Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=1)#[N:2].[H-].[Na+].I[CH3:30]>CN(C=O)C.O>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH3:30])[S:23]([CH3:26])(=[O:24])=[O:25])=[CH:18][CH:17]=1)#[N:2]
Reactant: CCn1c(-c2ccc(NS(C)(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(-c2ccc(N(C)S(C)(=O)=O)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.7 %

Procedure:
A solution of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]methanesulfonamide (130 mg, 0.35 mmol), prepared as in Example 1Y, in DMF (10 mL) is treated with NaH (21 mg, 0.53 mmol), and stirred at room temperature for 10 min. Iodomethane (0.03 mL, 0.53 mmol) is added, and the mixture is stirred at room temperature for 18 h. The reaction mixture is then diluted with H2O, and extracted with EtOAc (2×). The organic phases are washed with H2O and saturated NaCl and then dried and concentrated. Purification by flash chromatography over silica gel (EtOAc/CH2Cl2, 0-1%) gives 60 mg (45%) of N-[4-(3-cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenyl]-N-methyl methanesulfonamide as a white solid.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[OH:11][NH:12][CH:13]([CH2:36][C@@H:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:38])[CH2:14][S:15]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[C:31][Si](C)(C)C)=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)(=[O:17])=[O:16]>C(Cl)Cl>[OH:11][N:12]([CH:13]([CH2:14][S:15]([N:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[CH:31])=[CH:28][CH:29]=2)[CH2:22][CH2:23]1)(=[O:16])=[O:17])[CH2:36][C@@H:37]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH3:38])[CH:1]=[O:3]
Reactant: O=CO
Reactant: C[C@@H](CC(CS(=O)(=O)N1CCN(c2ccc(C#C[Si](C)(C)C)cc2)CC1)NO)c1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: C#Cc1ccc(N2CCN(S(=O)(=O)CC(C[C@H](C)c3ccccc3)N(O)C=O)CC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 12.7 %

Procedure:
To formic acid (3.75 mL, 98 mmol) at 0° C. was added acetic anhydride (750 μL, 7.8 mmol) and the mixture was stirred at 0° C. for 10 minutes. This was added to a solution of 1-{[(4S)-2-(hydroxyamino)-4-phenylpentyl]sulfonyl}-4-[4-(trimethylsilylethynyl)phenyl]piperazine (720 mg, 94 wt %, 1.35 mmol) in CH2Cl2 (5 mL) cooled to 0° C. The reaction was brought quickly to RT and stirred for 20 minutes. Volatiles were then removed in vacuo, and the residue azeotroped with toluene (3×5 mL). The residue was then dissolved in MeOH (10 mL) and heated to 40° C. for two hours. The solution was then cooled to RT and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 40–85% EtOAc in iHexane) and evaporated in vacuo. The solid was dissolved in ether/CH2Cl2 and the insoluble contaminant removed by filtration to give the title compound as a pink foam (90 mg, 0.171 mmol, 15%).
Reaction SMILES: [CH3:1][C:2]([C:4]([CH3:6])=[CH2:5])=[CH2:3].[C:7]([O:15][CH3:16])(=[O:14])/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11]>C1(C)C=CC=CC=1>[CH3:3][C:2]1[CH2:1][C@@H:9]([C:10]([O:12][CH3:13])=[O:11])[C@H:8]([C:7]([O:15][CH3:16])=[O:14])[CH2:5][C:4]=1[CH3:6]
Reactant: C=C(C)C(=C)C
Reactant: COC(=O)/C=C/C(=O)OC
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CC(C)=C(C)C[C@H]1C(=O)OC
Yield: 85 %

Procedure:
2,3-dimethylbutadiene (9.84 g, 0.12mol) and dimethyl fumarate (14.4 g, 0.1 mol) were stirred together in toluene (40 ml) at 50° C. for 24 hr. The solvent was removed in vacuo and the solid residue recrystallised from diethyl ether, to give the title compound in 85% yield. N.m.r: δH (90 MHz, CD3OD) 3.71 (s,6H), 2.55 (m,2H), 2.10 (m,4H), 1.74 ppm (s,6H).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=[CH:19][C:20](ON1C(=O)CCC1=O)=[O:21].C(=O)([O-])O.[Na+].O>O1CCOCC1>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=[CH:19][C:20]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:21]
Reactant: O=C(C=Cc1ccccc1F)ON1C(=O)CCC1=O
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)CC[C@H](NC(=O)C=Cc1ccccc1F)C(=O)O
Yield: 57.1 %

