Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22]C(O)=O)=[CH:17][CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH2:5][C:4]([CH3:27])([CH3:26])[NH:3]1.C([N:31](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.Cl>C(#N)C.O>[NH2:31][CH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[CH:12]=[CH:11][N:10]=[C:9]([NH:8][CH:6]3[CH2:7][C:2]([CH3:1])([CH3:28])[NH:3][C:4]([CH3:26])([CH3:27])[CH2:5]3)[N:14]=2)=[CH:20][CH:19]=1
Reactant: CCN(CC)CC
Reactant: CC1(C)CC(Nc2nccc(-c3ccc(CCC(=O)O)cc3)n2)CC(C)(C)N1
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: O
Product: CC1(C)CC(Nc2nccc(-c3ccc(CCN)cc3)n2)CC(C)(C)N1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A suspension of 3-{4-[2-(2,2,6,6-tetramethyl-piperidin-4-ylamino)-pyrimidin-4-yl]-phenyl}-propionic acid (100 mg, 0.26 mmol) (Step A of Example 185), triethylamine (37 μl, 0.26 mmol) and diphenylphosphoryl azide (57 μl, 0.26 mmol) in 3 ml acetonitrile was heated for 18 hours at 70° C. Then, 1.2 ml 0.4N-HCl was added and the mixture was stirred for 1 hour at ambient temperature. The solution was diluted with water, extracted with ether and the aqueous phase was made basic with 2N-NaOH. Extraction with EtOAc and purification with preparative HPLC gave the title compound. Yield: 24 mg (26%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH:16]([CH3:19])[NH:15][C:14]3=[O:20])[CH:10]=[N:9]2)=[C:5]([CH3:21])[O:4][N:3]=1.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:15]1[CH:16]([CH3:19])[C:17](=[O:18])[N:13]([C:11]2[CH:10]=[N:9][N:8]([CH2:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:21])[CH:12]=2)[C:14]1=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)C2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)C(C)N(Cc3ccccc3)C2=O)cn1
Yield: 50 %

Procedure:
Prepared as in example 10-5 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5-methylimidazolidine-2,4-dione (example 10-41) and benzyl bromide. Yield: 50%. 1H NMR (CDCl3, 400 MHz): δ 1.44 (s, 3H), 2.19 (s, 3H), 3.88 (s, 3H), 4.18 (d, J=8 Hz, 2H), 4.22 (t, 1H, J=4 Hz)), 5.06 (s, 2H), 7.39-7.29 (m, 5H), 7.94 (s, 1H), 8.10 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.02 μM.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:22][CH2:23][CH2:24][C:25](Cl)=[O:26].C(=O)(O)[O-].[Na+]>C1C=CC=CC=1.CN(C1C=CN=CC=1)C>[Cl:22][CH2:23][CH2:24][C:25]([NH:1][C:2]1[C:10]2[NH:9][C:8]3[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(N)cccc3c2C1
Reactant: O=C(Cl)CCCl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2[nH]c3c(NC(=O)CCCl)cccc3c2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 6-amino-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate (4.62 g, 16.08 mmol) in benzene (100 mL) was added a catalytic amount of DMAP. An inert atmosphere was created and chloropropionyl chloride (2)(1.68 mL) was added dropwise to the reaction mixture. After stirring at room temperature for 20 min, the reaction mixture was transferred to a separatory funnel containing 50% solution of sodium bicarbonate and was extracted with CH2Cl2 (3×250 mL). The combined organics were dried over Na2SO4 and concentrated in vacuo to give tert-butyl 6-[(3-chloropropanoyl)amino]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole-2-carboxylate as a white solid in 99% yield: 1H NMR (DMSO, 500 MHz) δ 1.38–1.53 (m, 9H), 2.75–2.99 (m, 2H), 3.65–3.78 (m, 4H), 3.88–3.97 (m, 2H), 4.53 (brs, 2H), 6.88–6.96 (m, 1H), 7.15–7.22 (m, 1H), 7.31–7.37 (m, 1H), 9.72 (brs, 1H), 10.44 (brs, 1H) ppm.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=O)=[N:2]1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[NH2:23])[C:16]([O:18][CH3:19])=[O:17]>[N+](C1C=CC=CC=1)([O-])=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[NH:12][C:13]3[CH:14]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[CH:20]=[CH:21][C:22]=3[N:23]=2)=[N:2]1
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: O=[N+]([O-])c1ccccc1
Product: COC(=O)c1ccc2nc(-c3n[nH]c4ccccc34)[nH]c2c1
Temperature: 145 °C
Yield: 21.4 %

