Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:15][C@H:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH2:17]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:15][C@@H:16]1[CH2:17][N:18]([C:22]2[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=2)[CH2:19][CH2:20][N:21]1[C:2]1[N:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: C[C@@H]1CN(c2ccc(S(C)(=O)=O)cc2)CCN1
Reactant: CC(C)(C)OC(=O)c1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H]1CN(c2ccc(S(C)(=O)=O)cc2)CCN1c1nccc(C(=O)OC(C)(C)C)n1
Temperature: 100 °C
Reaction time: 24 h
Yield: 85.1 %

Procedure:
Tert-butyl 2-chloropyrimidine-4-carboxylate (70 mg, 0.326 mmol) and (R)-3-methyl-1-(4-(methylsulfonyl)phenyl)piperazine (166 mg, 0.652 mmol) were dissolved in acetonitrile (2 ml), followed by addition of N,N-diisopropylethylamine (0.11 ml, 0.652 mmol), and then the resulting liquid was stirred at 100° C. under nitrogen stream for 24 hours. The resulting reaction liquid was concentrated under reduced pressure, and then the residue thus obtained was subjected to MPLC (50% EtOAc/Hexanes), to obtain 120 mg of pale yellow solid (85%).
Reaction SMILES: C([O:8][C:9]1[C:14]2[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]#[N:36])=[CH:25][CH:24]=3)[C:16]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:17][C:13]=2[C:12]([CH3:37])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH2:18]([C:16]1[N:15]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH2:35][NH2:36])=[CH:27][CH:28]=2)[C:14]2[C:9]([OH:8])=[CH:10][CH:11]=[C:12]([CH3:37])[C:13]=2[N:17]=1)[CH2:19][CH2:20][CH3:21]
Reactant: [H][H]
Reactant: CCCCc1nc2c(C)ccc(OCc3ccccc3)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Pd]
Solvent: CO
Product: CCCCc1nc2c(C)ccc(O)c2n1Cc1ccc(-c2ccccc2CN)cc1

Procedure:
3.3 g (7.1 mmol) of 4'-[(7-benzyloxy-2-n-butyl-4-methyl-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl are dissolved in 100 ml of methanol and hydrogenated at ambient temperature in the presence of 0.5 g of palladium (10% on carbon) at 5 bar of hydrogen. After 3 hours the catalyst is filtered off. 20 ml of 20% strength ammonia in methanol is added to the filtrate and the mixture is hydrogenated again at 70° C. in the presence of 0.5 g of Raney nickel at 5 bar of hydrogen. After 4 hours of the catalyst is filtered off under suction and the filtrate is evaporated to dryness in vacuum. The crude crystalline product is suspended in ether, filtered under suction, washed using ether and dried in vacuum.
Reaction SMILES: [Na+].[Cl-].[Cl-].[K+].[C:5]([O-:8])([OH:7])=O.[Na+].[O:10]=[CH:11][C@@H:12]([C@H:14]([C@@H:16]([C@@H:18]([CH2:20][OH:21])[OH:19])[OH:17])[OH:15])O>>[CH2:11]([OH:10])[C@H:12]1[O:7][C@H:5]([O:8][C@:12]2([CH2:11][OH:10])[O:19][C@H:18]([CH2:20][OH:21])[C@@H:16]([OH:17])[C@@H:14]2[OH:15])[C@H:18]([OH:19])[C@@H:16]([OH:17])[C@@H:14]1[OH:15]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Product: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O

