Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C@H:5]2[CH2:4]N1CC(C)(C)C(O)=O.Cl.[NH2:19][C:20]([CH3:27])([CH3:26])[CH2:21][C:22]([O:24]C)=[O:23]>>[O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][NH:9][CH2:10][C@H:5]2[CH2:4][N:19]1[C:20]([CH3:27])([CH3:26])[CH2:21][C:22]([OH:24])=[O:23]
Reactant: CC(C)(CN1C[C@@H]2CNCCN2C1=O)C(=O)O
Reactant: COC(=O)CC(C)(C)N
Agent: Cl
Product: CC(C)(CC(=O)O)N1C[C@@H]2CNCCN2C1=O

Procedure:
The title compound was prepared in analogy to Compound Q in Example 19 by using methyl 3-amino-3-methyl-butanoate hydrochloride salt (Compound AP-1) instead of ethyl 3-amino-2,2-dimethyl-propanoate hydrochloride salt.
Reaction SMILES: FC1C=CC2N(C(CC3N(C)C=CN=3)=C(C3C=CC(F)=CC=3)N=2)C=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]=[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]3[C:40]=2[CH:41]=O)=[CH:28][CH:27]=1.[CH3:43][C:44]1[O:45][CH:46]=[N:47][N:48]=1>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[N:33]=[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]3[C:40]=2[CH2:41][C:46]2[O:45][C:44]([CH3:43])=[N:48][N:47]=2)=[CH:30][CH:31]=1
Reactant: Cc1nnco1
Reactant: O=Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: Cn1ccnc1Cc1c(-c2ccc(F)cc2)nc2ccc(F)cn12
Product: Cc1nnc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)o1

Procedure:
The title compound was prepared according to Method C and the experimentals described for compound 199 from 2-(4-chlorophenyl)imidazo[1,2-a]pyridine-3-carbaldehyde and 2-methyl-1,3,4-oxadiazole. M/e+ 325 for C17H14ClN4O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.22 (d, J=6.6 Hz, 1H), 7.80 (d, J=8.4 Hz, 2H), 7.67 (d, J=9.1 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.27 (t, J=6.9 Hz, 1H), 6.91 (d, J=6.6 Hz, 1H), 4.58 (s, 2H), 2.50 (s, 3H) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pt]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1cccc1-c1cccc([N+](=O)[O-])c1
Agent: [Pt]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC1c1cccc(N)c1
Reaction time: 96 h
Yield: 61.6 %

Procedure:
The product of Step 1 (7.5 g, 26.01 mmol), was dissolved in ethanol (125 ml), and treated with 5 wt % Platinum on charcoal (750 mg), and stirred under 1 atm of H2 for 4 days. The reaction was filtered and the filtrate evaporated in vacuo. The residue was purified by silica gel chromatography eluting with a mixture of ether/dichloromethane (5:95) to afford the title compound (4.2 g, 62%); MS (ES+) m/e 263 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+].I[CH2:39][CH2:40][CH2:41][N:42]1[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[NH:44][C:43]1=[O:51]>CN(C)C=O.C(OCC)(=O)C>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:39][CH2:40][CH2:41][N:42]3[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=4[NH:44][C:43]3=[O:51])[CH2:8][CH2:7]2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23]
Reactant: O=c1[nH]c2ccccc2n1CCCI
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)c1
Temperature: 55 °C
Reaction time: 5 h
Yield: 59.1 %

