Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][OH:5])(=O)C.CC(C)([O-])C.[K+].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[CH:23][CH:22]=[C:21]2[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:16][C:15]=1F)#[N:13].C(OCC)(=O)C>CN(C=O)C.[Cl-].[Na+].O>[NH2:13][C:12]1[C:14]2[CH:19]=[CH:18][C:17]([N:20]3[C:24]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)=[CH:23][CH:22]=[C:21]3[CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:16][C:15]=2[O:5][N:4]=1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(OC)cc2)n1-c1ccc(C#N)c(F)c1
Reactant: CC(=O)NO
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CCc1ccc(-c2ccc(OC)cc2)n1-c1ccc2c(N)noc2c1
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
In 4 mL of dry DMF was dissolved acetohydroxamic acid (57 mg, 0.765 mmol), followed by potassium t-butoxide (86 mg, 0.765 mmol) at ambient temperature. After this mixture had been stirred for 30 min, compound 47-1 (200 mg, 0.510 mmol) was added and stirred overnight. The reaction mixture was poured into a mixture of brine (30 mL) and ethyl acetate (30 mL). The organic phase was separated, the aqueous layer was extracted EA (20 mL×3). The combined organic phase was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by silica gel column chromatography (PE:EA=1:1) to afford 47-2 as a yellow oil (80 mg, 39%).
Reaction SMILES: [H-].[Na+].[C:3]1(=[O:16])[NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]CCCC1>>[C:3]1(=[O:16])[NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C1CCCCCCCCCCCN1
Agent: [H-]
Agent: [Na+]
Product: O=C1CCCCCCCN1
Reaction time: 2 h

Procedure:
0.3 mol % of sodium hydride and 0.3 mol % of the co-catalyst according to the Example 15 were dissolved in molten laurolactam. After 120 minutes at 160°C the polymerizate contained almost the equilibrium amount of the polyamide. Similar result was obtained with caprylolactam.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C=O)C>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:19])=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13]
Reactant: O=C(O)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(CBr)c(C(F)(F)F)c1

Procedure:
1.00 g of 4-(bromomethyl)-3-(trifluoromethyl)benzoic acid was dissolved in dichloromethane (q.s.), then 2 drops of anhydrous N,N′-dimethylformamide were added. Then 2 ml of oxalyl chloride was added dropwise to the mixture. The reaction mixture was reacted at room temperature for 5 h, and concentrated to provide the product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9]Br)[CH:3]=1.[C-:11]#[N:12].[K+].O>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[CH2:9][C:11]#[N:12]
Reactant: [C-]#N
Reactant: Cc1cc(Br)cc(CBr)c1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cc(Br)cc(CC#N)c1
Temperature: 55 °C
Reaction time: 3 h
Yield: 56.8 %

Procedure:
The crude 1-bromo-3-(bromomethyl)-5-methylbenzene obtained from step 5 (188 g, ˜0.71 M) was dissolved in ethanol (470 mL) by warming in an oil bath (50-60° C.). Potassium cyanide (69.57 g, 1.068 M) was added, then distilled water (235 mL). The mixture was heated to reflux and stirred for 3 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was diluted with ether, washed with water, dried with MgSO4, filtered, and evaporated in vacuo. The residue was dissolved in dichloromethane and ethyl acetate-hexane (1:20) and loaded onto a silica gel column and eluted with ethyl acetate-hexane (from 1:20 to 1:6) to afford 85 g (53% for 2 steps) of 3-bromo-5-methylbenzyl cyanide (5) as a pale brown oil.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:13]3[C:14]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=4)=[N:15][N:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=34)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(S)C.[H-].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH3:28][C:24]1[N:23]=[C:22]([C:14]2[C:13]([C:7]3[C:6]4[C:11](=[CH:12][C:3]([OH:2])=[CH:4][CH:5]=4)[N:10]=[CH:9][CH:8]=3)=[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]3[N:15]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc2c(-c3c(-c4cccc(C)n4)nn4ccccc34)ccnc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCS
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nn3ccccc3c2-c2ccnc3cc(O)ccc23)n1
Temperature: 80 °C
Yield: 92.2 %

