Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=1)=[O:27])[C:23](O)=[O:24]>>[Cl:36][C:34]1[CH:35]=[C:30]([CH:31]=[C:32]([Cl:37])[CH:33]=1)[CH2:29][NH:28][C:26](=[O:27])[CH:22]([CH3:21])[C:23]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:24]
Reactant: CC(C(=O)O)C(=O)NCc1cc(Cl)cc(Cl)c1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Product: CC(C(=O)NCc1cc(Cl)cc(Cl)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
The title compound, MS: m/e=523.3 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-methyl-N-(3,5-dichloro-benzyl)-malonamic acid.
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[NH2:17][C@@H:12]1[C@H:11]([NH:10][C:7]2[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[N:27]=3)[CH:6]=2)[CH2:16][CH2:15][O:14][CH2:13]1
Reactant: Cc1cccc(Nc2cc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(Nc2cc(N[C@@H]3CCOC[C@@H]3N)nnc2C(N)=O)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 28.6 %

Procedure:
tert-butyl (3R,4R)-4-(6-carbamoyl-5-(6-methylpyridin-2-ylamino)pyridazin-3-ylamino)tetrahydro-2H-pyran-3-ylcarbamate (60 mg, 83% pure, 0.112 mmol) was dissolved in dichloromethane (0.85 mL) and cooled to 0° C. Trifluoroacetic acid (0.35 mL, 4.49 mmol) was added drop-wise, then the mixture was warmed to room temperature. After 3 h, the mixture was concentrated in vacuo then water, sodium bicarbonate solution and ethyl acetate were added. The aqueous phase was extracted with ethyl acetate. Sodium chloride was added to the aqueous layer and it was further extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by chromatography (silica, 0-10% methanol in dichloromethane) gave 6-((3R,4R)-3-amino-tetrahydropyran-4-ylamino)-4-(6-methyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide (11 mg, 28%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.61 (s, 1H) 8.39 (br. s., 1H) 8.12 (s, 1H) 7.65 (br. s., 1H) 7.60 (t, J=7.7 Hz, 1H) 6.95 (d, J=7.2 Hz, 1H) 6.85 (d, J=7.6 Hz, 1H) 6.75 (d, J=8.3 Hz, 1H) 4.10 (br. s., 1H) 3.79-3.89 (m, 1H) 3.66-3.75 (m, 1H) 3.49-3.57 (m, 1H) 3.37-3.47 (m, 1H) 3.00-3.08 (m, 1H) 1.94-2.12 (m, 1H) 1.76-1.92 (m, 1H) 1.63-1.73 (m, 1H). MS (EI/CI) m/z: 344 [M+H].
Reaction SMILES: Br[CH2:2][C:3]1[CH:19]=[CH:18][C:6]2[NH:7][C:8](=[O:17])[C:9]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:10]=3[NH:11][C:5]=2[CH:4]=1.[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][NH:24][CH3:25]>C(OCC)(=O)C>[Cl:16][C:13]1[CH:14]=[CH:15][C:9]2[C:8](=[O:17])[NH:7][C:6]3[CH:18]=[CH:19][C:3]([CH2:2][N:24]([CH2:23][CH2:22][N:21]([CH3:26])[CH3:20])[CH3:25])=[CH:4][C:5]=3[NH:11][C:10]=2[CH:12]=1
Reactant: O=C1Nc2ccc(CBr)cc2Nc2cc(Cl)ccc21
Reactant: CNCCN(C)C
Solvent: CCOC(C)=O
Product: CN(C)CCN(C)Cc1ccc2c(c1)Nc1cc(Cl)ccc1C(=O)N2
Temperature: 25 °C
Yield: 58.5 %

