Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([N:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[CH:9]=[C:8]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][O:26][C:27]4[CH:35]=[CH:34][CH:33]=[C:32]5[C:28]=4[CH:29]=[C:30]([C:36]([NH2:38])=O)[NH:31]5)[CH2:19][CH2:18]3)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1.C(Cl)Cl>[C:36]([C:30]1[NH:31][C:32]2[C:28]([CH:29]=1)=[C:27]([O:26][CH2:25][CH2:24][CH2:23][N:20]1[CH2:21][CH2:22][N:17]([C:8]3[N:7]=[C:6]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[N:11]=[C:10]([N:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)[CH:9]=3)[CH2:18][CH2:19]1)[CH:35]=[CH:34][CH:33]=2)#[N:38]
Reactant: NC(=O)c1cc2c(OCCCN3CCN(c4cc(N5CCCC5)nc(N5CCCC5)n4)CC3)cccc2[nH]1
Solvent: C1COCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc2c(OCCCN3CCN(c4cc(N5CCCC5)nc(N5CCCC5)n4)CC3)cccc2[nH]1
Reaction time: 18 h

Procedure:
A solution of 4-[3-[4-[2,4-dipyrrolidino-6-pyrimidinyl]-1-piperazinyl]propoxy]indole-2-carboxamide (0.45 g) in dioxane (12 ml), under nitrogen, is mixed with pyridine (0.33 ml), cooled to 12° and treated during 5 min. with a solution of trifluoroacetic anhydride (0.31 ml) in dioxane (2.5 ml). The mixture is stirred at 12° for 15 min. and at 20°-25° for 18 hr. It is again cooled to 12° and treated with additional trifluoroacetic anhydride (0.1 ml) in dioxane (1 ml). The mixture is kept at 12° for 15 min. and at 20°-25° for 4 hr. It is then diluted with methylene chloride; washed with saturated sodium bicarbonate, water and saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed over silica gel (275 ml) with eluting with ammonium hydroxide/methanol/methylene chloride (0.5/5/94.5). The product isolated from this column is crystallized from methanol to give the title compound, mp of an analytical sample 147°-149°;, Anal. calc'd for C28H36N8O: C, 67.17; H, 7.25; N, 22.38. Found: C, 66.80; H, 7.34; N, 21.78. ##STR7##
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:49]1[C:57]2[C:52](=[CH:53][C:54]([C:58]3[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=3)=[CH:55][CH:56]=2)[CH:51]=[CH:50]1>CN(C=O)C>[NH:49]1[C:57]2[C:52](=[CH:53][C:54]([C:58]3[CH:59]=[C:60]([NH:64][C:22]([C:17]4[C:18](=[O:21])[O:19][C:20]5[C:15]([CH:16]=4)=[CH:14][CH:13]=[CH:12][C:11]=5[OH:10])=[O:24])[CH:61]=[CH:62][CH:63]=3)=[CH:55][CH:56]=2)[CH:51]=[CH:50]1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2ccc3[nH]ccc3c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2ccc3[nH]ccc3c2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 65 %

Procedure:
DIEA (0.014 mL, 0.073 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.015 g, 0.066 mmol) and HATU (0.030 g, 0.073 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-Indol-5-yl)-phenylamine (0.015 g, 0.066 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.017 g of product in 61% yield: LCMS (ESI) m/z 397 (MH+).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[O:6]([CH:13]([CH3:17])[CH2:14][CH2:15][OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[S:1]([O:16][CH2:15][CH2:14][CH:13]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:17])(=[O:4])(=[O:3])[NH2:2]
Reactant: CC(CCO)Oc1ccccc1
Reactant: NS(=O)(=O)Cl
Product: CC(CCOS(N)(=O)=O)Oc1ccccc1
Yield: 67 %

