Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].C(O)(=O)C.[CH:6]([NH2:8])=[NH:7].[CH3:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([O:15][C:16](=[CH:19]N(C)C)[CH:17]=O)=[CH:13][CH:12]=1.[O-]CC.[Na+]>C(O)C>[CH3:9][O:10][C:11]1[CH:24]=[CH:23][C:14]([O:15][C:16]2[CH:17]=[N:7][CH:6]=[N:8][CH:19]=2)=[CH:13][CH:12]=1
Reactant: N=CN
Reactant: COc1ccc(OC(C=O)=CN(C)C)cc1
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(Oc2cncnc2)cc1
Reaction time: 40 h
Yield: 64.8 %

Procedure:
Sodium metal (4.1 g) was dissolved in absolute ethanol (90 ml) and formamidine acetate (18.4 g) and 2-(p-methoxyphenoxy)-3-(dimethylamino)acrolein (13.0 g) were added to the ethanolic solution of sodium ethoxide. The mixture was heated under reflux, with stirring, for 40 hr and then the solvent was removed, by distillation under reduced pressure. The residue was treated with water (200 ml) and chloroform (200 ml), the chloroform layer was separated and the chloroform removed by distillation under reduced pressure. The residue was purified by column chromatography over silica gel using chloroform as eluent to give 5-(p-methoxyphenoxy)pyrimidine as an oil (7.7 g) which was characterised by p.m.r. spectroscopy.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]#[N:16])[N:5]([NH:7]C(=O)OC(C)(C)C)[CH:6]=1.O1CCOCC1.[ClH:23].O1CCOCC1.CCCCCC>C(OCC)C>[ClH:23].[NH2:7][N:5]1[CH:6]=[C:2]([Br:1])[CH:3]=[C:4]1[C:15]#[N:16]
Reactant: CC(C)(C)OC(=O)Nn1cc(Br)cc1C#N
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CCCCCC
Product: N#Cc1cc(Br)cn1N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 1 L, 3-neck flask was fitted with a mechanical stirrer, nitrogen inlet, thermocouple and thermocontroller, cooling bath and an addition funnel. tert-Butyl (4-bromo-2-cyano-1H-pyrrol-1-yl)carbamate (19 g, 66 mmol) was added and dissolved with 1,4-dioxane (50 mL), then the stirred orange solution was cooled to 0° C. and HCl/dioxane (4N, 100 mL, 8 eq.) was slowly added from the addition funnel, maintaining an internal temperature around 25° C. After 2 hours, the solution became cloudy and stirring at room temperature was continued for 7 hours. The reaction was monitored for completion by TLC (silica gel, 1:3 EtoAc/hexane, UV; Note: the free base may be observed as a high-Rf spot and can be misinterpreted as incomplete reaction). The reaction mixture was diluted with diethyl ether (150 mL) and the precipitated solids were collected by suction filtration and washed with ether (200 mL). Drying (vacuum oven at 50° C.) afforded the desired product as 10.9 g (93%) of a white solid. 1H-NMR (DMSO): δ 7.24 (d, 1H, J=2 Hz), 6.93 (d, 1H, J=2 Hz), 6.2 (bs, 3H, J=2.8, 4.4 Hz); MS: GC/MS, m/z=[M+H].
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[N:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[CH2:38][NH2:39].[F:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][CH2:49][S:50][C:51]2[N:59]=[CH:58][CH:57]=[CH:56][C:52]=2[C:53](O)=[O:54])=[CH:43][CH:42]=1>C(Cl)Cl.CCCCCC.CC(=O)OCC>[F:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][CH2:49][S:50][C:51]2[C:52]([C:53]([NH:39][CH2:38][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][N:32]=3)=[O:54])=[CH:56][CH:57]=[CH:58][N:59]=2)=[CH:43][CH:42]=1
Reactant: O=C(O)c1cccnc1SCCCc1ccc(F)cc1
Reactant: NCc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCc1ccccn1)c1cccnc1SCCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46 %