Procedure:
The Ringer solution contained: 124 mM NaCl, 3 mM KCl, 1.3 mM NaH2PO4. 2 mM MgCl2H2O, 2 mM MgCl2-6H2O, 26 mM NaHCO3, and 10 mM Dextrose. The pH was adjusted to 7-7.5 using bubbled 95% O2-5% CO2. This Ringer solution was used for storing nerves and for filling the two stimulating pools (500 ul) and the recording “intracellular” pool.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].Br[C:10]1[N:11]=[C:12]([O:31][CH3:32])[C:13]([C:18]2[CH:28]=[CH:27][C:21]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:20][C:19]=2[O:29][CH3:30])=[N:14][C:15]=1[CH2:16][CH3:17]>C1COCC1>[CH2:16]([C:15]1[N:14]=[C:13]([C:18]2[CH:28]=[CH:27][C:21]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:20][C:19]=2[O:29][CH3:30])[C:12]([O:31][CH3:32])=[N:11][C:10]=1[O:6][CH:3]([CH2:4][CH3:5])[CH2:2][CH3:1])[CH3:17]
Reactant: CCc1nc(-c2ccc(OC(F)(F)F)cc2OC)c(OC)nc1Br
Reactant: CCC(O)CC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1nc(-c2ccc(OC(F)(F)F)cc2OC)c(OC)nc1OC(CC)CC
Temperature: 50 °C

Procedure:
To a stirred solution of 3-pentanol (88 mg, 1 mmol) in THF (1 mL) is added 60% sodium hydride (12 mg, 0.3 mmol) and after 0.5 h [4-(5-bromo-6-ethyl-3-methoxypyrazin-2-yl)-3-methoxyphenoxy]trifluoromethane (41 mg, 0.1 mmol) is added. The mixture is heated to 50° C. for 12 h, cooled and partitioned between ethyl acetate and water. The organic layer is washed with water, brine, dried (sodium sulfate), filtered and concentrated. The residue is purified by preparative TLC eluting with 50% ether in hexanes to give {4-[6-Ethyl-5-(ethylpropoxy)-3-methoxypyrazin-2-yl]-3-methoxyphenoxy}trifluoromethane, a colorless oil (19 mg). NMR (CDCL3, 400 MHz) □0.98 (t, 6 H), 1.22 (t, 3 H), 1.78 (m, 4 H) 2.80 (q, 2 H), 3.80 (s, 3 H), 3.88 (s, 3 H), 5.05 (quintet, 1 H), 6.8 (s, 1 H), 6.90 (d, 1 H), 7.37 (d, 1 H); MS 345 (M+1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2.F[C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18]>CS(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18])[CH2:8][CH2:7]2
Reactant: Clc1ccc2c(c1)CCN2
Reactant: N#Cc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1cccc(N2CCc3cc(Cl)ccc32)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
A slurry of 2.64 g (0.11 mole, 1.1 equivalents) sodium hydride in 15.36 g (0.1 mole) 5-chloroindoline and 50 ml sieve dried DMSO was permitted to stir at room temperature under nitrogen for 2 hours. While cooling in an ice bath, a solution of 12.11 g (0.1 mole) 3-fluorobenzonitrile in 15 ml sieve dried DMSO was then added dropwise over 15 minutes. AT the end of the addition, the ice bath was removed and the reaction mixture was permitted to warm to room temperature and stir overnight (20 hours). The product was poured onto ice and then extracted twice with CHCl3. The combined organic portions (400 ml) were washed four times with water (400 ml portions), 4N HCl (three 300 ml portions) brine (300 ml), dried over Na2SO4, and concentrated to give 28.03 g (25.47 g theory) of a solid. Recrystallization from hot absolute ethanol containing 5-10% CHCl3 afforded 11.12 g (43.66% overall) of 3-(5-chloro-1-indolinyl)benzonitrile, m.p. 120°-121° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][C:4](=O)[CH2:3]1.[CH2:10]1CC2C(CC(CC2)=O)CC1>>[CH3:1][CH:2]1[CH2:7][C:6](=[CH2:8])[CH2:5][CH:4]([CH3:10])[CH2:3]1
Reactant: CC1CC(=O)CC(C)C1
Reactant: O=C1CCC2CCCCC2C1
Product: C=C1CC(C)CC(C)C1

Procedure:
The title compound was prepared as described in Example 45A substituting 3,5-dimethylcyclohexanone, commercially available from Aldrich, for 2-decalone.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5]CC)=[O:4].[NH2:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20](=[O:22])[CH3:21].[OH-].[Na+]>C(#N)C>[C:20]([C:16]1[S:17][CH:18]=[CH:19][C:15]=1[NH:14][CH:2]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:3]([OH:5])=[O:4])(=[O:22])[CH3:21]
Reactant: CC(=O)c1sccc1N
Reactant: CCOC(=O)C(Br)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CC(=O)c1sccc1NC(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 34.1 %

