Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[F:30][C:31]([F:53])([F:52])[CH2:32][CH2:33][C:34]([C:36]1[CH:37]=[N:38][C:39]([C:42]2[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=2)=[CH:40][CH:41]=1)=O>C1(C)C=CC=CC=1>[F:30][C:31]([F:53])([F:52])[CH2:32][CH2:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([C:42]2[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=2)=[N:38][CH:37]=1)=[CH:2][O:3][CH3:4]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(CCC(F)(F)F)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC=C(CCC(F)(F)F)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
Methoxymethyltriphenylphosphonium chloride (7.4 g, 21.6 mmol) is suspended in anhydrous toluene (25 mL) and potassium tert-butoxide (2.4 g, 21.6 mmol) is added at room temperature in one portion. The mixture is allowed to stir under nitrogen for 1 h. Meanwhile, 4,4,4-Trifluoro-1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-butan-1-one (5.0 g, 14.4 mmol) is dissolved in another portion of the toluene (25 mL), and kept at room temperature. The mixture is then cooled to 0° C. with ice water, and then the ketone is transferred by cannula. The reaction is allowed to stir at 0° C. for 10 min, then the ice bath is removed. The reaction is allowed to warm to room temperature and monitored by HPLC. Upon complete conversion, the reaction is carefully quenched with saturated ammonium chloride solution, and diluted with ethyl acetate, then extracted. The organic layer is washed with water and brine, dried over anhydrous sodium sulfate, then filtered and concentrated. The 5-(4,4,4-Trifluoro-1-methoxymethylene-butyl)-2-(4-trifluoromethyl-phenyl)-pyridine (4.1 g, 10.9 mmol) is isolated as a mixture of regioisomers after column chromatography, 76% yield.
Reaction SMILES: Cl[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14]([N+:16]([O-:18])=[O:17])=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.Br.[NH:20]([C:22]1[S:23][CH2:24][CH2:25][N:26]=1)[NH2:21].C([O-])(=O)C.[Na+]>CO>[S:23]1[CH2:24][CH2:25][NH:26][C:22]1=[N:20][N:21]=[C:2]1[C:15]2[C:14]([N+:16]([O-:18])=[O:17])=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: O=[N+]([O-])c1cccc2nc3ccccc3c(Cl)c12
Reactant: NNC1=NCCS1
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1cccc2[nH]c3ccccc3c(=NN=C3NCCS3)c12
Reaction time: 8 h

Procedure:
5.0 g of 9-chloro-1-nitroacridine, 3.8 g of 2-hydrazino-2-thiazoline hydrobromide and 3.17 g of anhydrous sodium acetate are dissolved in 250 ml of dry methanol, heated on a steam-bath for 1 hour and then left to stand overnight. The precipitated material is filtered and recrystallized from methanol. There is obtained 1-nitro-9-acridanone (2-thiazolidinylidene)hydrazone which beings to decompose from 152°.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([O:13][C@H:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][CH2:16][C@H:15]2[C:21]([CH3:29])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:22])[O:10][C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:31](=[O:40])[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.B(F)(F)F.CCOCC.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([N:8]1[CH:12]([C:11]([O:13][C@H:14]2[CH2:19][C@H:18]([CH3:20])[CH2:17][CH2:16][C@H:15]2[C:21]([CH3:29])([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH3:22])=[O:10])[CH:31]([CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:40][C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCCc1ccccc1
Reactant: C[C@@H]1CC[C@@H](C(C)(C)c2ccccc2)[C@@H](Oc2cn(Cc3ccccc3)c(=O)o2)C1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@H]1CC[C@@H](C(C)(C)c2ccccc2)[C@@H](OC(=O)C2C(CCc3ccccc3)OC(=O)N2Cc2ccccc2)C1
Temperature: -78 °C
Yield: 98 %