Procedure:
To a solution of 7-methoxy-4-[2-(6-methyl-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline (1.3 g, 3.57 mmol) in DMF (36 mL), add ethanethiol (5.3 mL, 71.4 mmol), followed by sodium hydride (60% dispersion in mineral oil, 2.9 g, 71.4 mmol). After all of the gas has evolved, the mixture is heated at 80° C. for 4 hours, then cooled to room temperature. Saturated aqueous NH4Cl (5 mL) is added, and the mixture concentrated. The residue is dissolved in methylene chloride, washed with water and concentrated to give the title compound 1.16 g (93%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:12])[CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[C:22]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=O)=[CH:17][CH:16]=1>>[OH:12][C:4]1[CH:3]=[C:2]2[C:10]([N:11]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C:21]([C:18]3[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:20][CH:19]=3)=[N:1]2)=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: Nc1cc(O)c(C(=O)O)cc1N
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2nc3cc(O)c(C(=O)O)cc3nc2-c2ccc(OC)cc2)cc1
Yield: 12.4 %

Procedure:
The diaryl product was obtained using the same synthetic methods as shown in Example 25, step 7, using 4,5-diamino-2-hydroxybenzoic acid (168 mg, 1.00 mmol, 1.00 equiv) and 1,2-bis(4-methoxyphenyl)ethane-1,2-dione (270 mg, 1.00 mmol, 1.00 equiv) as reactants, yielding 50 mg (12%) of 7-hydroxy-2,3-bis(4-methoxyphenyl)quinoxaline-6-carboxylic acid as a red solid.
Reaction SMILES: CC(O[C:6](=[O:18])[NH:7][C@@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH:15]=[O:16])[C:9]1=[O:17])(C)C.C(O)(C(F)(F)F)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+].[Cl:43][C:44]1[CH:53]=[C:52]2[C:47]([C:48]([N:55]3[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]3)=[CH:49][C:50]([NH2:54])=[N:51]2)=[CH:46][CH:45]=1>>[NH2:54][C:50]1[CH:49]=[C:48]([N:55]2[CH2:56][CH2:57][N:58]([C:6]([NH:7][C@H:8]3[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([CH:15]=[O:16])[C:9]3=[O:17])=[O:18])[CH2:59][CH2:60]2)[C:47]2[C:52](=[CH:53][C:44]([Cl:43])=[CH:45][CH:46]=2)[N:51]=1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCCN(C=O)C1=O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(C=O)C3=O)CC2)c2ccc(Cl)cc2n1

Procedure:
As described for example 213, [(3R)-1-formylhexahydro-2-oxo-1H-azepin-3-yl]-carbamic acid-1,1-dimethylethyl ester, TFA, triphosgene, NaHCO3 (sat.), and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product as a light yellow solid. LC-MS: 445 (M++1). 1H NMR (CDCl3): δ 1.30 (m, 1H), 1.65 (m, 1H), 1.80˜2.30 (m, 4H), 3.09 (dd, 1H), 3.14 (m, 4H), 3.68 (m, 4H), 4.62 (br.dd, 1H), 4.82 (ddd, 1H), 4.90 (br.s, 2H), 5.84 (d, 1H), 6.16 (s, 1H), 7.18 (dd, 1H), 7.62 (d, 1H), 7.72 (d, 1H), 9.47 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21](I)[N:20]=[CH:19]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:24]([NH:28][S:29]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([C:21]2[N:20]=[CH:19][N:18]([C:10]3[N:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:9]=3)[CH:22]=2)[CH:37]=1)(=[O:31])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1cc(-c2cccc(Cl)c2)nc(-n2cnc(I)c2)n1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4cccc(Cl)c4)cc(C(F)(F)F)n3)cn2)c1

