling, to a mixture of 1.38 g of methyl 4-mercaptobenzoate and 1.36 g of 1-[2-hydroxy-2-(2,6-dimethoxyphenyl)ethyl]imidazole, and the resulting mixture was stirred at a temperature between 0° and 5° C. for 2 hours. The reaction mixture was then treated and purified by the same method as described in Example 13, to give 2.02 g of the title compound as a colorless oil.
Reaction SMILES: [NH2:1]/[C:2](/[C:7]#[N:8])=[C:3](\[NH2:6])/[C:4]#[N:5].[CH:9](OCC)(OCC)OCC>>[NH:6]1[C:3]([C:4]#[N:5])=[C:2]([C:7]#[N:8])[N:1]=[CH:9]1
Reactant: CCOC(OCC)OCC
Reactant: N#C/C(N)=C(/N)C#N
Product: N#Cc1nc[nH]c1C#N

Procedure:
In another 5-step synthesis, diaminomaleonitrile can be reacted with triethyl orthoformate to give the imidazole-4,5-dinitrile which, after alkylation with dimethyl sulfate, hydrolysis and partial decarboxylation by heating in acetic anhydride, gives the compound of the formula Ia (R1 =CH3, X1 =COOH).
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[C:5]([CH2:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17]C)[CH:15]=2)[N:10]([CH3:19])[CH2:9]1)=[O:6])[CH2:2][CH3:3].B(Br)(Br)Br.CO>ClCCl.C(OCC)C>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([CH2:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[N:10]([CH3:19])[CH2:9]1)=[O:6])[CH2:21][CH3:22]
Reactant: CCCN(CCC)C(=O)CC1CN(C)c2ccc(OC)cc21
Agent: BrB(Br)Br
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: CCCN(CCC)C(=O)CC1CN(C)c2ccc(O)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(di-n-propylaminocarbonylmethyl)-5-methoxy-1-methylindoline (62 mg, 0.20 mmol) in 1.0 mL of dry dichloromethane was added boron tribromide (0.116 mL, 1.20 mmol) at 0° C. After the reaction mixture was stirred at room temperature for 30 min, methanol (0.2 mL) was added. After the reaction mixture was diluted with diethyl ether, the solution was washed with saturated NaHCO3 aqueous solution and brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo to obtain crude 3-(di-n-propylaminocarbonylmethyl)-1-methylindolin-5-ol. The title compound was synthesized using the same procedure employed for Example 2 (2), but with the above product instead of 1-benzylindolin-5-ol. The product was obtained as a white solid (28.6 mg, 2 steps 32%) having the following characteristics.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:12][OH:13])[CH:7]=[C:8]([CH2:10][OH:11])[CH:9]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:12][OH:13])[CH:7]=[C:8]([CH2:10][OH:11])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(CO)cc(CO)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(CO)cc(CO)c1
Reaction time: 5 h

Procedure:
To a solution of 5-Nitro-m-xylene-α,α′-diol (890 mg, 5.4 mmol) in methanol (50 mL) was added Pd/C (10%, 287 mg). A hydrogen atmosphere was introduced and the mixture was hydrogenated under pressure (H2, 5˜8 psi) for 5 hours at room temperature. The solution was filtered through celite and the filtrate was evaporated by rotary evaporation in vacuo to give 5-amino-m-xylene-α,α′-diol, which was then dissolved in THF (10 mL)/DMF (15 ml). 4-methyldithio-4,4-dimethyl butanoic acid (1.05 g, 5.4 mmol) dissolved in THF (5 ml) was added at room temperature followed by the addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.1 g, 10.8 mmol) and 4-dimethylamino pyridine (66 mg, 0.54 mmol). The obtained mixture was stirred at room temperature overnight then quenched with 10% ammonium chloride, extracted with ethylacetate, washed and dried. It was filtered and the solvents were removed by rotary evaporation in vacuo. The residue was purified by flash chromatography (CH2Cl2/MeOH, 15:1, 10:1, 7:1) to furnish 5-(N-4-methyldithio-4,4-dimethylbutanoyl)-amino-1,3-bis-(hydroxymethyl)-benzene as a white solid (729 mg).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([CH:28]([CH3:30])[CH3:29])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=O)[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7].Cl.[NH2:32][OH:33]>N1C=CC=CC=1>[CH3:1][CH2:2][C@@H:3]([CH:28]([CH3:30])[CH3:29])[CH2:4][CH2:5][C@H:6]([C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C:15](=[CH:16][C:17](=[N:32][OH:33])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1)[CH3:7]
Reactant: NO
Reactant: CC[C@H](CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CC[C@H](CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=NO)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Temperature: 25 °C
Yield: 50 %

