Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: IC1C=CC(C2NC([C@@H](N3C(=O)[C@@H](CCC(O)=O)NC3=O)C(C)C)=NC=2)=CC=1.C1(C[C@H]2NC(=O)[N:35]([C@H:39]([C:48]3[NH:49][C:50]([C:54]4[CH:59]=[CH:58][C:57]([I:60])=[CH:56][C:55]=4[F:61])=[C:51]([CH3:53])[N:52]=3)[C@H:40]([C:42]3C=CC=CC=3)[CH3:41])C2=O)CC1.C(O[C:68]([NH:70][C@H:71]([C:75]1[CH:80]=[CH:79][C:78]([O:81][CH2:82][C:83](=[O:87])N(C)C)=[CH:77][CH:76]=1)[C:72]([OH:74])=O)=[O:69])(C)(C)C.ClN1C(=O)CCC1=O>>[F:61][C:55]1[CH:56]=[C:57]([I:60])[CH:58]=[CH:59][C:54]=1[C:50]1[NH:49][C:48]([C@@H:39]([N:35]2[C:72](=[O:74])[C@@H:71]([C:75]3[CH:76]=[CH:77][C:78]([O:81][CH2:82][CH2:83][OH:87])=[CH:79][CH:80]=3)[NH:70][C:68]2=[O:69])[CH:40]([CH3:41])[CH3:42])=[N:52][C:51]=1[CH3:53]
Reactant: CN(C)C(=O)COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: Cc1nc([C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](CC3CC3)C2=O)[nH]c1-c1ccc(I)cc1F
Agent: CC(C)[C@@H](c1ncc(-c2ccc(I)cc2)[nH]1)N1C(=O)N[C@H](CCC(=O)O)C1=O
Agent: O=C1CCC(=O)N1Cl
Product: Cc1nc([C@H](C(C)C)N2C(=O)N[C@H](c3ccc(OCCO)cc3)C2=O)[nH]c1-c1ccc(I)cc1F

Procedure:
Prepared by the same method as described in example 1 except that (i) steps A, B and C were omitted; (ii) 1-(2-fluoro-4-iodo-phenyl)-propan-1-one (prepared as described in example 13) was used in place of 1-(2-fluoro-4-iodo-phenyl)-ethanone in step 59-D; (iii) (S)-2-tert-butoxycarbonylamino-3-methylbutyric acid was used in place of (2S,3S)-2-tert-butoxycarbonylamino-3-phenyl-butyric acid in step 59-E and (iv) chlorination of the 5-position of the imidazole ring with N-chlorosuccinimide in step 59-F was omitted. HR-MS: calcd for C25H26FlN4O4 [M+H+] 593.1056. Found 593.1052.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:23](Cl)(=[O:25])[CH3:24]>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[C:23]([C:10]1[S:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1)(=[O:25])[CH3:24]
Reactant: CS(=O)(=O)c1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Reactant: CC(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Titanium (IV) chloride (2.7 ml) was added dropwise to a stirred solution of 2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene (5 g) and acetyl chloride (2.2 ml) in benzene (50 ml) at 5° to 10° C. The mixture was stirred at ambient temperature for 4 hours, poured into ice-water, and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium bicarbonate, dried and concentrated. The residue was recrystallized from a mixture of ethanol and ethyl acetate to give pale brown crystals of 5-acetyl-2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene (3.7 g).
Reaction SMILES: [OH:1][CH2:2][CH:3](CO)O.[OH:7][CH2:8][CH2:9][C:10](=[O:12])[CH3:11].C(OCC)(=O)CC(C)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O>[C:2]([O:7][CH2:8][CH2:9][C:10](=[O:12])[CH3:11])(=[O:1])[CH3:3]
Reactant: OCC(O)CO
Reactant: CC(=O)CCO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(=O)CC(C)=O
Product: CC(=O)CCOC(C)=O
Yield: 61 %

