Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][NH2:5])[CH3:3].Cl[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[NH:17][C:18](=O)[CH2:19][CH2:20][CH3:21]>C(O)C>[CH2:2]([O:4][N:5]1[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=[C:18]1[CH2:19][CH2:20][CH3:21])[CH3:3]
Reactant: CCCC(=O)Nc1cnc2ccccc2c1Cl
Reactant: CCON
Agent: Cl
Solvent: CCO
Product: CCCc1nc2cnc3ccccc3c2n1OCC
Temperature: 25 °C
Yield: 93.8 %

Procedure:
Ethoxyamine hydrochloride (2.34 g, 2.0 eq) was added to a solution of N-(4-chloroquinolin-3-yl)butyramide (3.0 g, 1.0 eq) in ethanol (75 mL). The reaction mixture was heated at reflux for 3 hours, cooled to ambient temperature, and then concentrated under reduced pressure. The residue was partitioned between dichloromethane and aqueous saturated sodium bicarbonate. The organic layer was separated and concentrated under reduced pressure to provide 2.89 g of 1-ethoxy-2-propyl-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:17]([CH3:26])=[CH:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)([OH:16])[CH2:10][C:11]1[N:12]=[N:13][NH:14][CH:15]=1>C(O)(=O)C.[Pd].[C]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:16])([CH:17]([CH3:26])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[CH2:10][C:11]1[N:12]=[N:13][NH:14][CH:15]=1
Reactant: CC(=Cc1ccc(F)cc1)C(O)(Cc1c[nH]nn1)c1ccc(F)cc1F
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(Cc1ccc(F)cc1)C(O)(Cc1c[nH]nn1)c1ccc(F)cc1F
Yield: 48 %

Procedure:
A 0.3 g portion of 2-(2,4-difluorophenyl)-2-[1-methyl-2-(4-fluorophenyl)-ethenyl]-1-triazolyl-2-ethanol was dissolved in 20 ml of acetic acid and subjected to 4 hours of hydrogenation under normal pressure in the presence of 0.02 g 10% Pd-carbon. After completion of the reaction, acetic acid was removed by evaporation under a reduced pressure, and the thus obtained residue was poured into water, neutralized with sodium bicarbonate and then extracted with ethyl acetate. The resulting organic layer was washed with water and dried on anhydrous magnesium sulfate. After removing the solvent by evaporation under a reduced pressure, the resulting residue was purified by a silica gel column chromatography to obtain 0.15 g of 2-(2,4-difluorophenyl)-1-triazolyl-3-methyl-4-(4-fluorophenyl)-2-butanol with a yield of 48%.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:20](=[O:21])[C:19]3[C:18]([O:22][CH:23]([CH3:25])[CH3:24])=[C:17]4[CH:26]=[CH:27][CH:28]=[CH:29][C:16]4=[C:15]([O:30][CH:31]([F:33])[F:32])[C:14]=3[C:13]2=[O:34])=[CH:8][CH:7]=1)C.C(O)(=O)C.Cl>O>[F:33][CH:31]([F:32])[O:30][C:15]1[C:14]2[C:13](=[O:34])[N:12]([C:9]3[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:35])=[O:3])=[CH:7][CH:8]=3)[C:20](=[O:21])[C:19]=2[C:18]([O:22][CH:23]([CH3:25])[CH3:24])=[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=12
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OC(F)F)c4ccccc4c3OC(C)C)C2=O)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC(C)Oc1c2c(c(OC(F)F)c3ccccc13)C(=O)N(c1ccc(CC(=O)O)cc1)C2=O
Temperature: 25 °C
Yield: 9 %

Procedure:
Ethyl(4-{4-[(difluoromethyl)oxy]-9-[(1-methylethyl)oxy]-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl}phenyl)acetate (0.14 g, 0.289 mmol) was heated to 100° C. in a 1:1 mixture of acetic acid:2N aqueous hydrochloric acid (8 ml) for 1 hour. The reaction was cooled to room temperature. On addition of water, the resulting white solid was collected by filtration and washed with water. This was dried in the vacuum oven to give the title compound (0.120 g, 0.026 mmol). LC/MS: Rt=3.36, [MH]+ 456.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1.Cl[CH2:15][CH2:16][CH2:17][O:18][CH3:19].[F-].[K+].[I-].[K+]>C(#N)C>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[N:8]([CH2:15][CH2:16][CH2:17][O:18][CH3:19])[C:7]=2[CH:13]=1
Reactant: COCCCCl
Reactant: O=C1COc2ccc(CO)cc2N1
Agent: [F-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COCCCN1C(=O)COc2ccc(CO)cc21