Procedure:
To a solution of tert-butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (1.2 g, 2.84 mmol) and potassium carbonate (0.59 g, 4.3 mmol) in N,N-dimethylformamide (20 mL), was added 1-(3-iodopropyl)-1,3-dihydro-2H-benzimidazol-2-one (0.86 g, 2.84 mmol). After stirring at 55° C. for 5 hours, the reaction mixture was diluted with ethyl acetate (100 mL), washed with water and brine. The organic phase was dried over MgSO4, filtered, concentrated and isolated by Biotage flash chromatography (2-10% methanol/dichloromethane) to obtain the title compound (1 g, 59%); 1H NMR (DMSO-d6): δ 1.51 (s, 9H), 1.60 (d, 2H, J=13.2 Hz), 1.82 (t, 2H, J=6.4 Hz), 2.35 (t, 2H, J=6.4 Hz), 2.53-2.60 (m, 4H), 2.65-2.71 (m, 4H), 3.85 (t, 2H, J=6.8 Hz), 4.56-4.60 (m, 2H), 6.76 (t, 1H, J=14.4 Hz), 6.85 (d, 2H, J=8 Hz), 6.95-6.97 (m, 3H), 7.17-7.24 (m, 3H), 7.48-7.54 (m, 2H), 7.78 (s, 1H), 7.82 (dt, 1H, J=7.2 and 1.6 Hz) 10.81 (s, 1H); MS for C35H41N5O4 m/z 596 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[OH:22].Cl[CH2:24][C:25]#[N:26]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:19])([F:20])[F:21])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[O:22][CH2:24][C:25]#[N:26]
Reactant: Oc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Reactant: N#CCCl
Product: N#CCOc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F

Procedure:
2-Fluoro-5-(7-trifluoromethyl[1,8]naphthyridin-4-yl)phenol (50.0 mg, 0.16 mmol) was alkylated with chloroacetonitrile (24.6 μL, 29.4 mg, 0.39 mmol) as described in Example 47, affording[2-fluoro-5-(7-trifluoromethyl[1,8]-naphthyridin-4-yl)phenoxy]acetonitrile (33.4 mg, 59%). δH (400 MHz, CDCl3) 4.94 (2H, s), 7.23-7.29 (2H, m), 7.40 (1H, dd, J 8.2 and 10.6), 7.56 (1H, d, J 4.3), 7.85 (1H, d, J 8.6), 8.53 (1H, d, J 8.6), 9.28 (1H, d, J 4.7). m/z (ES+) 348 [MH]+.
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:18][O:19][C:20]1([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1.CO.C([BH3-])#N.[Na+]>C(O)(=O)C.O1CCCC1>[CH2:14]([O:13][C:11](=[O:12])[C:10]1[CH:9]=[CH:8][C:7]([N:1]2[CH2:2][CH2:3][N:4]([CH:23]3[CH2:24][CH2:25][C:20]([O:19][CH3:18])([CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:21][CH2:22]3)[CH2:5][CH2:6]2)=[CH:17][CH:16]=1)[CH3:15]
Reactant: COC1(C2CCCCC2)CCC(=O)CC1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N2CCN(C3CCC(OC)(C4CCCCC4)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 42.9 %

Procedure:
To an ice cooled solution of ethyl 4-(piperazin-1-yl)benzoate (1.23 g) and 1-methoxy-1,1′-bicyclohexane-4-one (916 mg) in a mixed solvent of methanol (20 ml), tetrahydrofuran (15 ml) and acetic acid (0.74 ml) was added sodium cyanoborohydride (301 mg) in a stream of nitrogen. The mixture was stirred at this temperature for 1.5 hours and at room temperature for 7.5 hours. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate solution. Dichloromethane was added to the solution. The organic layer was taken, washed with sodium hydrogen carbonate solution and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (3:1 hexane-methanol elution) to give 4-[4-(1-methoxy-1,1′-bicyclohexan-4-yl)piperazinyl]benzoic acid ethyl ester (801 mg).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].C([N:24]([CH2:27][CH3:28])[CH2:25]C)C.CNC1CCN([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])CC1>>[C:40]([O:39][C:37]([CH:5]1[CH2:14][CH2:28][CH:27]([N:24]([CH3:25])[S:2]([C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9]4[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=4[C:7]=3[CH:6]=2)(=[O:4])=[O:3])[CH2:7][CH2:6]1)=[O:38])([CH3:41])([CH3:42])[CH3:43]
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Reactant: CCN(CC)CC
Product: CN(C1CCC(C(=O)OC(C)(C)C)CC1)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]cc(C(=O)O)c3c2c1