Procedure:
The title compound was prepared by procedures of Example 33 from sulfamoyl chloride and 3-phenoxy-1-butanol. The viscous oil obtained was purified by high pressure chromatography using a Waters Associates Prep LC/System 500A; Prepak 500® silica and methylene chloride as eluting agent at a flow rate of 200 ml/min. Fractions containing the title compound were combined and the solvent was evaporated under reduced pressure to give 12.7 g (67%) of title compound as yellow, viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[CH:10]12[C:19](=O)[O:18][C:16](=[O:17])[CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15]2>C(O)(=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[C:16](=[O:17])[CH:11]3[CH:10]([CH2:15][CH2:14][CH2:13][CH2:12]3)[C:19]2=[O:18])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: O=C1OC(=O)C2CCCCC12
Solvent: CC(=O)O
Product: O=C1C2CCCCC2C(=O)N1c1ccc(Cl)cc1F

Procedure:
9.44 parts of 4-chloro-2-fluoroaniline were then added to a solution of 10 parts of cyclohexane-1,2-dicarboxylic anhydride in 75 parts of glacial acetic acid. After refluxing for 6 hours, the reaction mixture was poured into 200 parts of ice. The resulting crystals were filtered and recrystallized from 70 parts of methanol at -40° C. to yield 12.4 parts of white crystals of 2-(4-chloro-2-fluorophenyl)-3a,4,5,6,7,7a-hexahydro-1H-isoindole-1,3(2H)dione melting at 94°-95.5°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([N:13]=[O:14])[CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1>C(OC(=O)C)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:9]=[C:10]([O-:12])[O+:14]=[N:13]2)=[CH:6][CH:7]=1
Reactant: O=NN(CC(=O)O)c1ccc(F)cc1
Solvent: CC(=O)OC(C)=O
Product: [O-]c1cn(-c2ccc(F)cc2)n[o+]1
Temperature: 70 °C
Yield: 106.6 %

Procedure:
N-(4-fluorophenyl)-N-nitrosoglycine (11.5 g, 54.7 mmol) was dissolved in acetic anhydride (100 mL) and heated to 70° C. for 14 h. The reaction mixture was cooled and then poured into ice water (300 mL) After for stirring for 30 m, the reaction mixture was filtered to provide 10.50 g (100%) of the title product.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][S:8][C:4]=2[CH:3]=[N:2]1.[I:9]I.[OH-].[K+].S(=O)(O)[O-].[Na+]>CN(C)C=O.O>[I:9][C:3]1[C:4]2[S:8][CH:7]=[CH:6][C:5]=2[NH:1][N:2]=1
Reactant: c1cc2[nH]ncc2s1
Reactant: II
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Ic1n[nH]c2ccsc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
To a solution of 1H-thieno[3,2-c]pyrazole (160 mg, 1.29 mmol) and iodine (490 mg, 1.94 mmol) in dimethyl formamide (5 mL) is added potassium hydroxide (220 mg, 3.87 mmol). The mixture is stirred at room temperature for 30 minutes. A solution of sodium bisulfite (200 mg) in water (2 mL) is then added. It is extracted twice with diethyl ether. The combined organic layers are dried over magnesium sulfate and concentrated. The residue is chromatographed (n-heptane-ethyl acetate, 90:100) to afford 195 mg (60%) of 3-iodo-1H-thieno[3,2-c]pyrazole as a beige powder. LC/MS: RT=2.50 minutes, 250.90 m/e (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[C:25]1([C@H:31]2[CH2:36][NH:35][CH2:34][CH2:33][NH:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:35]4[CH2:34][CH2:33][NH:32][C@@H:31]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:36]4)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Reactant: c1ccc([C@H]2CNCCN2)cc1
Product: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCN[C@@H](c5ccccc5)C4)c(F)cc3cc2c1=O
Yield: 51.9 %

Procedure:
Working under the conditions of Example 26, but starting with 3-ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.38 g) and (S)-2-phenylpiperazine (0.8 g), (S)-3-ethoxycarbonyl-7,9-difluoro-1-methyl-4-oxo -8-(3-phenyl-1-piperazinyl)-1,4-dihydrobenzo[b][1,8]naphthyridine (1.02 g) is obtained in the form of a yellow solid, m.p. 216° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.[CH3:12][NH2:13]>C1C=CC=CC=1>[CH3:12][NH:13][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1
Reactant: CN
Reactant: O=c1[nH]nc2ccc(Cl)nn12
Solvent: c1ccccc1
Product: CNc1ccc2n[nH]c(=O)n2n1