Procedure:
Under argon atmosphere, in 3 ml of methylene chloride was dissolved 202.8 mg (0.5 mmol) of 3-benzyl-5-((1S,2S,5R)-5-methyl-2-(1-methyl-1-phenylethyl)cyclohexyloxy)-2(3H)-oxazolone, and after the solution was cooled to −78° C., 67.1 mg (0.5 mmol) of hydrocinnamaldehyde and 63 μl (0.1 mmol) of boron trifluoride diethyl etherate were added to the solution and the mixture was reacted for 1.0 hour. After the temperature of the mixture was raised up to the room temperature, 15 ml of a saturated aqueous sodium hydrogen carbonate solution was added to the resulting reaction mixture and the mixture was extracted with 15 ml of methylene chloride. The organic layer was washed twice with 15 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 264.9 mg (0.49 mmol) of 3-benzyl-4-((1S,2S,5R)-5-methyl-2-(1-methyl-1-phenylethyl)cyclohexyloxy)carbonyl-5-(2-phenylethyl)-2-oxazolidinone as pale yellowish viscous liquid. A formation ratio of cis/trans isomers was cis isomer/trans isomer=29/71 according to 1H-NMR, and they were each single diastereomer. Yield based on 3-benzyl-5-((1S,2S,5R)-5-methyl-2-(1-methyl-1-phenylethyl)cyclohexyloxy)2(3H)oxazolone was 98.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])/[C:16]/3=[CH:23]\[C:24]2[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=2[CH3:33])(=[O:12])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][S:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17](=[O:22])/[C:16]/3=[CH:23]\[C:24]2[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:38]3[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]3)=[O:31])[C:25]=2[CH3:33])(=[O:12])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)cc(Cl)c4)cc32)c(C)c1C(=O)O
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)cc(Cl)c4)cc32)c(C)c1C(=O)N1CCN(C)CC1

Procedure:
5-[5-(3,5-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.24 mmol) was coupled with 1-methyl-piperazine (30 mg, 1.2 eq.) using HOBt (1.2 eq.), EDAC.HCl (1.2 eq.) and TEA (3 eq.) to give the titled compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH2:5][N:6]([CH3:8])[CH3:7].[Mg].[CH2:15]=[O:16]>>[CH3:7][N:6]([CH2:5][C:4]1[CH:9]=[CH:10][C:11]([O:12][CH3:13])=[C:2]([CH:3]=1)[CH2:15][OH:16])[CH3:8]
Reactant: C=O
Reactant: COc1ccc(CN(C)C)cc1Br
Agent: [Mg]
Product: COc1ccc(CN(C)C)cc1CO

Procedure:
Successive reaction of 3-bromo-4-methoxy-N,N-dimethylbenzylamine with magnesium and formaldehyde (in a similar manner to Example 7) gave 5-dimethylaminomethyl-2-methoxybenzyl alcohol, m.p. 67°-69°, which was heated under reflux for 4 hours with cysteamine hydrochloride in acetic acid to give, after basification and chloroform extraction, 2-(5-dimethylaminomethyl-2-methoxybenzylthio)ethylamine, as an oil. This oil was heated under reflux with 1.1 molar equivalents of 2-nitroamino-5-(3-pyridylmethyl)-4-pyrimidone in ethanol for 28 hours to give 2-[2-(5-dimethylaminomethyl-2-methoxybenzylthio)-ethylamino]-5-(3-pyridylmethyl)-4-pyrimidone which was treated with hydrogen chloride in ethanol and purified as the trihydrochloride salt m.p. 232°-235° (recrystallised from methanol-ethanol).
Reaction SMILES: C([N:8]1[CH2:14][CH:13]2[C:15]([CH3:17])([OH:16])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)C1C=CC=CC=1.N#N>CO.[Pd]>[CH3:17][C:15]1([OH:16])[CH:13]2[CH2:12][CH2:11][CH:10]1[CH2:9][NH:8][CH2:14]2
Reactant: CC1(O)C2CCC1CN(Cc1ccccc1)C2
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: CC1(O)C2CCC1CNC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.3 %