Procedure:
The same procedures as in Example 129 were carried out from L-glutamine (2.0 g), 2,5-dioxopyrrolidin-1-yl 3-(2-fluorophenyl)acrylate (3.6 g), sodium hydrogencarbonate (1.2 g), water (60 mL), and dioxane (160 mL), to give the captioned compound (2.3 g, 58%) as crystals.
Reaction SMILES: [C:1]1([C:7]2[N:19]=[C:10]3[C:11]4[C:16]([CH2:17][CH2:18][N:9]3[N:8]=2)=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C>[C:1]1([C:7]2[N:19]=[C:10]3[C:11]4[C:16]([CH:17]=[CH:18][N:9]3[N:8]=2)=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nc3n(n2)CCc2ccccc2-3)cc1
Solvent: CCOC(C)=O
Product: c1ccc(-c2nc3c4ccccc4ccn3n2)cc1
Yield: 56 %

Procedure:
Following substantially the same procedures of Example 58, and starting from 2-phenyl-5,6-dihydro-s-triazolo[5,1-a]isoquinoline, the title compound is prepared. Yield 56%, m.p. 157°-8° C (from ethyl acetate).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>>[N:11]1([C:9]2[N:8]=[C:7]3[C:3]([NH:4][CH:5]=[N:6]3)=[CH:2][N:10]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: C1CNCCN1
Reactant: Clc1ncnc2nc[nH]c12
Product: c1nc2nc(N3CCNCC3)ncc2[nH]1

Procedure:
In Step 3, a 6-chloropurine (4) undergoes a displacement reaction with a piperazine (5) to provide a piperazinyl purine of Formula (I). The reaction can proceed in the presence of a suitable base, such as triethylamine or diisopropylethylamine, in a solvent such as methanol, ethanol, or isopropanol, at an elevated temperature such as about 50 to 100° C. Alternatively the reaction can be accomplished using microwave irradiation.
Reaction SMILES: [NH2:1][NH2:2].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([S:10]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([CH:22]=2)[C:18](OC)=[O:19])(=[O:12])=[O:11])[CH2:6][CH2:5]1>CO>[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([S:10]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([CH:22]=2)[C:18]([NH:1][NH2:2])=[O:19])(=[O:12])=[O:11])[CH2:6][CH2:5]1
Reactant: COC(=O)c1cncc(S(=O)(=O)N2CCN(C)CC2)c1
Reactant: NN
Solvent: CO
Product: CN1CCN(S(=O)(=O)c2cncc(C(=O)NN)c2)CC1
Yield: 79.9 %

Procedure:
Hydrazine (11.78 mg, 0.367 mmol) was added to the methyl 5-((4-methylpiperazin-1-yl)sulfonyl)nicotinate (55 mg, 0.184 mmol) in methanol (10 mL) and refluxed for overnight. The reaction was monitored by TLC, after completion of the reaction, Solvent was removed by vacuum and then compound was purified by column chromatography (3% methanol/DCM) afforded the title compound 5-((4-methylpiperazin-1-yl)sulfonyl)nicotinohydrazide (45 mg, 0.147 mmol, 80% yield) as a solid. 1HNMR (400 MHz, CDCl3): δ 9.07 (s, 1H), 9.02 (s, 1H), 8.33 (s, 1H), 7.46 (bs, 1H), 4.09 (bs, 2H), 3.05 (m, 4H), 2.43 (m, 4H), 2.21 (s, 3H). ESI-MS: 300.1 [M+H]+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[O:12]1[CH2:17][CH2:16][CH:15]([CH:18]=O)[CH2:14][CH2:13]1>CCO.O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:18]([CH:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: O=CC1CCOCC1
Solvent: O
Solvent: CCO
Product: O=C1CC(C2CCOCC2)Oc2ccc(Br)cc21
Yield: 19.8 %