Procedure:
A mixture of Example 512A (50 mg, 0.15 mmol) and N,N,N′-trimethylethylenediamine (300 μL, 2.3 mmol) was heated at 50° C. overnight, cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated under vacuum to provide 31.5 mg (59%) of the desired product.
Reaction SMILES: [CH:1]1[C:9]([NH2:10])=[CH:8][C:7]2[CH2:11][CH2:12][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=13.[C:19](Cl)(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>ClCCl>[CH:1]1[C:9]([NH:10][C:19](=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:8][C:7]2[CH2:11][CH2:12][N:5]3[C:6]=2[C:2]=1[C:3]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:4]=13
Reactant: Nc1cc2c3c(c1)c1c(n3CC2)CCCCCC1
Reactant: CCCCCC(=O)Cl
Solvent: ClCCl
Product: CCCCCC(=O)Nc1cc2c3c(c1)c1c(n3CC2)CCCCCC1
Yield: 36.1 %

Procedure:
Following the procedure of Example 1, Step 4, 4,5,7,8,9,10,11,12-octahydrocycloocta[b]pyrrolo[3,2,1-hi]indol-2-amine (0.15 g, 0.54 mmol), hexanoyl chloride (0.075 mL, 0.54 mmol) and poly-(4-vinylpyridine) (500 mg) in dichloromethane (12 mL) provided N-4,5,7,8,9,10,11,12-octahydrocycloocta[b]pyrrolo[3,2,1-hi]indol-2-ylhexanamide (66 mg). MS (ES) m/z 339.2; HPLC purity 100% at 210-370 nm, 11.2 min.; 100% at 250 nm, 11.2 min. (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 ((Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C22H30N2O+H+, 339.24309; found (ESI, [M+H]+), 339.2433.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[C:21]([F:30])=[C:20]([Cl:31])[C:19]=1[F:32]>CN(C=O)C>[Cl:31][C:20]1[C:21]([F:30])=[C:22]([C:24]2([C:26]([F:29])([F:28])[F:27])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:23]=[C:18]([Cl:17])[C:19]=1[F:32]
Reactant: CC1(C)OB(O)c2ccc(C(Cl)=NO)cc21
Reactant: C=C(c1cc(Cl)c(F)c(Cl)c1F)C(F)(F)F
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4F)(C(F)(F)F)C3)cc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 21.4 %

Procedure:
To a solution of N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]-oxaborole-5-carbimidoyl chloride (3.0 g, 12.63 mmol) and 1,3-dichloro-2,4-difluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)-benzene (3.93 g, 14.19 mmol) in DMF (20 mL) at rt was added TEA (2.7 mL, 18.95 mmol). The reaction mixture was stirred for 12 h, poured into ice-water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE-EA (1:1) to give the title compound 5-(5-(3,5-dichloro-2,4-difluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol [1.3 g, yield: 21.4% (3 steps)] as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 9.23 (s, 1 H), 7.87 (t, J=7.5 Hz, 1H), 7.83 (s, 1H), 7.75 (s, 2H), 4.59 (d, J=18.5 Hz, 1H), 4.37 (d, J=18.5 Hz, 1H), 1.50 (s, 3H), 1.48 (s, 3H) ppm; HPLC purity: 100.0% at 220 nm and 100.0% at 254 nm; MS: m/z=479.8 (M+1, ESI+).
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)[CH:9]=1)=[N+]=[N-]>CO.[Ni]>[NH2:1][CH2:4][C:5]1[N:6]=[CH:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)[CH:9]=1
Reactant: [N-]=[N+]=NCc1cn(-c2ccc(I)cc2)cn1
Agent: [Ni]
Solvent: CO
Product: NCc1cn(-c2ccc(I)cc2)cn1

Procedure:
A solution of 4-azidomethyl 1-(4-iodophenyl)imidazole 1-4 (0.725 g, 2.23 mmol) over Ra—Ni (50% aq. slurry, 300 mg) in MeOH (12 mL) was hydrogenated under balloon H2 for 3 h. The mixture was filtrated through CELITE. The filtrate was concentrated in vacuo to give 4-aminomethyl 1-(4-iodophenyl)imidazole I-2 as a solid (0.603 g). MS 300.0 (M+H)
Reaction SMILES: [CH3:1][C:2]([S:9][CH2:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)([CH3:8])[C:3]([O:5]CC)=[O:4].O.[OH-].[Li+]>O1CCOCC1.O>[CH3:8][C:2]([S:9][CH2:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)SC[C@@H]1CCCCO1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(SC[C@@H]1CCCCO1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 153.4 %