Procedure:
100 mg of 4-stigmasta-ene-3-one (0.24 mmol) is solubilized in 10 ml of pyridine in a 50 ml flask, then 100 mg of hydroxylamine hydrochloride is added. Stirring is maintained for 24 hours at ambient temperature, and the solvent is evaporated off under reduced pressure. Water then ethyl acetate is added in order to carry out an extraction. Then the organic phase is washed with an acidified aqueous solution (HCl 1%). The ethyl acetate is evaporated off under reduced pressure. A white powder is obtained with a yield greater than 50%.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:14])[CH3:13].[H][H]>CO.[Pd]>[CH3:1][C:2]([CH3:16])([CH3:15])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12](=[O:14])[CH3:13]
Reactant: [H][H]
Reactant: CC(=O)Nc1ccccc1C#CC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(=O)Nc1ccccc1CCC(C)(C)C
Yield: 94.2 %

Procedure:
3.23 g (15 mmol) of N-[2-(3,3-dimethylbut-1-ynyl)phenyl]acetamide (XIII-1) were initially charged in 40 ml of methanol. 0.5 g of palladium-on-carbon (5%) was added, and the mixture is then hydrogenated in an autoclave at a hydrogen pressure of 4 bar for 20 h. Removal of the catalyst and the solvent gave 3.1 g (94% of theory) of N-[2-(3,3-dimethylbutyl)phenyl]acetamide of logP (pH 2.3)=2.69.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14](I)=[CH:13][N:12]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][N:20]1[CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH:22]=[N:21]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.O.CCO.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:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:11]2[CH:16]=[CH:15][C:14]([C:23]3[CH:22]=[N:21][N:20]([CH3:19])[CH:24]=3)=[CH:13][N:12]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(I)cn2)CC1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: Cn1cc(-c2ccc(C3(NC(=O)OC(C)(C)C)CC3)nc2)cn1
Temperature: 100 °C
Yield: 125.9 %

Procedure:
To a mixture of [1-(5-iodo-pyridin-2-yl)-cyclopropyl]-carbamic acid tert-butyl ester (500 mg, 1.39 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 433 mg, 2.1 mmol) and Pd(dppf)Cl2.dichloromethane complex (113 mg, 0.14 mmol) in 1.5 mL of DME/H2O/EtOH (7:3:2) in a sealable microwave tube was added 1M aqueous K3PO4 solution (2.1 mL). The tube was sealed and heated in the microwave at 100° C. for 10 min. The crude reaction was filtered through a pad of silica gel, washing with MeOH, and concentrated. The residue was partitioned between 30 mL of EtOAc and 10 mL of water. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give an oil. This material was purified by normal phase flash chromatography on silica gel (0→3.5% MeOH/CH2Cl2) to give 0.55 g of {1-[5-(1-methyl-1H-pyrazol-4-yl)-pyridin-2-yl]-cyclopropyl}-carbamic acid tert-butyl ester as a brown solid. The compound was used in subsequent steps without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:15]=[C:14]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:13]=1[OH:26])([O-])=O.NCCNCCN>C1(C)C(C)=CC=CC=1>[OH:26][C:13]1[C:14]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:15][C:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:17][C:12]=1[N:11]1[N:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[N:1]1
Reactant: CC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)C)c1
Agent: NCCNCCN
Solvent: Cc1ccccc1C
Product: CC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)C)c1
Yield: 90 %

Procedure:
Example 1 is repeated, except that an equivalent amount of 2-nitro-2'-hydroxy-3', 5'-di-tert.-butylazobenzene (91% pure) is used instead of 2-nitro-2'-hydroxy-5'-methylazobenzene and a mixture of 40 g of xylene and 60 g of diethylenetriamine instead of 80 g of xylene and 20 g of diethylenetriamine. The hydrogenation is carried out at 50° C. After work up of the hydrogenation solution, the product is crystallized from a mixture of 40 g of xylene and 160 g of methanol. The product (title compound) is isolated in a yield of 90% of theory. Melting point: 152°-154° C.
Reaction SMILES: [I-:1].[NH+]1C=CC=C[CH:3]=1.[CH:8]([NH:10][C:11]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:12]=1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)=[O:9].CI.C(NC1C=CC=CC=1CCC1C=CC=CN=1)=O>>[I-:1].[CH:8]([NH:10][C:11]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:12]=1[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N+:16]=1[CH3:3])=[O:9]
Reactant: COc1ccc(NC=O)c(CCc2ccccn2)c1
Reactant: c1cc[nH+]cc1
Agent: O=CNc1ccccc1CCc1ccccn1
Agent: [I-]
Solvent: CI
Product: COc1ccc(NC=O)c(CCc2cccc[n+]2C)c1
Yield: 95 %

