Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C(N(CC)CC)C.[CH2:24]([CH:27]([CH2:31][CH2:32][CH3:33])[C:28](Cl)=[O:29])[CH2:25][CH3:26]>C(Cl)(Cl)Cl>[CH2:24]([CH:27]([CH2:31][CH2:32][CH3:33])[C:28]([N:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:29])[CH2:25][CH3:26]
Reactant: CCCC(CCC)C(=O)Cl
Reactant: O=C1CC[C@@H](C(=O)OCc2ccccc2)N1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCC(CCC)C(=O)N1C(=O)CC[C@H]1C(=O)OCc1ccccc1

Procedure:
50.3 g (230 mmol) of benzyl (L)-pyroglutamate, prepared according to Example II(1), are dissolved in 200 ml of chloroform and 36.3 g (359 mmol) of triethylamine at ordinary temperature. A solution of 37.4 g (230 mmol) of dipropylacetyl chloride in 50 ml of chloroform is run in and the mixture is heated under reflux for 5 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][C:13]([N+]([O-])=O)=[CH:12][C:11]=3[C:7]=2[C:6]([C:19]([OH:21])=[O:20])=[CH:5][CH:4]=1.[ClH:22].O.N([O-])=O.[Na+]>O.Cl.Cl[Cu]>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:22])=[CH:12][C:11]=3[C:7]=2[C:6]([C:19]([OH:21])=[O:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)O)c2c1oc1ccc([N+](=O)[O-])cc12
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(C(=O)O)c2c1oc1ccc(Cl)cc12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Intermediate 29 (350 mg, 1.13 mmol) was suspended in mixture of concentrated hydrochloric acid:water (1: 1) (5 ml) and stirred at 50° C. for 30 min. The suspension was cooled to 0° C. and a solution of sodium nitrite (83 mg, 1.2 mmol) in water (2 ml) was added dropwise in 15 min. The reaction was stirred for 90 min. at 0-5° C. and then this suspension was added to a pre-cooled solution of CuCl (123 mg, 1.24 mmol) in concentrated HCl (5 ml). The reaction was allowed to come to room temperature and further heated to 80-90° C. for 2 h. The reaction mixture was then poured into water (100 ml) and the solid was filtered and then purified by column chromatography using 20% ethyl acetate-chloroform as the eluent to obtain 250 mg of the product as white solid; mp: 264-276° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[F:16].Cl.[NH2:19][C@@H:20]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([F:43])([F:42])[F:41])[CH2:21][N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH:19][C@@H:20]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]([F:43])([F:41])[F:42])[CH2:21][N:22]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])=[O:13])=[CH:9][C:8]=1[F:16]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1ncc(Cl)c1-c1ccc(C(=O)O)cc1F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Cl)c1-c1ccc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1F
Reaction time: 1 h
Yield: 35.8 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-3-fluorobenzoic acid (100 mg, 0.43 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione-HCl (151 mg, 0.43 mmol) [prepared according to Preparation 3], diisopropylethyl amine (0.4 mL, 2.14 mmol) in DCM (5 mL) was added PyBrop (330 mg, 0.71 mmol) in one portion. After 1 h, the reaction contents were partitioned between H2O/DCM. The aqueous phase was washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica) affording the title compound (90 mg, 36%) as a white solid: LCMS (ES) m/z=585 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[CH:17]12[O:22][CH:21]1[CH2:20][O:19][CH2:18]2>>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][C@@H:21]2[CH2:20][O:19][CH2:18][C@H:17]2[OH:22])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: C1OCC2OC12
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Product: CC(C)(C)c1cc(S[C@@H]2COC[C@H]2O)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
2,6-bis(1,1-Dimethylethyl)-4-mercaptophenol (1.85 g, 0.0078 mole) and the compound of Example 1 (0.64 g, 0.0074 mole) were added to a degassed (Argon) solution of 50% sodium hydroxide (5 ml) and isopropyl alcohol (50 ml). The reaction was heated to reflux for 24 hours. The reaction was cooled to room temperature and poured into water (125 ml). The solution was made acidic with 1N hydrochloric acid and extracted 3 times with 100 ml of diethyl ether. The combined diethyl ether extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to an oily solid in a rotary evaporator. The product was purified by silica gel chromatography and recrystallized from hexane (m.p. ca. 104° C.). The structure was supported by NMR and infrared spectroscopy and elemental analysis.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([OH:40])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2].[N:43]1[CH:48]=[CH:47][CH:46]=[N:45][C:44]=1[CH2:49]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1.O>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:38])([F:39])[F:37])[CH:27]=3)[C:22]([O:40][CH2:49][C:44]3[N:45]=[CH:46][CH:47]=[CH:48][N:43]=3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2]
Reactant: OCc1ncccn1
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(OCc3ncccn3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-hydroxypyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (150 mg) is dissolved in tetrahydrofuran (1 ml), then thereto are added pyrimidin-2-ylmethanol (41 mg) and triphenylphosphine (98 mg). After adding dropwise 40% diethyl azodicarboxylate-toluene solution (163 μl) under ice-cooling, the mixture is stirred at room temperature for 1 hour and 30 minutes. Water is added to the reaction mixture and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=2:1) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(pyrimidin-2-ylmethoxy)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (118 mg). MS (m/z): 692 [M+H]+
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=O)[C:6]([CH3:11])([CH3:10])[CH2:7][O:8]C.[C:13](#[N:15])[CH3:14].Cl>C1(C)C=CC=CC=1>[CH3:3][O:4][CH2:5][C:6]([CH3:11])([CH3:10])[C:7](=[O:8])[CH2:14][C:13]#[N:15]
Reactant: CC#N
Reactant: COCC(C)(C)C(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCC(C)(C)C(=O)CC#N