Procedure:
The method described in Example 5 is followed starting with glycerol and 4-hydroxy-2-butanone, suitably protected at the hydroxy group with an acetyl radical. 4-acetoxy-2-butanone is prepared starting from ethyl acetoacetate, protected at the carbonyl group as diethylacetal, by reduction with lithium-aluminium hydride, followed by restoring the keto group by means of silica in the presence of water (A: Banerje 8 G. P. Kalena, Synth. Commun (1982) 12, 225). 1,3-dioxolane-2-methyl-2'-(2-hydroxyethyl-4-acetylthiomethylene distills at 164°-170° C. (10 mm Hg). Yield 61%.
Reaction SMILES: [C:1]1([C:7]([CH3:12])([OH:11])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>CCOCC>[C:1]1([C:7]([CH3:12])([OH:11])[C:8]([O:10][CH2:18][CH3:19])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: CC(O)(C(=O)O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: CCOC(=O)C(C)(O)c1ccccc1

Procedure:
(±)-Phenyllactic acid (4.96 g) and 1/2 ml concentrated sulfuric acid in 150 ml absolute ethanol is refluxed for 18 hours. Solvent is stripped, the residue is dissolved in ether, and extracted with saturated sodium bicarbonate solution. The ether is dried, filtered, and stripped to leave (±)-ethyl phenyllactate. NMR (CDCl3): δ1.3 (t, 3H), 3.0(d of d, 1H), 3.1 (d of d, 1H), 4.2 (q, 2H), 4.4 (d of d, 1H), 7.3 (m, 5H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>N1C=CC=CC=1.C(OCC)(=O)C.[Cu]>[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:2]2[CH:3]=[N:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)=[CH:24][CH:23]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Oc3ccc(F)cc3)cn2)CC1
Temperature: 120 °C
Yield: 26.7 %

Procedure:
A mixture of tert-butyl 4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (684 mg, 2.0 mmol), 4-fluorophenol (1.1 g, 5.0 mmol), copper (650 mg, 10.0 mmol) and Cs2CO3 (6.5 g, 20.0 mmol) in pyridine (15 mL) was heated at 120° C. for 12 h. The mixture was cooled to RT, diluted with ethyl acetate (200 mL) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=20/1) to afford the title compound (200 mg, 27%) as a brown solid. MS (ES+) C19H23FN4O3 requires: 374. found: 319 [M−56+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[CH:27]([NH:30][C:31]([CH:33]1[CH2:38][O:37][CH2:36][CH2:35][NH:34]1)=[O:32])([CH3:29])[CH3:28]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:34]2[CH2:35][CH2:36][O:37][CH2:38][CH:33]2[C:31](=[O:32])[NH:30][CH:27]([CH3:28])[CH3:29])[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: CC(C)NC(=O)C1COCCN1
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)NC(C)C)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 35 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.6 g, 1.2 mmol) was reacted with N-isopropylmorpholine-3-carboxamide (0.21 g, 1.2 mmol) according to the procedure as described in Example 24 to give the title compound as a yellow solid (0.25 g, 35%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:16]3[CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:28]([N:20]1[CH2:21][C:16]2[C:15]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[N:14][C:13]([C:10]3[CH:11]=[CH:12][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:8][CH:9]=3)=[N:18][C:17]=2[CH2:19]1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CNC3)cc1
Reactant: O=C(Cl)c1ccccc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CN(C(=O)c2ccccc2)C3)cc1

Procedure:
Compound ed was prepared according to the procedure described in Example 5 by reacting 1-ethyl-3-(4-(4-morpholino-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea with benzoyl chloride. LC-MS: m/z=+501 (M+H)+.
Reaction SMILES: S(=O)(=O)=O.[BrH:5].[CH3:6][C:7]1[C:8]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[N:9][CH:10]=[CH:11][CH:12]=1.BrBr>FC(Cl)(F)C(Cl)(Cl)F>[Br:5][C:11]1[CH:12]=[C:7]([CH3:6])[C:8]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[N:9][CH:10]=1
Reactant: Br
Reactant: Cc1cccnc1CCCCN
Agent: BrBr
Agent: O=S(=O)=O
Solvent: FC(F)(Cl)C(F)(Cl)Cl
Product: Cc1cc(Br)cnc1CCCCN
Yield: 46.1 %