Procedure:
N-tert-Butyl-3-{1-[6-(3-chloro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 4-(3-chloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (example E.72) (0.68 g, 1.5 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.46 g, 1.8 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.2 g) which was subsequently deprotected.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:16][C:17]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH3:31])=[CH:25][CH:24]=2)[CH:20]=[CH:19][C:18]=1B(O)O>C(O)C.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>[F:1][C:2]1[CH:3]=[C:4]([C:18]2[CH:19]=[CH:20][C:21]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][CH3:31])=[CH:25][CH:24]=3)=[CH:22][C:17]=2[F:16])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CCCc1ccc(-c2ccc(B(O)O)c(F)c2)cc1
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: CCO
Product: CCCc1ccc(-c2ccc(-c3cc(F)cc(F)c3)c(F)c2)cc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
Under a nitrogen atmosphere, a suspension solution containing 3,5-difluorobromobenzene (71 g), potassium carbonate (75 g), tetrakis(triphenylphosphine)palladium (0) (2.2 g), and ethanol (250 mL) was heated to 70° C., and a solution in which 2-fluoro-4-(4-propylphenyl)phenylboronic acid (100 g, prepared by a method disclosed in EP 2123623) had been dissolved in ethanol (200 mL) was dropped thereinto. Then, the resulting solution was stirred at 70° C. for 5 hours. The solution was cooled with ice and filtered to separate precipitated crystals and an inorganic salt, the obtained solid was dissolved in a solution containing hexane and toluene (4:1), and then the solution was purified by silica gel column chromatography. The purified product was recrystallized from ethanol to yield 18.7 g of 3,5-difluoro-[2-fluoro-4-(4-propylphenyl)phenyl]benzene.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[C:16](=[O:17])[NH:15][N:14]=[CH:13]2)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>CC(C)=O>[CH3:1][C:2]1[N:3]=[C:4]([N:12]2[C:16](=[O:17])[N:15]([CH2:30][C:29]3[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:34])[F:35])=[CH:33][CH:32]=3)[N:14]=[CH:13]2)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1sc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)nc1C
Yield: 60 %

Procedure:
To a solution of ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate (0.17 g, 0.68 mmol) and potassium carbonate (0.14 g, 1.03 mmol) in acetone (10 mL) was added 4-(trifluoromethyl)benzyl bromide (0.21 g, 0.89 mmol). The reaction mixture was heated to reflux for 3 hours. The solvent was removed in vacuo and the residue was washed with water and hexanes to afford the title compound in 60% yield (0.17 g): 1H NMR (300 MHz, CDCl3) δ 8.29 (s, 1H), 7.61 (d, J=8.3 Hz, 2H), 7.50 (d, J=8.3 Hz, 2H), 5.07 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 2.67 (s, 3H), 1.35 (t, J=7.1 Hz, 3H); MS (ES+) m/z 413.2 (M+1).
Reaction SMILES: [CH2:1]([S:8]([C:11]1[CH:12]=[C:13]([O:21]COC)[C:14](=[O:20])[N:15](COC)[CH:16]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1.CO>[CH2:1]([S:8]([C:11]1[CH:12]=[C:13]([OH:21])[C:14](=[O:20])[NH:15][CH:16]=1)(=[O:9])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCOc1cc(S(=O)(=O)Cc2ccccc2)cn(COC)c1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=c1[nH]cc(S(=O)(=O)Cc2ccccc2)cc1O
Temperature: 120 °C
Yield: 44.5 %

Procedure:
To a solution of 5-(benzylsulfonyl)-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 40; 75 mg, 0.212 mmol) in dioxane (0.7 ml) and methanol (0.8 ml) was added hydrogen chloride (4.0 M in dioxane, 1.597 ml, 6.39 mmol) and the reaction irradiated in the microwave with heating to 120° C. for 10 minutes. The resulting white precipitate that had formed was filtered and washed with ethanol to yield 5-(benzylsulfonyl)-3-hydroxypyridin-2(1H)-one (25 mg, 44%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH:17]([F:19])[F:18])[C:13]([CH3:20])=[N:12]1.[H][H]>C(O)C.[Pt]=O>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH:17]([F:19])[F:18])[C:13]([CH3:20])=[N:12]1
Reactant: [H][H]
Reactant: Cc1nn(-c2ccc([N+](=O)[O-])cc2F)c(=O)n1C(F)F
Agent: O=[Pt]
Solvent: CCO
Product: Cc1nn(-c2ccc(N)cc2F)c(=O)n1C(F)F
Yield: 91.6 %