Procedure:
To a solution of 2.17 g (6.18 mmol) of ethyl 2-methyl-2-{[(2S)-oxan-2-ylmethyl]sulfanyl}propanoate (70%) in THF/water (1/1, 40 mL) are added 1.39 g (18.52 mmol) of lithium hydroxide monohydrate. The reaction is stirred at room temperature for 2 d, then concentrated under reduced pressure to remove the organic solvent. The aqueous residue is washed with diethyl ether (200 mL), then acidified with 6N aqueous HCl solution and extracted with ethyl acetate (3×20 mL). The combined organic extracts are dried (MgSO4), filtered and the filtrate is concentrated under reduced pressure to give 2.07 g of 2-methyl-2-{[(2S)-oxan-2-ylmethyl]sulfanyl}propanoic acid (58 wt % by NMR, residual solvent). Yield: 89%, ES-MS: m/z 219 [M+H]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.29-1.42 (1 H, m), 1.45-1.61 (9 H, m), 1.65-1.73 (1 H, m), 1.80-1.90 (1 H, m), 2.71-2.75 (1 H, m), 2.78-2.84 (1 H, m), 3.37-3.49 (2 H, m), 4.00 (1 H, dt, J=11.41, 2.16 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:3]=1.[K].[C:25]1([CH2:31][CH2:32][S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[Cl:17][C:6]1[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:3]=[C:2]([NH:36][S:33]([CH2:32][CH2:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:34])=[O:35])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16]
Reactant: NS(=O)(=O)CCc1ccccc1
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1Cl
Agent: [K]
Solvent: CN(C)C=O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccncc2)nc1NS(=O)(=O)CCc1ccccc1
Yield: 78.1 %

Procedure:
A solution of 4,6-dichloro-5-(2-methoxyphenoxy)-2-(4-pyridyl)-pyrimidine (2 g) and 2-phenyl-ethanesulfonic acid amide potassium salt (2.82 g, Referential Example 1e) in DMF (50 ml) was stirred at rt for 16 h. Bulk of the solvent was evaporated before it was diluted with diethyl ether (50 ml). The mixture was acidified with 10% aq. citric acid. The precipitate that formed was collected, washed with diethyl ether (100 ml) and dried to give 2-phenyl-ethanesulfonic acid [6-chloro-5-(2-methoxy-phenoxy)-2-pyridin-4-yl-pyrimidin-4-yl]-amide (2.23 g) as a beige powder. LC-MS: tR=4.93 min, [M+1]+=497.22, [M−1]−=494.96.
Reaction SMILES: [CH3:1][O:2][CH:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[CH3:4].[C:14](Cl)(=[O:18])[C:15]([Cl:17])=[O:16]>C(OCC)C>[CH3:1][O:2][CH:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14](=[O:18])[C:15]([Cl:17])=[O:16])=[CH:6]1)[CH3:4]
Reactant: COC(C)n1ccc2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: COC(C)n1cc(C(=O)C(=O)Cl)c2ccccc21
Temperature: 0 °C
Reaction time: 5 h
Yield: 31.1 %

Procedure:
To a solution of 1-(1-methoxyethyl)indole (4 gm, 23 mmol) (prepared as in step a) above) in anhydrous diethyl ether at 0° C. was added oxalyl chloride (4.2 mL, 48 mmol) over 5 minutes. The resulting slurry was stirred at 0° C. for 5 hours, and filtered to afford 1.9 gm of [1-(1-methoxy-ethyl)-1H-indol-3-yl]-oxo-acetyl chloride. (Yield 31%). The material was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:24]1[N:25]([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)[N:26]=[N:27][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:35][C:32]4[CH:31]=[CH:30][C:29]([N:25]5[N:26]=[N:27][CH:28]=[N:24]5)=[CH:34][CH:33]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: Oc1ccc(-n2ncnn2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(-n5ncnn5)cc4)ncnc32)CC1
Yield: 19.2 %

