Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:19][C:14]3=[N:15][CH:16]=[CH:17][N:18]=[C:13]3[C:12]=2[CH2:20][CH2:21][CH2:22][NH2:23])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:24]([N:26]([CH2:30][CH3:31])[C:27](Cl)=[O:28])[CH3:25].C(N(CC)CC)C.O>O1CCCC1.C(OCC)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:19][C:14]3=[N:15][CH:16]=[CH:17][N:18]=[C:13]3[C:12]=2[CH2:20][CH2:21][CH2:22][NH:23][C:27]([N:26]([CH2:30][CH3:31])[CH2:24][CH3:25])=[O:28])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(CC)C(=O)Cl
Reactant: CC(C)(C)c1ccc(-c2[nH]c3nccnc3c2CCCN)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)NCCCc1c(-c2ccc(C(C)(C)C)cc2)[nH]c2nccnc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 3-(6-(4-tert-butylphenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl)propylamine [0.0324 mmol, Example 24] in tetrahydrofuran (1.5 mL) was treated with diethylcarbamyl chloride (0.0324 mmol) and triethylamine (0.0788 mmol). The solution was stirred at room temperature for 12 hours and water and ethyl acetate were added. The layers were separated and the organic solution was dried over magnesium sulfate. The drying agent was filtered and the solvent was evaporated. The residue was purified by column chromatography (silica gel, ethyl acetate followed by 10% methanol in ethyl acetate) to give the title compound as a yellow solid. MS: 408 (MH+). HPLC (Method C): RT=3.43 minutes.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[C:4]([O:12][CH3:13])[C:3]=1[O:14][CH2:15][O:16][CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[C:37](=[O:41])[O:36][CH2:35]3)O1>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:10][CH:9]([F:11])[O:8][C:5]1[CH:6]=[CH:7][C:2]([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[C:37](=[O:41])[O:36][CH2:35]3)=[C:3]([O:14][CH2:15][O:16][CH3:17])[C:4]=1[O:12][CH3:13]
Reactant: CC1(C)OB(c2ccc3c(c2)COC3=O)OC1(C)C
Reactant: COCOc1c(Br)ccc(OC(F)F)c1OC
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCOc1c(-c2ccc3c(c2)COC3=O)ccc(OC(F)F)c1OC
Temperature: 90 °C
Yield: 42.7 %

Procedure:
A stirring solution of 1-bromo-4-(difluoromethoxy)-3-methoxy-2-(methoxymethoxy)benzene (3 g, 9.58 mmol) in N,N-dimethylformamide (30 mL) was purged with argon for 1 h, to this cesium carbonate (9.36 g, 28.74 mmol), tetrakis(triphenylphosphine) palladium(0) (553 mg, 0.479 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isobenzofuran-1(3H)-one (2.98 g, 11.49 mol) were added and the resultant reaction mixture was heated to 90° C. for 4 h. The reaction mixture was cooled to RT, filtered and the filtrate was diluted with water and extracted with ethyl acetate (3×). The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) afforded 5-(4-(difluoromethoxy)-3-methoxy-2-(methoxymethoxy)phenyl)isobenzofuran-1(3H)-one as a solid (1.5 g, 42%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:42])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=C(C(F)(F)F)[CH:32]=2)[CH:26]=1)(C)(C)C.[C:44](O)([C:46]([F:49])([F:48])[F:47])=O>C(Cl)Cl>[CH2:15]([O:14][C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:42])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[CH:35][N:34]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:32]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1)[CH3:16]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C(F)(F)F)c3)c2)cc1C(F)(F)F
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C(F)(F)F)c3)c1)=N2

Procedure:
The title compound was prepared from (5-ethoxy-2-{3-oxo-3-[3-(2-trifluoromethyl-pyridin-4-yl)-phenyl]-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M248) (0.30 g, 0.49 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (220 mg, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([CH:23]=3)[CH2:12][NH:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][CH:15]=3.[CH3:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([CH:23]=3)[CH2:12][N:13]([C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:25]([CH3:24])=[CH:26][CH:27]=3)[C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][CH:15]=3
Reactant: Clc1cnc2nc1Nc1cccc(c1)NCc1cccc(c1)N2
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: Cc1ccc(C(=O)N2Cc3cccc(c3)Nc3ncc(Cl)c(n3)Nc3cccc2c3)cc1
Yield: 48 %