Procedure:
A mixture of 24.5 g (0.085 mole) of 1-(2-fluoro-4-nitrophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one and 0.30 g of platinum oxide in 250 mL of absolute ethanol was hydrogenated in a Parr hydrogenation apparatus. The calculated amount of hydrogen required was taken up in 45 minutes. The reaction mixture was filtered through a Buchner funnel, and the filtrate was evaporated under reduced pressure, leaving a dark brown solid residue. This residue was placed on a silica gel column and eluted with methylene chloride/ethyl acetate (75/25). After the product-containing fractions were combined, evaporation of the solvents under reduced pressure yielded 20.1 g of 1-(2-fluoro-4-aminophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][CH:10]=1>O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12](/[C:15](=[CH:6]/[C:2]2[NH:1][CH:5]=[CH:4][CH:3]=2)/[C:16]#[N:17])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc[nH]1
Reactant: N#CCc1ccc(Cl)cc1
Solvent: O
Product: N#C/C(=C\c1ccc[nH]1)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
A suspension of 1H-pyrrole-2-carbaldehyde (3.3 g, 34.7 mmol) and 4-chlorophenylacetonitrile (5.5 g, 33.0 mmol, 0.95 equivalents) in water (50 ml) was heated to 50° C. When all the solid material had melted, the vigorously stirred mixture was treated with 40% aqueous Triton B (14 ml, 5.6 mmol). Precipitation began almost immediately. Stirring was continued for 5 h at 50° C., breaking up lumps when necessary. The still warm suspension was filtered through a sintered glass funnel and washed with warm water. The yellow precipitate was dried at the pump (6.63 g). This is Compound 2 in TABLE 8.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:15])[C:4]([C:6]1[NH:14][C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5].[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.N1C=CC=CC=1>C(Cl)Cl>[F:16][C:17]1[CH:22]=[C:21]([N:14]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[CH:7]=[C:6]2[C:4]([N:3]([O:2][CH3:1])[CH3:15])=[O:5])[CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CON(C)C(=O)c1cc2cccnc2[nH]1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)c1cc2cccnc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
Activated molecular sieves (3.8 g) 4 Å were placed in an oven dried flask and cooled to room temperature under nitrogen. To the flask was charged with N-methoxy-N-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (0.29 g, 1.4 mmol), (3-fluorophenyl)boronic acid (0.59 g, 4.2 mmol), cupric acetate (0.38 g, 2.1 mmol), methylene chloride (35 mL) and then pyridine (0.46 mL, 5.6 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was filtered through a pad of Celite. The filtrate was concentrated and purified on silica gel (eluting with 0-50% EtOAc/hexane followed by 0-5% MeOH/dichloromethane) to give the desired product (0.35 g, 83%). LCMS calculated for C16H15FN3O2(M+H)+: m/z=300.1. Found: 300.0.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([N:14]([CH3:23])[C@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[CH:9]=[C:10]([C:11](O)=[O:12])[C:5]2=[N:4][N:3]=1.C(Cl)(=O)C(Cl)=O.[NH3:30].C1COCC1>C1COCC1>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([N:14]([CH3:23])[C@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[CH:9]=[C:10]([C:11]([NH2:30])=[O:12])[C:5]2=[N:4][N:3]=1
Reactant: Cc1nnc2c(C(=O)O)cc(N(C)[C@@H](C)c3ccccc3)nn12
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: Cc1nnc2c(C(N)=O)cc(N(C)[C@@H](C)c3ccccc3)nn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of compound (S)-3-methyl-6-(methyl(1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxylic acid (200 mg, 0.64 mmol) in anhydrous THF (10 mL) was added oxalyl chloride (0.3 mL) dropwise. The reaction mixture was stirred at room temperature for 2 hrs, then 2N NH3/THF (1 mL) solution was added, and stirred for another 2 hrs. The mixture was concentrated in vacuum and the residue was purified by flash column chromatography (silica-gel, DCM: MeOH=20:1) to give product (S)-3-methyl-6-(methyl(1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazine-8-carboxamide (Compound 7) as a yellow solid (180 mg, 90%). 1H NMR (300 MHz, DMSO) δ 8.66 (s, 1H), 8.40 (s, 1H), 7.66 (s, 1H), 7.26˜7.36 (m, 5H), 5.71˜5.74 (q, 1H), 2.90 (s, 3H), 2.59 (s, 3H), 1.61 (d, J=6.9 Hz, 3H). LRMS (M+H+) calcd. 310; found 310.
Reaction SMILES: CC([O:4][C@@H:5]1[C@@:9]2([CH3:30])[CH2:10][CH2:11][C@@H:12]3[C@@:17]4([CH3:29])[CH2:18][C@H:19](N5CCOCC5)[C@@H:20]([OH:22])[CH2:21][C@@H:16]4[CH2:15][CH2:14][C@H:13]3[C@@H:8]2[CH2:7][C@@H:6]1[N+:31]1(CC=C)[CH2:35][CH2:34][CH2:33][CH2:32]1)=O.[Br-].[OH-].C[N+](C)(C)C>C(#N)C>[O:22]1[C@H:20]2[CH2:19][C@H:18]3[C@:17]([CH3:29])([CH2:16][C@@H:21]12)[C@@H:12]1[C@H:13]([C@H:8]2[C@@:9]([CH2:10][CH2:11]1)([CH3:30])[C@@H:5]([OH:4])[C@@H:6]([N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)[CH2:7]2)[CH2:14][CH2:15]3
Reactant: C=CC[N+]1([C@H]2C[C@H]3[C@@H]4CC[C@H]5C[C@H](O)[C@@H](N6CCOCC6)C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]2OC(C)=O)CCCC1
Agent: C[N+](C)(C)C
Agent: [Br-]
Agent: [OH-]
Solvent: CC#N
Product: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12
Reaction time: 0.42 h