Procedure:
A sample of 3-benzyl-8-methyl-3-azabicyclo[3.2.1]octan-8-ol (110 mg, 0.48 mmol) was dissolved in MeOH (20 ml) and the atmosphere was replaced with N2 (3×). 10% Pd/C (cat.) was added and the atmosphere was replaced with H2 (3×). The resulting reaction mixture was stirred at RT at balloon pressure overnight. When TLC showed no more UV active spot the Pd/C was filtered off (always keeping wet with MeOH) and the filtrate was concentrated which gave 8-methyl-3-azabicyclo[3.2.1]octan-8-ol (70 mg, 99% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>O1CCCC1.C(OCC)C>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C:8]([C:9]#[N:10])([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:27]
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(Cl)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Combine 4-chlorophenylacetonitrile (50.0 mmol) and tetrahydrofuran (140 mL). Cool to about 5° C. Add dropwise a solution of sodium bis(trimethylsilyl)amide (800 mL, 1 M in tetrahydrofuran, 800 mmol). When the addition is complete, warm the reaction mixture to ambient temperature and allow to stir for 1 hour. Transfer the above solution via cannula into a cooled (−8° C.) solution of ethyl bromoacetate.(84.5 mL, 762 mmol) in tetrahydrofuran (500 mL) at such a rate that the temperature of the reaction mixture does not rise above about 20° C. Allow to stir at ambient temperature. After 18 hours, dilute with diethyl ether (1.5 L) and extract with saturated aqueous solution of ammonium chloride, then water, and then saturated aqueous solution of sodium chloride. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to give the title compound. Elemental Analysis calculated for C16H18ClNO4: C 59.35; H 5.60; N 4.33; Found: C 59.27; H 5.54; N 4.33.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[N:22][C:23]#[N:24])OC2C=CC=CC=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:27]([NH2:30])[CH2:28][CH3:29]>>[C:23]([NH:22][C:14]([NH:13][C:5]1[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=[C:3]([C:2]([F:25])([F:1])[F:26])[CH:4]=1)=[N:30][CH2:27][CH2:28][CH3:29])#[N:24]
Reactant: CCCN
Reactant: N#CN=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Oc1ccccc1
Product: CCCN=C(NC#N)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 28 %

Procedure:
N-[3,5-bis(trifluoromethyl)phenyl]-N'-cyano-O-phenylisourea (0.94 mmol, 350 mg) and n-propylamine (1 ml) was stirred in a sealed flask for 19 h at 75° C. After concentration the residue was dissolved in dichloromethane, washed with 1 N aqueous HCl (2×), water, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (ethyl acetate/heptane 1:2) to give the title compound (90 mg, 28%) as white crystals. Mp 142.5-143.5° C.; 1H-NMR (CDCl3): δ 0.95 (t, 3H), 1.65 (sextet, 2H), 3.35 (q, 2H), 5.45 (br, 1H), 7.68 (br s, 1H), 7.80 (br s, 2H), 8.35 ppm (br, 1H); MA calc for C13H12F6N4 : C, 46.16%; H, 3.58%; N, 16.56%. Found: C, 46.31%; H, 3.65%; N, 16.23%.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]([OH:21])=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C)C=O>[CH2:32]([O:20][C:19](=[O:21])[C@@H:18]([C@@H:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:22][CH:23]([CH3:25])[CH3:24])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](C(=O)OCc1ccccc1)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.0 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleric acid in 10 ml of dimethylformamide was treated in succession with 2.0 g of potassium carbonate and 0.45 ml of benzyl bromide. The mixture was stirred at room temperature for 1 hour and then the solvent was evaporated and the residue was dissolved in ethyl acetate and washed with water until the water washings were neutral (pH=7). Drying over anhydrous magnesium sulfate and evaporation gave 1.28 g of (E)-benzyl-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvalerate in the form of an orange oil.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:27]=[C:26]([C:28](Cl)=[O:29])[CH:25]=[C:24]([Cl:31])[N:23]=1>>[Cl:21][C:22]1[CH:27]=[C:26]([CH:25]=[C:24]([Cl:31])[N:23]=1)[C:28]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])=[O:29]
Reactant: O=C(Cl)c1cc(Cl)nc(Cl)c1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1cc(Cl)nc(Cl)c1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and 2,6-dichloropyridine-4-carboxylic acid chloride, there is obtained ethyl N-(2,6-dichloroisonicotinoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 151°-152° C.;
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:15]1[C:19](=[O:20])[O:18][C:17]([CH3:22])([CH3:21])[O:16]1)[C:10](=[O:14])SCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>C(Cl)Cl.[Pd]>[CH2:1]([O:8][C@H:9]([C@@H:15]1[C:19](=[O:20])[O:18][C:17]([CH3:22])([CH3:21])[O:16]1)[CH:10]=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCSC(=O)[C@H](OCc1ccccc1)[C@H]1OC(C)(C)OC1=O
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Product: CC1(C)OC(=O)[C@@H]([C@H](C=O)OCc2ccccc2)O1
Yield: 40.1 %

