Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[C:13]([F:14])=[CH:12][C:10]([NH2:11])=[CH:9][C:8]=2[F:15])[CH:6]=1.FC1C=C(C=C(F)C=1N1C=CN=C1)N.[C:30](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:31]>ClCCl>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[C:8]([F:15])=[CH:9][C:10]([N:11]=[C:30]=[S:31])=[CH:12][C:13]=2[F:14])[CH:6]=1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: Nc1cc(F)c(-n2cnc(Cl)c2)c(F)c1
Agent: Nc1cc(F)c(-n2ccnc2)c(F)c1
Solvent: ClCCl
Product: Fc1cc(N=C=S)cc(F)c1-n1cnc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.5 %

Procedure:
Step J (3): Dichloromethane (15 mL) was added to a flask charged with a 1:1 mixture of 4-(4-chloro-1H-imidazol-1-yl)-3,5-difluoroaniline/3,5-difluoro-4-(1H-imidazol-1-yl)aniline (1.0 g, 4.36 mmol) and 1,1′-thiocarbonyldipyridin-2(1H)-one (1.012 g, 4.36 mmol). The resulting mixture was stirred for 16 h at rt. The crude reaction mixture was concentrated and the crude products were purified using silica gel chromatography (60% EtOAc/hexanes) to afford 4-chloro-1-(2,6-difluoro-4-isothiocyanatophenyl)-1H-imidazole (195 mg, 0.718 mmol, 17% yield). LC-MS (M+H)+ 272.0. 1H NMR (500 MHz, chloroform-d) δ ppm 7.57 (d, J=1.83 Hz, 1 H) 7.07 (d, J=1.53 Hz, 1 H) 6.94-7.04 (m, 2 H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[NH:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7].[CH:35]1([CH2:38]Br)[CH2:37][CH2:36]1>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[C:14](=[O:23])[N:13]([CH2:38][CH:35]3[CH2:37][CH2:36]3)[CH2:12]2)[CH2:10][CH2:9]1)=[O:7]
Reactant: BrCC1CC1
Reactant: Cc1ccccc1N1C(=O)NCC12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Product: Cc1ccccc1N1C(=O)N(CC2CC2)CC12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=540.4 (M+H+), was prepared in accordance with the general method of example 99 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-2-one and cyclopropyl methyl bromide.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][Si](C)(C)C)([CH3:4])[CH3:3].[CH2:11]([N:14]=[C:15]=[O:16])[CH:12]=[CH2:13].[Cl-].[Al+3].[Cl-].[Cl-].CS(O)(=O)=O.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1.[Ti](Cl)(Cl)(Cl)Cl.[Cl-].[Zn+2].[Cl-].O.ClCCl.ClC1C=CC=CC=1Cl.ClCCCl>[CH2:11]([NH:14][C:15](=[O:16])[C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[CH:12]=[CH2:13]
Reactant: C=CCN=C=O
Reactant: C[Si](C)(C)C#C[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: ClCCCl
Product: C=CCNC(=O)C#C[Si](C)(C)C

Procedure:
A solution of bis(trimethylsilyl)acetylene and allyl isocyanate in dry solvent is treated with an excess (at least 2 molar equivalents) of an acid catalyst. The preferred acid catalysts include aluminum chloride, ferric chloride and methanesulfonic acid; the most preferred acid catalyst is methanesulfonic acid. Acid catalysts which have been found not to work include: titanium tetrachloride, zinc chloride (in diethyl ether), Amberlyst 15 and Dowex 50 ion exchange resins, and gaseous hydrochloric acid in dioxane. 1,2-dichloroethane and o-dichlorobenzene are preferred solvents, the most preferred solvent is dichloromethane. The concentration of bis(trimethylsilyl) acetylene in the above reaction is preferred to be 1 molar or lower. The reaction is monitored by gas chromatography, and when product formation is complete the mixture is poured into water or saturated sodium bicarbonate and extracted with ethyl acetate. The organic phase is washed with water and brine, dried over sodium sulfate, filtered and evaporated to give an oil. When methanesulfonic acid is used as the catalyst, the oil may be used without further purification. When aluminum chloride is used as the catalyst, the oil is distilled under vacuum in a Kugelrohr apparatus (from about 100 to about 130° C. at from about 0.5 to about 1.0 Torr) to give the N-allyl-3-trimethylsilylpropiolic amide.
Reaction SMILES: N[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9][C:10]1[C:11]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:12][C:13]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3C(=O)[C:19]3[C:14]=2[C:15]=1[CH:16]=[CH:17][CH:18]=3.CN([CH:40]=[O:41])C.Cl.N([O-])=O.[Na+]>O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:29]([O:28][C:11]1[CH:12]=[C:13]2[C:26]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:40](=[O:41])[C:19]3[CH:18]=[CH:17][C:16]4[C:2]5[C:3]([S:9][C:10]=1[C:15]=4[C:14]2=3)=[CH:4][CH:5]=[CH:6][C:7]=5[CH3:8])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CN(C)C=O
Reactant: CCCCCCCCOc1cc2c3c(cccc3c1Sc1cccc(C)c1N)C(=O)c1ccccc1-2
Agent: [Cu+2]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: CCCCCCCCOc1cc2c3ccccc3c(=O)c3ccc4c5c(C)cccc5sc1c4c32
Temperature: 0 °C
Reaction time: 2 h