Procedure:
A solution of ethyl 2-bromo-2-phenylacetate (349 μl, 2.00 mmol) and 1-(3-aminothiophen-2-yl)ethanone (282 mg, 2.00 mmol) in acetonitrile (2 ml) was heated under microwave irradiation at 100° C. for 1 hour. Acetonitrile was evaporated, and the residue was dissolved in EtOH (2 ml), and sodium hydroxide (80.0 mg, 2.00 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours, and then ethanol was evaporated under vacuum. The residue was taken up with water and washed with EtOAc. The pH of the aqueous phase was adjusted to 3 with HCl, and the aqueous phase was back-extracted with EtOAc. The organic phase was dried over Na2SO4, filtered and evaporated to dryness to obtain 2-(2-acetylthiophen-3-ylamino)-2-phenylacetic acid (188 mg, 34% yield), which was used in the next step without any further purification.
Reaction SMILES: [OH:1][C:2]([CH3:28])([CH:9]=[CH:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[CH2:3][C:4]([O:6]CC)=[O:5].[OH-].[Na+].[Br:31]Br.C(=O)([O-])O.[Na+]>CO>[OH:1][C:2]1([CH3:28])[CH:9]([Br:31])[CH:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)[O:6][C:4](=[O:5])[CH2:3]1
Reactant: CCOC(=O)CC(C)(O)C=CCCc1ccc(OCc2ccc(F)cc2)cc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(O)CC(=O)OC(CCc2ccc(OCc3ccc(F)cc3)cc2)C1Br

Procedure:
The carboxylic acid (900 mg) prepared by hydrolyzing 1.03 g of ethyl 3-hydroxy-3-methyl-7-[p-(p-fluorobenzyloxy)phenyl]-4-heptenoate with 4 N sodium hydroxide solution in methanol, was treated with 0.2 ml of bromine in an aqueous sodium hydrogen carbonate solution and the reaction mixture was worked up according to the method described in Example 1 (b). The product was recrystallized from a mixture of acetone and ethyl ether (1:10) to yield 1.2 g of the desired compound melting at 160°-163° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[C@H:27]([CH2:28][OH:29])[CH2:26][O:25][C:24]4=[O:30])=[N:21][CH:22]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:31]I>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[C@H:27]([CH2:28][O:29][CH3:31])[CH2:26][O:25][C:24]4=[O:30])=[N:21][CH:22]=3)=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)nc3)CC2)c(C)c1
Reactant: CI
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cn1

