Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C(OC(C)(C)C)=O)[CH:6]=[C:5]2[C:18]1[CH:19]=[N:20][C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2.[Cl-].[Li+].C([Sn](CCCC)(CCCC)[C:35]1[S:39][C:38]([NH:40]C(=O)OC(C)(C)C)=[N:37][CH:36]=1)CCC>CN(C=O)C.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>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[C:18]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:35]4[S:39][C:38]([NH2:40])=[N:37][CH:36]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH:19]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(NC(=O)OC(C)(C)C)s1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cnc3ccccc3c2)c2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccc3[nH]cc(-c4cnc5ccccc5c4)c3c2)s1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 5-bromo-3-(quinolin-3-yl)-1H-indole-1-carboxylate (104 mg, 0.246 mmol), Pd(PPh3)4 (14 mg, 0.012 mmol), Lithium chloride (83 mg, 1.965 mmol) and DMF (2.0 ml, 0.246 mmol) in a microwave reaction vessel was sealed and heated at 100° C. for 5 min. A solution of tert-butyl 5-(tributylstannyl)thiazol-2-ylcarbamate (240 mg, 0.491 mmol) in DMF (1.0 mL) was then added and the reaction was heated at 100° C. for additional 17 h. The mixture was filtered through a pad of Celite and the filtrate was evaporated to dryness. The above crude product was dissolved in DCM (0.5 mL) followed by the addition of TFA (0.5 mL). The reaction was stirred at RT for 1 h then evaporated in vacuo to dryness. The residue was purified by silica gel chromatography to 5-(3-(quinolin-3-yl)-1H-indol-5-yl)thiazol-2-amine (6.7 mg, 8.0%) as a yellow solid. MS (ESI, pos. ion) m/z: 343 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 6.98 (s, 2H), 7.32 (d, J=9.0 Hz, 1H), 7.38 (s, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.62 (t, J=7.5 Hz, 1H), 7.70 (t, J=7.3 Hz, 1H), 7.98 (s, 1H), 8.00-8.05 (m, 2H), 8.10 (d, J=8.0 Hz, 1H), 8.62 (s, 1H), 9.29 (d, J=2.0 Hz, 1H), 11.65 (s, 1H).
Reaction SMILES: [OH-].[Na+].[C:3]([CH2:5][C:6]([OH:8])=[O:7])#[N:4].[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[OH:18])[CH:13]=O.Cl>>[C:3]([C:5](=[CH:13][C:12]1[CH:15]=[CH:16][C:17]([OH:18])=[C:10]([OH:9])[CH:11]=1)[C:6]([OH:8])=[O:7])#[N:4]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: N#CCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#CC(=Cc1ccc(O)c(O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2N aqueous sodium hydroxide solution (175 ml, 350 mmol) heated at 60° C. were added cyanoacetic acid (7.2 g, 86.7 mmol) and 3, 4-dihydroxybenzaldehyde (12.0 g, 86.9 mmol), and the resulting mixture was stirred for 30 minutes. The reaction mixture was allowed to cool at room temperature and gradually mixed with dilute hydrochloric acid until the reaction mixture became acidic. The product was filtered and dried to give α-cyano-3, 4-dihydroxycinnamic acid (hereinafter referred to as "Compound A" (10.0 g, 56% in yield).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([C:17](=[O:19])[CH3:18])[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][C:21]([CH:23]([O:26][CH3:27])[O:24][CH3:25])=O.N1CCCC1>C1(C)C=CC=CC=1>[CH3:25][O:24][CH:23]([O:26][CH3:27])[C:21]1([CH3:20])[CH2:18][C:17](=[O:19])[C:12]2[CH:11]=[C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[CH:15]=[CH:14][C:13]=2[O:16]1
Reactant: COC(OC)C(C)=O
Reactant: CC(=O)c1cc(S(=O)(=O)c2ccccc2)ccc1O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: COC(OC)C1(C)CC(=O)c2cc(S(=O)(=O)c3ccccc3)ccc2O1

Procedure:
In 100 ml of toluene were dissolved 10 g of the compound obtained in step 4, 6.5 ml of pyruvic aldehyde dimethyl acetal and 1.5 ml of pyrrolidine. The resultant solution was heated to reflux for 16 hours and concentrated reduced pressure to obtain residue, which was purified by silica gel column chormatography using as an eluent a mixture of hexane and ethyl acetate (2:1) to obtain 11 g of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CN.O.[N:16]1(O)[C:20]2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:20][NH:16][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)=[O:12]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
In 5 mL of N,N-dimethylformamide, 500 mg (3.1 mmol) of 1H-indole-5-carboxylic acid, 750 mg (9.3 mmol) of 40% methylamine, 477 mg (3.1 mmol) of benzotriazole-1-ol hydrate and 713 mg (3.8 mmol) of (3-dimethylaminopropyl)ethylcarbodiimide hydrochloride were dissolved and the solution was stirred at room temperature for three hours, and then the solvent was distilled under reduced pressure. The obtained residue was dissolved in ethyl acetate and washed with a saturated sodium hydrogencarbonate solution (50 mL, twice) and a saturated saline (50 mL) in the order named. The organic layer was dried and then concentrated to obtain 397 mg (73%) of a crude product of 1H-indole-5-carboxylic acid methylamide. The product was used in the next reaction without further purification.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:11][C:12]([OH:14])=[O:13].O>O1CCCC1>[CH:3]1([O:9][CH2:11][C:12]([OH:14])=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: OC1CCCCC1
Reactant: O=C(O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COC1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
To a suspension of 60% sodium hydride (8.79 g) in tetrahydrofuran (500 mL) was added cyclohexanol (10 g) and the mixture was stirred at 0° C. for 0.5 hour. To the mixture was added bromoacetic acid (13.9 g) under ice-water cooling and the mixture was heated under reflux for 2 hours. After adding water to the mixture and organic solvent was evaporated in vacuo. The aqueous solution was diluted with water, washed with ether, acidified with 1 N hydrochloric acid, and extracted with ether. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo to give (cyclohexyloxy)acetic acid as colorless oil (13.3 g).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([CH:12]=1)[C:7]([N:9]([CH3:11])[CH3:10])=[O:8].[Br-].[CH2:17]([O:19][C:20](=[O:24])[CH2:21][CH2:22][Zn+])[CH3:18]>O1CCCC1.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>[CH2:17]([O:19][C:20](=[O:24])[CH2:21][CH2:22][C:2]1[CH:3]=[CH:4][C:5]([N+:13]([O-:15])=[O:14])=[C:6]([C:7](=[O:8])[N:9]([CH3:11])[CH3:10])[CH:12]=1)[CH3:18]
Reactant: CCOC(=O)CC[Zn+]
Reactant: CN(C)C(=O)c1cc(I)ccc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc([N+](=O)[O-])c(C(=O)N(C)C)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5-Iodo-N,N-dimethyl-2-nitrobenzamide (2.00 g) was dissolved in tetrahydrofuran (20 mL) and bis(triphenylphosphine)palladium(II) dichloride (0.128 g) was added thereto. After cooling down to 0° C., 0.5M 3-ethoxy-3-oxopropylzinc bromide solution (22.5 mL) was added dropwise thereto, the mixture was stirred at room temperature overnight. The reaction solution was concentrated, dissolved in ethyl acetate (100 mL), washed successively with 1N hydrochloric acid (30 mL) and saturated brine (30 mL), and dried over sodium sulfate. Further, the mixture was purified by column chromatography on silica gel (ethyl acetate:hexane=3:2, v/v) to give the title compound (1.52 g) as a brown oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[S:6][CH:7]=[C:8]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[N:9]=2)[CH2:3][CH2:2]1.[C:19]1([CH2:25][C:26](O)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>CN(C=O)C.C1COCC1>[CH:1]1([N:4]([C:5]2[S:6][CH:7]=[C:8]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[N:9]=2)[C:26](=[O:27])[CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:3][CH2:2]1