Procedure:
520 mg (2.74 mmol) of EDC hydrochloride, 250 mg (1.64 mmol) of HOBT, 0.9 ml (5.48 mmol) of DIPEA and 180 mg (1.64 mmol) of pyridin-2-yl-methanamine were added in succession to a solution of 400 mg (1.37 mmol) of 2-(3-(4-fluorophenyl)-propylthio)nicotinic acid in DCM (6 ml), and the mixture was stirred for 4 h at RT. Dilution with water (40 ml) and extraction with DCM (3×50 ml) were then carried out. The combined organic phases were washed with a sat. NH4Cl sol. and water, dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 22:3) of the residue yielded 240 mg (0.63 mmol, 46%) of 2-[3-(4-fluorophenyl)-propylsulfanyl]-N-(pyridin-2-yl-methyl)-pyridine-3-carboxylic acid amide. MS: m/z 382.1 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=1[C:16]([CH3:21])([CH3:20])[CH2:17][CH2:18][OH:19])=[O:6].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=1[C:16]([CH3:21])([CH3:20])[CH2:17][CH:18]=[O:19])=[O:6]
Reactant: Cc1cc(C)c(C(C)(C)CCO)c(OC(=O)CCCBr)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1cc(C)c(C(C)(C)CC=O)c(OC(=O)CCCBr)c1
Temperature: 24 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
2.5 g of 3-[2-(4-bromobutyryloxy)-4,6-dimethylphenyl]-3,3-dimethylpropan-1-ol in solution in 160 cm3 of dichloromethane are added dropwise, at 24° C., to 3.1 g of pyridinium chlorochromate in suspension in 900 cm3 of dichloromethane. After stirring for 2 hours at 24° C., the reaction mixture is filtered on 630 g of silica (particle size 0.063-0.2 mm), eluting successively with pure dichloromethane, and then a mixture of dichloromethane and ethyl acetate (80/20 by volume). 2.4 g of 3-[2-(4-bromobutyryloxy)-4,6-dimethylphenyl]-3,3-dimethylpropanal are thus obtained in the form of a colorless viscous oil.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[OH:8][CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=O)[N:10]1[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[N:22][C:23]([O:29][CH3:30])=[CH:24][CH:25]=2)[N:20]=1.O.C(OCC)(=O)C>CN(C)C=O>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9](=[O:8])[N:10]1[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[N:22][C:23]([O:29][CH3:30])=[CH:24][CH:25]=2)[N:20]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Reactant: CN(C)CCCN
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3NCCCN(C)C)nc2n1
Yield: 32.3 %

Procedure:
3-Dimethylaminopropylamine (5.1 g) is added at a temperature in the region of 20° C. to a solution of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (12.4 g) in anhydrous dimethylformamide (200 cc), and the reaction mixture is heated to reflux for 8 hours. After being cooled, the reaction mixture is poured into a mixture of water (1200 cc) and ethyl acetate (500 cc) and filtered to remove an insoluble product. The aqueous phase is separated after settling has occurred and then extracted with ethyl acetate (2×250 cc). The organic phases are combined, washed with water (5×80 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 60° C. After recrystallization in ethyl acetate, 3-(3-dimethylaminopropylamino)-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (5.1 g), m.p. 128° C., is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:6]=[C:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH3:12].N1CCCC1>CO.[Ni].[H][H]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH3:12]
Reactant: [H][H]
Reactant: COc1ccc(C=C2CCCN2C)cc1OC
Agent: [Ni]
Solvent: C1CCNC1
Solvent: CO
Product: COc1ccc(CC2CCCN2C)cc1OC
Yield: 78 %

Procedure:
Dissolve 12.2 g of 3,4-dimethoxybenzylidene-1-methylpyrrolidine in methanol and reduce the pyrrolidine in the thus-obtained solution with Raney nickel/hydrogen. Filter off the catalyst and distil off the methanol before distilling the residue to obtain 9.6 g (79%) of the title compound with a b.p. of 90° at 0.005 mm of Hg. The m.p. of the picrate (from ethanol) is 105° to 106°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1.[Na]>C(O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([NH:19][CH2:20][CH2:21][C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[O:16])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Reactant: NCCc1cccs1
Agent: [Na]
Solvent: CCO
Product: O=C(NCCc1cccs1)C1CCN(Cc2ccccc2)CC1

Procedure:
22.15 g of ethyl 1-benzyl-4-piperidinecarboxylate and 1 equivalent of the product obtained in Step B are added to a solution of 4.12 g of sodium in 103 ml of anhydrous ethanol. After 12 hours' reaction at reflux, the reaction mixture is evaporated. The residue is taken up in dichloromethane and washed with water, and then the organic phase is dried, filtered and evaporated, enabling an oil to be obtained which crystallises in diisopropyl ether.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]SN1C(=O)C=CC1=O>C(#N)C>[C:4]1([C:3]([C:2]2[CH:1]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH2:3])[CH:5]=[CH:6][CH:7]=[CH:1][CH:2]=1
Reactant: C=CCCCCCSN1C(=O)C=CC1=O
Solvent: CC#N
Product: C=C(c1ccccc1)c1ccccc1
Yield: 2000 %