Procedure:
By reaction and treatment in the same manner as in Example 73 and using (R)-3-{5-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]pyridin-2-yl}-4-hydroxymethyloxazolidin-2-one (340 mg) described in Example 246 and methyl iodide (62 μL), the title compound (157 mg) was obtained.
Reaction SMILES: [I:1][C:2]1[C@H:3]([OH:12])[C@@H:4]2[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]2[CH:11]=1.N1C=CN=C1.[Si:18](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C.CCOC(C)=O>[C:31]([Si:18]([O:12][C@@H:3]1[C@H:4]2[C@H:5]([O:6][C:7]([CH3:9])([CH3:10])[O:8]2)[CH:11]=[C:2]1[I:1])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC1(C)O[C@@H]2[C@@H](C=C(I)[C@@H]2O)O1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)O[C@@H]2[C@@H](C=C(I)[C@@H]2O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3aS,4R,6aR)-5-iodo-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (5-3) (1.5 g, 5.3 mmol, 1 equiv) was dissolved in DMF (6 mL) and imidazole (1.3 g, 18/4 mmol, 3.5 equiv) was added followed by TBDPS-Cl (3.0 mL, 11.6 mmol, 2.2 equiv). The resulting mixture was stirred at ambient temperature for 30 minutes. Upon disappearance of starting material, the mixture was diluted with 50 mL EtOAc and washed with water (2×50 mL). The organic layer was dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (120 g SiO2, 0-20% EtOAc in hexanes) to yield tert-butyl((3aR,4R,6aR)-5-iodo-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yloxy)diphenylsilane (5-4) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.82 (t, J=8 Hz, 4H); 7.34-7.44 (m, 6H); 6.33 (s, 1H); 4.61 (dd, J=5.5, 2.0 Hz, 1H); 4.46 (dd, J=5.5, 2.0 Hz, 1H); 3.91 (t, J=5.5 Hz, 1H); 1.40 (s, 3H); 1.21 (s, 3 II); 1.16 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:16])([CH3:15])[CH2:7][C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[CH3:17].Br[C:19]1[C:20]([F:30])=[C:21]([CH:24]=[C:25]([F:29])[C:26]=1[O:27][CH3:28])[CH:22]=[O:23]>>[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH3:17])=[C:2]([C:19]3[C:20]([F:30])=[C:21]([CH:24]=[C:25]([F:29])[C:26]=3[O:27][CH3:28])[CH:22]=[O:23])[CH:11]=2)[C:6]([CH3:16])([CH3:15])[CH2:7][C:8]1=[O:14])[CH3:13]
Reactant: COc1c(F)cc(C=O)c(F)c1Br
Reactant: CCN1C(=O)CC(C)(C)c2cc(C)c(Br)cc21
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3c(F)c(C=O)cc(F)c3OC)cc21
Yield: 14 %

Procedure:
The intermediate 3-(1-ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-2,5-difluoro-4-methoxy-benzaldehyde was prepared in a similar manner to example 7a using 7-bromo-1-ethyl-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (example 2b) and 3-bromo-2,5-difluoro-4-methoxy benzaldehyde. 14% yield. 1H NMR (300 MHz; CDCl3): 1.21 (t, J=6.9 Hz, 3 H), 1.32 (s, 3 H), 1.33 (s, 3 H), 2.13 (s, 3 H), 2.53 (s, 2 H), 3.81 (2 s, 3 H), 4.02 (q, J=6.9 Hz, 1 H), 6.81 (s, 1 H), 7.23 (s, 1 H), 7.68 (dd, J1=6.3 Hz, J2=11.7 Hz, 1 H), 10.25 (2 s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH2:10][C:11]([C:13]2[N:14]=[N:15][N:16]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:17]=2)=O)=[CH:4][CH:3]=1.[NH2:28][NH2:29].O>CCO.CC(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[NH:29][N:28]=[C:11]([C:13]3[N:14]=[N:15][N:16]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[CH:17]=3)[CH:10]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: COc1ccc(Cn2cc(C(=O)CC(=O)Cc3ccc(F)cc3)nn2)cc1
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COc1ccc(Cn2cc(-c3cc(Cc4ccc(F)cc4)[nH]n3)nn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a mixture of 4-(4-fluorophenyl)-1-[1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl]butane-1,3-dione (0.6 g, 1.6 mmol) and anhydrous EtOH/AcOH (20 mL/5 mL) was added dropwise NH2NH2.H2O (1.0 mL, 9.6 mmol) at 0° C. and the mixture was stirred at RT overnight. The mixture was evaporated, the residue washed with anhydrous Et2O (4×5 mL) and the resulting precipitate was dried in oven to yield the title compound (0.5 g, 84.0%) as a yellow solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][CH2:2][C:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCl)Nc1ccccn1
Temperature: 25 °C
Yield: 80.1 %