Procedure:
70 g (0.14M) of 3-[(2-amino-3-methylphenyl)thio]-2-octyloxy-7H-benzo[de]anthracene-7-one and 1200 ml of DMF were placed into a 2 liter three-necked flask, equipped with a mechanical stirrer and a thermometer. The flask was set onto an ice bath. While stirring, 235 mg of 36% of hydrochloric acid has been added at a temperature not exceeding 20° C. After the reaction mixture was cooled to 0° C., 13.1 g of a sodium nitrite solution in 70 ml of water was added portionwise and held for an hour. Then 0.5 g of copper sulfate (II) has been added at 10° C. and heated till 100° C. The mixture was held for 2 hours, cooled and filtered. The dark red colored precipitate was washed with ethanol and water. The yield=60 g (89. Tm=207-209° C.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35][S:36]([NH2:39])(=[O:38])=[O:37]>>[CH:1]1([CH2:7][NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:39][S:36]([CH3:35])(=[O:38])=[O:37])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(NCC3CCCCC3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCC3CCCCC3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12

Procedure:
In the same manner as in Example 1, step 6 and using 7-cyclohexylmethylamino-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.08 g, 0.17 mmol) obtained in step 2 and methanesulfonamide (0.11 g, 0.87 mmol), compound a-8 (80 mg, 32%) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([OH:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:17][CH:13]2[CH2:14][CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:12]2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Reactant: O=C(OCc1ccccc1)N1CCCC(O)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2OC2CCCN(C(=O)OCc3ccccc3)C2)CC1
Reaction time: 8 h
Yield: 58.7 %

Procedure:
3-Hydroxy-piperidine-1-carboxylic acid benzyl ester (2.34 g, 8.6 mmol) was dissolved in THF (40 mL) at r.t. 4-(2-Hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (2.4 g, 8.6 mmol) and triphenylphosphine (2.7 g, 10.32 mmol) were added. Diisopropyl azodicarboxylate (2.05 mL, 10.32 mmol) was added dropwise to the solution. The mixture was stirred overnight, and then concentrated under reduced pressure and purified using silica gel chromatography (100% ethyl acetate) to afford the title compound (2.5 g, 55%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:10]=[CH:11][N:12](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:13]=2)=[CH:4][CH:3]=1.[O:33]=[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]1[C:40]1[CH:47]=[CH:46][C:43]([CH2:44]Br)=[CH:42][CH:41]=1>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[N:10]([CH2:44][C:43]3[CH:46]=[CH:47][C:40]([N:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]4=[O:33])=[CH:41][CH:42]=3)[CH:11]=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=c1ccccn1-c1ccc(CBr)cc1
Reactant: Brc1ccc(Oc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Solvent: CC#N
Product: O=c1ccccn1-c1ccc(Cn2cncc2Oc2ccc(Br)cc2)cc1
Temperature: 60 °C

Procedure:
A mixture of 4-(4-bromophenyloxy)-1-trityl-1H-imidazole (0.345 g, 0.72 mmol) and the bromide from Example 1, Step 3 (0.19 g, 0.72 mmol) in anhydrous acetonitrile (10 mL) was heated under reflux at 60° C. for 24 h. The resultant solution was concentrated, and the residue dissolved in methanol. The methanolic solution was heated under reflux for 3 h, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 1:1 v/v 5% methanol in chloroform and chloroform saturated with ammonia gas. Collection and concentration of appropriate fractions provide the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[C:4]#[N:5].I[CH2:12][C:13]([F:16])([F:15])[F:14].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(O)ccc1F
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(OCC(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.9 %