Procedure:
To a stirred solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (943.9 mg, 4.39 mmol) in EtOH (5.6 mL) and H2O (9.4 mL) was added tetrahydro-2H-pyran-4-carbaldehyde (500 mg, 4.39 mmol) and borax (1.67 g, 4.39 mmol). The mixture was refluxed overnight. Then the mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was dissolved in CH2Cl2 and filtrated. The filtrate was concentrated in vacuo to give the crude product, which was purified by column chromatography to give 6-bromo-2-(tetrahydro-2H-pyran-4-yl)chroman-4-one (270 mg, 20%). 1H-NMR (CDCl3, 400 MHz): 1.54 (m, 2H), 1.78 (m, 1H), 1.95 (m, 1H), 2.75 (m, 2H), 3.44 (m, 3H), 4.09 (m, 2H), 4.15 (m, 1H), 6.89 (m, 1H), 7.56 (m, 1H), 8.01 (m, 1H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][C:9]1([CH3:24])[S:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[NH:11][C@H:10]1[C:21]([OH:23])=[O:22]>O>[C:1]([N:11]1[C@@H:10]([C:21]([OH:23])=[O:22])[C:9]([CH3:24])([CH3:8])[S:13][C@H:12]1[C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(C2N[C@@H](C(=O)O)C(C)(C)S2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)N1[C@@H](C(=O)O)C(C)(C)S[C@H]1c1ccc(C)cc1
Temperature: 100 °C

Procedure:
5.6 ml of acetic anhydride are added to a hot suspension containing 2.51 g (10 mmoles) of 5,5-dimethyl-2-(4-methylphenyl)-thiazolidine-4(S)-carboxylic acid in 5.6 ml of water, then the mixture is heated at 100° C. for 5 minutes. On cooling, crystals are precipitated which are recrystallized from isopropanol to give the title compound in a yield of 2.15 g (73.3%), m.p.: 214°218° C., [α]D19 =-101° (c=0.71, methanol).
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[F:13][C:14]1[N:19]=[CH:18][C:17]([C:20]23[CH2:27][CH2:26][CH2:25][N:24]2[CH2:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=1.[Cl:28]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:28][C:15]1[CH:16]=[C:17]([C:20]23[CH2:27][CH2:26][CH2:25][N:24]2[CH2:23][CH2:22][CH2:21]3)[CH:18]=[N:19][C:14]=1[F:13]
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: Fc1ccc(C23CCCN2CCC3)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Fc1ncc(C23CCCN2CCC3)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.4 %

Procedure:
n-BuLi (2.5M in hexanes, 0.232 mL, 0.58 mmol) was added to di-isopropylamine (0.077 mL, 0.58 mmol) in THF and stirred at room temperature for 15 minutes, then cooled to -78° C. 7a-(6-Fluoro-3-pyridinyl)-hexahydro-1H-pyrrolizine (115 mg, 0.56 mmol, from Example 12d) and hexachloroethane (400 mg, 1.7 mmol) were added. The mixture was slowly warmed to room temperature and stirred overnight. The reaction was quenched with 2N HCl, and the mixture was washed with Et2O. The aqueous layer was basified with 15% NaOH and extracted with methylene chloride. The organic extracts were combined, dried, (MgSO4) and concentrated. The residue was chromatographed (silica gel; CHCl3 /MeOH, 99:1) to afford the title compound as an oil (45 mg, 34%): 1H NMR (CDCl3, 300 MHz) δ1.60-1.72 (m, 2H), 1.80-2.06 (m, 6H), 2.64-2.72 (m, 2H), 3.14-3.27 (m, 2H), 8.00 (dd, J=8.8, 2.0 Hz, 1H), 8.15 (dd, J=2.0, 1.0 Hz, 1H); MS (CI/NH3) m/z: 241 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=2[F:17])[CH:5]=[CH:4][N:3]=[CH:2]1.C[Al](C)C.[NH:22](/[C:26](/[CH3:32])=[CH:27]\[C:28](OC)=[O:29])[C:23]([CH3:25])=O>C(Cl)Cl>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:28](=[O:29])[CH:27]=[C:26]([CH3:32])[N:22]=[C:23]3[CH3:25])=[CH:12][C:11]=2[F:17])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Reactant: Nc1ccc(NCCCn2ccnc2)c(F)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(NCCCn3ccnc3)c(F)c2)c(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.1 %