Procedure:
N-Methylene hexylsulfanylmaleimide (25 mg, 0.116 mmol) was dissolved in acetonitrile (21 mL) and 1,1-diphenylethyene (203 μL, 1.16 mmol) to provide a 0.005M solution. The resulting solution was degassed for 30 minutes and irradiated in pyrex glassware for 5 minutes with stirring. Solvent was removed in vacuo and purification by flash chromatography (gradient elution in petroleum ether to 30% ethyl acetate in petroleum ether) afforded (4RS,5RS,7RS) 2-aza-2-methylenecyclohexane-4-hexylsulfanyl-5-phenyl-bicyclo[3.2.0]heptan-1,3-dione and (4RS,5SR,7RS) 2-aza-2-methylenecyclohexane-4-hexylsulfanyl-5-phenyl-bicyclo[3.2.0]heptan-1,3-dione as a colourless oil (30 mg, 0.075 mmol) as a mix of diastereoisomers (10:1) in 64% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[CH:11]([F:13])[F:12])=[CH:4][C:3]=1[CH3:16].[NH2:17][C:18]1[CH:22]=[CH:21][NH:20][N:19]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:11]([F:13])[F:12])[N:19]3[N:20]=[CH:21][CH:22]=[C:18]3[N:17]=2)=[CH:4][C:3]=1[CH3:16]
Reactant: Cc1cc(C(=O)CC(=O)C(F)F)ccc1Cl
Reactant: Nc1cc[nH]n1
Solvent: CC(=O)O
Product: Cc1cc(-c2cc(C(F)F)n3nccc3n2)ccc1Cl
Yield: 62.4 %

Procedure:
A mixture of 1-(4-chloro-3-methyl-phenyl)-4,4-difluoro-butane-1,3-dione (7.18 g, 29.1 mmol) and commercially available 3-aminopyrazole (2.42 g, 29.1 mmol) in acetic acid (70 mL) was refluxed for 4.5 h and evaporated. The crude product was further purified by crystallization (ethyl acetate/hexane) to yield 5-(4-chloro-3-methyl-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine (5.33 g, 62%) as an off-white solid. MS (EI) 293.2 [(M)+]; mp 107° C.
Reaction SMILES: Br[CH:2]([CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=1)[CH:3]=O.[NH2:17][C:18]1[N:23]=[C:22]([NH2:24])[CH:21]=[C:20]([OH:25])[N:19]=1>>[NH2:17][C:18]1[NH:23][C:22]2[NH:24][CH:3]=[C:2]([CH2:5][CH2:6][C:7]3[CH:12]=[CH:11][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:9][CH:8]=3)[C:21]=2[C:20](=[O:25])[N:19]=1
Reactant: Nc1cc(O)nc(N)n1
Reactant: COC(=O)c1ccc(CCC(Br)C=O)cc1
Product: COC(=O)c1ccc(CCc2c[nH]c3[nH]c(N)nc(=O)c23)cc1

Procedure:
reacting 2-bromo-4-(4-carbomethoxyphenyl)butanal with 2,4-diamino-6-hydroxypyrimidine to give methyl 4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoate;
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]/[CH:11]1[CH2:13][S:12]1)[CH3:2].S1CC1>C1C=CC=CC=1>[S:12]1[CH2:13][CH:11]=[CH:10][CH:9]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14]
Reactant: CCOC(=O)CCCC/C=C/C1CS1
Agent: C1CS1
Solvent: c1ccccc1
Product: CCOC(=O)CCCCC1C=CCS1
Yield: 78.6 %

Procedure:
A solution of thiirane (E)-ethyl 7-(thiiran-2-yl)hept-6-enoate (40 mg, 0.19 mmol) and Cu(hfacac)2 (4.7 mg, 10 μmol) in benzene (20 mL) was heated at 120° C. for 1.5 h in a pressure tube. Concentration of the solvent in vacuo afforded a residue, which was purified by column chromatography (n-pentane) to give Ethyl 5-(2,5-dihydrothiophen-2-yl)pentanoate (32 mg, 80%) as a colorless oil.
Reaction SMILES: [CH:1]([CH:4]1[NH:8][C:7](=[O:9])[CH2:6][NH:5]1)([CH3:3])[CH3:2].[OH-].[Na+].[Cl:12][CH:13]([Cl:17])[C:14](Cl)=[O:15]>C(OC)(C)(C)C.O>[Cl:12][CH:13]([Cl:17])[C:14]([N:5]1[CH2:6][C:7](=[O:9])[NH:8][CH:4]1[CH:1]([CH3:3])[CH3:2])=[O:15]
Reactant: CC(C)C1NCC(=O)N1
Reactant: O=C(Cl)C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)C1NC(=O)CN1C(=O)C(Cl)Cl
Reaction time: 10 h
Yield: 49 %