Procedure:
The desired compound was prepared as a white powder according to the procedure of Example C22, step F, using 6-chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene and 4-methylbenzoic acid chloride as the starting materials in 48% yield. LCMS for C25H21ClN5O (M+H)+: m/z=442.0.
Reaction SMILES: [CH3:1][Si:2]([CH3:48])([CH3:47])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:32][CH2:31][CH:30]([CH2:33][C:34](OCC)=O)[CH2:29][CH2:28]2)[CH:9]=1.C[Si](C)(C)CCOC[N:55](COCC[Si](C)(C)C)C1N2N=CC(I)=C2N=C(C2CCC(CC#N)CC2)C=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC(I)=C2N=C(C2CCC(CC(OCC)=O)CC2)C=1>>[CH3:45][Si:43]([CH3:46])([CH3:44])[CH2:42][CH2:41][O:40][CH2:39][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:47])([CH3:48])[CH3:1])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:28][CH2:29][CH:30]([CH2:33][C:34]#[N:55])[CH2:31][CH2:32]2)[CH:9]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(CC#N)CC2)nc2c(I)cnn12
Reactant: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)CC1
Agent: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(CC#N)CC2)nc2c(-c3cnc4ccccc4c3)cnn12

Procedure:
2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetonitrile was synthesized in a manner similar to the synthesis of ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate, but with 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetonitrile substituted for ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:33][C:34]2[CH:38]=[C:37]([CH3:39])[NH:36][N:35]=2)=[N:4][C:5]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH:16]3[CH2:21][CH2:20][N:19](CC4C=CC(OC)=CC=4)[C:18](=[O:31])[CH2:17]3)=[C:11]([CH3:32])[CH:10]=2)=[N:6][CH:7]=1>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[C:3]([NH:33][C:34]2[CH:38]=[C:37]([CH3:39])[NH:36][N:35]=2)=[N:4][C:5]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH:16]3[CH2:21][CH2:20][NH:19][C:18](=[O:31])[CH2:17]3)=[C:11]([CH3:32])[CH:10]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(CN2CCC(c3cc(C)c(Nc4ncc(Cl)c(Nc5cc(C)[nH]n5)n4)cc3C)CC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNC(=O)C4)cc3C)ncc2Cl)n[nH]1
Temperature: 25 °C

Procedure:
A solution of 4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)-1-(4-methoxybenzyl)piperidin-2-one (45 mg) in TFA (0.5 mL) was heated to 100° C. for 24 hr. After cooling down to room temperature, the mixture was concentrated and purified by preparative RP-HPLC to provide 4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)piperidin-2-one. ESMS m/z 426.2 (M+H+).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][NH2:7])[N:3]=[CH:2]1.[CH3:8][C:9]([O:12][C:13]([N:15]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[N:16]([C:24]1[C:29]([F:30])=[C:28](Cl)[N:27]=[C:26]([Cl:32])[N:25]=1)[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14])([CH3:11])[CH3:10].C(N(CC)CC)C>C1COCC1.O>[CH3:11][C:9]([O:12][C:13]([N:15]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[N:16]([C:24]1[C:29]([F:30])=[C:28]([NH:7][CH2:6][C:4]2[N:3]=[CH:2][S:1][CH:5]=2)[N:27]=[C:26]([Cl:32])[N:25]=1)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[O:14])([CH3:8])[CH3:10]
Reactant: NCc1cscn1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(NCc2cscn2)c1F
Reaction time: 8 h
Yield: 67.8 %

Procedure:
To a suspension of (1,3-thiazol-4-ylmethyl)amine (0.1491 g, 1.308 mmol) in THF (10 mL) was added a solution of tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (0.649 g, 1.308 mmol) and triethylamine (0.22 mL, 1.5784 mmol) in THF (2 mL). Additional THF (3 mL) was added, and the reaction was stirred overnight. Then the reaction mixture was diluted with water, and the aqueous layer was extracted with ethyl acetate. The organics were dried (Na2SO4) and concentrated. The resulting crude material was purified by silica gel chromatography (0-100% ethyl acetate in hexanes) to produce tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[(1,3-thiazol-4-ylmethyl)amino]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate as a yellow oil (0.51 g, 68%). LCMS: (M-2Boc)=375.0.
Reaction SMILES: [OH:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][C:8]3[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=3/[C:10](=[CH:11]/[CH2:12][CH2:13][NH:14][CH3:15])/[C:4]=2[CH:3]=1>Cl.CO>[OH:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][C:8]3[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=3/[C:10](=[CH:11]\[CH2:12][CH2:13][NH:14][CH3:15])/[C:4]=2[CH:3]=1
Reactant: CNCC/C=C1/c2ccccc2COc2ccc(O)cc21
Agent: Cl
Solvent: CO
Product: CNCC/C=C1\c2ccccc2COc2ccc(O)cc21
Temperature: 140 °C