Procedure:
A suspension of 1.79 g of 6-hydroxymethyl-4H-benzo[1,4]oxazin-3-one, 2.20 ml of 1-chloro-3-methoxypropane, 10 g of KF on aluminium oxide and 0.033 g of potassium iodid in 150 ml of acetonitrile is stirred under reflux for 72 hours. The reaction mixture is cooled and clarified by filtration, and the filltrate is evaporated to dryness. The title compound is obtained from the residue by flash chromatography (SiO2 60 F). Rf (CH2Cl2/MeOH 9:1)=0.60; Rt =2.74.
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([BH3-])#N.[Na+]>CO.Cl>[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([NH:10][CH2:9][CH2:8][NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: NCCNc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: c1ccc(CN2CCC(NCCNc3ccccc3)CC2)cc1
Temperature: 25 °C

Procedure:
To the solution of 12.6 g of N-phenylethylenediamine in 200 ml of methanol, 50 ml of 4.1 N ethanolic hydrogen chloride are added dropwise followed by 18.9 g of 1-benzyl-4-piperidone in 100 ml of methanol. Then, 9.45 g sodium cyanoborohydride are added in portions while stirring at room temperature. After 72 hours the mixture is filtered, the residue dissolved in water and the solution made basic with 12.5% aqueous sodium hydroxide. It is extracted with methylene chloride, dried and evaporated to yield the 1-benzyl-4-(2-phenylaminoethylamino)-piperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([F:28])[C:26]=1[F:27])[C:21](O)=[O:22].C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:21](=[O:22])[C:20]3[CH:24]=[C:25]([F:28])[C:26]([F:27])=[C:18]([F:17])[CH:19]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(c1cc(F)c(F)c(F)c1)N1CCC(CCO)(c2ccc(Cl)c(Cl)c2)C1
Reaction time: 18 h

Procedure:
Combine 3-(3,4-dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (286 mg, 1.1 mmol), 3,4,5-trifluoro-benzoic acid (1 mmol), N,N-diisopropylethylamine (0.19 mL, 1.1 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (0.21 g, 1.1 mmol), and 1-hydroxybenzotriazole hydrate (HOBT) (0.15 g, 1.1 mmol) in dichloromethane (10 mL). After 18 hour, dilute with dichloromethane and extract with 1M hydrochloric acid solution, 5% sodium bicarbonate solution, and water. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound: Rf =0.45 (silica gel, 10% methanol/dichloromethane).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:15]1[CH2:19][CH2:18][C@H:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)OCc2ccccc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)[C@H]1CCNC1
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (2.5 mL) was added to a solution of benzyl (S)-1-tert-butoxycarbonylpyrrolidine-3-carboxylate (Intermediate 192, 0.859 g) and DCM (10 mL) at room tempertaure. The mixture was stirred for 4 hours then concentrated in vacuo. The residue was azetroped with toluene then ethyl acetate to give benzyl (S)-pyrrolidine-3-carboxylate trifluoroacetic acid salt (1 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].Cl[C:7]1[CH:17]=[C:10]2[N:11]=[C:12]([CH3:16])[CH:13]=[C:14]([CH3:15])[N:9]2[N:8]=1>CN(C)C=O>[CH2:3]([S:5][C:7]1[CH:17]=[C:10]2[N:11]=[C:12]([CH3:16])[CH:13]=[C:14]([CH3:15])[N:9]2[N:8]=1)[CH3:4]
Reactant: Cc1cc(C)n2nc(Cl)cc2n1
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSc1cc2nc(C)cc(C)n2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% oily sodium hydride (2.0 g) is suspended in 20 ml of dimethylformamide. A solution of 3.7 ml of ethylmercaptan dissolved in 10 ml of dimethylformamide under ice cooling is added to the suspension below 10° C. and stirred for 30 minutes at room temperature. 2-Chloro-5,7-dimethylpyrazolo [1,5-a]pyrimidine (6.6 g) is added to the mixture and stirred for 5 hours at 80°-90° C. After cooling, the reaction solution is poured into ice water and extracted with toluene. The extract is washed with water and then distilled to remove the solvent. The residue is purified by silica gel chromatography (eluent: dichloromethane) to give 4.0 g of the title compound as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:29]=[CH:28][C:17]4[N:18]=[C:19]([NH:21][C@H:22]5[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]5)[S:20][C:16]=4[CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:4]=[N:3]1.CCN(C(C)C)C(C)C.[CH:39]1([S:42](Cl)(=[O:44])=[O:43])[CH2:41][CH2:40]1>CN1C(=O)CCC1>[CH:39]1([S:42]([N:24]2[CH2:25][CH2:26][CH2:27][C@H:22]([NH:21][C:19]3[S:20][C:16]4[CH:15]=[C:14]([O:13][C:11]5[CH:10]=[CH:9][N:8]=[C:7]([C:5]6[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=6)[CH:12]=5)[CH:29]=[CH:28][C:17]=4[N:18]=3)[CH2:23]2)(=[O:44])=[O:43])[CH2:41][CH2:40]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Cn1cc(-c2cc(Oc3ccc4nc(N[C@H]5CCCNC5)sc4c3)ccn2)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cn1cc(-c2cc(Oc3ccc4nc(N[C@H]5CCCN(S(=O)(=O)C6CC6)C5)sc4c3)ccn2)cn1
Reaction time: 16 h
Yield: 66.7 %