Reactant: c1cnc2[nH]cc(-c3csc(NC4CC4)n3)c2c1
Reactant: O=C(O)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cc1ccccc1)N(c1nc(-c2c[nH]c3ncccc23)cs1)C1CC1
Temperature: 180 °C
Yield: 12.3 %

Procedure:
Cyclopropyl-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-yl]-amine (50 mg, 0.39 mmol), phenylacetic acid (63 mg, 0.47 mmol) and N-(1-methanesulfonyl)benzotriazole (93 mg, 0.47 mmol) were placed in a microwave reaction vessel (Personal Chemistry, Uppsala, Sweden). 5% DMF-THF (4 mL) was added followed by triethylamine (0.163 mL, 1.17 mmol) and the mixture heated in the sealed tube at 180° C. for 15 minutes. Upon cooling to room temperature the reaction was concentrated and then purified by prepartative TLC (thin layer chromatography) and eluted with ethylacetate and hexane (3:1). Extraction of the silica gel with 5% MeOH-EtOAc was carried out to give product (15 mg, 10%). Alternatively, Cyclopropyl-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-yl]-amine (50 mg, 0.39 mmol), phenylacetic acid (63 mg, 0.47 mmol) and fluoro-N,N′,N′,N′-tetramethylformamidiniun hexafluorophosphate (148 mg, 0.59 mmol) were placed in a microwave reaction vessel (Personal Chemistry, Uppsala, Sweden). 5% DMF-THF (4 mL) was added followed by triethylamine (0.163 mL, 1.17 mmol) and the mixture heated in the sealed tube at 180° C. for 15 minutes. Upon cooling to room temperature the reaction was concentrated and then purified by prepartative TLC (thin layer chromatography) and eluted with ethylacetate and hexane (3:1). Extraction of the silica gel with 5% MeOH-EtOAc was carried out to give product (18 mg, 12%). The material was isolated as an HCl salt. LC/MS MH+ =375.2, LC/MS RT: 3.39 min. 1H NMR (500 MHz, DMSO-d6, ppm) 11.92 (s,1H), 8.63 (d,1H, J=7.88 Hz), 8.29 (dd,1H, J=4.71, 1.49 Hz), 8.96 (d,J=2.58,1H), 7.44 (s,1H), 7.36-7.19 (m,6H), 4.27 (s,2H), 3.29 (t, 1H,J=3.78), 1.33 (m,2H), 1.06 (m,2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].[C:15](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.C(OC(=O)C1C=C(OCCOC)C(OCCOC)=CC=1N)C>[CH3:15][O:9][C:8](=[O:10])[C:7]1[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[N+:12]([O-:14])=[O:13]
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: O=C([O-])[O-]
Agent: CCOC(=O)c1cc(OCCOC)c(OCCOC)cc1N
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)ccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
5-Methoxy-2-nitro-benzoic acid (2.5 g) was dissolved in N,N-dimethylformamide (compound A′) (40 ml). Potassium carbonate (4.5 g) and methyl iodide (2.5 ml) were added to the solution at room temperature, and the mixture was then stirred at that temperature for 30 min. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was then subjected to separatory extraction with ethyl acetate. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a hexane-acetone system to give 5-methoxy-2-nitrobenzoic acid methyl ester (2.7 g, yield 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:17][CH2:16][C@@H:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH:13]=2)=[CH:8][CH:7]=1)[CH3:2].C[Si](C)(C)N[Si](C)(C)C.[Li].[C:33]([O:37][C:38](=[O:47])[C:39]1[CH:44]=[CH:43][C:42]([CH2:45]Br)=[CH:41][CH:40]=1)([CH3:36])([CH3:35])[CH3:34]>C1COCC1>[C:33]([O:37][C:38](=[O:47])[C:39]1[CH:40]=[CH:41][C:42]([CH2:45][CH:5]([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[CH2:17][CH2:16][C@@H:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH:13]=3)=[CH:10][CH:11]=2)[C:4]([O:3][CH2:1][CH3:2])=[O:22])=[CH:43][CH:44]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Reactant: CCOC(=O)Cc1ccc(C2=CC[C@H](C(C)(C)C)CC2)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(C(=O)OC(C)(C)C)cc1)c1ccc(C2=CC[C@H](C(C)(C)C)CC2)cc1