Procedure:
45 g (0.35 mole) of 2-isopropyl-4-oxo-imidazolidine (Example 3) were dissolved in 250 ml of methyl tert.- butyl ether, 17.2 g (0.43 mole) of sodium hydroxide in 20 ml of water were added, and 57 g (0.39 mole) of dichloroacetyl chloride were then added dropwise at from 10° to 15° C. The mixture was stirred for 10 hours and the solid precipitate was filtered off with suction, washed with water and dried under reduced pressure to give 41 g (49% theory) of 1-dichloroacetyl-2-isopropyl-4-oxoimidazolidine of melting point 172°-173° C.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1C1C=NN(C)C=1)=[O:11].CC1C=CC([N:35]2[CH:39]=[C:38]([CH3:40])[CH:37]=[N:36]2)=C(C=1)C(O)=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:35]1[CH:39]=[C:38]([CH3:40])[CH:37]=[N:36]1)=[O:11]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1ccc(-n2cc(C)cn2)c(C(=O)O)c1
Product: Cc1ccc(-n2cc(C)cn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 5-methyl-2-(4-methyl-1H-pyrazol-1-yl)benzoic acid. MS (ESI) 327 (M+H).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[CH3:22][C:23]1[CH:24]=[C:25](B2OC(C)(C)C(C)(C)O2)[S:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.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>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[CH2:4][CH2:5][CH2:6][C:2]=3[C:25]3[S:26][CH:27]=[C:23]([CH3:22])[CH:24]=3)[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: Cc1ccc2c(c1)c1c(n2C2=C(Br)CCC2)CCN(C)C1
Reactant: Cc1csc(B2OC(C)(C)C(C)(C)O2)c1
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: COCCOC
Solvent: O
Product: Cc1csc(C2=C(n3c4c(c5cc(C)ccc53)CN(C)CC4)CCC2)c1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a degassed stirred solution of 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), 4-methylthiophene-2-boronic acid pinacol ester (129 mg, 0.578 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,2-dimethoxyethane (4 mL)-water (2 mL) was purged with nitrogen followed by addition of Pd(PPh3)4 (16 mg, 0.0147 mmol). The reaction mixture was stirred at 90° C. for 45 min. The solvent was removed under reduced pressure, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(2-(4-methylthiophen-2-yl)cyclopent-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.3 (s, 1H), 7.0 (m, 3H), 6.78 (s, 1H), 4.7 (m, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 3.37 (s, 3H), 3.03 (m, 2H), 2.83 (m, 2H), 2.61 (m, 2H), 2.4 (s, 3H), 2.2 (m, 2H), 2.17 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[C:29]([S:33]([OH:36])(=[O:35])=[O:34])[CH:30]=[N:31][CH:32]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:28]=[C:29]([S:33]([OH:36])(=[O:35])=[O:34])[CH:30]=[N:31][CH:32]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: O=S(=O)(O)c1cncc(Br)c1
Product: O=S(=O)(O)c1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (300 mg, 1.0 mmol) and 5-Bromo-pyridine-3-sulfonic acid (example B.2, step 1) (214 mg, 1.0 mmol) according to general procedure II. Obtained as an orange solid (280 mg, 54%). MS (ISN) 510.9 [(M−H)−]; mp >288° C.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7].C(=O)([O-])[O-].[K+].[K+].[C:39](Cl)(=[O:41])[CH3:40]>CN(C)C=O>[C:39]([N:11]1[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=2)[C@H:9]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:10]1)(=[O:41])[CH3:40]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Reaction time: 3 h