Procedure:
To the solution of (S)-6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-N-(piperidin-3-yl)benzo[d]thiazol-2-amine (7.6 mg, 18 μmol) and DIPEA (35 μL, 200 μmol) in 400 μL of NMP was added cyclopropanesulfonyl chloride (10 mg, 98 μmol). The reaction solution was stirred at 55 for 16 hours. The crude reaction solution was purified on prep HPLC and evaporated in vacuo to give (S)—N-(1-(cyclopropylsulfonyl)piperidin-3-yl)-6-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzo[d]thiazol-2-amine (6.2 mg, 12 μmol) as white powder. ES/MS m/z 511.2 (MH+).
Reaction SMILES: C([O:4][C@H:5]1[C@H:18]([O:19]C(=O)C)[C@@H:17]([CH2:23][O:24]C(=O)C)[O:16][C@@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@@H:6]1[NH:28][C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])(=O)C.[Na]>CO>[C:29]([NH:28][C@@H:6]1[C@@H:5]([OH:4])[C@H:18]([OH:19])[C@@H:17]([CH2:23][OH:24])[O:16][C@H:7]1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: CCCCCCCCCCCCCCCC(=O)N[C@H]1[C@H](OCc2ccccc2)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na]
Solvent: CO
Product: CCCCCCCCCCCCCCCC(=O)N[C@H]1[C@H](OCc2ccccc2)O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
A solution of 5 grams of benzyl 3,4,6-tri-O-acetyl-2-deoxy-2-palmitamido-β-D-glucopyranoside (Compound 1b) in 140 ml. of methanol was refluxed for about 30 minutes after the addition of a piece of sodium metal. A sulfonic cation exchange resin was added to remove the sodium, followed by hot filtration. The filtrate was concentrated on a rotary evaporator to yield the desired product in the form of a gelatinous solid which was stored in an evacuated oven at 70° C. overnight.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.N1CCC[C@@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([O:27][C:28]1[CH:37]=[C:36](I)[CH:35]=[CH:34][C:29]=1[C:30]([O:32][CH3:33])=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[Cu]I.C(OCC)(=O)C.O.CS(C)=O>[CH2:20]([O:27][C:28]1[CH:37]=[C:36]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[CH:35]=[CH:34][C:29]=1[C:30]([O:32][CH3:33])=[O:31])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)c1ccc(I)cc1OCc1ccccc1
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: O=C(O)[C@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-n2cccn2)cc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
1H-Pyrazole (0.044 g), D-proline (0.013 g), potassium carbonate (0.15 g), and copper(I) iodide (0.010 g) were added to a dimethyl sulfoxide (1.5 mL) solution of methyl 2-(benzyloxy)-4-iodobenzoate (0.20 g), followed by stirring under a nitrogen atmosphere at 90° C. for 2 hours. The reaction mixture was cooled to room temperature, and then D-proline (0.013 g) and copper(I) iodide (0.010 g) were added thereto, followed by stirring under a nitrogen atmosphere at 100° C. for 2 hours. After cooling the reaction mixture to room temperature, water and ethyl acetate were added thereto, and the insoluble substance was removed by filtration. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 100-60% hexane/ethyl acetate] to obtain 0.12 g of methyl 2-(benzyloxy)-4-(1H-pyrazol-1-yl)benzoate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([NH:20][NH2:21])=[O:19])[CH:15]=[CH:14][C:12]=2[N:13]=1.[N:22]([C:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH2:26]1)[CH2:32]2)=[C:23]=S.CCN=C=NCCCN(C)C>CN(C=O)C.O>[C:25]12([NH:22][C:23]3[O:19][C:18]([C:16]4[CH:15]=[CH:14][C:12]5[N:13]=[C:9]([C:3]6[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=6[Cl:1])[NH:10][C:11]=5[CH:17]=4)=[N:20][N:21]=3)[CH2:32][CH:31]3[CH2:30][CH:29]([CH2:28][CH:27]([CH2:33]3)[CH2:26]1)[CH2:34]2
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: S=C=NC12CC3CC(CC(C3)C1)C2
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cccc(Cl)c1-c1nc2ccc(-c3nnc(NC45CC6CC(CC(C6)C4)C5)o3)cc2[nH]1
Temperature: 25 °C