Procedure:
20.5 g. of 6-chloro-1,2,4-triazolo[4,3-b]pyridazin-3(2H)-one (0.12 mol.) and a solution of 14.85 g. of methylamine (0.48 mol.) in 160 ml. of benzene are heated in an autoclave at 120° for 5 hours. After cooling, the precipitated product is filtered off and the filtrate is evaporated to dryness. Both portions of 6-methylamino-1,2,4-triazolo[4,3-b]pyridazin-3(2H)-one are treated with dilute aqueous hydrochloric acid, filtered off and recrystallized from water to give 15.8 g. (80%) of material, m.p. > 348° .
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:17]=[N:18][C:19]([C:22]3[CH:23]=[C:24]([CH:40]=[CH:41][CH:42]=3)[CH2:25][N:26]3[C:30]4[CH:31]=[C:32]([C:35]([F:38])([F:37])[F:36])[CH:33]=[CH:34][C:29]=4[S:28][C:27]3=[O:39])=[N:20][CH:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][C:16]2[CH:17]=[N:18][C:19]([C:22]3[CH:23]=[C:24]([CH:40]=[CH:41][CH:42]=3)[CH2:25][N:26]3[C:30]4[CH:31]=[C:32]([C:35]([F:36])([F:38])[F:37])[CH:33]=[CH:34][C:29]=4[S:28][C:27]3=[O:39])=[N:20][CH:21]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cnc(-c3cccc(Cn4c(=O)sc5ccc(C(F)(F)F)cc54)c3)nc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1sc2ccc(C(F)(F)F)cc2n1Cc1cccc(-c2ncc(OCC3CCNCC3)cn2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
424 mg (0.64 mmol) of 3-{3-[5-(1-tert-butoxycarbonylpiperidin-4-yl-methoxy)pyrimidin-2-yl]benzyl}-5-trifluoromethyl-3H-benzothiazol-2-one is dissolved in 20 ml of dioxane, and 6 ml of 4N HCl in dioxane are added. The mixture is stirred at room temperature for 24 h. A viscous precipitate forms in the process, which is filtered off with suction and stirred with isopropanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N+:11]([O-])=O)[C:5]=1[C:14]#[C:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]([C:25]([O:27][CH3:28])=[O:26])[CH3:24])=[CH:18][CH:17]=1.[Cl-].[NH4+].Cl>CO.[Fe]>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([NH2:11])[C:5]=1[C:14]#[C:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]([C:25]([O:27][CH3:28])=[O:26])[CH3:24])=[CH:18][CH:17]=1
Reactant: COC(=O)c1cc(F)cc([N+](=O)[O-])c1C#Cc1ccc(CN(C)C(=O)OC)cc1
Agent: [Fe]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: COC(=O)c1cc(F)cc(N)c1C#Cc1ccc(CN(C)C(=O)OC)cc1
Temperature: 65 °C
Yield: 94.8 %