Procedure:
To a solution of N1-(3-(1H-imidazol-1-yl)propyl)-2-fluorobenzene-1,4-diamine (1.00 g, 4.27 mmol) in CH2Cl2 (30 mL) was added trimethylaluminium (16.4 mL, 32.8 mmol, 2 M in toluene) slowly. The mixture was stirred at rt for 0.5 h, followed by the addition of a solution of methyl 3-acetaminocrotonate (1.00 g, 6.36 mmol) in CH2Cl2 (8 mL). The reaction mixture was stirred at rt for 24 h, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (50 mL×3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/MeOH (V/V)=20:1) to give the title compound as pale yellow oil (0.22 g, 15%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH2:25])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-].[Na+].[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[C:20]([S:21](=[O:24])(=[O:23])[NH2:22])=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[NH:25][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: ClCc1ccccc1
Reactant: CC(=O)Nc1ccc(Sc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1ccc(Sc2c(NCc3ccccc3)cc(C(=O)O)cc2S(N)(=O)=O)cc1

Procedure:
The starting material is prepared as follows: The solution of 4-(4-acetamidophenylmercapto)-3-amino-5-sulfamoylbenzoic acid in 50 ml of water containing 0.4 g of sodium hydroxide is adjusted to pH = 7.4 by the addition of 4N aqueous sodium hydroxide, whereupon 1.3 g of benzylchloride are added while stirring under nitrogen. As soon as the pH remains constant the mixture is filtered and the filtrate acidified with glacial acetic acid to a pH of 4-5. The precipitate formed is recrystallized from 50% aqueous ethanol, to yield the 4-(4-acetamidophenylmercapto)-3-benzylamino-5-sulfamoylbenzoic acid melting at 255°-258°.
Reaction SMILES: B(F)(F)F.[CH:5]([C:7]1[O:11][N:10]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:8]=1[CH3:17])=[O:6].[CH2:18]([Si](C)(C)C)[CH:19]=[CH2:20].C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:6][CH:5]([C:7]1[O:11][N:10]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:8]=1[CH3:17])[CH2:20][CH:19]=[CH2:18]
Reactant: CCOC(=O)c1noc(C=O)c1C
Reactant: C=CC[Si](C)(C)C
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCC(O)c1onc(C(=O)OCC)c1C
Temperature: -78 °C
Reaction time: 8 h

Procedure:
A solution of boron trifluoride diethyletherate (54.1 μl, 0.427 mmoL) in DCM (0.3 mL) was cooled to −78° C. In a separate flask a solution of ethyl 5-formyl-4-methylisoxazole-3-carboxylate (Intermediate C) (68 mg, 0.371 mmol) and allyltrimethylsilane (59.0 μl, 0.371 mmol) in DCM were cooled to −78° C. and this solution was added dropwise to the boron trifluoride diethyletherate solution. The reaction mixture was stirred at −78° C. for 1 hour and at room temperature overnight. To the resulting mixture was added a saturated solution of NaHCO3 (aq) (5 mL) and this was extracted with DCM (×3). The combined organic extracts were passed through a phase separating cartridge and the eluent was concentrated under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-50% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [CH:1]([C:4]1[CH:15]=[CH:14][C:7]2[NH:8][C:9](=[O:13])O[C:11](=[O:12])[C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:19]=1[CH2:20][NH:21][CH2:22]C(O)=O>CC1C=CC(C)=CC=1>[CH3:16][O:17][C:18]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:19]=1[CH2:20][N:21]1[C:11](=[O:12])[C:6]2[CH:5]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:15]=[CH:14][C:7]=2[NH:8][C:9](=[O:13])[CH2:22]1
Reactant: COc1ccc(CNCC(=O)O)c(OC)c1
Reactant: CC(C)c1ccc2[nH]c(=O)oc(=O)c2c1
Solvent: Cc1ccc(C)cc1
Product: COc1ccc(CN2CC(=O)Nc3ccc(C(C)C)cc3C2=O)c(OC)c1
Temperature: 150 °C