Procedure:
4-[4-(4-Tetrazol-2-yl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (16 mg, 19%) was prepared using the procedure described for the preparation of Example 41 by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 60 mg, 0.18 mmol) with 4-(2H-tetrazol-2-yl)phenol (ChemBridge Corporation, San Diego, Calif., USA; 29 mg, 0.18 mmol) in the presence of potassium carbonate (54 mg, 0.39 mmol).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:23])[CH2:21][CH3:22])=[CH:15][C:13]=3[N:14]=2)=[CH:6][CH:5]=1.[CH3:24]I>CN(C)C=O.C(OCC)(=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([N:19]([CH3:24])[C:20](=[O:23])[CH2:21][CH3:22])=[CH:15][C:13]=3[N:14]=2)=[CH:8][CH:9]=1
Reactant: CCC(=O)Nc1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(=O)N(C)c1ccc2oc(-c3ccc(Cl)cc3)nc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35 %

Procedure:
To sodium hydride (15 mg, 0.37 mmol) under nitrogen at 0° C. was slowly added a solution of N-(2-(4-chlorophenyl)benzo[d]oxazol-5-yl)propionamide (100 mg, 0.33 mmol) in dimethylformamide (10 mL). After 10 min at 0° C., methyl iodide (56 μL, 0.37 mmol) was added, and the solution was left warming up to room temperature for 16 h. The mixture was then diluted with ethyl acetate, and then washed three times with water. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 50:50 v/v to afford 36.4 mg (35%) of the title compound (LCMS RT=7.00 min, MH+ 315.0)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2)([O-])=O.C(O)C>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Reaction time: 9 h
Yield: 85.1 %

Procedure:
A mixture of ethyl 5-nitro-1H-indole-2-carboxylate (15.0 g, 0.0641 mol), 10% palladium-on-carbon catalyst, ethanol (300 ml) and tetrahydrofuran (300 ml) is hydrogenated at an initial pressure of 47 p.s.i. for 9 h and filtered through celite. The filtrate is concentrated and the residue is digested with hot diethyl ether. Concentration of the ether extract gave the titled product (11.14 g): MS (ES) m/z 205 (M+H+), 227 (M+Na+). *Uhlig, F.; Snyder, H. R. Adv. Org. Chem. 1960, 1, 35; Parmerter, S. M.; Cook, A. G.; Dixon, W. B. J. Am. Chem. Soc. 1958, 80, 4621-2.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)[CH2:3][N:4]([C:12]1[S:13][C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][N:21]=[CH:20]3)=[N:15][N:16]=1)C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C@@H:2]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:30][CH:29]=1)[CH2:3][NH:4][C:12]1[S:13][C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][N:21]=[CH:20]3)=[N:15][N:16]=1
Reactant: CC(C)(C)OC(=O)N(C[C@@H](N)Cc1ccc(C(F)(F)F)cc1)c1nnc(-c2ccc3ncncc3c2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](CNc1nnc(-c2ccc3ncncc3c2)s1)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.3 %