Procedure:
To a solution of 2-fluoro-5-hydroxy-benzonitrile (Alfa Aesar, 137 mg, 1.0 mmol) was added 2-iodo-1,1,1,-trifluoroethane (117 L, 1.2 mmol) and potassium carbonate (165 mg, 1.2 mmol) in DMF (20 mL) and stirred at RT for 24 hours. The reaction was dissolved into EtOAc and washed with water three times and the combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography using hexanes:ethyl acetate 5:1 to give the tile compound as white solid (105 mg, 48%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:18][CH:17]3[O:19][CH:13]([CH2:14][NH:15][CH2:16]3)[CH2:12]2)=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].C([O-])([O-])=O.[K+].[K+]>CC#N>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:18][CH:17]3[O:19][CH:13]([CH2:14][N:15]([CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:16]3)[CH2:12]2)=[CH:3][CH:2]=1
Reactant: c1cc(CCCCN2CC3CNCC(C2)O3)ccn1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCN1CC2CN(CCCCc3ccncc3)CC(C1)O2
Temperature: 50 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
3-[4-(4-Pyridinyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]nonane (0.25 g, 0.96 mmol, from step (ii) above), tert-butyl 2-bromoethylcarbamate (0.26 g, 0.98 mmol, see Preparation R above) and K2CO3 (0.4 g, 2.9 mmol) were mixed in CH3CN (10 mL) and stirred at 50° C. overnight. The reaction mixture was filtered, evaporated and purified by chromatography on silica (DCM:6% MeOH (satd. with NH3)). Additional purification by extraction with ether:KHSO4, basification of the organic phase and extraction with DCM gave the title compound in 51% yield.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1.[NH3:11]>C(OCC)(=O)C>[NH2:11][CH2:2][C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1
Reactant: O=c1cc(CCl)[nH]c(=O)[nH]1
Reactant: N
Solvent: CCOC(C)=O
Product: NCc1cc(=O)[nH]c(=O)[nH]1

Procedure:
A mixture of 100 g (0.623 mole) of 6-chloromethylpyrimidine-2,4-dione and 200 ml of anhydrous ammonia was allowed to react overnight in a sealed bomb at about 20° C. The solid residue was slurried in ethyl acetate, and was then separated by filtration and washed sequentially with water and methanol to provide 6-aminomethylpyrimidine-2,4-dione, m.p. 295°-297° C.
Reaction SMILES: CO[C:3]1[CH:31]=CC(CS[C@@H]2CN(C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H](C(O)=O)C2)=C[CH:4]=1.FC(F)(F)C(O)=O.[N+](C1C=CC(COC(N=C(NC(OCC2C=CC([N+]([O-])=O)=CC=2)=O)N[C@@H:53](C)[C:54]([NH:56][C@H:57]2[CH2:61]CN[CH2:58]2)=O)=O)=CC=1)([O-])=O>C(#N)C>[CH:3]([N:56]([CH2:54][CH3:53])[CH:57]([CH3:58])[CH3:61])([CH3:31])[CH3:4]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: C[C@H](NC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)N[C@H]1CCNC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-4-(4-methoxybenzyl)thio-1-(4-nitrobenzyloxycarbonyl)-L-proline (1.13 g) in anhydrous acetonitrile (10 ml), N,N'-carbonyldiimidazole (430 mg) was added, followed by stirring at room temperature for one hour. To the reaction mixture, N,N-diisopropylethylamine (0.42 ml) and the compound (2.26 g), which had been obtained in (2), in anhydrous tetraydrofuran (15 ml) were added. The reaction mixture was then treated in a similar manner to that described in Referential Example 16-(3), whereby the title compound (2.06 g) was obtained as an amorphous substance.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]([OH:9])=O)[NH:4][C:3]1=[O:10].C(N1CCOCC1)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:42][C:43]1[C:48]([C:49]([F:52])([F:51])[F:50])=[CH:47][CH:46]=[CH:45][C:44]=1[CH2:53][NH2:54]>ClCCl>[Cl:42][C:43]1[C:48]([C:49]([F:51])([F:52])[F:50])=[CH:47][CH:46]=[CH:45][C:44]=1[CH2:53][NH:54][C:7]([CH:5]1[CH2:6][N:2]([CH3:1])[C:3](=[O:10])[NH:4]1)=[O:9]
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Reactant: CN1CC(C(=O)O)NC1=O
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CN1CC(C(=O)NCc2cccc(C(F)(F)F)c2Cl)NC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.7 %