Procedure:
A suspension of 6-isopropyl-1H-benzo[d][1,3]oxazine-2,4-dione (3.0 g, 15 mmol) containing (2,4-dimethoxy-benzylamino)-acetic acid (3.7 g, 16 mmol) in p-xylene (40 mL) was heated under reflux (150° C.) for 2.5 h. After cooling to room temperature the precipitate was filtered off and washed with p-xylene (2×20 ml). Yield: 4.9 g (90%). m/z 367 (M—H−).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])=[CH:4][CH2:3]1.[F:27][C:28]([F:34])([F:33])[S:29](Cl)(=[O:31])=[O:30]>>[F:27][C:28]([F:34])([F:33])[S:29]([N:2]1[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])=[CH:4][CH2:3]1)(=[O:31])=[O:30]
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(C2=CCNCC2)c(F)c1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: Cl
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(C2=CCN(S(=O)(=O)C(F)(F)F)CC2)c(F)c1

Procedure:
(5R)-3-(4-(1,2,5,6-Tetrahydropyridin-4-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)-oxazolidin-2-one hydrochloride (380 mg, 1 mM) was treated with trifluoromethanesulfonyl chloride essentially as in Example 76. Crude material was purified by chromatography on a 5 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (444 mg). MS (ESP): 476 (MH+) for C18H17F4N5O4S
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].[C:15]1([CH2:21][CH2:22][CH:23]=[O:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:3][C@H:2]([C@@H:23]([OH:24])[CH2:22][CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Reactant: O=CCCc1ccccc1
Product: C[C@@H](C(=O)n1c(=O)oc2ccccc21)[C@@H](O)CCc1ccccc1

Procedure:
Prepared according to the method of paragraph C by reaction of N-propionyl-2-benzoxazolinone with 3-phenylpropanal. 1H-NMR (CDCl3, 400 MHz): δ 8.06 (m, 1H); 7.25 (m, 8H); 4.11 (dt, 1H, J=4,7); 3.96 (dq, 1H, J=3,7); 2.91 (m, 1H); 2.70 (m, 1H); 1.95 (m, 1H); 1.81 (m, 1H); 1.34 (t, 3H, J=7).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)=[O:15])[CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)=[O:15])[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)C1

Procedure:
A mixture comprising of 3,5-dichlorobenzyl 3-((tert-butoxycarbonyl)amino)pyrrolidine-1-carboxylate (1.8143 g, 4.66 mmol) and trifluoroacetic acid (14.36 ml, 186 mmol) in DCM (15.54 ml) was stirred at RT for 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with DCM and washed with water. The organic portion was separated, dried over MgSO4, filtered and concentrated under reduced pressure to form an orange oil which was used in the next step without further purification;
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]=[CH:5][C:6]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([NH:29][C@@H:30]3[CH2:32][C@H:31]3[CH3:33])(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[N:7][C:8]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[NH:14][CH2:13][CH2:12]2.[C:34](=O)([O-])[O-].[Cs+].[Cs+].CI>>[NH2:2][C:3]1[N:4]=[CH:5][C:6]([C:20]2[CH:21]=[CH:22][C:23]([S:26]([N:29]([CH3:34])[C@@H:30]3[CH2:32][C@H:31]3[CH3:33])(=[O:27])=[O:28])=[CH:24][CH:25]=2)=[N:7][C:8]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[NH:14][CH2:13][CH2:12]2
Reactant: C[C@@H]1C[C@H]1NS(=O)(=O)c1ccc(-c2cnc(N)c(-c3ccc4c(c3)CCNC4=O)n2)cc1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Cs+]
Solvent: CI
Product: C[C@@H]1C[C@H]1N(C)S(=O)(=O)c1ccc(-c2cnc(N)c(-c3ccc4c(c3)CCNC4=O)n2)cc1
Yield: 85.5 %