Procedure:
A mixture of 0.1 g of 1H-indazole-3-carboxaldehyde and 113.7 mg of methyl 3,4-diaminobenzoate in 10 ml of nitrobenzene is maintained at a temperature in the region of 145° C. for 3 hours and 45 minutes. After cooling to a temperature in the region of 20° C., the reaction mixture is purified on SPE (5 g of SCX phase, processing and washing with methanol, extraction with a 2N ammoniacal methanol solution). The ammoniacal solution collected during the detachment is then concentrated under reduced pressure at a temperature in the region of 40° C. 198.3 mg of an orange lacquer are obtained and are purified by preparative LC-MS. 42.7 mg of methyl 2-(1H-indazol-3-yl)-3H-benzimidazole-5-carboxylate are thus obtained in the form of a beige-coloured powder, the characteristics of which are as follows:
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][S:5][N:4]=1)[CH3:2].C1C(=O)N([Br:20])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:20][CH:1]([C:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][S:5][N:4]=1)[CH3:2]
Reactant: CCOC(=O)c1csnc1CC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CCOC(=O)c1csnc1C(C)Br

Procedure:
Following generally the procedure of Example 28, ethyl 3-ethyl-4-isothiazolecarboxylate is reacted with NBS and benzoyl peroxide to give ethyl 3-(1-bromoethyl)-4-isothiazolecarboxylate, which is then reacted with sodium bicarbonate and DMSO and the resulting ethyl 3-acetyl-4-isothiazolecarboxylate is treated with lithium hydroxide monohydrate to yield 3-acetyl-4-isothiazolecarboxylic acid.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:7][C:8]1[C:9]([C:1]#[C:2][CH:3]([OH:6])[CH2:4][CH3:5])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C#CC(O)CC
Reactant: O=C1Nc2ccc(F)c(I)c2/C1=C/c1ccc[nH]1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(O)C#Cc1c(F)ccc2c1/C(=C/c1ccc[nH]1)C(=O)N2

Procedure:
Using Method C above, 1-pentyn-3-ol (58.9 mg, 0.7 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.28 mmol) (Starting Material 5, supra) using (Ph3P)4Pd (32 mg) and CuI (5.3 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 10 h to yield rac-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-pentynyl)-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 64 mg, 70%).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].[CH:13]([O:16][CH2:17][CH3:18])=[CH:14][CH3:15]>ClC(Cl)C.CC(C)(C)/C(/O)=C/C(C(C(C(F)(F)F)(F)F)(F)F)=O.CC(C)(C)/C(/O)=C/C(C(C(C(F)(F)F)(F)F)(F)F)=O.CC(C)(C)/C(/O)=C/C(C(C(C(F)(F)F)(F)F)(F)F)=O.[Yb]>[CH2:17]([O:16][CH:13]1[CH:14]([CH3:15])[CH2:1][C:2]2[CH2:11][CH2:10][C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[C:3]=2[O:12]1)[CH3:18]
Reactant: CC=COCC
Reactant: C=C1CCc2ccccc2C1=O
Agent: CC(C)(C)/C(O)=C/C(=O)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Yb]
Solvent: CC(Cl)Cl
Product: CCOC1OC2=C(CCc3ccccc32)CC1C
Reaction time: 20 h
Yield: 203.2 %

Procedure:
A solution of 2-methylene-3,4-dihydronaphthalen-1-one (44.9 g, 282 mmol), tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionato)ytterbium[Yb(fod)3, 15.0 g, 14.2 mmo], and ethyl propenyl ether (300 g, 390 mL, 3.5 mol) in 830 mL of dichloroethane was heated at reflux under nitrogen with stirring for 20 hours. Evaporation of the solvent left 200 g of a brown liquid that was purified on a silica gel column with 15/85 ethylacetate/hexane as the eluent, yielding 140 g of product, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:10]=[C:11]([C:16](=O)[CH2:17][F:18])[C:12]([F:15])=[N:13][CH:14]=1.O.C(=O)(O)[O-]>CCOC(C)=O>[Br:8][C:9]1[CH:10]=[C:11](/[C:16](=[N:7]\[S@@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])/[CH2:17][F:18])[C:12]([F:15])=[N:13][CH:14]=1
Reactant: O=C(CF)c1cc(Br)cnc1F
Reactant: CC(C)(C)[S@](N)=O
Agent: O=C([O-])O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[S@@](=O)/N=C(/CF)c1cc(Br)cnc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Titan (IV)-ethoxide tech. (0.298 mL, 1.441 mmol) was added to a solution of (R)-2-methyl-2-propanesulfinamide (1.44 mmol) and 1-(5-bromo-2-fluoropyridin-3-yl)-2-fluoroethanone (170 mg, 0.720 mmol) in methylene chlorice (15 mL). The reaction mixture was stirred at room temperature (light-yellow solution) for 4 h (or until complete conversion by LCMS). The reaction mixture was poured into water and saturated aqueous bicarbonate solution and EtOAc were added. The suspension was stirred vigorously for 20 min. The organic phase was separated. The aqueous phase was extracted twice with EtOAc. The organic phases were combined and filtered through a pad of celite. The filtrate was washed with brine and dried over MgSO4. The solvent was removed under reduced pressure. The residue (239 mg of a yellow oil) was purified by column chromatography (silica gel, 10-70% hexanes/EtOAc) to yield (R,E)-N-(1-(5-bromo-2-fluoropyridin-3-yl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide as a yellow oil (106 mg; 43%). MS m/z=338.9 [M+H]+. Calculated for C11H13BrFN2OS: 339.2.
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].CC([N-]C(C)C)C.[CH3:27][S:28]SC.CCCCCC>C1COCC1>[CH3:27][S:28][C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1
Reactant: CSSC
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1(SC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 80.8 %