Procedure:
Analysis of rocuronium bromide, Compound I, was performed with a column & packing Hypersil silica; 5 μm, 250 mm×4.6 mm, Cat No. 30005-254630 or equivalent. Eluent A was tetramethylammonium hydroxide Buffer, 0.05M, pH 7.4, eluent B was acetonitrile, and the composition was 10:90, A:B. The stop time was 25 min., the flow rate was 2.0 mL/min., the detector was UV at 210 mn, the column temperature was 30° C., and the injection volume was 5 μl.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[C:12]([O:14][C:15]([F:18])([F:17])[F:16])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:4])=[O:3].[CH3:19][C:20]([S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]=1)(=[O:30])=[O:29])([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:21].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CS(C)=O.O.FC(F)(F)C(O)=O.CN(C)C=O>[CH3:21][C:20]([S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:39])([F:40])[F:38])[N:32]=1)(=[O:30])=[O:29])([CH:22]1[CH2:23][CH2:24][N:25]([C:7](=[O:9])[C:6]2[CH:10]=[CH:11][C:12]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:13][C:5]=2[S:2]([CH3:1])(=[O:3])=[O:4])[CH2:26][CH2:27]1)[CH3:19]
Reactant: CC(C)(C1CCNCC1)S(=O)(=O)c1cccc(C(F)(F)F)n1
Reactant: CS(=O)(=O)c1cc(OC(F)(F)F)ccc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C1CCN(C(=O)c2ccc(OC(F)(F)F)cc2S(C)(=O)=O)CC1)S(=O)(=O)c1cccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 10 ml vial was added 2-(methylsulfonyl)-4-(trifluoromethoxy)benzoic acid (16.9 mg, 0.059 mmol), 2-[(1-methyl-1-piperidin-4-ylethyl)sulfonyl]-6-(trifluoromethyl)pyridine (20 mg, 0.059 mmol), Bop reagent (31.6 mg, 0.071 mmol), diisopropylethyl amine (0.052 ml, 0.297 mmol) and 1 ml dimethylformamide. The resulting solution was stirred at room temperature for 1 hour. It was diluted with 1 m dimethyl sulfoxide, 0.5 ml water and 0.1 ml trifluoroacetic acid. This mixture was loaded on to reverse phase column directly and eluted with water acetonitrile gradient solvent to give the title compound as fluffy white solid after lyophilizing.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[CH:9]=[CH:8]1)[CH3:6])[CH3:2].[CH3:18][N:19]1[C:23]([CH2:24]O)=[CH:22][C:21]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)=[N:20]1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:24][C:23]3[N:19]([CH3:18])[N:20]=[C:21]([C:26]4[CH:27]=[CH:28][C:29]([O:32][C:33]([F:35])([F:34])[F:36])=[CH:30][CH:31]=4)[CH:22]=3)[CH:14]=2)[CH:9]=[CH:8]1)[CH3:6])[CH3:2]
Reactant: Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CO
Reactant: CCOC(=O)C(C)n1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(C)n1ccc2ccc(OCc3cc(-c4ccc(OC(F)(F)F)cc4)nn3C)cc21