Procedure:
The crude compound 9 (140 g) was dissolved in methanol (1.05 L). Iron powder (325 mesh, 76.2 g, 1.36 mol) was added followed by addition of saturated aqueous ammonium chloride (210 ml). The solution was heated to 65° C. Aqueous hydrochloric acid (16 wt %, 32 ml) was added. The reaction was heated at 65° C. for 2 hours. HPLC analysis indicated the completion of the reaction. The reaction mixture was cooled to room temperature. Solid was removed by filtration. The filter cake was washed with methanol (2 L). The combined methanol solution was concentrated to dryness. The residue was partitioned between ethyl acetate (800 ml) and diluted aqueous hydrochloric solution (0.5 M, 300 ml). Organic layer was separated. Aqueous layer was extracted with ethyl acetate (3×200 ml). The combined organic solution was washed with brine (200 ml). The solution was then concentrated to dryness to afford 122.8 g of crude product as dark oil. This crude product was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 2.87 (d, br, 3H), 3.491 (s, 3H), 3.932 (s, 3H), 4.486 (s, br, 2H), 6.60 (dd, 1H, J=2.7 Hz and J=9.9 Hz), 7.04 (dd, 1H, J=2.4 Hz and J=9.0 Hz), 7.237 (s, br, 2H), 7.52 (d, 2H, J=8.1 Hz).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:17])[C:5]([C:12]([O:14]CC)=[O:13])=[CH:6][NH:7]2.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([F:38])[CH:34]=2)[CH:29]=1.[OH-].[Li+].Cl>CN(C=O)C>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:17])[C:5]([C:12]([OH:14])=[O:13])=[CH:6][N:7]2[CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([F:38])[CH:34]=2)[CH:29]=1
Reactant: Fc1ccc2cc(CBr)ccc2c1
Reactant: CCOC(=O)c1c[nH]c2cccc(F)c2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: O=C(O)c1cn(Cc2ccc3cc(F)ccc3c2)c2cccc(F)c2c1=O
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a mixture of ethyl 5-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (0.050 g, 0.21 mmol), potassium carbonate (0.088 g, 0.64 mmol) and potassium iodide (3 mg, 0.02 mmol) was added the above 2-(bromomethyl)-6-fluoronaphthalene in 1 mL of DMF. The reaction was stirred overnight at 40° C. and 1 mL of a saturated aqueous lithium hydroxide solution was then added to the reaction. After stirring for 30 min, the solution was acidified with 4 N HCl and the product was extracted three times with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by reverse phase HPLC to provide the 5-fluoro-1-[(6-fluoro-2-naphthyl)methyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid which gave a mass ion (ES+) of 366 for M+H+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[C:5]2[CH2:12][CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16].[C:19]([N:26]1[CH2:31][CH2:30][CH:29](O)[CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].N(C([O-])=O)=NC([O-])=O>O1CCCC1>[C:22]([O:21][C:19]([N:26]1[CH2:31][CH2:30][CH:29]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[N:7][CH:6]=[C:5]3[CH2:12][CH2:13][CH2:14][C:15]([F:18])([F:16])[F:17])[CH2:28][CH2:27]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: Oc1ccc2cncc(CCCC(F)(F)F)c2c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: O=C([O-])N=NC(=O)[O-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3cncc(CCCC(F)(F)F)c3c2)CC1
Reaction time: 8 h
Yield: 26.8 %

Procedure:
100 mg of compound 88, 118 mg of Boc-(4-hydroxy)piperidine and 416 mg of Diphenyl-[4-[1H,1H,2H,2H-perfluorodecyl]phenyl]phosphine were dissolved in 5 mL of dry tetrahydrofuran. 208 mg of Bis (1H, 2H, 2H, 3H, 3H-perfluorononyl)-azodicarboxylate were added and the reaction was allowed to stir overnight. The mixture was evaporated to dryness and filtered over a 5 g Fluoro-Flash cartridge. The obtained crude product was purified by preparative HPLC to yield 46 mg of the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:25])=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([NH:7][CH2:8][CH:9]([OH:21])[CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:6].CC(O)=O.[O:30]1[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1.[BH3-]C#N.[Na+]>CO>[CH2:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][N:11]1[CH2:10][CH:9]([OH:21])[CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:22]=[CH:23][CH:24]=[C:2]([NH:1][CH:33]2[CH2:34][CH2:35][O:30][CH2:31][CH2:32]2)[C:3]=1[CH3:25]
Reactant: Cc1c(N)cccc1C(=O)NCC(O)CN1CCc2ccccc2C1
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1c(NC2CCOCC2)cccc1C(=O)NCC(O)CN1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.6 %