Procedure:
(R)—S-Ethyl 2-(benzyloxy)-2-((R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)ethanethioate (2.3 g, 7.09 mmol) was dissolved in CH2Cl2 (50 mL) and 10% palladium on carbon (0.377 g, 0.355 mmol) was added and stirred under nitrogen. Triethylsilane (1.70 mL, 10.6 mmol) was dissolved in CH2Cl2 (5 mL) and added dropwise. The reaction was allowed to stir overnight. The reaction was filtered, concentrated and purified over silica gel (5 to 10% EtOAc in hexanes) to afford a small amount of product and a large amount of starting material. The isolated starting material was subjected to the conditions described above and combined with the product isolated from the first batch to afford (R)-2-(benzyloxy)-2-((R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde (750 mg, 2.84 mmol, 40% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:12]=O)[S:10][CH:11]=1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9](/[CH:12]=[CH:22]/[CH:23]=[O:24])[S:10][CH:11]=1
Reactant: O=Cc1cc(-c2ccccn2)cs1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=C/C=C/c1cc(-c2ccccn2)cs1

Procedure:
The title compound is prepared by a procedure analogous to Reference Example 30 by substituting 4-(2-pyridinyl)-2-thiophenecarboxaldehyde (prepared as described in Reference Example 91) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 216 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[CH2:8][C@H:7]1[C:12]([OH:14])=O)=[O:5])[CH3:2].Cl.[NH2:16][CH2:17][C:18]#[N:19]>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C:9](=[O:11])[CH2:8][C@H:7]1[C:12](=[O:14])[NH:19][CH2:18][C:17]#[N:16])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(=O)C[C@H]1C(=O)O
Reactant: N#CCN
Agent: Cl
Product: CCOC(=O)[C@@H]1CC(=O)C[C@H]1C(=O)NCC#N

Procedure:
The reaction of (1R,2R)-4-oxo-cyclopentane-1,2-dicarboxylic acid monoethyl ester and aminoacetonitrile hydrochloride performed in analogy to example 1, step 8 yielded the title compound as a pale brown solid. MS: 237.3 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]3[CH:15]=[N:16][C:17]([C:18]#[N:19])=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[F:20][C:2]([F:1])([F:21])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[CH:15]=[N:16][C:17]([C:18]#[N:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1ncn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ncn2c1NCC=C2c1cccc(C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
To a stirred mixture of 10.0 g of 4-(α,α,α-trifluoro-m-tolyl)imidazo[1,5-a]pyrimidine-8-carbonitrile (prepared as described in U.S. Pat. No. 4,236,005, Ex. 28) in 150 ml of glacial acetic acid, under nitrogen, at ice bath temperature, was added portionwise 4.15 g of sodium cyanoborohydride. The reaction mixture was stirred in the cold for 30 minutes then at room temperature for 21/2 hours. Then about 50 ml of water was added to the reaction mixture. The precipitate was collected by filtration, washed with water and dried in vacuo to give 8.8 g of the desired product, mp 241°-243° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[CH2:10]([SH:12])[CH3:11]>>[CH2:10]([S:12][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:11]
Reactant: CCS
Reactant: OCc1ccccc1O
Product: CCSCc1ccccc1O
Yield: 47.8 %

Procedure:
A mixture of 49.6 g (0.4 mol) of 2-hydroxymethyl-phenol and 124 g (2 mol) of ethylmercaptan was heated for 5 hours to 170° C. in a stirred autoclave. Working up as in Example 1 gave 32.2 g (96% of theory) of 2-ethylthiomethyl-phenol.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)[CH:12]=[N:11][CH:10]=1.[OH-].[Na+]>ClCCl>[Cl:8][C:9]1[N:14]=[C:13]([N:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[CH:12]=[N:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cncc(Cl)n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cncc(N2CCNCC2)n1
Reaction time: 1 h