Procedure:
8-[(4-tert-Butoxycarbonyl-cyclohexyl)-methyl-sulfamoyl]-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid is prepared according to synthesis 178, from 653 mg (2 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid, 334 mL (2.4 mmol) of triethylamine and 557 mg (2.6 mmol) of 4-methylamino-1-tert-butoxycarbonyl-piperidine to give, after purification by precipitation and trituration in water, 770 mg (76%) of 8-[(4-tert-butoxycarbonyl-cyclohexyl)-methyl-sulfamoyl]-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid in the form of a beige solid.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]([CH2:29][O:30][C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])=[C:27]3[C:22]([NH:23][C:24]([CH3:42])([CH3:41])[C:25](=[O:40])[N:26]3[CH3:39])=[CH:21][CH:20]=2)=[C:15]([O:43][CH3:44])[CH:14]=1)=[O:11])=O)(C)(C)C.[ClH:45]>O1CCOCC1.CCCCCC>[ClH:45].[NH2:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]([CH2:29][O:30][C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[CH3:38])=[C:27]3[C:22]([NH:23][C:24]([CH3:42])([CH3:41])[C:25](=[O:40])[N:26]3[CH3:39])=[CH:21][CH:20]=2)=[C:15]([O:43][CH3:44])[CH:14]=1)=[O:11]
Reactant: COc1cc(NC(=O)CNC(=O)OC(C)(C)C)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCCC
Product: COc1cc(NC(=O)CN)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
7-(4-tert-Butoxycarbonylaminoacetylamino-2-methoxyphenyl)-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 15-31, 10.5 mg, 0.0173 mmol) was dissolved in 1,4-dioxane (0.2 mL), 4N 1,4-dioxane solution of hydrochloride (41.3 μL, 0.165 mmol) was added thereto. After the reaction mixture was stirred for 4 hours at room temperature, it was diluted with hexane (10 mL). The precipitated solid was filtered to give the titled compound (7.8 mg) as a pale yellow solid. (Yield 83%)
Reaction SMILES: [Cl:1][C:2]1[C:13]([CH:14]=O)=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH2:8][CH3:9])[C:6]#[N:7].[C:16]([O-:19])([O-])=O.[K+].[K+].O.[CH3:23]O>>[CH3:16][O:19][C:6](=[NH:7])[CH:5]([O:4][C:3]1[CH:10]=[CH:11][CH:12]=[C:13]([C:14]#[CH:23])[C:2]=1[Cl:1])[CH2:8][CH3:9]
Reactant: CCC(C#N)Oc1cccc(C=O)c1Cl
Reactant: CO
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C#Cc1cccc(OC(CC)C(=N)OC)c1Cl
Temperature: 0 °C
Reaction time: 48 h

Procedure:
Dimethyl-1-diazo-2-oxypropylphosphonate (0.48 g, 2.5 mmol) was added to a solution of 2-(2-chloro-3-formyl-phenoxy)-butyronitrile (0.4 g, 1.8 mmol) in MeOH (40 ml) at room temperature under argon. The solution was cooled to 0° C. and K2CO3 was added. After the addition stirring was continued for 48 h at room temperature. Reaction mixture was then poured into cold water (0° C.) and extracted twice with ethylacetate. The combined organic layers were dried with MgSO4 and evaporated. The crude product was chromatographed on silica with ethylacetate/cyclohexane to yield 2-(2-chloro-3-ethynyl-phenoxy)-butyrimidic acid methyl ester (0.32 g, light yellow oil); 1H-NMR (CDCl3) 1.05 t, 3H, 1.85-2.03 m, 2H, 3.39, s, 1H, 4.52 dd, 1H, 6.78 d, 1H, 7.12 t, 1H, 7.19 d, 1H, 7.72, br s, 1H.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[CH:38]=[N:39][C:40]([F:43])=[CH:41][CH:42]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.O1CCCC1>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:37]4[CH:38]=[N:39][C:40]([F:43])=[CH:41][CH:42]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(-c4ccc(F)nc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Cc1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(-c2ccc(F)nc2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 120.1 %