Procedure:
To a solution of 3-amino-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-2-methylbenzamide (200 mg, 0.59 mmol) in MeOH (8 mL) was added AcOH (0.05 mL) and dihydro-2H-pyran-4(3H)-one (118 mg, 1.18 mmol). The mixture was stirred at 25° C. for 2 h. NaBH3CN (186 mg, 2.95 mmol) was added and the resulting mixture was stirred at 25° C. for 2 h. The reaction solution was concentrated and the residue was washed with water and extracted with EA. The organic layer was concentrated, and the residue was purified by prep-HPLC to give the title compound (24 mg, Yield 9.6%). 1H NMR (CD3OD, 400 MHz): δ 8.41 (s, 1H), 7.35-7.23 (m, 3H), 7.20 (d, J=7.0 Hz, 1H), 7.11 (t, J=7.8 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 6.70 (d, J=7.3 Hz, 1H), 4.44 (s, 2H), 4.33 (brs, 1H), 3.99 (d, J=11.5 Hz, 2H), 3.66-3.43 (m, 7H), 3.38-3.16 (m, 4H), 2.15 (s, 3H), 2.01 (d, J=12.8 Hz, 2H), 1.63-1.48 (m, 2H). LCMS (m/z): 424.2 (M+1).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([CH:20]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=4[F:32])[N:23]=[C:22]([C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])[CH2:21]3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[ClH:40]>C(OCC)(=O)C>[ClH:40].[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[N:24]1[CH:20]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:19]=2)[CH2:21][C:22]([C:33]([F:39])([F:38])[C:34]([F:35])([F:36])[F:37])=[N:23]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)ccn2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccnc(N3CCNCC3)c2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-[2-(4-BOC-piperazin-1-yl)-pyridin-4-yl]-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (320.0 mg, 0.6 mmol) prepared in Example 192 was added to a saturated solution of hydrochloric acid in ethyl acetate (3.0 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give 300.0 mg of the titled compound as a brown liquid.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21](O)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[N:37]([CH3:38])[CH2:36][CH2:35][N:34]([CH3:39])[C:33]2=[O:40])=[CH:28][CH:27]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:23]3[C:18]([CH:19]=[N:20][C:21]([NH:25][C:26]4[CH:27]=[CH:28][C:29]([CH:32]5[C:33](=[O:40])[N:34]([CH3:39])[CH2:35][CH2:36][N:37]5[CH3:38])=[CH:30][CH:31]=4)=[N:22]3)=[CH:17][CH:16]=2)[CH:10]=1)(=[O:7])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN1CCN(C)C(c2ccc(N)cc2)C1=O
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2ccc3cnc(O)nn23)c1
Product: CN1CCN(C)C(c2ccc(Nc3ncc4ccc(-c5cccc(S(=O)(=O)NC(C)(C)C)c5)n4n3)cc2)C1=O

Procedure:
N-tert-Butyl-3-{2-[4-(1,4-dimethyl-3-oxo-piperazin-2-yl)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-benzenesulfonamide was prepared from N-tert-butyl-3-(2-hydroxy-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-benzenesulfonamide and 3-(4-amino-phenyl)-1,4-dimethyl-piperazin-2-one in an analogous manner to Example 1052a. Product isolated as an orange foam (90 mg, 56%). LCMS (m/e) 548 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.97 (s, 1H), 8.74 (s, 1H), 8.21 (d, 1H, J=7.9 Hz), 7.89 (d, 1H, J=7.8 Hz), 7.64-7.54 (m, 3H), 7.42 (d, 2H, J=8.3 Hz), 7.10 (d, 1H, J=4.8 Hz), 6.91-6.83 (m, 2H), 4.86 (s, 1H), 3.83-3.70 (m, 2H), 3.27-3.17 (m, 1H), 3.04 (s, 3H), 3.06-2.98 (m, 1H), 2.75-2.65 (m, 1H), 2.21 (s, 3H), 1.14 (s, 9H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11](=[O:28])[N:12]([CH:20]1[CH2:25][CH2:24][C:23](=[O:26])[NH:22][C:21]1=[O:27])[C:13]([CH3:19])=[N:14]2)(C)(C)C.[ClH:30]>CO.C(Cl)Cl.CCOCC>[ClH:30].[NH2:7][CH2:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11](=[O:28])[N:12]([CH:20]1[CH2:25][CH2:24][C:23](=[O:26])[NH:22][C:21]1=[O:27])[C:13]([CH3:19])=[N:14]2
Reactant: Cc1nc2cccc(CNC(=O)OC(C)(C)C)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 8 h