Temperature: 25 °C
Yield: 40.1 %

Procedure:
To [4-((R)-4-tert-Butyl-cyclohex-1-enyl)-phenyl]-acetic acid ethyl ester (95 mg. 0.32 mmol) in anhydrous THF (5 mL), chilled to −78° C. was added 380 uL (0.38 mmol) of 1M lithium hexamethyldisilazane in THF. The resulting solution was stirred for 1 hr before 4-Bromomethylbenzoic acid tert-butyl ester (94 mg, 0.35 mmol) was added. The reaction mixture was allowed to warm to rt overnight then quenched with saturated NH4Cl solution. After partitioning between ethyl acetate and brine the organic portion was dried over Na2SO4 and concentrated under reduced pressure. Purification of the crude by prep TLC (Analtech, 2 mm silica plates) using an hexane/ethyl acetate (10:1) gave 63 mg of product. 1H NMR (500 MHz, CDCl3): 7.83 (d, J=8.5 Hz, 2 H), 7.31 (d, J=8.5 Hz, 2 H), 7.20 (d, J=8 Hz, 2 H), 7.14 (d, J=8 Hz, 2 H), 6.12 (m, 1H), 4.03 (q, J=7 Hz 2 H), 3.80 (t, J=8.5 Hz, 1H), 3.41 (dd, =14, 8.5 Hz, 1 H), 3.03 (dd, J=14, 7 Hz, 1 H), 2.56-2.4 (m, 2H), 2.35-2.2 (m, 1H). 2.05-1.9 (m, 2H), 1.56 (s, 9 H), 1.36-1.2 (m, 2 H), 1.11 (t, J=7 Hz, 3 H), 0.89 (s, 9H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[C:4]#[N:5].C(=O)(O)O.[NH2:15][C:16]([NH2:18])=[NH:17]>CC(N(C)C)=O>[I:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]2[C:3]=1[C:4]([NH2:5])=[N:17][C:16]([NH2:18])=[N:15]2
Reactant: N#Cc1c(F)cccc1I
Reactant: N=C(N)N
Agent: O=C(O)O
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2c(I)cccc2n1
Temperature: 165 °C
Yield: 19.5 %

Procedure:
2-Fluoro-6-iodobenzonitrile (700 mg; 2.83 mmol) is dissolved in dimethylacetamide (5 mL) with guanidine carbonate (766 mg; 4.25 mmol). The vessel is purged with N2, sealed, and heated to 165° C. for 5 hours. After cooling to room temperature, the reaction mixture is placed in the freezer overnight. The precipitate which has formed is removed by filtration and purified by recrystallization from 50% EtOH/water. The resulting solids are filtered and dried at room temperature to yield 158 mg of 5-iodoquinazoline-2,4-diamine.
Reaction SMILES: COC1C=CC(C(Cl)=O)=CC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.[CH3:34][O:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([N:44]=[C:45]=[S:46])=[O:43])=[CH:38][CH:37]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:34][O:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]([N:44]=[C:45]=[S:46])=[O:43])=[CH:40][CH:41]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31][C:45]([NH:44][C:42](=[O:43])[C:39]2[CH:40]=[CH:41][C:36]([O:35][CH3:34])=[CH:37][CH:38]=2)=[S:46])=[CH:29][CH:28]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: COc1ccc(C(=O)Cl)cc1
Agent: COc1ccc(C(=O)N=C=S)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ncnc4cc(OC)c(OC)cc34)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
4-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-methoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (71 mg, yield 86%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.CN.C[CH2:20][N:21](C(C)C)C(C)C>Cl.CCCCO>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:21][CH3:20])[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(Nc2cc(Cl)ncn2)cc1
Agent: CN
Agent: Cl
Solvent: CCCCO
Product: CNc1cc(Nc2ccc(OC)cc2)ncn1
Temperature: 120 °C
Yield: 91 %

Procedure:
100 mg of 6-chloro-N-(4-methoxyphenyl)pyrimidine-4-amine in the form of a hydrochloride, 57 mg of methylamine and 238 mg of DIPEA were dissolved in 1 mL of n-BuOH in a screw cap vial and the mixture obtained was heated to 120° C. for 1 hour. Progress of the reaction was monitored by TLC. Upon termination of the reaction n-BuOH. was evaporated off and the evaporation residue was subjected to crystallization from n-BuOH/EtOH solvent mixture. N4-(4-Methoxyphenyl)-N6-methylpyrimidine-4,6-diamine was obtained in the form of a light yellow solid.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:29]([NH:31][C@H:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:30])[NH:16][C:17]([C:19]1[N:20]([CH3:28])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=O)C1C=CC=CC=1.CO.[ClH:46]>[C].[Pd].C1COCC1>[ClH:46].[CH3:28][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[C:19]1[C:17]([NH:16][C@H:15]([C:29]([NH:31][C@H:32]1[CH2:36][CH2:35][CH2:34][C@H:33]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:30])[CH2:14][CH2:13][CH2:12][NH2:11])=[O:18]
Reactant: Cn1c(C(=O)N[C@@H](CCCNC(=O)OCc2ccccc2)C(=O)N[C@H]2CCC[C@H]2C(=O)OC(C)(C)C)cc2ccccc21
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cn1c(C(=O)N[C@@H](CCCN)C(=O)N[C@H]2CCC[C@H]2C(=O)OC(C)(C)C)cc2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of tert-butyl (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-[(1-methyl-1H-indol-2-yl)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylate (3.0 g), methanol (50 ml), and THF (50 ml) were added 1 M hydrochloric acid (5.1 ml) and palladium-carbon (5.4 g) under ice-cooling, followed by stirring at room temperature for 3 hours under a hydrogen atmosphere. The insolubles of the reaction mixture were separated by filtration through Celite and the filtrate was concentrated under reduced pressure to obtain tert-butyl (1R,2S)-2-({N2-[(1-methyl-1H-indol-2-yl)carbonyl]-L-ornithyl}amino)cyclopentanecarboxylate hydrochloride (2.6 g).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]2[C:14]([Cl:20])=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.CC(C[AlH]CC(C)C)C>CCOCC>[Cl:20][C:14]1[C:13]([S:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][OH:2])=[CH:5][CH:6]=2)(=[O:11])=[O:12])=[CH:18][CH:17]=[C:16]([CH3:19])[N:15]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)c2ccc(C)nc2Cl)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)c2ccc(CO)cc2)c(Cl)n1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
4-(2-Chloro-6-methylpyridine-3-sulfonyl)-benzoic acid methyl ester, synthesized following the procedure of Example 9 parts A–D in 39% overall yield, (1.29 g, 3.96 mmol) was dissolved in 25 mL of dry ether and cooled to −78° C. To that a 1 M solution of DIBAL-H in hexanes (8.71 mL, 8.71 mmol) was added and the reaction mixture was allowed to warm to 25° C. and stirred for 4 h. The reaction was quenched with water followed by 1 N HCl (40 mL), stirred for 15 min, neutralized with 50% NaOH and extracted with ether and the ether extracts were combined, washed with brine, dried and stripped in vacuo to give 1.15 g of [4-(2-chloro-6-methylpyridine-3-sulfonyl)-phenyl]-methanol.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:15]([C:17]1[N:22]=[C:21]([CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:20]=[CH:19][CH:18]=1)#[N:16]>N1C=CC=CC=1>[O:6]=[C:4]1[C:3]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:2]=2[S:1][C:15]([C:17]2[N:22]=[C:21]([CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:20]=[CH:19][CH:18]=2)=[N:16]1
Reactant: CC(C)(C)OC(=O)CCc1cccc(C#N)n1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1S
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CCc1cccc(-c2nc(=O)c3ccc(C(F)(F)F)cc3s2)n1
Yield: 34.2 %

Procedure:
2-Mercapto-4-trifluoromethylbenzoic acid (1.59 g, 7.2 mmol) and tert-butyl 3-(6-cyano-2-pyridyl)propanoate (1.32 g, 5.7 mmol) were dissolved in pyridine (15 ml), and the mixture was refluxed for 15 hrs. The reaction mixture was concentrated under reduced pressure, subjected to a silica gel column chromatography, eluted with hexane-ethyl acetate (3:1, v/v) and recrystallized from ethyl acetate-hexane to give the titled compound (0.85 g, 34%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C@H:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[S:5][CH:6]=1.C(N1CCC[C@H]1C(O)=O)(OCC1C=CC=CC=1)=O>>[CH3:1][C:2]1[N:3]=[C:4]([C@@H:7]2[CH2:11][CH2:10][CH2:9][NH:8]2)[S:5][CH:6]=1
Reactant: Cc1csc([C@H]2CCCN2)n1
Agent: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Product: Cc1csc([C@@H]2CCCN2)n1

Procedure:
(S)-4-methyl-2-(pyrrolidin-2-yl)thiazole was prepared following the same procedure as in the preparation of (R)-4-methyl-2-(pyrrolidin-2-yl)thiazole starting from the commercially available Cbz-L-proline (Aldrich).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH2:17])[N:8]=1.[CH3:21][N:22]=[C:23]=[S:24]>C(#N)C>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9]([S:13][CH2:14][CH2:15][CH2:16][NH:17][C:23]([NH:22][CH3:21])=[S:24])[N:8]=1
Reactant: CN=C=S
Reactant: NCCCSc1cncc(NC(N)=NCC(F)(F)F)n1
Solvent: CC#N
Product: CNC(=S)NCCCSc1cncc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-[2-(2,2,2-trifluoroethyl)guanidino]-6-(3-aminopropylthio)pyrazine in warm acetonitrile (15 ml.) was allowed to cool to room temperature. A solution of methylisothiocyanate (0.15 g.) in acetonitrile (1 ml.) was added and the mixture stirred overnight. Evaporation to dryness gave a yellow solid which was recrystallised from a small volume of ethyl acetate to yield 2-[2-(2,2,2-trifluoroethyl)guanidino]-6-[3-(3-methylthioureido)propylthio]pyrazine (0.32 g.), m.p. 165°-167°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[N:5]=[C:4]([C:19]2[S:23][C:22]([C:24]([CH:27]3[CH2:31][CH2:30][NH:29][CH2:28]3)([OH:26])[CH3:25])=[N:21][CH:20]=2)[CH:3]=1.[O-:32][C:33]#[N:34].[K+].O.Cl>O1CCCC1>[OH:26][C:24]([CH:27]1[CH2:31][CH2:30][N:29]([C:33]([NH2:34])=[O:32])[CH2:28]1)([C:22]1[S:23][C:19]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:12]=[CH:11][N:10]=3)[N:5]=2)=[CH:20][N:21]=1)[CH3:25]
Reactant: N#C[O-]
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnc(C(C)(O)C3CCNC3)s2)c1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2cnc(C(C)(O)C3CCN(C(N)=O)C3)s2)c1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
To the solution of 1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]-1-(pyrrolidin-3-yl)ethanol (20 mg, 0.044 mmol, 1:1 mix of diastereomers) in tetrahydrofuran (0.4 mL) was added potassium cyanate (25 mg, 0.308 mmol), water (1.2 mL) and HCl (2 M in water, 0.14 mL, 0.280 mmol). The mixture was stirred at 55° C. for 3 hours then cooled to room temperature. The mixture was purified on reversed phase HPLC (Sunfire prep C18 OBD 5 uM, acetonitrile/water+0.1% TFA) to afford 3-{1-hydroxy-1-[5-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}pyridin-2-yl)-1,3-thiazol-2-yl]ethyl}pyrrolidine-1-carboxamide as a 1:1 mixture of diastereomers. MS ESI calc'd. for C22H23F3N6O2S [M+H]+ 493. found 493. 1H NMR (500 MHz, CD3OD) δ 8.65-8.60 (m, 1H, two sets of doublets overlap from two diastereomers), 8.39 (d, 1H, two singlets from two diastereomers), 7.86 (s, 1H), 7.51 (d, 1H, two singlets from two diastereomers), 7.46-7.42 (m, 1H, two sets of doublets overlap from two diastereomers), 7.05 (s, 1H), 3.65-2.82 (m, 5H, two sets of peaks from two diastereomers), 2.50 (s, 3H), 2.20-2.00 (m, 2H), 1.69 (s, 3H). rhSyk activity=+++.