Procedure:
To a room temperature slurry of 4-(5-amino-6-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazin-2-yl)-N-((1R,2R)-2-methylcyclopropyl)benzenesulfonamide hydrochloride (110 mg, 0.227 mmol) and cesium carbonate (222 mg, 0.681 mmol) was added methyl iodide (16.0 μL, 0.251 mmol). At completion, the reaction was filtered and concentrated, then flashed over silica gel (5-10% MeOH/DCM eluent) to provide 4-(5-amino-6-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazin-2-yl)-N-methyl-N-((1R,2R)-2-methylcyclopropyl)-benzenesulfonamide (90 mg, 86% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.55 (s, 1H), 8.25 (d, J=7.8 Hz, 1H), 8.16 (d, J=8.5 Hz, 2H), 7.92 (d, J=8.5 Hz, 2H), 7.83 (dd, J=8.0, 1.5 Hz, 1H), 7.70 (s, 1H), 5.95 (br. s, 1H), 5.14 (br. s, 2H), 3.66 (dt, J=7.0, 2.3 Hz, 2H), 3.14 (t, J=7.0 Hz, 2H), 2.76 (s, 3H), 1.48-1.53 (m, 1H), 1.27-1.35 (m, 1H), 1.06 (d, J=6.3 Hz, 3H), 0.96-1.02 (m, 1H), 0.47 (dd, J=12.3, 6.0 Hz, 1H); MS (EI) m/z=464.5 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][C:13]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)=[CH:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(OCC)(=O)C.[ClH:39]>C(O)C>[ClH:39].[F:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][C:13]([CH2:23][NH:24][CH3:25])=[CH:12]2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2cccc(F)c2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cc(-c2cccnc2F)n(S(=O)(=O)c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To a solution of tert-butyl ({1-[(3-fluorophenyl)sulfonyl]-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl}methyl)methylcarbamate (194 mg) in ethanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (4 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound (yield 90 mg, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([NH2:15])[CH:9]=1)=[O:6].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[S:30])[CH:25]=[CH:26][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([NH:15][C:29]([NH:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:20])([F:31])[F:32])[CH:23]=2)=[S:30])[CH:9]=1)=[O:6]
Reactant: Nc1cc(NC(=O)c2ccc(Cl)c(Cl)c2)ccc1F
Reactant: FC(F)(F)c1cccc(N=C=S)c1
Product: O=C(Nc1ccc(F)c(NC(=S)Nc2cccc(C(F)(F)F)c2)c1)c1ccc(Cl)c(Cl)c1
Yield: 46 %

Procedure:
Prepared according to the procedure described for Example 60 using 3,4-dichloro-N-(3-amino-4-fluorophenyl)-benzamide from Example 22 (0.69 g, 2.3 mmol) and 3-trifluoromethylphenyl isothiocyanate (0.47 g, 2.3 mmol) to afford the product (0.532 g); m.p. 172-174° C.
Reaction SMILES: [CH2:1]([C:3]([CH3:16])([O:6][C:7]([NH:9][CH2:10][C:11]([O:13]CC)=[O:12])=[O:8])[CH2:4][CH3:5])[CH3:2].[OH-].[Li+]>CO.O>[CH2:1]([C:3]([CH3:16])([O:6][C:7]([NH:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])[CH2:4][CH3:5])[CH3:2]
Reactant: CCOC(=O)CNC(=O)OC(C)(CC)CC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(C)(CC)OC(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
300 mg (1.30 mmol) of ethyl {[(1-ethyl-1-methylpropoxy)carbonyl]-amino}acetate was dissolved in 2.5 ml of a solvent mixture of methanol:water (2.3:1). 1.56 ml of 1 N aqueous lithium hydroxide solution was added to the obtained solution. After stirring at room temperature for 2 hours, “DOWEX” (50W-X2 100 to 200 mesh H form) (an exchange resin of The Dow Chemical Company) was added to the reaction mixture under gentle stirring until pH of the mixture had become 5. The resin was obtained by the filtration under suction and then the filtrate was concentrated under reduced pressure and then dried to obtain the title compound.