Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31]>C1COCC1>[N:23]1([CH2:22][CH2:21][NH:20][S:17]([C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:29](=[O:32])[CH:30]=[CH2:31])=[CH:16][CH:15]=2)(=[O:19])=[O:18])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: C=CC(=O)Cl
Reactant: Nc1ccc(S(=O)(=O)NCCN2CCOCC2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccc(S(=O)(=O)NCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.1 %

Procedure:
Diisopropylethylamine (0.09 ml, 0.5 mmol) was added in one portion to a stirred solution of 4-amino-N-(2-morpholin-4-yl-ethyl)-benzenesulfonamide (0.1 g, 0.35 mmol) in THF (3 ml) at room temperature. To this mixture was added acryloyl chloride (0.03 ml, 0.38 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time, the mixture was concentrated under vacuum and the resulting residue purified by Prep HPLC to give the title compound (6 mg, 5% yield) as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([NH2:12])=[O:11])=[N:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CC#N>[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:2]=1)(=[O:11])[NH2:12]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NC(=O)c1n[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Cn1nc(C(N)=O)c2ccccc21
Temperature: 25 °C

Procedure:
To a suspension of 1H-indazole-3-carboxamide [90004-04-9] (2.00 g, 12.4 mmol) and potassium carbonate (4.12 g, 29.8 mmol) in CH3CN (60 mL) was added tert-butyl bromoacetate (2.20 mL, 14.9 mmol) dropwise at RT, and the resulting mixture was heated to reflux for 16 h. The mixture was then cooled to RT and filtered, the solid was washed with CH3CN and the filtrate was concentrated under vacuum. The residual oil was used directly in the next reaction step without further purification. MS (LC/MS): 276.0 [M+H]+; tR (HPLC conditions k): 3.22 min.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=1)#[N:2].[F:18][C:19]1[CH:20]=[C:21]([SH:28])[C:22](=[CH:26][CH:27]=1)[C:23](O)=[O:24]>N1C=CC=CC=1>[F:18][C:19]1[CH:27]=[CH:26][C:22]2[C:23](=[O:24])[N:2]=[C:1]([C:3]3[N:8]=[C:7]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=3)[S:28][C:21]=2[CH:20]=1
Reactant: O=C(O)c1ccc(F)cc1S
Reactant: CC(C)(C)OC(=O)CCc1cccc(C#N)n1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CCc1cccc(-c2nc(=O)c3ccc(F)cc3s2)n1
Yield: 54.1 %

Procedure:
tert-Butyl 3-(6-cyano-2-pyridyl)propanoate (1.5 g, 6.5 mmol) and 4-fluorothiosalicylic acid (1.7 g, 9.7 mmol) were dissolved in pyridine (10 ml), and the mixture was refluxed for 15 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected, concentrated and recrystallized from hexane-ethyl acetate to give the titled compound (1.36 g, 54%) as white crystals.
Reaction SMILES: Cl[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([NH2:15])=[O:14])=[CH:12][C:7]=2[S:6][C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1.C1(C)C=CC=CC=1.[N:27]1([CH2:33][CH2:34][O:35][CH2:36][CH2:37][OH:38])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CN(C=O)C>[OH:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][N:27]1[CH2:32][CH2:31][N:30]([C:2]2[C:8]3[CH:9]=[CH:10][C:11]([C:13]([NH2:15])=[O:14])=[CH:12][C:7]=3[S:6][C:5]3[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=3[N:3]=2)[CH2:29][CH2:28]1
Reactant: NC(=O)c1ccc2c(c1)Sc1ccccc1N=C2Cl
Reactant: OCCOCCN1CCNCC1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc2c(c1)Sc1ccccc1N=C2N1CCN(CCOCCO)CC1
Temperature: 110 °C