Procedure:
The pyridinium iodide is obtained by treating 2-(2-formamido-5-methoxyphenethyl)pyridine with methyl iodide according to the procedure described in Example 2 (c) for 2-(o-formamidophenethyl)pyridine. Analytically pure 2-(2-formamido-5-methoxyphenethyl)-1-methylpyridinium iodide is obtained in a yield of 95% and has a melting point of 184°-186.5° C. (corr.).
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][C@@:13]1([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])[CH2:18][O:17][C@@H:16]([CH2:19][O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:15][C@H:14]1[CH2:28][OH:29]>ClCCl>[CH2:21]([O:20][CH2:19][C@@H:16]1[O:17][CH2:18][C@@:13]([NH:12][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[S:11])([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])[C@H:14]([CH2:28][OH:29])[CH2:15]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: N[C@@]1(c2ccc(F)cc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2ccc(F)cc2F)CO[C@@H](COCc2ccccc2)C[C@H]1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzoyl isothiocyanate (17.8 mL, 132 mmol) was added to a solution of [(2R,4R,5S)-5-amino-2-[(benzyloxy)methyl]-5-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl]methanol (C6) (48.7 g, 134 mmol) in dichloromethane (1.34 L), and the reaction mixture was allowed to stir at room temperature for 18 hours. Removal of solvent in vacuo afforded the product as a white solid, which was used without additional purification. Yield: 72.2 g, assumed quantitative. LCMS m/z 527.2 [M+H+]. 1H NMR (400 MHz, CD3OD), characteristic peaks: δ 7.89-7.93 (m, 2H), 7.62-7.67 (m, 1H), 7.50-7.56 (m, 2H), 7.42-7.54 (br m, 1H), 7.31-7.36 (m, 2H), 7.17-7.28 (m, 3H), 6.86-6.98 (m, 2H), 4.57 (AB quartet, JAB=11.9 Hz, ΔνAB=11.8 Hz, 2H), 3.84-3.91 (m, 1H), 3.64 (br dd, half of ABX pattern, J=10.6, 6.0 Hz, 1H), 3.58 (dd, half of ABX pattern, J=10.6, 3.8 Hz, 1H), 3.44-3.54 (br m, 1H), 2.32-2.59 (br m, 1H), 1.82-2.06 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[CH:21]=[C:22]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:22]3[CH:23]=[CH:24][C:25]([CH3:26])=[C:20]([CH3:19])[CH:21]=3)=[O:33])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1ccc(-c2ocnc2C(=O)O)cc1C
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3ccc(C)c(C)c3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3,4-dimethyl-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.08 min; [M+H]+=405.12.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[CH:11]=[CH:10][O:9][C:8]=12.[Li][CH2:13]CCC.CI>C1COCC1>[CH3:1][O:2][C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[CH:11]=[C:10]([CH3:13])[O:9][C:8]=12
Reactant: COc1nccc2ccoc12
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COc1nccc2cc(C)oc12
Temperature: -78 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of 7-methoxyfuro[2,3-c]pyridine (2.9 g, 19.6 mmol) in THF (20 mL) stirred under an atmosphere of argon was added n-BuLi (7.8 mL, 19.6 mmol) at −78° C.; the mixture was transferred to a −30° C. ice bath and was stirred for 2 h. The mixture was cooled to −78° C. and MeI (4.2 g, 29.4 mmol) was added. After the mixture was stirred at rt for 18 h, the reaction mixture was quenched with water (30 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with brine (30 mL×3), dried over Na2SO4 and concentrated in vacuo to afford the title compound (3.2 g, 100%) as a yellow solid. The material was carried forward without any further purification. LCMS (M+H)+=164.
Reaction SMILES: [C:1]1([C:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([CH2:19][C:20]([NH:22][NH2:23])=[O:21])#[N:18]>CN(C)C=O>[C:17]([C:19]1[C:20](=[O:21])[NH:22][N:23]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)#[N:18]
Reactant: N#CCC(=O)NN
Reactant: O=C(C(=O)c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccccc2)c(-c2ccccc2)n[nH]c1=O
Yield: 95 %

Procedure:
Benzil 63.1 grams (0.3 mole) along with 30 grams (0.3 mole) of cyanoacetohydrazide in 200 mls of dimethylformamide was heated at 110° C. for five hours. The solution was cooled and the precipitant solid was filtered and washed with ethyl alcohol. The filtrate was vacuum distilled and the residual solid was washed with ethyl alcohol and filtered. There was isolated 74.5 grams, a 95% yield, of a solid which melted at 280°-281° C. Calculated for C17H11N3O, C, 74.7; H, 4.1; N, 15.4. Found: C, 74.4; H, 4.16; N, 15.2. The infrared spectra showed the nitrile at 4.5μ; the ##STR57## band for an amide at 6.0μ.