Procedure:
A mixture of (Z)-2-Hydroxy-11-(3-methylaminopropylidene)-6,11-dihydrodibenzo[b,e]oxepin (2.5 mg) is dissolved in a mixture of hydrochloric acid (1 ml) and methanol (9 ml) and heated at 140° C. (oil bath) for 4 hr. The product is isolated by means of HPLC and evaporation of solvents.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3[N:9]2[C:12]([CH3:15])=[N:13][N:14]=3)=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:26]1[CH:27]=[N:28][CH:29]=[C:30]([CH3:34])[C:31]=1[O:32][CH3:33].O1CCOCC1.C([O-])(=O)C.[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3[N:9]2[C:12]([CH3:15])=[N:13][N:14]=3)=[CH:4][C:3]=1[C:26]1[CH:27]=[N:28][CH:29]=[C:30]([CH3:34])[C:31]=1[O:32][CH3:33]
Reactant: COc1c(C)cncc1Br
Reactant: Cc1nnc2n1-c1cc(F)c(B3OC(C)(C)C(C)(C)O3)cc1CC2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(C)cncc1-c1cc2c(cc1F)-n1c(C)nnc1CC2
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 8-fluoro-1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline (122-6; 0.247 g, 0.00375 mol) and 3-Bromo-4-methoxy-5-methyl-pyridine (0.909 g, 0.0045 mol) in the mixture of 1,4-dioxan (10 mL) and water (10 mL) was added Potassium acetate (1.109 g, 0.0112 mol). Reaction mass was purged with argon for 20 min. Then catalyst Pd(dppf)2Cl2 (0.153 g, 0.000187 mol) was added and allowed to stir at 80° C. for 12 h. The reaction mixture was filtered through CELITE bed and filter bed was thoroughly washed with ethyl acetate. The collected organic parts were concentrated under vacuum to afford the crude compound, which was purified by silica gel column chromatography to obtain title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.27 (s, 1H), 7.65-7.62 (d, J=12 Hz, 1H), 7.57-7.55 (d, J=8 Hz, 1H), 3.54 (s, 3H), 3.03-2.97 (m, 4H), 2.71 (s, 3H), 2.28 (s, 3H). LCMS (M+1): 325.1.
Reaction SMILES: [OH-:1].[K+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([C:17]2[N:22]=[CH:21][C:20](Br)=[CH:19][N:18]=2)[CH:14]=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.Cl>C(O)CO.[S]>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([C:17]2[N:22]=[CH:21][C:20]([OH:1])=[CH:19][N:18]=2)[CH:14]=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: [OH-]
Reactant: Brc1cnc(-c2cccc(OCc3ccccc3)c2)nc1
Agent: Cl
Agent: [K+]
Agent: [S]
Solvent: OCCO
Solvent: O
Product: Oc1cnc(-c2cccc(OCc3ccccc3)c2)nc1
Reaction time: 3 h
Yield: 80.5 %