Procedure:
To a solution of 11-chloro-dibenzo[b,f][1,4]thiazepine-3-carboxylic acid amide, prepared as described in the previous step, (0.40 g) in DMF (1.5 mL) and toluene (1.5 mL) was added 2-(2-piperazin-1-yl-ethoxy)-ethanol (0.50 g, 2.9 mmol). The solution was heated in a 110° C. oil bath under nitrogen for 5 hours, concentrated, and purified (silica gel, 2-5% methanol-dichloromethane containing ammonia eluent) to give the title compound as an off white solid. LC-MS: m/z 427 (M+1).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[F:8][C:9]([F:42])([F:41])[C:10]1[CH:11]=[C:12]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:13][NH:14][CH:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]2[CH:29]=[C:30]([Br:33])[CH:31]=[CH:32][C:16]1=2.N1C=CC=CC=1>ClCCl>[C:1]([N:14]([CH2:13][C:12]1[CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=[C:10]([C:9]([F:8])([F:41])[F:42])[CH:11]=1)[CH:15]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]2[CH:29]=[C:30]([Br:33])[CH:31]=[CH:32][C:16]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(Br)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)(C)C)c2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Add 3,5-bis(trifluoromethyl)benzylamine (1.49 g, 6.13 mmol) followed by titanium isopropoxide (1.60 mL, 5.47 mmol) to a solution of tert-butyl 8-bromo-5-oxo-2,3,4,5-tetrahydro benzo[b]azepine-1-carboxylate (1.49 g, 4.38 mmol) in tetrahydrofuran (17.5 mL) at room temperature under nitrogen and stir the solution for 14 h. Dilute the reaction with methanol (35 mL) and slowly add sodium borohydride (0.248 g, 6.57 mmol) to the reaction and stir at room temperature for 3 h. Add 2 N NaOH (20 mL) and water (20 mL) to the reaction and stir for 0.5 h. Filter the mixture and wash the solids with ethyl acetate (3×75 mL). Separate the filtrate and wash the organic layer with brine (25 mL), then dry the solution over sodium sulfate, filter and remove the solvent under reduced pressure to afford tert-butyl 5-(3,5-bistrifluoromethylbenzylamino)-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate as a white solid. Add acetic anhydride (6.0 mL, 64.0 mmol) dropwise to a suspension of tert-butyl 5-(3,5-bistrifluoromethylbenzylamino)-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (2.42 g, 4.26 mmol) and pyridine (5.2 mL, 64.0 mmol) in dichloromethane (17 mL) under nitrogen cooled to 0° C. After the addition is complete, remove the cooling bath and warm the reaction to room temperature and stir for 12 h. Dilute the mixture with dichloromethane (25 mL) and wash with 2 M potassium hydrogen sulfate and saturated aqueous sodium bicarbonate (25 mL each). Dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using chromatography on silica gel, eluting with hexanes/ethyl acetate (60:40), to afford the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[CH2:7]([OH:10])[C:8]#[CH:9]>C(NC(C)C)(C)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[S:4]1[CH:5]=[CH:6][C:2]([C:9]#[C:8][CH2:7][OH:10])=[CH:3]1
Reactant: C#CCO
Reactant: Brc1ccsc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Product: OCC#Cc1ccsc1
Yield: 48.2 %

Procedure:
To a suspension of bis(triphenylphosphine)-palladium (II) chloride (300 mg, 0.42 mmol) and copper (I) iodide (100 mg, 0.50 mmol) in diisopropylamine (100 ml) under nitrogen was added 3-bromothiophene (4.9 g, 30 mmol). After reflux under nitrogen for 1.5 h a solution of propargyl alcohol (3.0 g, 33 mmol) in diisopropylamine (50 ml) was added. After reflux for 5 h the reaction mixture was cooled, filtered and concentrated in vacuo. The residue was submitted to flash chromatography using ether/petroleum ether (1:1) as eluent to give 2 g (48%) of 3-(3-thienyl)-2-propyn-1-ol as a crude product.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[S:5][C:6]=1[CH:7]([OH:9])[CH3:8].[Cl:20][C:21]1[CH:28]=[C:27](O)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Cl:20][C:21]1[CH:28]=[C:27]([O:9][CH:7]([C:6]2[S:5][C:4]([C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)=[N:3][C:2]=2[CH3:1])[CH3:8])[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]
Reactant: N#Cc1ccc(O)cc1Cl
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)Oc1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.3 %

Procedure:
2.0 g 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol and 1.18 g 2-chloro-4-hydroxybenzonitrile were dissolved in 50 ml tetrahydrofuran. At −20° C. 2.74 g triphenylphosphine and 1.82 g diethylazodicarboxylate were added. The cooling bath was removed and the reaction mixture stirred at room temperature for four hours. Then the reaction mixture was poured on 100 ml ice cold saturated NH4Cl solution and extracted five times with portions of 80 ml ethyl acetate. The combined organic layers were washed with 100 ml brine then dried over MgSO4. The solvent was evaporated in vacuo and the resulting residue purified by chromatography on silica gel with the eluent n-heptane: ethyl acetate=4:1 to obtain 2.1 g 2-chloro-4-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-benzonitrile as pale yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 6 h
Yield: 71.9 %