Procedure:
To a stirred brown solution of [3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-carbamic acid tert-butyl ester (10.4 g, 25.9 mmol) in methanol (108 mL) and methylene chloride (108 mL), was added 2 M HCl in ether (304 mL), and the mixture was stirred overnight. Solvent was evaporated, and the residue was stirred in ether (200 mL) for 2 hours. The suspension was filtered to give 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride as a light yellow solid (8.9 g, 102% crude yield). The product was used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23](OC(C)(C)C)=[O:24])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.F[C:31](F)(F)C(O)=O.C(OC(=O)C)(=O)C.C(N(CC)CC)C>ClCCl.O1CCCC1>[C:23]([N:20]1[CH2:21][CH2:22][N:17]([C:14]2[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=3)=[N:16][CH:15]=2)[CH2:18][CH2:19]1)(=[O:24])[CH3:31]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(CCc3ccc(CO)cc3)nc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)N1CCN(c2ccc(CCc3ccc(CO)cc3)nc2)CC1
Reaction time: 2.5 h
Yield: 66.8 %

Procedure:
To a solution of tert-butyl 4-(6-{2-[4-(hydroxymethyl)phenyl]ethyl}pyridin-3-yl)piperazine-1-carboxylate (198.8 mg, 0.500 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid (3 ml) at room temperature, and the mixture was stirred for 2.5 hrs. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted twice with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Anhydrous tetrahydrofuran (3 ml) was added to the residue, and acetic anhydride (0.047 ml, 0.50′mmol) and triethylamine (0.069 ml, 0.50 mmol) were added. After stirring at room temperature for 3 hrs, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol:dichloromethane=1:20→4:10) to give (4-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}phenyl)methanol (113.4 mg, yield 66.8%) as a silghtly yellow solid.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][CH:7]([NH:10][C:11]3[C:16](Cl)=[C:15]([CH2:18][CH3:19])[N:14]=[CH:13][N:12]=3)[CH2:6][CH2:5]2)[O:3]C1.[ClH:21]>O1CCCC1.C1(C)C=CC=CC=1>[Cl:21][C:11]1([NH:10][CH:7]2[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]2)[CH:16]=[C:15]([CH2:18][CH3:19])[N:14]=[CH:13][NH:12]1
Reactant: Cl
Reactant: CCc1ncnc(NC2CCC3(CC2)OCCO3)c1Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCC1=CC(Cl)(NC2CCC(=O)CC2)NC=N1

Procedure:
70 g (0.235 mol) of 4-(5-chloro-6-ethylpyrimidin-4-ylamino) cyclohexanone ethylene ketal (starting material for Example C) were stirred at 50° C. for 8 hours in a mixture of 250 ml of tetrahydrofuran and 250 ml of 2N hydrochloric acid. For work-up, the mixture was diluted with 250 ml of toluene, and the organic phase was extracted by stirring with sodium carbonate solution and water. Stripping off the solvent mixture gave 53.4 g (90% of theory) of product, which can be reacted without further purification.
Reaction SMILES: C([S:4][CH:5]([CH3:21])[CH2:6][C:7]([N:9]1[CH2:16][C:15]([O:19][CH3:20])([O:17][CH3:18])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.N>>[SH:4][CH:5]([CH3:21])[CH2:6][C:7]([N:9]1[CH2:16][C:15]([O:19][CH3:20])([O:17][CH3:18])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8]
Reactant: COC1(OC)C[C@@H](C(=O)O)N(C(=O)CC(C)SC(C)=O)C1
Agent: N
Product: COC1(OC)C[C@@H](C(=O)O)N(C(=O)CC(C)S)C1

Procedure:
The product from part (a) is hydrolyzed with concentrated ammonia according to the procedure of Example 4 to yield (S)-1-(3-mercapto-3-methyl-1-oxopropyl)-4,4-dimethoxy-L-proline.