Procedure:
In analogy to the procedure described for example 3 c], [rac]-2-(6-hydroxy-indol-1-yl)-propionic acid ethyl ester (J. E. D. Barton, D. Cartwright, C. J. Mathews, Brit. UK Pat. Appl. (1992), GB 2253848 A1) was reacted with [2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-methanol (example 11 d]) in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give [rac]-2-{6-[2-methyl-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-propionic acid ethyl ester as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[C:4]([CH3:30])[CH:5]=[C:6]([CH2:8][N:9]2[CH2:29][CH2:28][C:12]3([O:16][C:15](=[O:17])[N:14]([C:18]4[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=4)[CH2:13]3)[CH2:11][CH2:10]2)[CH:7]=1.[OH-].[K+].C(O)(=O)C>C(O)C>[CH3:1][C:2]1[C:3]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[C:4]([CH3:30])[CH:5]=[C:6]([CH2:8][N:9]2[CH2:29][CH2:28][C:12]3([O:16][C:15](=[O:17])[N:14]([C:18]4[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=4)[CH2:13]3)[CH2:11][CH2:10]2)[CH:7]=1
Reactant: COC(=O)c1ccc(N2CC3(CCN(Cc4cc(C)c(-c5ccc(F)cc5)c(C)c4)CC3)OC2=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cc(CN2CCC3(CC2)CN(c2ccc(C(=O)O)cc2)C(=O)O3)cc(C)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17 %

Procedure:
To a mixture of half of the crude methyl 4-{8-[(4′-fluoro-2,6-dimethylbiphen-4-yl)methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl}benzoate from Step 3 (˜0.065 mmol) in ethanol (1 mL) was added excess aqueous potassium hydroxide and the reaction was stirred at room temperature for 24 hours. The mixture was then acidified with acetic acid and the title product (5.4 mg) was isolated by mass directed reverse phase (C18) chromatography (0.1% ammonium hydroxide) and evaporation of the product fractions.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[O:28])=[CH:18][C:17]=3F)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][S:33][CH2:32][CH2:31]1>CS(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]4=[O:28])=[CH:18][C:17]=3[N:30]3[CH2:35][CH2:34][S:33][CH2:32][CH2:31]3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(-n3ccccc3=O)cc2F)cn1)c1ccc(Cl)s1
Reactant: C1CSCCN1
Solvent: CS(C)=O
Product: O=C(NCc1cn(-c2ccc(-n3ccccc3=O)cc2N2CCSCC2)cn1)c1ccc(Cl)s1

Procedure:
A solution of 5-chloro-N-((1-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide prepared in Example 11 (70 mg, 0.16 mmol) and thiomorpholine (1 mL) in DMSO (1 mL) was heated at 150° C. for 3 days. The mixture was purified by HPLC to give the title compound (25 mg). MS 512.0 and 514.0 (M+H, Cl pattern).