Procedure:
To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (100 g, 0.584 mol) and morpholine (60 g, 0.689 mol) in dimethyl sulfoxide (60 mL) was added potassium carbonate (120 g, 0.870 mol). The mixture was stirred at 70° C. for 6 hours, and then poured into ice-water. The precipitate was collected by filtration and washed by water, dried to afford the product 4-(3-methoxy-4-nitrophenyl)morpholine (100 g, yield 72%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23]>CN(C=O)C>[CH3:23][O:22][CH:21]([O:24][CH3:25])[CH2:20][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[N:8]1
Reactant: COC(CBr)OC
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(Cn1ncc2cc([N+](=O)[O-])ccc21)OC
Temperature: 55 °C
Yield: 23.4 %

Procedure:
To a stirred mixture of 3.00 g (18.4 mmol) of 5-nitroindazole and 5.08 g (36.9 mmol) of K2CO3 in 61 mL of DMF was slowly added 3.42 g (20.2 mmol) of 2-bromo-1,1-dimethoxy-ethane and the mixture heated to 55° C. for 12 hours. The mixture was cooled to room temperature, filtered through a bed of celite. The filtrate was evaporated to dryness and the residue purified via column chromatography (30–80% ethyl acetate/hexanes) to provide 1.08 g of the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm 3.25 (m, 6 H), 4.61 (d, J=5.43 Hz, 2 H), 4.78 (t, J=5.43 Hz, 1 H), 7.91 (m, 1 H), 8.23 (m, 1 H), 8.43 (s, 1 H), 8.82 (m, 1 H); MS (DCI/NH3) m/z 252 [M+H]+.
Reaction SMILES: [CH3:1][Li].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:12])=[C:8]([CH:11]=1)[CH:9]=[O:10]>C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:12])=[C:8]([CH:9]([OH:10])[CH3:1])[CH:11]=1
Reactant: O=Cc1cc(Br)ccc1Cl
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(O)c1cc(Br)ccc1Cl
Reaction time: 15 h
Yield: 89.3 %

Procedure:
Methyl lithium (11.6 mL, 16.3 mmol, 1.4M in ether) was added to a cooled −78° C. solution of 5-bromo-2-chloro-benzaldehyde (2.75 g, 12.5 mmol) dissolved in THF (40 mL). The reaction mixture was stirred for 15 hours and then quenched with saturated NH4Cl and extracted with EtOAc. The organic extracts were washed with 1N HCl, brine, dried over Na2SO4 and concentrated to an oil. The oil was purified by flash column chromatography (0% to 10% EtOAc in hexanes) to give the title compound as a solid (2.63 g, 91%). 1H NMR (400 MHz, CDCl3): δ 6.32 (d, J=6.3 Hz, 3 H), 2.00 (d, J=3.8 Hz, 1 H), 5.24 (m, 1 H), 7.19 (d, J=8.6 Hz, 1 H), 7.33 (dd, J=8.6, 2.5 Hz, 1 H), 7.75 (d, J=2.5 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=[O:5].[Cl:22][CH2:23][C:24](Cl)=O>C(O)(=O)C>[Cl:22][CH2:23][C:24]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:13])[C:4](=[O:5])[C:3]2[C:2](=[C:17]([C:18]([F:21])([F:19])[F:20])[CH:16]=[CH:15][CH:14]=2)[N:1]=1
Reactant: Nc1c(C(=O)Nc2ccccc2Cl)cccc1C(F)(F)F
Reactant: O=C(Cl)CCl
Solvent: CC(=O)O
Product: O=c1c2cccc(C(F)(F)F)c2nc(CCl)n1-c1ccccc1Cl
Yield: 60.5 %

Procedure:
Prepared according to Procedure B with 1m (500 mg, 1.59 mmol) and chloroacetyl chloride (0.38 mL, 4.77 mmol) in acetic acid (10 mL). Purified by recrystallization from isopropanol to afford 359 mg of a white crystalline solid (61%). 1H NMR (CDCl3) δ: 8.51 (dd, J=1.0, 8.0 Hz, 1H); 8.14 (d, J=7.3 Hz, 1H); 7.65 (dd, J=2.5, 5.6 Hz, 1H); 7.62 (d, J=3.9 Hz, 1H); 7.48-7.60 (m, 3H); 4.44 (d, J=12 Hz, 1H), 4.12 (d, J=12 Hz, 1H). MS (ES): m/z 373.0 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].Cl.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][N:37]([CH3:40])[C:36](=[O:41])[CH:35]=1.CN1C=CN=C1.CCN=C=NCCCN(C)C>ClCCl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:31][CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][N:37]([CH3:40])[C:36](=[O:41])[CH:35]=4)=[O:23])=[CH:20][CH:19]=3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: Cn1ccc(CCN)cc1=O
Reactant: COc1ccc(Nc2cc(-c3ccc(C(=O)O)cc3)nn3ccnc23)nc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(Nc2cc(-c3ccc(C(=O)NCCc4ccn(C)c(=O)c4)cc3)nn3ccnc23)nc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.9 %