Procedure:
A solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (2.0 g, 7.75 mmol) in THF (100.0 mL) was cooled to −78° C. followed by drop wise addition of LDA (1.80 M in THF, 8.80 mL, 15.56 mmol) and the mixture stirred at the same temperature for 45 min followed by addition of dimethyl disulfide (2.21 mL, 23.25 mmol) at −78° C. The temperature of the reaction was slowly raised up to rt and left to stir for 6 h. The reaction was then cooled to 0° C. and quenched by drop wise addition of saturated NH4Cl solution (50 mL), extracted with EtOAc (3×100 mL) and the combined organics washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 5% EtOAc:hexane to obtain the product as an orange viscous liquid (1.90 g, 83% yield). MS: 304.19 [M+H]+.
Reaction SMILES: [C:1]([C:11]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:12]=1[C:13](N(C)OC)=[O:14])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:25]([Mg]Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[C:1]([C:11]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:12]=1[C:13](=[O:14])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CCCCCCCCC#Cc1cc(OC)ccc1C(=O)N(C)OC
Solvent: C1CCOC1
Product: CCCCCCCCC#Cc1cc(OC)ccc1C(=O)Cc1ccccc1
Yield: 91 %

Procedure:
2-(1-Decyn-1-yl)-N-methyl-N,4-bis(methyloxy)benzamide (192) (0.80 g, 2.41 mmol) was treated with benzylmagnesium chloride in THF to give 0.80 g (91%) of compound 193 as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.85-0.90 (m, 3H), 1.20-1.37 (m, 8H), 1.40-1.50 (m, 2H), 1.55-1.65 (m, 2H), 2.45 (t, J=7.2 Hz, 2H), 3.83 (s, 3H), 4.45 (s, 2H), 6.83 (dd, J1=8.7 Hz, J2=2.7 Hz, 1H), 6.98 (d, J=2.8 Hz, 1H), 7.70-7.26 (m, 3H), 7.27-7.33 (m, 2H), 7.66 (d, J=8.8 Hz, 1H). LCMS (ESI): m/z 363 (M+H)+, m/z 361 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][C:4]=1[NH2:15].[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[C:16]([NH:24][C:25]([NH:15][C:4]1[CH:5]=[C:6]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1ccc(N2CCOCC2)cc1N
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: COc1ccc(N2CCOCC2)cc1NC(=S)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methoxy-5-morpholin-4-yl-phenylamine (4.6 g, 22 mmol) in acetone (140 ml) is added a solution of benzoyl isothiocyanate (3.4 ml, 25 mmol) in acetone (80 ml) and the reaction mixture is stirred for further 30 min at ambient temperature. After removal of the volatile components in vacuo, the product is isolated by flash chromatography (silica, eluent ethyl acetate/n-hexane 1:4, then 1:2) as a yellow solid (8.0 g, 97%). MS: m/e=272 (M+).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:21]2[CH2:25][C:24](OC)=[CH:23][C:22]2=[O:28])[C:8]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[N:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:30][O:31][CH2:32][C@@H:33]([OH:35])[CH3:34].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[CH:1]1([CH2:6][C@H:7]([N:21]2[CH2:25][C:24]([O:35][C@@H:33]([CH3:34])[CH2:32][O:31][CH3:30])=[CH:23][C:22]2=[O:28])[C:8]([NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH2:16][C:17]([OH:20])([CH3:18])[CH3:19])[N:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Reactant: COC[C@H](C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: COC[C@H](C)OC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Temperature: 25 °C
Yield: 7.4 %