Procedure:
A solution of sulphur trioxide (150 ml) in 1,1,2-trifluorotrichloroethane (550 ml) was added over 30 min to a suspension of 4-(3-methyl-2-pyridyl)butylamine hydrobromide (14.2 g) [prepared by reacting 4-(3-methyl-2-pyridyl)butylamine with hydrobromic acid (0.89M)] in 1,1,2-trifluorotrichloroethane and to this mixture was added liquid bromine (5.56 g). The mixture was heated under reflux for ca 16 hr. The solvent was removed by distillation and unbrominated starting material was removed by acetylation as described in Example 1(b) to yield 4-(5-bromo-3-methyl-2-pyridyl)-butylamine (6.49 g) as an oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](=[O:15])[CH2:13]Br)=[CH:10][CH:9]=1.[CH3:18][N:19]1[C:23]([OH:24])=[C:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])[C:21]([CH3:35])=[N:20]1>C(C(C)=O)C.C(Cl)Cl>[CH3:18][N:19]1[C:23]([O:24][CH2:13][C:12](=[O:15])[C:11]2[CH:16]=[CH:17][C:8]([CH3:7])=[CH:9][CH:10]=2)=[C:22]([C:25](=[O:34])[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:27]=2[Cl:33])[C:21]([CH3:35])=[N:20]1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: Cc1nn(C)c(O)c1C(=O)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)COc2c(C(=O)c3ccc(Cl)cc3Cl)c(C)nn2C)cc1
Reaction time: 2 h
Yield: 68.2 %

Procedure:
In a four necked flask, 2 g of 1,3-dimethyl-4-(2,4-dichlorobenzoyl)-5-hydroxy pyrazole was dissolved in 35 ml of methyl ethyl ketone, and 2 g of anhydrous potassium carbonate was added to the solution and 1.4 g of 4-methylphenacyl bromide was added dropwise to the mixture under stirring. The reaction was carried out for 2 hours under refluxing. The reaction mixture in the flask was cooled and filtered and methyl ethyl ketone was distilled off to obtain the precipitate of the reaction product. The precipitate was dissolved in methylene chloride and the solution was sequentially washed with water, an aqueous solution of sodium bicarbonate and water, and after drying over anhydrous sodium sulfate, methylene chloride was distilled off from the solution to obtain a crude product. The product was separated by a silica gel column with developing solvent (CH2Cl2 : 99.5% C2H5OH=100: 3) to obtain 1.87 g of brown oily product of 1,3-dimethyl-4-(2,4-dichlorobenzoyl)-5-(4-methyl benzoylmethoxy) pyrazole.
Reaction SMILES: I.CS[C:4](=[NH:18])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH3:19][NH:20][CH3:21]>C(N(CC)CC)C>[CH3:19][N:20]([CH3:21])[C:4]([NH2:18])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CSC(=N)Nc1ccccc1N1CCOCC1
Reactant: CNC
Agent: I
Solvent: CCN(CC)CC
Product: CN(C)C(N)=Nc1ccccc1N1CCOCC1

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-2-thiopseudourea hydroiodide (3.8 g), a 33% ethanolic solution of dimethylamine (5 ml) and triethylamine (25 ml) was heated at 80° C. for 8 hours. Triethylamine was removed by evaporation under reduced pressure and the residue treated with a mixture of ice and water to give 1,1-dimethyl-2-(2-morpholinophenyl)guanidine (m.p. 141°-143° C.) which was recrystallised from hexane.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH3:14])=[CH:4][C:3]=1[C:15]([NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([CH2:31][CH3:32])([CH3:30])[CH3:29])=[CH:24][C:23]=1[C:33]([CH2:36][CH3:37])([CH3:35])[CH3:34])=[O:16].[N+:38]([C:41]1[CH:50]=[CH:49][C:44]([O:45]CCO)=[CH:43][CH:42]=1)([O-:40])=[O:39].CS(O)(=O)=O>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH2:13][CH2:14][O:45][C:44]2[CH:49]=[CH:50][C:41]([N+:38]([O-:40])=[O:39])=[CH:42][CH:43]=2)=[CH:4][C:3]=1[C:15]([NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([CH2:31][CH3:32])([CH3:30])[CH3:29])=[CH:24][C:23]=1[C:33]([CH2:36][CH3:37])([CH3:34])[CH3:35])=[O:16]
Reactant: CCOc1cc(C(=O)NCCCOc2ccc(C(C)(C)CC)cc2C(C)(C)CC)c(O)c2ccccc12
Reactant: O=[N+]([O-])c1ccc(OCCO)cc1
Agent: CS(=O)(=O)O
Product: CCC(C)(C)c1ccc(OCCCNC(=O)c2cc(OCCOc3ccc([N+](=O)[O-])cc3)c3ccccc3c2O)c(C(C)(C)CC)c1