Procedure:
Chloroacetylchloride (60 g, 0.53M) was added with stirring to a mixture of 2-aminopyridine (50 g, 0.53M) and diisopropylethylamine (75 ml, 0.53M) in dichloromethane (500 ml) keeping the temperature below 5° C. After the reaction mixture was warmed to room temperature it was filtered and washed with water. The organic layer was dried (MgSO4) and evaporated under reduced pressure to give 72.6 g of a brown solid.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16](O)=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[CH:24][C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[OH:68][C:69]1[CH:83]=[C:82]2[C:72]([NH:73][CH:74]=[C:75]2[CH2:76][C@@H:77]([C:79]([OH:81])=[O:80])[NH2:78])=[CH:71][CH:70]=1>CN(C=O)C>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([NH:78][CH:77]([CH2:76][C:75]4[C:82]5[C:72](=[CH:71][CH:70]=[C:69]([OH:68])[CH:83]=5)[NH:73][CH:74]=4)[C:79]([OH:81])=[O:80])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[CH:24][C:23]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[N:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@@H](Cc1c[nH]c2ccc(O)cc12)C(=O)O
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3ncc(-c4ccccc4)nc3c1)n2C1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC(Cc1c[nH]c2ccc(O)cc12)C(=O)O)c1ccc2c(c1)nc(-c1ccc3ncc(-c4ccccc4)nc3c1)n2C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 205 (100 mg, 0.22 mmol) was activated in 2 mL of DMF with 92 mg (0.24 mmol) of HBTU and 85 μL of DIEA for 10 minutes at room temperature. 5-hydroxy-L-tryptophane (56 mg) dissolved in 1 mL DMF was added, followed by 44 μL of DIEA. The mixture was stirred at room temperature for 1 h, then was evaporated to dryness. The oil was purified using RP-HPLC column to give the pure Compound 236.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=1.[Cl-].[Al+3].[Cl-].[Cl-]>[N+](CC)([O-])=O>[O:3]=[S:2]1(=[O:4])[C:10]2[CH:11]=[C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:14][C:9]=2[NH:8][C:6](=[O:7])[NH:5]1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CS(=O)(=O)Nc1ccc(N)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC[N+](=O)[O-]
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)NC(=O)N2
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 77.4 %

Procedure:
Chloro-sulfonyl-isocyanate (1.7 mL, 19.6 mmol) was dissolved in nitroethane (10 mL) and chilled to −40° C. under nitrogen. N-(4-Amino-phenyl)-methanesulfonamide (Example 3b, 3g, 16.1 mmol) was added dropwise as a pre-dissolved solution in nitroethane (25 mL). The mixture was stirred at −40° C. for 15 min. Aluminum chloride (8 g, 60 mmol) was added and the mixture was heated at 110° C. for 30 min while stirring. The mixture was poured onto ice (150 g). Upon melting, the product was extracted into ethyl acetate (5×250 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to afford the desired product, N-(1,1,3-trioxo-1,2,3,4-tetrahydro-1λ6-benzo[1,2,4]thiadiazin-7-yl)-methanesulfonamide (3.63 g, 12.46 mmol, 77% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 3.00 (3H, s), 7.22 (1H, d, J=8.5 Hz), 7.46 (1H, dd, J1=8.8 Hz, J2=2.7 Hz), 7.51 (1H, d, J=2.4 Hz), 9.92 (1H, s), 11.20 (1H, s).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18](/[C:21](=[N:23]/[O:24][CH2:25][CH2:26][N:27]5C(=O)C6C(=CC=CC=6)C5=O)/[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.NN>CO>[NH2:27][CH2:26][CH2:25][O:24]/[N:23]=[C:21](/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1)\[CH3:22]
Reactant: C/C(=N\OCCN1C(=O)c2ccccc2C1=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: NN
Solvent: CO
Solvent: O
Product: C/C(=N\OCCN)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 36.9 %

Procedure:
To a solution of (E)-2-(2-(1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethylideneaminooxy)ethyl)isoindoline-1,3-dione (70 mg, 0.142 mmol) in MeOH (10 mL) was added hydrazine monohydrate (35.6 mg, 0.711 mmol). The solution was heated at reflux for 30 h and concentrated in vacuo. The crude was purified by column chromatography to afford 19 mg (37%) of the title compound. 1H-NMR (400 MHz, DMSO-d6+D2O) δ ppm 9.35 (s, 1H), 8.98 (s, 1H), 8.35 (d, 1H), 8.02 (s, 1H), 8.01 (d, 1H), 7.81 (d, 1H), 7.53 (m, 1H), 6.20 (s, 2H), 4.47 (s, 2H), 3.22 (s, 2H), 2.34 (s, 3H). LCMS (method B): [MH]+=363, tR=1.57 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([F:17])([F:18])[F:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C(F)(F)F)CC1
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CC(F)(F)F)CC1
Temperature: 0 °C
Yield: 77.4 %