Procedure:
A solution of the above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene 57 (200 mg), 6-fluoropyridine-3-boronic acid 58 (117 mg), tri-tert-butylphosphine•tetrafluoroboric acid adduct (24 mg), potassium fluoride (80 mg) and tris(dibenzylideneacetone) dipalladium (0) (27 mg) in tetrahydrofuran (8 ml) was stirred at room temperature for 2 days under argon atmosphere. Added thereto was a saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10-70:30) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(6-fluoro-3-pyridyl)-2-thienylmethyl)-4-methylbenzene 59 (44 mg) as colorless crystals. APCI-Mass m/Z 631 (M+NH4). (3) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(6-fluoro-3-pyridyl)-2-thienylmethyl)-4-methylbenzene 59 (39 mg) was dissolved in 1,4-dioxane (4 ml)-tetrahydrofuran (4 ml), and added thereto was 2N sodium hydroxide (2 ml). The mixture was stirred at room temperature for one hour. The mixture was made acidic by addition of an aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure to give the desired 1-(β-D-glucopyranosyl)-3-(5-(6-fluoro-3-pyridyl)-2-thienylmethyl)-4-methylbenzene 60 (34 mg) as colorless powder. APCI-Mass m/Z 463 (M+NH4).
Reaction SMILES: CCN(CC)CC.I[CH2:9][CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[SH:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH2:32][CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[C:24]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)=[O:25])=[CH:19][CH:18]=1>CN(C=O)C>[O:36]1[CH2:37][CH2:38][CH:33]([CH2:32][CH:23]([C:20]2[CH:21]=[CH:22][C:17]([S:16][CH2:9][CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[CH:18][CH:19]=2)[C:24]([NH:26][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)=[O:25])[CH2:34][CH2:35]1
Reactant: ICC1CCOCC1
Reactant: O=C(Nc1nccs1)C(CC1CCOCC1)c1ccc(S)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1nccs1)C(CC1CCOCC1)c1ccc(SCC2CCOCC2)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of 2-(4-methoxymethylsulfanylphenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylpropionamide (EXAMPLE 77, 1.29 g, 3.28 mmol) in THF (50 mL) was added to a stirred solution of AgNO3 (0.59 g, 3.28 mmol) in EtOH (85 mL) at 40° C. The mixture was protected from light and stirred at 40° C. for 21 h. The solvents were evaporated off under reduced pressure, then the remaining solid was triturated with i-PrOH (60 mL), THF (60 mL), and Et2O (60 mL). After air-drying, the solid was stirred vigorously with CH2Cl2 (200 mL) and 6M HCl (82 mL) for 4 h under Ar. The layers were separated, then the aqueous phase was extracted with CH2Cl2 (2×100 mL). The combined organic extracts were filtered through Celite, washed with brine (100 mL) and dried (MgSO4). Filtration and solvent evaporation furnished 2-(4-mercaptophenyl)-3-(tetrahydropyran-4-yl)-N-thiazol-2-ylpropionamide: m/z (ES+)=349.2 [M+H]+. NEt3 (0.14 mL, 1006 μmol) and a solution of 4-iodomethyltetrahydropyran (151 mg, 668 μmol) in anhydrous DMF (3 mL) were added to a stirred solution of this benzenethiol (197 mg, 565 μmol) in anhydrous DMF (7 mL) at 0° C. The mixture was warmed to 20° C., before being stirred for 16 h. The solvents were evaporated off under reduced pressure, then the residue was partitioned between CH2Cl2 (25 mL) and 2% aqueous citric acid (10 mL). The aqueous layer was extracted with CH2Cl2 (10 mL), then the combined organic layers were washed with H2O (10 mL), saturated aqueous Na2CO3 (10 mL), H2O (10 mL), and brine (10 mL). After drying (MgSO4), filtration and solvent evaporation gave a residue that was subjected to flash chromatography (IH-EtOAc, 3:1 to 0:1) to furnish the title compound: RTA=3.61 min; m/z (ES+)=447.3 [M+H]+.
Reaction SMILES: CCCCCCCCCCCCCCC.[C:16]([OH:20])([CH3:19])([CH3:18])[CH3:17].[C:21]([N:24]1[CH2:28][CH2:27][CH:26]=[CH:25]1)(=[O:23])[CH3:22].[O:29]1CCC[CH2:30]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:16]([O:20][C:30](=[O:29])[C@@H:25]1[CH2:26][CH2:27][CH2:28][N:24]1[C:21](=[O:23])[CH3:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(=O)N1C=CCC1
Reactant: CC(C)(C)O
Reactant: C1CCOC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCCCCCCCCCCCC
Product: CC(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 21 h
Yield: 1 %