Procedure:
Combine 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (100 mg, 0.310 mmol) and 1-isothiocyanato-adamantane (78 mg, 0.403 mmol) in DMF (2 mL) and heat to 70° C. for 1 hr. Add EDCI (119 mg, 0.620 mmol) and heat the reaction for 1 hr. Allow the reaction to cool to room temp and dilute with water (10 mL). Collect the resulting precipitate by filtration and purify the solid by reverse-phase HPLC (35-65% ACN/H2O+5 mM NH4OH) to afford the title compound as a white solid: 1H NMR (400 MHz, MeOD) δ ppm 1.74-1.82 (m, 6H) 2.12 (s, 6H) 2.15 (br. s., 3H) 7.55-7.63 (m, 3H) 7.76 (br. s., 1H) 7.93 (br. s., 1H) 8.18 (br. s., 1H); MS (m/z) 480.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:13]([NH2:18])(=[O:17])[CH:14]([CH3:16])[CH3:15]>>[C:13]([NH:18][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6])(=[O:17])[CH:14]([CH3:16])[CH3:15]
Reactant: COC(=O)c1cc(C)nc(Cl)c1
Reactant: CC(C)C(N)=O
Product: COC(=O)c1cc(C)nc(NC(=O)C(C)C)c1

Procedure:
The title compound is prepared in quantitative yield (1.27 g, yellow syrup) from methyl 2-chloro-6-methylisonicotinate (1.00 g, 5.39 mmol) and isobutyramide by the similar manner in Step-1 of Carboxylic acid-4.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:25][C:26]1[CH:27]=[C:28]([NH:32][NH2:33])[CH:29]=[CH:30][CH:31]=1>>[Cl:25][C:26]1[CH:27]=[C:28]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:33]2)[CH:29]=[CH:30][CH:31]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(C(F)(F)F)cc2)ccc1=O
Reactant: NNc1cccc(Cl)c1
Product: O=c1ccn(-c2ccc(C(F)(F)F)cc2)nc1-c1ccnn1-c1cccc(Cl)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethyl-phenyl)-1H-pyridazin-4-one (A-22) and 3-chloro-phenylhydrazine according to the method described for example 1. MS: M=417.2 (M+H)+
Reaction SMILES: [C:1]1([C:7]2[C:14]3[S:13][C:12]([NH2:15])=[N:11][C:10]=3[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[S:18][C:19]([C:23](Cl)=[O:24])=[C:20]([CH3:22])[N:21]=1.C1(C)C=CC=CC=1.C(O)C(N)(CO)CO>CN(C1C=CN=CC=1)C.C1COCC1>[C:1]1([C:7]2[C:14]3[S:13][C:12]([NH:15][C:23]([C:19]4[S:18][C:17]([Cl:16])=[N:21][C:20]=4[CH3:22])=[O:24])=[N:11][C:10]=3[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nc2[nH]nc(-c3ccccc3)c2s1
Reactant: Cc1nc(Cl)sc1C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: NC(CO)(CO)CO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1nc(Cl)sc1C(=O)Nc1nc2[nH]nc(-c3ccccc3)c2s1
Temperature: 70 °C
Reaction time: 18 h
Yield: 21 %