Procedure:
A solution of trifluoroacetic acid (TFA; 6 mL) in dichloromethane (24 mL) was added to a stirred solution of the product of step 1 above (5.79 g, 19.4 mmol) in dichloromethane (20 mL) at 0° C. After 1 h and 1.5 h of stirring, additional portions (10 mL and 5 mL) of TFA were added. Crushed ice and 5 M aqueous NaOH were added and the mixture was extracted with dichloromethnae (12×200 mL). The combined organic layers were dried (K2CO3), filtered and concentrated in vacuo. This furnished 3.48 g (90%) of the title compound as a light yellow solid.
Reaction SMILES: [C:1]([O:7][CH2:8][O:9][C:10]([C@@H:12]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:13][C@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15](Cl)=[O:16])=[O:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:43][CH2:44][CH2:45][C:46]([O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:47].C(N(CC)CC)C>C(Cl)Cl>[CH2:49]([O:48][C:46](=[O:47])[CH2:45][CH2:44][NH:43][C:15](=[O:16])[C@@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:13][C@@H:12]([C:10]([O:9][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:11])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: CC(C)(C)C(=O)OCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)OCOC(=O)[C@@H](Cc1ccccc1)C[C@H](Cc1ccccc1)C(=O)NCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(Pivaloyloxymethoxycarbonyl)-2,4-(R*,R*) -dibenzylbutyryl chloride (1.2 g) in 10 ml of methylene chloride is added slowly to a solution of 1.15 g of benzyl 3-aminopropionate p-toluenesulfonic acid salt and 0.46 ml of triethylamine in 20 ml of methylene chloride. The reaction is stirred overnight at room temperature. The solution is washed with 2N hydrochloric acid, then with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated to give N-[4-pivaloyloxymethoxycarbonyl-(R*,R*)-2,4-dibenzylbutyryl]-3-aminopropionic acid benzyl ester.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:34])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:18]=[N:19][C:20]([NH:23][C:24]4[CH:25]=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.N1C=CC=CC=1.Cl[C:42]([O:44][CH2:45][CH:46]([CH3:48])[CH3:47])=[O:43]>CN(C=O)C>[CH2:45]([O:44][C:42](=[O:43])[NH:34]/[C:3](=[N:2]\[OH:1])/[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[N:18]=[N:19][C:20]([NH:23][C:24]4[CH:25]=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)[CH:46]([CH3:48])[CH3:47]
Reactant: CC(C)COC(=O)Cl
Reactant: N=C(CC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nn3)cc2)CC1)NO
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)COC(=O)N/C(CC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)nn3)cc2)CC1)=N\O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of N-Hydroxy-2-(4-{4-[6-(6-trifluoromethyl-pyridin-3-ylamino)-pyridazin-3-yl]-phenyl}-cyclohexyl)-acetamidine (0.13 g, 0.28 mmol, 1.0 equiv) in 2 Ml DMF was added pyridine (0.023 Ml, 0.31 mmol, 1:1 equiv). The solution was cooled to 0° C., then isobutyl chloroformate (0.04 Ml, 0.31 mmol, 1.1 equiv) was added dropwise via syringe. The reaction was allowed to warm to room temperature and stirred for 2 h. Extractive aqueous workup afforded the title compound which was used in the next step without further purification. (M+H)+571.4.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[O:16][CH:17]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:19]=1>C1(C)C(C)=CC=CC=1>[C:20]1([C:18]2[N:19]=[C:15]([N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]3)[O:16][CH:17]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nc(-c2ccccc2)co1
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccccc3)co2)CC1
Yield: 36.4 %

Procedure:
A solution of tert-butyl piperazine-1-carboxylate (1.21 g, 6.51 mmol) and 2-chloro-4-phenyl-1,3-oxazole (390 mg, 2.17 mmol) in xylene (50 ml) was stirred at 155° C. for 12 hours. The solvent was distilled off under reduced pressure. The residue was poured to water, and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=9:1) to give 260 mg (12.1%) of the desired product as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.COC1C=CC(C2O[CH:22]=[N:21][C:20]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=CC=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][CH:22]=[N:21][C:20]=2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncoc1-c1ccc(OC)cc1
Reactant: O=C(Cl)c1ccc(Br)cc1
Product: CCOC(=O)c1ncoc1-c1ccc(Br)cc1

Procedure:
Prepared from 4-bromobenzoyl chloride according to the procedure outlined for ethyl 5-(4-methoxyphenyl)oxazole-4-carboxylate in example M-1. 1H NMR (DMSO) δ 1.42 (3H, t), 4.42 (2H, q), 7.61 (2H, d), 7.92 (1H, s), 7.99 (2H, d). LCMS (1) Rt: 2.10 min; m/z (ES+) 268/270 MH+-Et.