Procedure:
A solution of 4.76 g (85.3 mmol) of potassium hydroxide in 20 ml of ethylene glycol is added dropwise over the course of 2 hours at 180° C. to 7.26 g (21.3 mmol) of 2-(3-benzyloxyphenyl)-5-bromopyrimidine and 0.035 g (1.08 mmol) of sulfur in 60 ml of ethylene glycol. The mixture is kept at 180° C. for a further 3 hours, poured into water and acidified by means of 37% strength hydrochloric acid, and the solid which precipitates is isolated by filtration. Purification by chromatography (silica gel/hexane: ethyl acetate=32) gives 4.77 g of 2-(3-benzyloxyphenyl)-5-hydroxypyrimidine. ##STR28##
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:36])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27](=[O:34])(=[O:33])[NH:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:17][C:16]=1[F:35])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.CCOC(C)=O>[C:29]([NH:28][S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:36])=[C:16]([F:35])[CH:17]=1)(=[O:34])=[O:33])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)C2CCCN2C(=O)OC(C)(C)C)c(F)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)C2CCCN2)c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-(2′-tert-Butylsulfamoyl-3-fluoro-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.3 g, 2.5 mmol) was dissolved in 40 mL DCM, cooled in an ice bath, added 10 mL trifluoroacetic acid, stirred at 0° C. for 30 minutes then at ambient temperature for one hour. Concentrated solution, redissolved in EtOAc (150 mL), washed with saturated NaHCO3 (2×100 mL), water (100 mL), brine (100 mL), dried with MgSO4, filtered and concentrated to yield title compound as a white solid. (1 g, 91%) APCI (AP−): 418.2 (M−H)−.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[S:24][C:23]([C:25](=O)[CH2:26][CH2:27][C:28](=O)[CH:29]([C:37]2[CH:42]=[CH:41][C:40]([S:43]([CH:46]3[CH2:48][CH2:47]3)(=[O:45])=[O:44])=[CH:39][CH:38]=2)[CH2:30][CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[N:22][N:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:55].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Si:1]([O:18][CH2:19][C:20]1[S:24][C:23]([C:25]2[NH:55][C:28]([CH:29]([C:37]3[CH:42]=[CH:41][C:40]([S:43]([CH:46]4[CH2:47][CH2:48]4)(=[O:44])=[O:45])=[CH:39][CH:38]=3)[CH2:30][CH:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[CH:27][CH:26]=2)=[N:22][N:21]=1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: CC(C)(C)[Si](OCc1nnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)s1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)[Si](OCc1nnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1)(c1ccccc1)c1ccccc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a solution of 1-[5-({[tert-butyl(diphenyl)silyl]oxy}methyl)-1,3,4-thiadiazol-2-yl]-5-[4-(cyclopropylsulfonyl)phenyl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (168 mg) in acetic acid (2.3 mL) was added ammonium acetate (283 mg), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (122 mg, yield 74%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio).
Reaction SMILES: [O:1]=[C:2]1[NH:11][CH:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[S:20][CH3:21])[C:9]2[C:8](=[O:22])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1.[CH:33]([N:36]([CH:39](C)C)CC)(C)C.C1C([N+]([O-])=[O:49])=CC=C([Cl-]C([O-])=O)C=1.CN.C(=O)(OC1C=CC([N+]([O-])=O)=CC=1)N>C(#N)C.CN(C)C1C=CN=CC=1>[CH3:33][NH:36][C:39]([N:11]1[CH:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[S:20][CH3:21])[C:9]2[C:8](=[O:22])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[C:2]1=[O:1])=[O:49]
Reactant: CCN(C(C)C)C(C)C
Reactant: CSc1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Agent: CN
Agent: CN(C)c1ccncc1
Agent: NC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: CNC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1SC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-[2,5-dioxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4,5,6,7,8-octahydroquinazoline-4-yl]-3-methylsulfanyl-benzonitrile (INTERMEDIATE 6; 82 mg; 0.179 mmol) and diisopropylethylamine (100 μL; 0.588 mmol) in acetonitrile (1 mL) is added 4-nitrophenylchloroformate (170 mg; 0.843 mmol) and 4-dimethylaminopyridine (210 mg; 1.719 mmol) in little portions over 19 h at room temperature. Methylamine (1M in THF; 1 mL; 1.00 mmol) is added to the mixture containing the 4-nitro-phenyl carbamate intermediate and the mixture is stirred at room temperature for 30 min. The reaction mixture is purified by reversed phase HPLC (Sunfire, gradient of acetonitrile in water, 0.1% TFA). Yield: 63 mg. ESI mass spectrum: [M+H]+=515; Retention time HPLC: 1.11 min (Z018_S04).
Reaction SMILES: [NH2:1][C:2](=[S:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[CH:10]([CH3:21])[C:11](=O)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1>CN(C=O)C.CCOC(C)=O>[Br:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][C:11]1[N:1]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[S:8][C:10]=1[CH3:21]
Reactant: CC(Br)C(=O)Cc1cccc(Br)c1
Reactant: CCOC(=O)C(N)=S
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(Cc2cccc(Br)c2)c(C)s1
Temperature: 70 °C
Reaction time: 12 h