Procedure:
tert-Butyl (S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl(5-(quinazolin-6-yl)-1,3,4-thiadiazol-2-yl)carbamate was obtained as a semi-pure yellow solid from tert-butyl 5-(quinazolin-6-yl)-1,3,4-thiadiazol-2-ylcarbamate using the procedure described previously. To a stirred mixture of tert-butyl (S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl(5-(quinazolin-6-yl)-1,3,4-thiadiazol-2-yl)carbamate (17 mg, 32 μmol) in DCM (2.0 mL) was added TFA (2.0 mL). The overall mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue taken up in DCM. The mixture was washed with aqueous NaHCO3 (5 mL) and water (5 mL). The separated aqueous layer was extracted with DCM (2×5 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography (eluting with a gradient of DCM to 10% MeOH in DCM) to provide N—((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-5-(quinazolin-6-yl)-1,3,4-thiadiazol-2-amine as a white solid (1.0 mg, 7% yield). LCMS (M+H) 431.1 calc. for C20H18F3N6S 431.1. 1H NMR (400 MHz, CDCl3): δ ppm 9.43 (d, J=2.74 Hz, 1H) 9.35 (d, J=3.13 Hz, 1H) 8.46 (d, J=8.22 Hz, 1H) 8.19 (s, 1H) 8.09 (d, J=5.87 Hz, 1H) 7.60 (d, J=5.87 Hz, 1H) 7.36 (d, J=6.65 Hz, 2H) 3.66 (d, J=13.89 Hz, 1H) 3.40-3.51 (m, 1H) 2.07 (s, 1H) 1.38-1.79 (m, 2H) 1.26 (s, 2H). 2H obscured.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][O:9][C:10](=[O:24])[NH:11][C:12]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[C:14]([N+:21]([O-])=O)[CH:13]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[H][H]>[C].[Pd].C(O)C>[C:1]([O:6][CH2:7][CH2:8][O:9][C:10](=[O:24])[NH:11][C:12]1[CH:13]=[C:14]([NH2:21])[CH:15]=[C:16]([NH2:18])[CH:17]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)C(=O)OCCOC(=O)Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)C(=O)OCCOC(=O)Nc1cc(N)cc(N)c1
Temperature: 20 °C
Reaction time: 1.17 h

Procedure:
4.8 g of 5% palladium carbon, 48.0 g (0.141 mol) of 2-(3,5-dinitrophenylcarbamoyloxy)ethyl isobutyrate (compound 8) and 700 ml of ethanol were placed in a 5-l autoclave equipped with a thermocouple thermometer and a mixing blade, and the autoclave was sealed. The atmosphere inside the autoclave was replaced by hydrogen and the hydrogen pressure was raised to 5 kg/cm2. The autoclave contents were stirred at room temperature (20° C.). Ten minutes later, the autoclave inside temperature rose to 34° C. and the autoclave inside pressure dropped to 1 kg/cm2. Then, hydrogen was introduced to raise the pressure to 5 kg/cm2, and stirring was continued. 20 minutes later, the temperature became 30° C. and the pressure dropped to 2.5 kg/cm2. Hydrogen was again introduced to raise the pressure to 5 kg/cm2, and stirring was continued. Since the temperature began to drop and the pressure became constant (3 kg/cm2), stirring was continued for 70 minutes (the temperature dropped to 23° C.). The atmosphere inside the autoclave was replaced by nitrogen, and the autoclave contents were taken out and filtered to remove palladium carbon. The filtrate was concentrated by the use of an evaporator. The resulting concentrate was placed under reduced pressure by the use of a rotary pump to distil off the solvent to obtain 2-(3,5-diaminophenylcarbamoyloxy)ethyl isobutyrate (compound 9) as a brown viscous liquid. Yield: 33.7 g (85%)
Reaction SMILES: [I:1][C:2]#[C:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:14][CH3:15].[F:16][C:17]([F:29])([F:28])[C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[CH2:21][N:22]=[N+:23]=[N-:24]>>[I:1][C:2]1[N:22]([CH2:21][C:20]2[CH:25]=[CH:26][CH:27]=[C:18]([C:17]([F:16])([F:29])[F:28])[CH:19]=2)[N:23]=[N:24][C:3]=1[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:14][CH3:15]
Reactant: [N-]=[N+]=NCc1cccc(C(F)(F)F)c1
Reactant: COc1cc(C=O)ccc1OCC#CI
Product: COc1cc(C=O)ccc1OCc1nnn(Cc2cccc(C(F)(F)F)c2)c1I