Procedure:
By heating a mixture of 5 g of Intermediate 2, 12 g of β-(4-nitrophenoxy)ethanol, and 0.3 g of methanesulfonic acid to 140-150° C for 3 hours under a reduced pressure, the desired product was obtained. The solvent used for the recrystallization of the product was acetonitrile. The melting point of the product was 166-168° C.
Reaction SMILES: [C:1](/[C:3](/[CH:6](OC)OC)=[CH:4]\[O-])#[N:2].[Na+].Cl.[S:13]1[CH:17]=[C:16]([NH2:18])[C:15]([NH2:19])=[CH:14]1>CO>[NH2:19][C:15]1[C:16]2=[N:18][CH:4]=[C:3]([C:1]#[N:2])[CH:6]=[C:17]2[S:13][CH:14]=1
Reactant: COC(OC)/C(C#N)=C/[O-]
Reactant: Nc1cscc1N
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N#Cc1cnc2c(N)csc2c1
Reaction time: 0.08 h
Yield: 23.3 %

Procedure:
To a solution of sodium (E)-2-cyano-3,3-dimethoxyprop-1-en-1-olate (1012 mg, 6.13 mmol) in methanol (12 mL) was added concentrated hydrochloric acid (503 μL 6.13 mmol). The solution was stirred for 5 minutes, and then a solution of thiophene-3,4-diamine (700 mg, 6.13 mmol) in methanol (12 mL) was added. The solution was stirred at reflux for 3 hours, and then a solution of concentrated HCl (1.0 mL) in methanol (2 mL) was added. The reaction was stirred at reflux for an additional two hours, quenched with TEA (3 mL), and concentrated. The crude product was purified via silica gel chromatography, eluting with 0-100% ethyl acetate in heptanes, to provide the title compound (250 mg, 1.427 mmol). MS m/z=176 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:15][CH2:14]2)=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C=O)C>[CH3:24][C:22]([O:21][C:20]([NH:19][CH:16]1[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][NH:10][C:3]2[C:2]([NH:1][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:7][CH:6]=[C:5]([O:8][CH3:9])[N:4]=2)[CH2:18][CH2:17]1)=[O:26])([CH3:23])[CH3:25]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(N)c(NCCN2CCC(NC(=O)OC(C)(C)C)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)CNc1ccc(OC)nc1NCCN1CCC(NC(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
A mixture of 1,1-dimethylethyl [1-(2-{[3-amino-6-(methyloxy)-2-pyridinyl]amino}ethyl)-4-piperidinyl]carbamate (2.8 g, 7.6 mmol), ethyl bromoacetate (0.85 ml, 1.3 g, 7.6 mmol) and potassium carbonate (2 g, 15.2 mmol) in acetonitrile (40 ml) and DMF (20 ml) was stirred under argon overnight. The mixture was filtered, washing with acetonitrile, and evaporated. The residue was dissolved in the minimum volume of DCM (20 ml) and washed with water (20 ml). The organic extract was added to a silica column which was then eluted with 0-100% ethyl acetate in hexane affording a brown oil (1.3 g, 38%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[C:7]([NH:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[O:8].[F:17][C:18]([F:35])([C:23]1[C:27]([C:28]([F:31])([F:30])[F:29])=[C:26]([C:32](Cl)=[O:33])[NH:25][N:24]=1)[C:19]([F:22])([F:21])[F:20]>ClCCl.[Ag]C#N>[Cl:16][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:32]([C:26]2[NH:25][N:24]=[C:23]([C:18]([F:17])([F:35])[C:19]([F:20])([F:21])[F:22])[C:27]=2[C:28]([F:31])([F:29])[F:30])=[O:33])=[CH:15][C:6]=1[C:7](=[O:8])[NH:9][CH2:10][C:11]([F:12])([F:13])[F:14]
Reactant: O=C(Cl)c1[nH]nc(C(F)(F)C(F)(F)F)c1C(F)(F)F
Reactant: Nc1ccc(Cl)c(C(=O)NCC(F)(F)F)c1
Agent: N#C[Ag]
Solvent: ClCCl
Product: O=C(NCC(F)(F)F)c1cc(NC(=O)c2[nH]nc(C(F)(F)C(F)(F)F)c2C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 11 %