Procedure:
To a vial charged with 3-phenyl-1H-pyrazolo[3,4-d]thiazol-5-ylamine (30 mg, 0.139 mmol), PS-DMAP (Argonaut resin, 558 mg, 6 equiv.), and a stirring bar was added THF (2 mL) and 2-chloro-4-methyl-thiazole-5-carbonyl chloride solution in toluene (0.52 M, 1.3 mL, ca. 5 equiv.). The reaction mixture was stirred at 70° C. for 18 hours, then cooled to room temperature and treated with PS-trisamine (Argonaut resin, 674 mg, 20 equiv.) for 2 hours. The resin was filtered, washed with THF and the solvent was evaporated. The resulting crude mixture was treated with MeOH (1 mL) and a 4 N aqueous solution of NaOH (0.25 mL). The reaction mixture was further stirred at room temperature for 2 hours, then a 1 N aqueous solution of HCl was added to adjust the pH to 7, and the mixture was extracted with EtOAc (3×). Purification on silica gel with 0-10% MeOH in CH2Cl2 as eluent provided 11 mg (21% yield) of 2-chloro-4-methyl-thiazole-5-carboxylic acid (3-phenyl-1H-pyrazolo[3,4-d]thiazol-5-yl)-amide as an off-white solid. 1H-NMR (d6-DMSO) δ: 7.75 (d, 2H), 7.54 (t, 2H), 7.39 (t, 1H), 2.65 (s, 3H); HPLC/MS m/z: 376.0 [MH]+.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:9]2[C@@:5]([C:12]([O:14][CH3:15])=[O:13])([O:6][C:7]([CH3:11])([CH3:10])[O:8]2)[O:4][C@@H:3]1[CH2:16]OS(C1C=CC(C)=CC=1)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C=O)C>[N:28]([CH2:16][C@@H:3]1[O:4][C@@:5]2([C:12]([O:14][CH3:15])=[O:13])[O:6][C:7]([CH3:11])([CH3:10])[O:8][CH:9]2[C@@H:2]1[OH:1])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@]12O[C@H](COS(=O)(=O)c3ccc(C)cc3)[C@H](O)[C@H]1OC(C)(C)O2
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@]12O[C@@H](CN=[N+]=[N-])[C@@H](O)C1OC(C)(C)O2
Temperature: 100 °C
Yield: 52 %

Procedure:
To a solution of 17 (400 mg, 1.0 mmol) in DMF (2 mL) was added NaN3 (97 mg, 1.5 mmol). The reaction mixture was heated at 100° C. (oil bath) for 20 h. The solvent was removed in vacuo and the residue was partitioned between EtOAc/H2O. The EtOAc layer was washed with H2O (2×20 mL), brine (1×20 mL) and dried over MgSO4. EtOAc was evaporated and the crude material was purified by silica gel chromatography using EtOAc/Hexane. Product 15 was obtained as a white solid (140 mg; yield 52%).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH:12]([C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[C:16]=1[NH2:17])([CH3:14])[CH3:13]>>[CH:22]([C:18]1[CH:19]=[CH:20][CH:21]=[C:15]([CH:12]([CH3:14])[CH3:13])[C:16]=1[N:17]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])([CH3:24])[CH3:23]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=C1OC(=O)c2ccccc21
Product: CC(C)c1cccc(C(C)C)c1N1C(=O)c2ccccc2C1=O