Procedure:
Synthesized from 4-(3-iodoprop-2-ynyloxy)-3-methoxybenzaldehyde and 3-trifluoromethyl-benzylazide using general procedure; 0.398 g, 0.769 mmol, 97%; mp=130-134° C. (dec.); IR (υ[cm−1]) 3123, 1702, 1689, 1588, 1506, 1329, 1262, 1133, 1123, 994, 792; 1H NMR (600 MHz, CDCl3) δ=9.83 (s, 1H), 7.59 (d, J=7.6, 1H), 7.56 (s, 1H), 7.47 (t, J=7.7, 1H), 7.41 (dd, J=15.8, 6.7, 2H), 7.39 (s, 1H), 7.21 (d, J=8.1, 1H), 5.62 (s, 2H), 5.27 (s, 2H), 3.88 (s, 3H); 13C NMR (151 MHz, CDCl3) δ=191.2, 153.1, 150.5, 147.5, 135.0, 131.6, 131.6 (q, J=32.7), 131.1, 129.9, 126.7, 125.9 (q, J=3.6), 125.1 (q, J=3.7), 123.9 (q, J=272.4), 113.5, 109.7, 81.2, 62.9, 56.3, 54.0; HRMS (ESI-TOF) (m/z): [M+H]+ calcd for C19H16F3IN3O3, 518.0183; found 518.0186.
Reaction SMILES: O.[OH-].[Na+].[Cl:4][CH2:5][C:6]([NH:8][CH:9]([C:15]1[N:16]=[CH:17][S:18][CH:19]=1)[C:10]([O:12]CC)=[O:11])=[O:7]>CO>[Cl:4][CH2:5][C:6]([NH:8][CH:9]([C:15]1[N:16]=[CH:17][S:18][CH:19]=1)[C:10]([OH:12])=[O:11])=[O:7]
Reactant: CCOC(=O)C(NC(=O)CCl)c1cscn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(CCl)NC(C(=O)O)c1cscn1

Procedure:
In 15 ml of dimethylacetamide is dissolved 4 g of ethyl 2-aminothiazol-4-ylacetate and, under ice-cooling, 3.62 g of chloroacetyl chloride is added dropwise. The mixture is stirred under ice-cooling for 30 minutes and, then, at room temperature for another 30 minutes. Then, following the addition of 50 ml of water, the mixture is extracted twice with 100 ml portions of ethyl acetatetetrahydrofuran. The extract is washed with 100 ml of a 5% aqueous solution of sodium hydrogen carbonate and, then, with 100 ml of a saturated aqueous solution of sodium chloride, followed by drying. The solvent is then distilled off. By the above procedure is obtained 2.95 g of ethyl 2-chloroacetamidothiazol-4-ylacetate as an oily product. The entire amount of this oil is suspended in 100 ml of methanol and, under ice-cooling, 12 ml of water containing 761 mg of sodium hydroxide is added. The mixture is stirred at room temperature for 30 minutes, at the end of which time a major portion of the methanol as distilled off under reduced pressure. To the residue is added 10 ml of water. The water layer is washed with 50 ml of ethyl acetate and after the addition of 20 ml of ethyl acetate, it is adjusted to pH 2 with 10% hydrochloric acid. The mixture is shaken well and the organic layer is taken, washed with a saturated aqueous solution of sodium chloride and dried. The solvent is then distilled off. By the above procedure is obtained 1.51 g of 2-chloroacetamidothiazol-4-ylacetic acid as colorless crystals, melting point: 202°-203° C.
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([O:29][CH3:30])[CH:21]=1.[C:31]([NH:35][C:36](=[O:50])[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:38]=1)([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C>ClCCl>[NH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:47]2[CH2:46][CH2:45][N:44]([CH2:43][C:39]3[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=3)[C:36]([NH:35][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:50])[CH2:49][CH2:48]2)=[O:26])=[C:22]([O:29][CH3:30])[CH:21]=1
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Reactant: COc1cc(N)ccc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(N)ccc1C(=O)N1CCN(Cc2cccc(C(=O)NC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.4 %

Procedure:
1-Propanephosphonic acid cyclic anhydride (12.91 g, 20.2 mmol, 12.91 mL) was added dropwise to a solution of 4-amino-2-methoxybenzoic acid (1.70 g, 10.1 mmol), N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (3.07 g, 11.2 mmol) and triethylamine (3.08 g. 30.3 mmol, 4.23 mL) in dichloromethane. The reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure and the residue was taken up with ethyl acetate, washed with water, sodium hydrogen carbonate and brine. The organic phase was concentrated under vacuum to afford the title compound (1.39 g). MS (ESI) m/z 425.4 [M+H]+