Procedure:
A suspension of 212 mg (0.84 mmol) of 5-amino-2-chloro-N-(2,2,2-trifluoroethyl)benzamide and 168 mg (1.26 mmol) of silver(I) cyanide in 5.0 ml of dichloromethane is admixed with a solution of 265 mg (0.84 mmol) of 3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carbonyl chloride in 3.0 ml of dichloromethane and stirred for 16 h at room temperature. The suspension is then filtered over silica gel and the product is eluted with a mixture of dichloromethane and methanol (1:1). The solvents are removed under reduced pressure on a rotary evaporator and the resulting crude product is taken up in ethyl acetate. The organic phase is washed successively twice with 1M hydrochloric acid and once with saturated sodium chloride solution. The organic phase is then dried over magnesium sulphate, filtered and concentrated by evaporation under reduced pressure on a rotary evaporator. The crude product is then triturated with a mixture of dichloromethane, methyl tert-butyl ether and cyclohexane (1:1:1). The crude product obtained from the mother liquor is then purified by means of preparative HPLC. In this way, 49 mg of N-{4-chloro-3-[(2,2,2-trifluoroethyl)carbamoyl]phenyl}-3-(pentafluoroethyl)-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (11%) were obtained as a colourless solid.
Reaction SMILES: [SH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C([N:18]1[CH:22]=[CH:21]N=C1)(N1C=CN=C1)=O.O>CN(C)C=O>[CH3:4][C:3]1[CH:2]=[C:22]([NH:18][C:4]([C:3]2[C:2](=[S:1])[NH:10][CH:9]=[CH:8][CH:7]=2)=[O:6])[CH:21]=[C:8]([CH3:9])[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1cccnc1S
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)cc(NC(=O)c2ccc[nH]c2=S)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
2-Mercaptonicotinic acid (90 g, 0.58 mol) was suspended in N,N-dimethylformamide (660 mL) under ice-cooling, then carbonyldiimidazole (110 g, 0.70 mol) was added thereto, and the whole was stirred for 2 hours at room temperature. Water (5.4 mL) was added thereto, and the whole was stirred for 40 minutes, and then 3,5-xylydine (76 mL, 0.61 mol) was added thereto and the resulting mixture was stirred at 60° C. for 16 hours. The mixture was allowed to stand, and then water (1.3 L) was added, and the precipitated solid was filtered off. The solid was dried at 45° C. under reduced pressure to give 130 g of the title Reference Compound as a yellow solid (Yield: 89%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[OH:18][C@@:19]1([C:47]([F:50])([F:49])[F:48])[CH2:35][C:24]2[N:25]([CH3:34])[N:26]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C:23]=2[C@@H:22]([C:36]2[CH:45]=[CH:44][C:39]([C:40]([O:42]C)=O)=[CH:38][C:37]=2[CH3:46])[CH2:21][CH2:20]1.[CH3:51][C:52]1[C:57]([NH2:58])=[CH:56][CH:55]=[CH:54][N:53]=1>C1COCC1>[OH:18][C@@:19]1([C:47]([F:49])([F:48])[F:50])[CH2:35][C:24]2[N:25]([CH3:34])[N:26]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C:23]=2[C@@H:22]([C:36]2[CH:45]=[CH:44][C:39]([C:40]([NH:58][C:57]3[C:52]([CH3:51])=[N:53][CH:54]=[CH:55][CH:56]=3)=[O:42])=[CH:38][C:37]=2[CH3:46])[CH2:21][CH2:20]1
Reactant: Cc1ncccc1N
Reactant: COC(=O)c1ccc([C@H]2CC[C@](O)(C(F)(F)F)Cc3c2c(-c2ccccn2)nn3C)c(C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccnc2C)ccc1[C@H]1CC[C@](O)(C(F)(F)F)Cc2c1c(-c1ccccn1)nn2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.3 %