Procedure:
A mixture of ethyl 2-amino-2-thioxoacetate (50.9 mg, 0.38 mmol) and 3-bromo-1-(3-bromophenyl)butan-2-one (0.38 mmol, crude from previous step) in DMF (2 mL) was stirred at 70° C. for 12 h. The mixture was diluted with EtOAc and washed with H2O. The organic layer was concentrated, and purified by silica gel column chromatography(0-50% EtOAc/Hexane) to yield a yellowish solid (71 mg, 55% over 2 steps). MS (ES+) C14H14BrNO2S requires: 339, 341 found: 340, 342 [M+H]+(1:1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][N:4]([CH2:20][CH2:21][Br:22])[C:5]1[C:6]([N+:17]([O-:19])=[O:18])=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=O.C(Br)(=O)C(Br)=O.[NH2:29][CH2:30][CH2:31][CH2:32][OH:33].CCOC(C)=O.O(C(C)C)C(C)C>C1C=CC=CC=1.CN(C=O)C.O>[OH:33][CH2:32][CH2:31][CH2:30][NH:29][C:10](=[O:12])[C:9]1[CH:13]=[C:5]([N:4]([CH2:3][CH2:2][Br:1])[CH2:20][CH2:21][Br:22])[C:6]([N+:17]([O-:19])=[O:18])=[CH:7][C:8]=1[N+:14]([O-:16])=[O:15]
Reactant: NCCCO
Reactant: O=C(O)c1cc(N(CCBr)CCBr)c([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C(Br)C(=O)Br
Solvent: CN(C)C=O
Solvent: c1ccccc1
Solvent: CC(C)OC(C)C
Product: O=C(NCCCO)c1cc(N(CCBr)CCBr)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A suspension of powdered 5-[bis(2-bromoethyl)amino]-2,4-dinitrobenzoic acid (2) (1.10 g, 2.49 mmol) in benzene (170 mL) was treated at 20° C. with oxalyl bromide (1.10 mL, 11.7 mmol) and DMF (2 drops). The mixture was stirred at 20° C. for 2 h, then concentrated under reduced pressure, and re-evaporated to dryness in the presence of benzene under high vacuum. The resulting acid bromide was dissolved in Me2CO (20 mL) and the solution was treated at −5° C. with a cold solution of 3-amino-1-propanol (0.39 g, 5.19 mmol) in water (10 mL). The mixture was shaken at room temperature for 5 min, then diluted with water and extracted with EtOAc (2×). The organic extract was worked up and the resulting residue was chromatographed on silica gel, eluting with EtOAc, to give IIa-8 (1.06 g, 85%): mp (EtOAc/i-Pr2O) 85-86° C.; 1H NMR [(CD3)2SO] δ 8.64 (t, J=5.6 Hz, 1 H, CONH), 8.53 (s, 1 H, H-3), 7.41 (s, 1 H, H-6), 3.77-3.64 (m, 8 H, N(CH2CH2Cl)2), 4.46 (br s, 1 H, OH), 3.49 (t, J=6.3 Hz, 2 H, CH2OH), 3.33-3.25 (m, partially obscured, 2 H, CONHCH2), 1.68 (pent, J=6.72 Hz, 2 H, CH2CH2CH2). Anal. (C14Hl18Br2N4O6) C, H, N, Br.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:16][OH:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH:16]=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](CO)NC(=O)OCc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)[C@@H](C=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a stirred solution of N-benzyloxycarbonyl-L-valinol (8.80 g, 0.037 mol) and triethylamine (30.00 g, 41.3 mL, 0.30 mol) in 100 mL dimethylsulfoxide under a nitrogen atmosphere was added a solution of sulfur trioxide pyridine complex (20.62 g, 0.130 mol) in dimethylsulfoxide (100 mL) dropwise via an addition funnel. An ice water bath was used to maintain the temperature of the reaction mixture below room temperature during the addition. After 30 min the cooling bath was removed and the reaction was allowed to warm to room temperature over 2 h. The brown solution was acidified with cold 2N HCl to approximately pH 2 and extracted with ether (3×150 mL). The combined organic layers were washed with brine, dried (anhydrous magnesium sulfate) and evaporated to give 7.40 g of N-benzyloxycarbonyl-L-valinal (84.8%) as a yellow oil. The resulting material can be used without purification or further purified using column chromatography (silica gel, 9:1 hexanes:ethyl acetate).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]3[O:14][C:13]([SH:15])=[N:12][N:11]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:16][C:17]1[C:22]([CH2:23]Br)=[C:21]([F:25])[C:20]([F:26])=[C:19]([F:27])[C:18]=1[F:28]>CCO>[F:16][C:17]1[C:22]([CH2:23][S:15][C:13]2[O:14][C:10]([C:7]3[CH:8]=[CH:9][C:4]4[NH:3][CH:2]=[N:1][C:5]=4[CH:6]=3)=[N:11][N:12]=2)=[C:21]([F:25])[C:20]([F:26])=[C:19]([F:27])[C:18]=1[F:28]
Reactant: Fc1c(F)c(F)c(CBr)c(F)c1F
Reactant: Sc1nnc(-c2ccc3nc[nH]c3c2)o1
Solvent: CCO
Product: Fc1c(F)c(F)c(CSc2nnc(-c3ccc4[nH]cnc4c3)o2)c(F)c1F

Procedure:
1 (0.33 g, 1.5 mmol), TEA (0.209 mL, 1.5 mmol) and pentafluorobenzylbromide (0.204 mL, 1.5 mmol) were dissolved in 10 mL of EtOH and kept under reflux overnight. The solvent was removed and the remaining oil was purified by flash-chromatography on silica gel, applying a CHCl3/MeOH gradient.