Procedure:
A solution of (S)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide (prepared as in Example 1, 35 mg, 0.09 mmol) in a hydrochloric acid (gas) saturated acetic acid (5 mL) solution was heated in a sealed tube at 75° C. for 2 h. After that, the reaction mixture was cooled to room temperature, and concentrated. The residue was added to (S)-1-methoxy-propan-2-ol (162 mg, 1.76 mmol), and toluene-4-sulfonic acid hydrate (10 mg). The mixture was heated to 90° C., for 18 h. The reaction mixture was concentrated and the residue was dissolved in dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, and dried over magnesium sulfate. The crude product was purified using reverse phase HPLC (Biosystems MDS-SCIEX LC/MS, Pursuit C-18 2×10 mm, water/acetonitrile 0.05% trifluoroacetic acid) to afford (S)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-((S)-2-methoxy-1-methyl-ethoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionamide (3 mg, 9%) as a white foam: LR-ES-MS m/z calculated for C23H36N4O5 [M]+ 448, observed [M+H]+ 449; 1H NMR (300 MHz, CDCl3) δ ppm 1.08-1.25 (m, 2H) 1.16 (s, 6H) 1.32 (d, J=6.3 Hz, 3H) 1.43-2.07 (m, 9H) 3.40 (s, 3H) 3.44-3.59 (m, 2H) 3.66 (br. s., 1H) 3.90-4.00 (d, J=17.8 Hz, 1H) 3.95 (s, 2H) 4.08 (d, J=17.8 Hz, 1H) 4.34-4.47 (m, 1H) 4.80 (dd, J=8.9, 6.5 Hz, 1H) 5.12 (s, 1H) 6.67 (d, J=2.0 Hz, 1H) 7.30 (d, J=2.0 Hz, 1H) 8.85 (br. s., 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25]([OH:27])=O)[CH:4]=[N:3]1.[CH:28]1([NH:33][CH3:34])[CH2:32][CH2:31][CH2:30][CH2:29]1.C(N(C(C)C)C(C)C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>O1CCCC1>[CH:28]1([N:33]([CH3:34])[C:25]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[O:27])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CNC1CCCC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1)C1CCCC1
Temperature: 70 °C
Reaction time: 22 h
Yield: 92.8 %

Procedure:
A mixture of 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 0.269 mmole), cyclopentyl-methylamine (107 mg, 1.08 mmole), N-ethyldiisopropylamine (376 ul, 2.15 mmole) and 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate, 404 ul, 0.673 mmole) in tetrahydrofurane (4 ml) was stirred for 22 hours at 70° C. The solvent was evaporated, the residue was triturated with sodium hydrogencarbonate solution. The precipitated solid was filtered off, washed with water and dried affording N4-cyclopentyl-N4,1-dimethyl-N5-(2-morpholino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-4,5-dicarboxamide (113 mg, 92.7%) as an off-white solid. mp.: 222-4° C., MS: m/z=453.5 (M+H+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][NH2:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][C:37]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:41])[C:38](O)=[O:39].CCN(CC)CC.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:34][NH:35][C:38](=[O:39])[C:37]([CH3:36])([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH3:41])[C@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C(=O)O)c1ccccc1
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN)C(C)C)ccc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC(=O)C(C)(C)c2ccccc2)C(C)C)ccc1OC
Reaction time: 8 h

Procedure:
To a solution of (3R,4R)-3-aminomethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.405 mmol) and α,α-dimethylphenylacetic acid (101 mg, 0.608 mmol) in CH2Cl2 (3 mL) is subsequently added Et3N (0.085 mL, 0.608 mmol), 1-hydroxy-7-azabenzotriazole (84 mg, 0.608 mmol; commercially available from ABCR, AV24631) and N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide HCl (118 mg, 0.608 mmol). Stirring is continued overnight at room temperature, the mixture is then diluted with CH2Cl2, and the organic layer is subsequently washed with 2N HCl, saturated aqueous NaHCO3 and brine, dried (MgSO4) and concentrated. Purification by RP-HPLC on a PrepC18 OBD column (dimensions: 30×100 mm; 5 μM particle size, SunFire Ltd) and using a 95-5% gradient of MeCN/H2O 5:95 (containing 0.1% TFA) to MeCN/H2O 95:5 (containing 0.1% TFA) over 20 min gives the title compound as colorless oil. MS [M]+=640.2. tR (HPLC, Nucleosil C18HD column, 20-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 5.2 min.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[N:9][C:10]3[N:14]([CH2:15][CH3:16])[N:13]=[CH:12][C:11]=3[C:6]=2[N:5]2[N:17]=[C:18]([CH3:20])[CH:19]=[C:4]2[N:3]=1.C(N(CC)CC)C.[F:28][C:29]([F:38])([F:37])[C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33]>C(O)CCC>[CH2:15]([N:14]1[C:10]2[N:9]=[CH:8][C:7]3[C:2]([NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[C:30]([C:29]([F:28])([F:37])[F:38])[CH:31]=4)=[N:3][C:4]4[N:5]([N:17]=[C:18]([CH3:20])[CH:19]=4)[C:6]=3[C:11]=2[CH:12]=[N:13]1)[CH3:16]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCn1ncc2c1ncc1c(Cl)nc3cc(C)nn3c12
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CCn1ncc2c1ncc1c(Nc3cccc(C(F)(F)F)c3)nc3cc(C)nn3c12
Yield: 72.9 %