Procedure:
1 M lithium bis(trimethylsilyl)amide in toluene (0.24 mL, 0.24 mmol) was added dropwise to a solution of rac-methyl 4-((4R,7R)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methylbenzoate (0.034 g, 0.07 mmol) and 2-methylpyridin-3-amine (0.012 g, 0.11 mmol, Appollo) in THF (2 mL) at about 0° C. The mixture was allowed to warm to rt. After about 2 h, the mixture was cooled to about 0° C. 2-Methylpyridin-3-amine (0.008 g, 0.07 mmol) and 1 M lithium bis(trimethylsilyl)amide in toluene (0.07 mL, 0.07 mmol) were added then the mixture was allowed to warm to rt. After about 5 h a saturated aqueous NH4 Cl solution (20 mL) was added and then mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (20 mL), dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 2-6% MeOH/DCM). The appropriate fractions were concentrated in vacuo. The product was recrystallized from Et2O to give rac-4-((4R,7R)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methyl-N-(2-methylpyridin-3-yl)benzamide (0.005 g, 12%): LC-MS (Table 1, Method g) Rt=1.86 min, m/z 536 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 9.85 (s, 1H), 8.44-8.41 (m, 1H), 8.32-8.29 (m, 1H), 7.82-7.78 (m, 1H), 7.75-7.67 (m, 3H), 7.60-7.56 (m, 1H), 7.26-7.22 (m, 1H), 7.18-7.14 (m, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.21 (s, 1H), 5.61-5.55 (m, 1H), 3.93 (s, 3H), 3.40-3.32 (m, 2H), 2.61 (s, 3H), 2.40 (s, 3H), 2.36-2.26 (m, 1H), 1.93-1.83 (m, 1H), 1.80-1.71 (m, 2H).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[O:5][C:6]([C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:8]=1.[CH3:23][C:24]1[NH:25][CH:26]=[CH:27][N:28]=1>CN(C)C=O>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[N:8]=[C:4]([N:25]3[CH:26]=[CH:27][N:28]=[C:24]3[CH3:23])[O:5][C:6]=2[C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:11]=1
Reactant: Cc1ncc[nH]1
Reactant: CCOC(=O)C(=O)c1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1oc(-n2ccnc2C)nc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
Sodium hydride(oil, 60%, 710 mg) was gradually added to a mixture of ethyl 2-(2-chloro-4-[4-chlorophenyl)-5-oxazolyl]-2-oxoacetate(4.63 g), 2-methylimidazole(1.45 g) and N,N-dimethylformamide(50 ml) at 0° C. After stirring for 1 hour at room temperature, the reaction mixture was poured into ice water to give ethyl 2-[4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolyl]-2-oxoacetate(3.12 g, 59%). This was recrystallized from ethyl acetate-hexane to give colorless prisms. mp 126-127° C.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[CH:10]=[CH:11][C:12](O)=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.[NH2:21][NH2:22]>C1(C)C=CC=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:10]3[NH:22][NH:21][C:12](=[O:13])[CH2:11]3)[CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C=CC(=O)O)cc1OC1CCCC1
Reactant: NN
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C2CC(=O)NN2)cc1OC1CCCC1
Yield: 60.1 %

Procedure:
To a suspension of 3-cyclopentyloxy-4-methoxycinnamic acid (7.9 g, mmol) in toluene (25 ml) is added hydrazine hydrate (2.91 n-A, 60 mmol). The reaction mixture is heated to 100° (bath temperature) for 24 hours. Toluene is partially removed and ether carefully added, and the product allowed to crystallize. The solid is filtered to give crude product (6 g). A crystallization from chlorofom-hexane gives the pure product (5 g) m.p. 185°-186°. 1H NMR (CDCl3) δ 7.02 (1H, s, NH--CO), 6.88 (3H, m, arom), 4.79 (2H, m, carbinolic and benzylic), 4.28 (1H, m, NH), 3.84 (3H, s, CH3O--), 2.79 (2H, d, --CH2CO), 1.9 (5H, m, cyclopentyl C-H), 1.61 (3H, m, cyclopentyl C-H); IR(KBr),3420,3220,3160,2960,1700,1660 cm-1 ; MS m/z 276 (M)+.