Procedure:
A mixture of 1-methyl-2-oxo-4-imidazolidinecarboxylic acid (144 mg, 1 mmol), N-ethyl morpholine (0.767 ml, 6.00 mmol), 1-hydroxybenzotriazole hydrate (184 mg, 1.200 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (230 mg, 1.200 mmol) in dichloromethane (18 ml) was stirred at room temperature for 10 minutes. A solution of {[2-chloro-3-(trifluoromethyl)phenyl]methyl}amine (210 mg, 1.000 mmol) in dichloromethane (2 ml) was added and the reaction stirred at room temperature for hours. The mixture was diluted with dichloromethane and the mixture was washed with 3N citric acid solution. The organic phase was separated, washed with brine, dried and evaporated. The residue was purified by mass-directed automated HPLC to give the N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-1-methyl-2-oxo-4-imidazolidinecarboxamide (150 mg, 55%). LC/MS [M+H]+=336, retention time=2.22 minutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([C:8]([CH3:29])([CH3:28])[CH2:9][C:10]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[CH:14]=[CH:13]2)[CH:7]=1.Cl[C:32]([F:38])([F:37])C(OC)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[F:37][CH:32]([F:38])[O:30][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[C:8]([CH3:28])([CH3:29])[CH2:9][C:10]([OH:27])([C:23]([F:25])([F:26])[F:24])[CH2:11][N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[CH:14]=[CH:13]1
Reactant: COC(=O)C(F)(F)Cl
Reactant: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(CC(O)(Cn1ccc(=O)c2ccccc21)C(F)(F)F)c1cc(F)ccc1OC(F)F
Temperature: 60 °C

Procedure:
A mixture of 1-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one (0.05 g), methyl 2-chloro-2,2-difluoroacetate (0.014 mL) and cesium carbonate (0.195 g) in 1.5 mL of DMF was heated at 60° C. for 20 hours, cooled to room temperature, diluted with ethyl acetate, and washed with aqueous acetic acid, water, and brine. The residue was purified by reverse-phase HPLC using acetonitrile/water as the eluent. The product rich fractions were concentrated in vacuo and provided 1-[4-(2-difluoromethoxy-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1H-quinolin-4-one, m.p. 150° C.-155° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.Cl.[CH3:28][NH:29][CH3:30].C(N(CC)C(C)C)(C)C>>[CH3:26][O:25][C:4]1[CH:3]=[C:2]([N:29]([CH3:30])[CH3:28])[CH:7]=[CH:6][C:5]=1[C:8]1[O:9][C:10]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:11][N:12]=1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Reactant: CNC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N(C)C)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 3.7 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.57 mmol) was converted using dimethylamine hydrochloride (232 mg, 2.85 mmol) and N,N-diisopropylethylamine (294 mg, 2.28 mmol) instead of thiomorpholine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane 70:10:20 to 40:40:20, 8 mg, 4%) which was obtained as a light brown solid. MS: m/e=377.3 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[NH:7].[CH2:12]([O:14][C:15](=[O:24])[C:16](=[CH:20]N(C)C)[C:17](=O)[CH3:18])[CH3:13]>CCO>[CH2:12]([O:14][C:15]([C:16]1[C:17]([CH3:18])=[N:7][C:6]([C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([F:2])[CH:4]=2)=[N:8][CH:20]=1)=[O:24])[CH3:13]
Reactant: N=C(N)c1cccc(F)c1
Reactant: CCOC(=O)C(=CN(C)C)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnc(-c2cccc(F)c2)nc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
Na0 (0.66 g, 28.6 mmol) is added to anhydrous EtOH (100 mL) and stirred at rt for 15 min. 3-Fluorobenzamidine hydrochloride (4.87 g, 27.8 mmol) is added and the solution is stirred for 15 min. 2-Dimethylaminomethylene-3-oxo-butyric acid ethyl ester (5.3 g, 28.6 mmol,) is added and the reaction mixture is heated at reflux under N2 for 1 hours. The reaction is cooled to rt and concentrated in vacuo. The residue is dissolved in EtOAc (300 mL), washed with brine (2×100 mL), dried (Na2SO4), filtered, and concentrated to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid ethyl ester (6.8 g, 99%). MS: 261 (M+H); 1H NMR (300 MHz, CDCl3): δ 1.43 (t, J=7.0 Hz, 3H), 2.92 (s, 3H), 4.42 (q, J=7.0 Hz, 2H), 7.24 (m, 1H), 7.45 (m, 1H), 8.27 (m, 1H), 8.37 (m, 1H), 9.21 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([O:14][CH2:15][CH2:16]Br)[C:12]#[CH:13].[OH-].[Na+].O>CN(C)C=O>[Cl:1][C:2]1[N:6]([CH2:16][CH2:15][O:14][CH2:11][C:12]#[CH:13])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: C#CCOCCBr
Reactant: Clc1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOCCn1c(Cl)nc2ccccc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 53.1 %