Procedure:
A 70 mL stainless steel high pressure reactor having a Pyrex glass liner and a magnetic stir bar was charged with 5 mL of tetrahydrofuran, 0.5 mol of n-pentadecane internal standard, 0.5 mmol of tert-butyl alcohol, 40 mg of (PPh3)2PdCl2, and 55.5 mg of N-acetyl-2-pyrroline. The reactor was pressurized to 1000 psi with Co at room temperature, and the reaction mixture was stirred at 100° C. for 21 hours. Thereafter, the reactor was cooled to room temperature and vented to atmospheric pressure. The product mixture was analyzed by gas chromatography and mass spectrometry, and the analysis indicated 98.6% conversion of N-acetyl-2-pyrroline and 1.0% yield of N-acetylproline tert-butyl ester.
Reaction SMILES: Cl[C:2]1[C:3]([CH:15]2[CH2:17][CH2:16]2)=[C:4]([CH:12]2[CH2:14][CH2:13]2)[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.[O-:18][CH2:19][CH3:20].[Na+].O>C(O)C>[CH:15]1([C:3]2[C:2]([O:18][CH2:19][CH3:20])=[N:7][N:6]3[C:8]([NH2:11])=[N:9][N:10]=[C:5]3[C:4]=2[CH:12]2[CH2:14][CH2:13]2)[CH2:17][CH2:16]1
Reactant: CC[O-]
Reactant: Nc1nnc2c(C3CC3)c(C3CC3)c(Cl)nn12
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1nn2c(N)nnc2c(C2CC2)c1C1CC1
Reaction time: 1 h
Yield: 96.3 %

Procedure:
6-Chloro-7,8-dicyclopropyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.016, 0.1 g) was dissolved in ethanol (20 ml) while stirring and under argon. Thereafter, the reaction mixture was admixed with sodium ethoxide (110 mg) and stirred at RT for 1 h, then at 55° C. for 1 h. Subsequently, the mixture was left to stand overnight and then heated to reflux for 7.5 h. After standing over the weekend, the solvent was drawn off, and the residue was admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 100 mg of the title compound were obtained.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([NH:18][C:19](=O)[C@H:20]([OH:22])[CH3:21])=[CH:16][N:15]=[C:14]3[CH:24]=[CH:25][S:26][C:13]=23)[CH2:7][CH2:6]1)#[N:2]>C(O)(=O)C>[OH:22][C@@H:20]([C:19]1[N:11]([C@H:8]2[CH2:9][CH2:10][C@H:5]([CH2:4][CH2:3][C:1]#[N:2])[CH2:6][CH2:7]2)[C:12]2=[C:13]3[S:26][CH:25]=[CH:24][C:14]3=[N:15][CH:16]=[C:17]2[N:18]=1)[CH3:21]
Reactant: C[C@@H](O)C(=O)Nc1cnc2ccsc2c1N[C@H]1CC[C@H](CCC#N)CC1
Solvent: CC(=O)O
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CCC#N)CC1