Procedure:
To a stirred mixture of (2R)-1-[3,5-bis(trifluoro-methyl)benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (0.15 g) and potassium carbonate (0.14 g) in dimethylformamide (10 ml) was added acetyl chloride (0.04 ml) at room temperature. After being stirred for 3 hours, the reaction mixture was quenched with water (50 ml) and extracted with dichloromethane (50 ml). The organic layer was washed with aqueous sodium bicarbonate solution and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified on a silica gel column (10 g) eluting with a mixture of dichloromethane and methanol (20:1). The fractions containing object compound were collected and evaporated under reduced pressure. To the resulting oily product was added a mixed solvent of ethyl ether and diisopropyl ether, and the mixture was concentrated under reduced pressure. The obtained powder was collected by filtration and dried in vacuo to give (2R)-4-acetyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl) piperazine (0.09 g) as a powder.
Reaction SMILES: [CH:1]([NH:4][C:5]([C@H:7]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]([O:23][CH2:24][CH2:25][O:26][CH3:27])[CH:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].NC1C(N[C@@H]2CC[C@H](C(NC(C)C)=O)CC2)=CC(Cl)=NC=1>>[NH2:20][C:19]1[C:14]([NH:13][C@@H:10]2[CH2:11][CH2:12][C@H:7]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:8][CH2:9]2)=[CH:15][C:16]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[N:17][CH:18]=1
Reactant: COCCOc1cc(N[C@H]2CC[C@@H](C(=O)NC(C)C)CC2)c([N+](=O)[O-])cn1
Agent: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2N)CC1
Product: COCCOc1cc(N[C@H]2CC[C@@H](C(=O)NC(C)C)CC2)c(N)cn1

Procedure:
The title compound was prepared from cis-N-isopropyl-4-(2-(2-methoxyethoxy)-5-nitropyridin-4-ylamino)cyclohexanecarboxamide using a procedure analogous to that used in the preparation of cis-4-(5-amino-2-chloropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH:18]=O)=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[CH3:21][O:22][C:23]1[CH:48]=[C:47]([N+:49]([O-:51])=[O:50])[CH:46]=[CH:45][C:24]=1[CH2:25][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li+].CC([N-]C(C)C)C>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](/[CH:18]=[CH:25]/[C:24]1[CH:45]=[CH:46][C:47]([N+:49]([O-:51])=[O:50])=[CH:48][C:23]=1[O:22][CH3:21])=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cc2cc(OCc3ccccc3)ccc2[nH]1
Reactant: COc1cc([N+](=O)[O-])ccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Br-]
Agent: [Li+]
Product: COc1cc([N+](=O)[O-])ccc1/C=C/c1cc2cc(OCc3ccccc3)ccc2[nH]1
Reaction time: 5 h

Procedure:
The aldehyde (846) was reacted with (2-methoxy-4-nitrobenzyl) (triphenyl)phosphonium bromide (582) prepared as described in example 432 using the procedure described in method 2, except that the LDA and aldehyde were (sequentially) added at 0° C., the ratio of LDA;aldehyde was 1.5:1 and the reaction time was 5 h, to give (after crystallisation from CH2Cl2/pentane) the diene (583) as an orange solid (the pure E isomer) (63%), mp 156–159° C. 1H NMR (CDCl3) δ 8.23 (br s, 1H), 7.87 (dd, J=8.5, 2.1 Hz, 1H), 7.76 (d, J=2.2 Hz, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.48 (d, J=7.3 Hz, 2H), 7.39 (t, J=7.3 Hz, 2H), 7.32 (t, J=7.2 Hz, 1H), 7.28 (d, J=17.1 Hz, 1H), 7.26 (d, J=8.7 Hz, 1H), 7.20 (d, J=16.7 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 6.97 (dd, J=8.7, 2.5 Hz, 1H), 6.63 (br s, 1H), 5.11 (s, 2H), 4.01 (s, 3H). Found: C, 71.69; H, 4.94; N, 7.11. C24H20N2O4 requires C, 71.99; H, 5.03; N, 7.00.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:9]([NH:11][C:12](=[O:28])[C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18](=[O:27])[C@H:19]([CH3:26])[NH:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH2:23])[CH3:10]>CN(C)C=O>[CH2:9]([NH:11][C:12](=[O:28])[C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18](=[O:27])[C@H:19]([CH3:26])[NH:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH:23][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])[CH3:10]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)N
Reactant: O=C1CCCC(=O)O1
Solvent: CN(C)C=O
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)CCCC(=O)O
Temperature: 60 °C
Reaction time: 48 h

Procedure:
1.7 g of glutaric anhydride was added to a solution of 4.0 grams of alanyl-alanyl proline ethylamide in 25 ml of dimethylformamide and the reaction solution heated for 1 hour at 60 degrees C. Then, the solution was evaporated and the resultant non-crystalline evaporation residue dissolved in 30 ml of ethyl acetate. After 48 hours of standing at 3 degrees C., 3.6 g of separated product was filtered off with a melting point of 154 to 156 degrees C. ([α]D20 -137.3 degrees (c 0.3; 50% methyl alcohol).