Procedure:
A mixture of 4-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (50 mg, 0.265 mmol), 4-(2-aminoethyl)-1-methylpyridin-2(1H)-one hydrochloride (16 mg, 0.132 mmol), 1-methyl-1H-imidazole (118 mg, 1.45 mmol) and EDCI (276 mg, 1.45 mmol) in dichloromethane (10 mL) and DMF (3 mL) was stirred at room temperature for 16 h then extracted with ethyl acetate (50 mL). The combined extracts were washed with water (5 mL×2), then brine (5 mL×2). After drying and concentration, the residue was purified by chromatography (silica gel, 5 g, 200˜300 mesh, methanol:dichloromethane=1:30) to afford 4-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(2-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)ethyl)benzamide (27 mg, 21%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 9.94 (s, 1H), 8.67 (s, 1H), 8.53 (s, 1H), 8.20 (s, 1H), 8.03-7.94 (m, 4 h), 7.66 (s, 1H), 7.58 (d, 1H, J=6.6 Hz), 7.41 (d, 1H, J=8.4 Hz), 7.11 (d, 1H, J=8.4 Hz), 6.23 (s, 1H), 6.13 (d, 1H, J=7.2 Hz), 4.01 (s, 3H), 3.77 (s, 3H), 3.53-3.47 (m, 2H), 3.36 (s, 3H), 2.69 (t, 2H, J=6.6 Hz). LC-MS: [M+H]+, 526, tR=1.367 min, HPLC: 98.9% at 214 nm, 99.36% at 254 nm, tR=4.615 min.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=[O:12])[CH3:11]>C(O)(=O)C>[Br:1][CH2:11][C:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[Cl:3])=[O:12]
Reactant: BrBr
Reactant: CC(=O)c1ccccc1Cl
Solvent: CC(=O)O
Product: O=C(CBr)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bromine (3.8 mL, 65 mmol) was added dropwise to a solution of 1-(2-chloro-phenyl)-ethanone (10 g, 65 mmol) in acetic acid (75 mL) at 0° C. The mixture was then warmed to room temperature and stirred overnight. The mixture was evaporated to dryness and used in the next step without further purification.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][OH:5].[NH2:9][C:10]1[N:15]=[C:14](Cl)[C:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]#[N:26])=[CH:20][C:19]=2[F:27])=[C:12]([CH3:28])[N:11]=1>C(O)CCC>[NH2:9][C:10]1[N:15]=[C:14]([NH:1][C@@H:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][OH:5])[C:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]#[N:26])=[CH:20][C:19]=2[F:27])=[C:12]([CH3:28])[N:11]=1
Reactant: CCC[C@H](N)CCO
Reactant: Cc1nc(N)nc(Cl)c1Cc1ccc(CC#N)cc1F
Solvent: CCCCO
Product: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1F
Reaction time: 2 h

Procedure:
(S)-3-Aminohexan-1-ol (0.966 g) was added to a suspension of the product of example 33 step (iii) (1.2 g) in butan-1-ol (9 mL). The reaction was performed in the CEM Microwave, at 180° C. for 2 h. The solvent was evaporated under reduced pressure and the crude product was purified by flash silica chromatography, to give the subtitle compound as an orange solid, 0.98 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].N1C=CC=CC=1.Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cccc(Cl)c1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)C=Cc1cccc(Cl)c1

Procedure:
The starting material is prepared as follows: The mixture of 50 g of 3-chlorobenzaldehyde, 41 g of malonic acid and 36 ml of pyridine is heated on the steam bath for 3 hours. The residue is dissolved in 200 ml of water, the solution acidified with hydrochloric acid, filtered, and the residue recrystallized from aqueous ethanol, to yield the 3-chlorocinnamic acid melting at 150°-152°.
Reaction SMILES: [CH2:1]([NH:7][CH2:8][C:9]([NH2:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:12]I>CO>[CH2:1]([N:7]([CH2:8][C:9]([NH2:11])=[O:10])[CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CI
Reactant: CCCCCCNCC(N)=O
Solvent: CO
Product: CCCCCCN(C)CC(N)=O