Procedure:
To 4-(2,2,2-trifluoro-acetyl)-piperazine-1-carboxylic acid tert-butyl ester (6.06 g) in dry THF (60 mL) was added borane dimethyl sulfide complex (4.5 ml) and the reaction mixture was heated to reflux. After 2 h the reaction mixture was cooled to 0° C. and MeOH was carefully added, followed by water. The organics were extracted into ethyl acetate, dried (MgSO4) and the solvent removed in vacuo to yield 4-(2,2,2-trifluoro-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (4.46 g). Treatment with HCl in DCM/MeOH yielded the desired compound, which was isolated as the hydrochloride salt.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:18])=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(C(=O)O)c(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)Cl)c(C(F)(F)F)c1
Reaction time: 3 h

Procedure:
4-Methyl-2-(trifluoromethyl)benzoic acid (1 g, 4.90 mmol, commercially available from e.g. Fluorochem or ABCR) in dichloromethane (DCM) (40 mL) was cooled to 0° C., before oxalyl chloride (0.472 mL, 5.39 mmol) and a few drops of DMF (cat.) were added. The solution was then stirred under argon for 3 hours. The solvent was then evaporated in vacuo and the remaining residue was azeotroped with toluene (2×20 mL) to yield the product in 1.051 g.
Reaction SMILES: [N:1]1([C:8]2[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:16]1[C:25]2[C:20](=[C:21]([CH:26]([CH3:30])[C:27](O)=[O:28])[CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][N:17]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[N:1]1([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][NH:13][C:27](=[O:28])[CH:26]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:20]=3[CH:19]=[CH:18][N:17]=[CH:16]4)[CH3:30])=[CH:14][CH:15]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C(=O)O)c1cccc2cnccc12
Reactant: NCc1ccc(N2CCCCCC2)cc1
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1ccc(N2CCCCCC2)cc1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-(1-azepanyl)benzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 388 (M+H)+; MS (ESI−) m/z 366 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.53 (m, 7H), 1.72 (m, 4H), 3.85 (s, 2H), 4.03 (q, J 7.1, 1H), 6.76 (m, 3H), 7.26 (m, 2H), 7.58 (m, 1H), 7.71 (m, 1H), 8.10 (m, 2H), 8.72 (t, J 5.8, 1H), 9.91 (s, 1H); Anal. Calcd for C25H29N3O+2.15 HCl+2H2O: C, 59.82; H, 7.06. Found: C, 59.59; H, 7.28.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:34]=[CH:33][C:17]4[O:18][CH2:19][C:20]5[C:27]([C:28]6[NH:32][N:31]=[N:30][N:29]=6)=[CH:26][CH:25]=[CH:24][C:21]=5[CH:22](O)[C:16]=4[CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.[SH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39]>>[C:38]([CH2:37][CH2:36][S:35][CH:22]1[C:21]2[CH:24]=[CH:25][CH:26]=[C:27]([C:28]3[NH:29][N:30]=[N:31][N:32]=3)[C:20]=2[CH2:19][O:18][C:17]2[CH:33]=[CH:34][C:14]([O:13][CH2:12][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)=[CH:15][C:16]1=2)([OH:40])=[O:39]
Reactant: O=C(O)CCS
Reactant: OC1c2cc(OCc3ccc4ccc(Cl)cc4n3)ccc2OCc2c(-c3nnn[nH]3)cccc21
Product: O=C(O)CCSC1c2cc(OCc3ccc4ccc(Cl)cc4n3)ccc2OCc2c(-c3nnn[nH]3)cccc21

Procedure:
2-(7-Chloroquinolin-2-yl)methoxy-11-hydroxy-7-(tetrazol-5-yl)-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.