Procedure:
2-Chlorobenzimidazole (30.0 g) and 2-bromoethyl propargyl ether (41.0 g) are dissolved in N,N-dimethylformamide (300 ml), and thereto is added a 25% aqueous sodium hydroxide (40.0 g), and the mixture is stirred at 60° C. for 4 hours. Water (700 ml) is added to the reaction mixture, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and then concentrated. The resulting residue is distilled under reduced pressure to give 2-chloro-1-[2-(propargyloxy)ethyl]benzimidazole (24.5 g) as a colorless oily substance, b.p. 158°-160° C./1.2 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:4]=1[NH2:5].[Si:19]([O:36][CH2:37][CH2:38][N:39]1[CH:43]=[C:42](I)[CH:41]=[N:40]1)([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Si:19]([O:36][CH2:37][CH2:38][N:39]1[CH:43]=[C:42]([C:8]2[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([O:2][CH3:1])[CH:9]=2)[CH:41]=[N:40]1)([C:32]([CH3:35])([CH3:33])[CH3:34])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: CC(C)(C)[Si](OCCn1cc(I)cn1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(-c2cnn(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)ccc1N
Yield: 25.7 %

Procedure:
A solution of 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (383 mg, 1.537 mmol), 1-(2-(tert-butyldiphenylsilyloxy)ethyl)-4-iodo-1H-pyrazole (Preparation 65, 554 mg, 1.163 mmol) and Pd(dppf)Cl2.DCM (90 mg, 0.110 mmol) was dissolved in THF (6 mL) and 2M sodium carbonate in water (2 mL) and heated to 60° C. for 18 hours. The mixture was diluted with EtOAc and quenched with brine. The aqueous layer was extracted with EtOAc three times. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 20% EtOAc in cyclohexane to give the title compound (141 mg, 26%).
Reaction SMILES: [C:1]1([C:7](=[C:21]2[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][C:23]([CH3:30])([CH3:29])[CH2:22]2)[C:8]2[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([O:18]CC)=[O:17])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.CCO.[OH-].[Na+]>Cl.CCOC(C)=O>[C:1]1([C:7](=[C:21]2[CH2:22][C:23]([CH3:30])([CH3:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH2:26]2)[C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)/C=C/c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C)CC(=C(c2ccccc2)c2ccc(/C=C/C(=O)O)cc2)CC(C)(C)C1
Temperature: 25 °C

Procedure:
A mixture of 17 THF (35 mL) and absolute EtOH (35 mL) was charged with 1 N aqueous NaOH (46 mL) and heated to reflux. After 90 min the reaction was cooled to room temperature. The reaction was diluted with 1 N aqueous HCl (55 mL) and EtOAc (100 mL). The organic fraction iwa washed with water (2×75 mL) and brine (1000 mL) then dried (MgSO4) and concentrated to a white solid. This solid was triturated with hexane (25 mL) and recrystallized from CH3CN (100 mL) to yield: 1.87 g (84%) of the title compound 18 as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.35 (s, 1H), 7.59 (d, J=8.2 Hz, 2H), 7.53 (d, J=15.9 Hz, 1H), 7.15-7.31 (m, 7H), 6.45 (d, J=15.9 Hz, 1H), 1.91 (s, 2H), 1.89 (s, 2H), 1.26 (s, 2H), 0.88 (s, 6H), 0.87 (s, 6H). LCMS (ESI): m/z 373 (M−H)−.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)/[C:7](=[N:16]/C(=O)OCC)/[S:6]1)([CH3:4])([CH3:3])[CH3:2].[Si](I)(C)(C)C>C(Cl)(Cl)Cl.C(Cl)Cl>[C:1]([N:5]1[CH:9]=[C:8]([CH2:10][C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[C:7](=[NH:16])[S:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/N=c1\sn(C(C)(C)C)cc1Cc1ccco1
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)n1cc(Cc2ccco2)c(=N)s1
Temperature: 65 °C
Reaction time: 12 h

Procedure:
The product from Example 50D (300 mg, 0.97 mmol) in chloroform (20 mL) was treated with TMSI (389 mg, 1.95 mmol). The reaction mixture was stirred at 65° C. for 12 hrs, diluted with CH2Cl2, the organic was washed with H2O, dried over MgSO4, filtered and concentrated to afford the title compound. MS (DCI/NH4+) m/z 237 (M+H)+.