Procedure:
To a mixture of 3-{trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}propanenitrile (0.048 g, 0.16 mmol) and (R)-2-hydroxypropanoic acid (0.019 g, 0.21 mmol) in methylene chloride (0.96 mL) was added N,N-diisopropylethylamine (60 μL, 0.35 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (66 mg, 0.17 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was washed with water. The organic layers were concentrated and purified on silica gel (eluting with 0 to 10% MeOH in dichloromethane) to give (2R)—N-(7-{[trans-4-(2-Cyanoethyl)cyclohexyl]amino}thieno[3,2-b]pyridin-6-yl)-2-hydroxypropanamide. LCMS calculated for C19H25N4O2S (M+H)+: m/z=373.2. Found: 373.0. A solution of the amide intermediate in acetic acid (0.3 mL) was stirred at 105° C. for 5 h. The solvent in the reaction mixture was removed in vacuo, diluted with MeOH and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (6 mg, 10%). LCMS calculated for C19H23N4OS (M+H)+: m/z=355.2. Found: 355.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[CH:21])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:23]1[CH:24]=[CH:25][C:26]([O:38][CH3:39])=[C:27]([S:29]([NH:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])(=[O:31])=[O:30])[CH:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]#[C:21][C:23]4[CH:24]=[CH:25][C:26]([O:38][CH3:39])=[C:27]([S:29]([NH:32][C:33]([CH3:36])([CH3:37])[CH2:34][OH:35])(=[O:31])=[O:30])[CH:28]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Reactant: COc1ccc(Br)cc1S(=O)(=O)NC(C)(C)CO
Product: COc1ccc(C#Cc2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)cc1S(=O)(=O)NC(C)(C)CO

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-3-ethynyl-pyrazolo[1,5-a]pyrimidine (example C.5) (73 mg, 0.25 mmol) and 5-bromo-N-(2-hydroxy-1,1-dimethyl-ethyl)-2-methoxy-benzenesulfonamide (85 mg, 0.25 mmol) (Example B.7) according to general procedure II. Obtained as a yellow solid (38 mg, 28%). MS (ISP) 551.3[(M+H)+]; mp 253-256° C.
Reaction SMILES: [CH2:1]([C:4]([OH:6])=[O:5])[CH2:2][SH:3].[C:7]1([C:13](Cl)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[C:13]([S:3][CH2:2][CH2:1][C:4]([OH:6])=[O:5])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(O)CCS
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: O=C(O)CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 95.7 %

Procedure:
Mercaptopropionic acid 2 (3.14 g) was dissolved in 50 ml of methylene chloride. Triphenylmethylchloride 3 (8.36 g, 30 mmol) was added to that, and 19-hour protection reactions were carried out at room temperature. The precipitate generated through the protection reactions was filtered and gathered, and was rinsed with 40 ml of diethyl ether. The precipitate was then dried under reduced pressure, to form 9.86 g of 3-(tritylthio)propanoic acid 4, which is a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18](O)=[O:19])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.S(Cl)(Cl)=O.[CH3:25][NH:26][CH:27]([CH2:29][CH3:30])[CH3:28]>>[CH3:25][N:26]([CH:27]([CH3:28])[CH2:29][CH3:30])[C:18]([C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:17]=1)=[O:19]
Reactant: O=C(O)c1cc(-c2ccccc2Cl)nc2ccccc12
Reactant: CCC(C)NC
Solvent: O=S(Cl)Cl
Product: CCC(C)N(C)C(=O)c1cc(-c2ccccc2Cl)nc2ccccc12

Procedure:
The procedure of Example 3 is followed using 2-(2-chlorophenyl)-quinoline-4-carboxylic acid (5.7 g), thionyl chloride (15 ml) and N-methylbut-2-ylamine (15 ml) as the starting materials.