Procedure:
5.8 g of 5-chloro-8-ethyl-2-methyl-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidine (0.02 mol), 3 g of triethylamine and 3.3 g of 3-trifluoromethylaniline are refluxed in butyl alcohol for 24 hours with stirring. The solvent is removed in vacuo and the residue treated with 20 ml of water and filtered off. Recrystallization from alcohol yields 6 g of 8-ethyl-2-methyl-N-[3-(trifluoromethyl)phenyl]-8H-pyrazolo[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5-amine; yield (73%) m.p. 205°-206°.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH3:24][C:25]1[S:29][C:28]2=[N:30][CH:31]=[C:32]([C:33](O)=[O:34])[N:27]2[CH:26]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:33]([C:32]3[N:27]4[C:28]([S:29][C:25]([CH3:24])=[CH:26]4)=[N:30][CH:31]=3)=[O:34])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: Cc1cn2c(C(=O)O)cnc2s1
Product: Cc1cn2c(C(=O)NC[C@@H]3C[C@@H]4C[C@@H]4N3C(=O)c3nc(N)sc3-c3cccc(F)c3)cnc2s1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 2-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid. LC-MS (basic): tR=0.78 min; [M+H]+=497.1.
Reaction SMILES: C1[NH:3]C1.C(N(CC)CC)C.[F:11][C:12]([F:31])([F:30])[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:21](OCC(F)(F)F)=[CH:20][C:16]=1[C:17](Cl)=[O:18]>C(OCC)C>[F:11][C:12]([F:31])([F:30])[CH2:13][O:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH2:3])=[O:18]
Reactant: O=C(Cl)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: C1CN1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: NC(=O)c1ccccc1OCC(F)(F)F
Temperature: 25 °C

Procedure:
Ethyleneimine (2.9 g., 0.068 mole), triethylamine (6.8 g., 0.068 mole) and diethyl ether (250 ml.) are cooled to 0° C. and stirred while adding 2,5-di-(2,2,2-trifluoroethoxy)benzoyl chloride (22.8 g., 0.068 mole). The mixture is allowed to warm to room temperature and filtered. The filtrate is treated with 6.6 N isopropanol-hydrochloric acid mixture and filtered and the solvent evaporated in vacuo to give N-(2-chloroethyl)-2,5-di-(2,2,2-trifluoroethoxy-benzamide, m.p. 87°-88.5° C.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[C:5]([CH2:8][C:9](=O)[CH3:10])(=O)[CH3:6].[ClH:12]>C(O)C>[ClH:12].[SH:3][C:2]1[N:4]=[C:9]([CH3:10])[CH:8]=[C:5]([CH3:6])[N:1]=1
Reactant: CC(=O)CC(C)=O
Reactant: NC(N)=S
Agent: Cl
Solvent: CCO
Product: Cc1cc(C)nc(S)n1
Yield: 80 %

Procedure:
76 Grams (1.0 mole) of thiourea was suspended in a solution of 120 g. (1.2 moles) of acetylacetone in 2,500 ml. of ethanol. The resulting suspension was mixed with 250 ml. of concentrated hydrochloric acid, and then reacted under reflux for 2 hours. After completion of the reaction, the reaction liquid was cooled, whereby beautiful yellow needle-like crystals of 2-mercapto-4,6-dimethyl-pyrimidine hydrochloride were formed. The reaction liquid was allowed to stand overnight to sufficiently deposit the crystals, which were then recovered by filtration and dried to obtain 140 g. of 2-mercapto-4,6-dimethyl-pyrimidine hydrochloride in yield of 80 %.