Procedure:
In a flask of 100 ml, 7.9 gr (0.05 mol) of 2-(n-hexylamino)acetamide and 7.8 gr (0.055 mol) of methyl iodide were mixed in 50 ml of methanol. This solution was left for 1 month at room temperature, then evaporated. The residue was dissolved in a 1N NaOH solution until basic pH and extracted with ether. The ether phase was dried on MgSO4 and evaporated. The solid as obtained was chromatographed on a column of SiO2 by eluting with a benzene-methanol mixture (7:3). The desired product was thus obtained.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[NH:11][C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[F:25]>CN(C=O)C>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:11]1[C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[C:7]=2[CH:13]=[C:12]1[CH3:14]
Reactant: Fc1ccccc1CBr
Reactant: Cc1cc2c(ccc3nnc(C)n32)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1ccccc1F
Reaction time: 0.17 h

Procedure:
To a solution of 1,7-dimethyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (10.0 mg, 0.0537 mmol, from Example 2, Step 5) in DMF (1.5 mL) was added sodium hydride (0.0065 g, 0.16 mmol, 60% in mineral oil). After stirring for 10 minutes, 1-(bromomethyl)-2-fluorobenzene (0.010 g, 0.054 mmol, Aldrich) was added. After stirring for 45 minutes, the reaction was quenched with water, diluted with MeCN and filtered, then was purified by preparative HPLC-MS (Waters XBridge C18, eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) (7 mg, 40%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]2[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[CH:14][C:13]=2[N+:20]([O-])=O)=[N:8][C:7]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)=[O:5])[CH3:2].[Cl-].[NH4+].O1CCC[CH2:33]1>[Zn]>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([N:11]2[C:12]3[CH:17]=[C:16]([CH:18]=[O:19])[CH:15]=[CH:14][C:13]=3[N:20]=[CH:33]2)=[N:8][C:7]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)=[O:5])[CH3:2]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Product: CCOC(=O)c1sc(-n2cnc3ccc(C=O)cc32)nc1-c1cccc(Cl)c1
Reaction time: 1 h

Procedure:
To mixture of 3.0 g of 4-(3-chloro-phenyl)-2-(5-formyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid ethyl ester (VI.41b), 40 mL of tetrahydrofuran and 20 mL of saturated ammonium chloride solution, was added in three equal portions, at 30 minute intervals, 9 g of zinc powder. After the third portion of zinc powder was added, the orange color disappeared and the mixture turned clear. The solid was removed by filtration. The organic layer was separated. The aqueous layer was extracted twice with 30 mL of dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was stirred with 30 mL of acetic acid and 3 mL of trimethyl orthoformate for 1 hour. The mixture was concentrated under reduced pressure, 100 mL of water was and the pH adjusted to 9 by addition of 15% sodium hydroxide solution. The precipitate was collected by filtration and purified by silica gel chromatography, eluting with methanol-dichloromethane (gradient 0:100-2:98) to give 2.3 g of 4-(3-chloro-phenyl)-2-(6-formyl-benzoimidazol-1-yl)-thiazole-5-carboxylic acid ethyl ester (I.41a) as an off-white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:13]([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1ccc2[nH]ccc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
The solution of 1H-indole-5-carboxylic acid (1.0 g, 6.2 mmol, Aldrich) and K2CO3 (0.939 g, 6.8 mmol) in DMF (10 mL) was heated to 65° C., and Me2SO4 (0.78 g, 6.2 mmol) was added dropwise between 65-70° C. over 15 min. The reaction was stirred for 1 h at 80° C. then the mixture was poured into ice/water. The resulting precipitate was collected by filtration and dried in vacuo to give methyl 1H-indole-5-carboxylate (0.91 g, 5.2 mmol, 85.8%). MS (ESI, pos. ion) m/z: 176 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21][C:22]1[NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[N:23]=1)=[N:8][CH:7]=[CH:6]2.ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)Cl.C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([C:22]1[NH:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=1)=[O:39])=[N:8][CH:7]=[CH:6]2
Reactant: COc1cc2ccnc(-c3ccccc3Sc3nc4ccccc4[nH]3)c2cc1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc2ccnc(-c3ccccc3S(=O)c3nc4ccccc4[nH]3)c2cc1OC

Procedure:
The product of step (f) above was dissolved in 1:1 CH2Cl2 -CHCl3 (10 ml), treated with 85%m-Chloroperbenzoic acid (24 mg) at -5°, and worked up in aqueous NaHCO3 to give the title compound. NMR (CDCl3)d, 8.5 (d,1H), 8.35 (dd,1H), 7.26 (1H,s), 7.21 (1H,s), 7.7-7.2 (complex,8H), 4.30 (s,3H), 3.85 (s,3H)ppm, mp 250° (d).