Procedure:
7.41 g of phthalic anhydride and 8.86 g of 2,6-diisopropylaniline were mixed, and reacted at a temperature of 180° C. for 2 hours.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][CH:9]=[C:10]([C:12](OC)=[O:13])[N:11]=2)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O-]S([O-])(=O)=O.[Na+].[Na+]>C(OCC)C.C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[S:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1csc(N2CCOCC2)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: OCc1csc(N2CCOCC2)n1
Temperature: -78 °C
Reaction time: 4 h
Yield: 68.7 %

Procedure:
A solution of methyl 2-morpholinothiazole-4-carboxylate (0.76 g, 3.33 mmol) in ethyl ether (20 mL) was treated portion wise over 10 min. with lithium aluminum hydride (0.38 g, 10.01 mmol). The mixture was stirred at −78° C. for 4 hours, then slowly treated with ethyl acetate (10 mL) and sat. Na2SO4 (20 mL). The mixture was allowed to warm up to RT, diluted with ethyl acetate, washed with sat. NaHCO3 (1×), brine (1×), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified on silica gel chromatography (3×10 cm, 25% AcOEt/CH2Cl2 to 100% AcOEt) to give the title material as a beige solid (0.458 g) which was then distilled (bulb to bulb, 135-145° C./0.2 torr) and afforded the desired product (0.455 g, 68%) as a white solid. LC (Method F): 0.873 min. HRMS (ESI) calcd for C8H13N2O2S [M+H]+ m/z 201.07. found 201.2. 1H NMR (CDCl3, 400 MHz) δ ppm: 6.43 (s, 1H) 4.53 (d, J=3.9 Hz, 2H) 3.79 (m, 4H) 3.44 (m, 4H) 2.17 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:18]=1.Cl.N1C=CC=CC=1>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)=[CH:7][C:6]=2[CH:18]=1
Reactant: COc1ccc(-c2cc3cc(F)ccc3o2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc(-c2cc3cc(F)ccc3o2)cc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
Compound 83 was treated with Pyridine HCl (5 g) and heated to 200° C. After 1 hr, the reaction was cooled and diluted with water. The aqueous layer was extracted with EtOAc, dried over MgSO4, filtered and concentrated to give a solid (0.11 g, 13%); Mp=202–204° C.; 1NMR (DMSO-d6) δ 9.92 (br s, 1 H), 7.73 (d, 2 H, J=8.7 Hz), 7.58 (dd, 1 H, J=8.7 Hz, 4.4 Hz), 7.39 (dd, 1H J=8.8 Hz, 2.5 Hz), 7.17 (d, 1 H, J=1.0 Hz), 7.10–7.06 (m, 1 H), 6.88 (d, 2 H, J=8.8 Hz); MS 227 [M−H]−
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][CH:17]=[CH:16]2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH:29]2[CH2:31][CH2:30]2)O)=[C:23]([F:32])[CH:22]=1>ClCCl>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH:29]2[CH2:31][CH2:30]2)[C:16]2[C:15]3[C:19](=[C:11]([CH2:10][S:9][CH3:8])[CH:12]=[CH:13][CH:14]=3)[NH:18][CH:17]=2)=[C:23]([F:32])[CH:22]=1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: OC(c1ccc(Cl)cc1F)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C(c3ccc(Cl)cc3F)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.13 ml (1.73 mmol) of trifluoroacetic acid was added to 256 mg (1.45 mmol) of the compound from Example 8A and 290 mg (1.45 mmol) of the compound from Example 151A in 20 ml of dichloromethane, and the mixture was stirred at RT for 2 h. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 273 mg (51% of theory) of the title compound.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH3:5].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1>CCOCC>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]([OH:14])[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CCCCC[Mg]Br
Solvent: CCOCC
Product: CCCCCC(O)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 63 %

Procedure:
n-Pentylmagnesium bromide (12.1 mL of a 2.0 M solution in Et2O, 24.0 mmol) was added to a solution of 4-bromobenzaldehyde 5 (4.0 g, 22.0 mmol) at −78° C. The reaction was then warmed to room temperature for 0.5 h and quenched with saturated aqueous NH4Cl. The mixture was extracted with EtOAc and the organic portion was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. FCC (silica gel, 9:1 hex/EtOAc) gave 3.6 g (63%) of the alcohol 6 as a clear, colorless oil.