Procedure:
60% sodium hydride in mineral oil (667.2 mg, 16.68 mmol) in toluene (15 mL) is heated to reflux. A solution of 3-methoxy-2,2-dimethyl-propionic acid methyl ester (1.742 g, 11.916 mmol) and acetonitrile (0.878 mL, 16.68 mmol) in toluene (5 mL) is added dropwise through an additional funnel into the NaH suspension in toluene. After the addition, the reaction is stirred at reflux for 3 hours. After cooling, the reaction mixture is neutralized to PH˜7 by adding 1N HCl aqueous solution. The mixture is extracted with ethyl acetate 3 times. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7]([C:13](OC)=[O:14])=[CH:8]2.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7]([CH2:13][OH:14])=[CH:8]2
Reactant: COC(=O)C1=Cc2cccc(OC)c2CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Product: COc1cccc2c1CCC(CO)=C2
Reaction time: 2.5 h
Yield: 101 %

Procedure:
To a solution of methyl (5-methoxy-3,4-dihydro-2-naphthyl)formate (0.75 g) in toluene (10 ml) was added dropwise a solution of diisobutylaluminum hydride [1.02N in toluene (6.7 ml)] at 4° C.~6° C. under nitrogen atmosphere. The reaction mixture was stirred under same conditions for 2.5 hours. The mixture was poured into a saturated ammonium chloride solution, and the organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give crude (5-methoxy-3,4-dihydro-2-naphthyl)methanol as a colorless oil (0.66 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2].[S:30]1[CH2:34][C:33](=[O:35])[NH:32][C:31]1=[O:36].C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:21])=[O:22])[CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[C:34]3[S:30][C:31](=[O:36])[NH:32][C:33]3=[O:35])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C(COc2ccc(C=O)cc2)S(=O)(=O)c2ccc(C)cc2)nc1
Reactant: O=C1CSC(=O)N1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCc1ccc(C(COc2ccc(C=C3SC(=O)NC3=O)cc2)S(=O)(=O)c2ccc(C)cc2)nc1
Temperature: 125 °C

Procedure:
To 1 g (0.0023 mol) 4-[2-(5-ethyl-pyridin-2-yl)-2-tosyl-ethoxy]-benzaldehyde dissolved in 15 mL toluene was added 0.27 g (0.0023 mol) thiazolidin-2,4-dione. To this 0.21 g (0.0035 mol) acetic acid and 0.3 g (0.0035 mol) piperidine were added. Reaction mixture was refluxed at 120-130° C. for 4 hr. After completion of reaction on TLC, substantial work-up gave the titled product. Yield of the product was 0.36 g (30%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]#[N:9].Cl[CH2:11][CH2:12][N:13]([CH2:21][CH2:22]Cl)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>>[C:17]([O:16][C:14]([N:13]1[CH2:21][CH2:22][C:7]([C:8]#[N:9])([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:11][CH2:12]1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: N#CCc1ccccn1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccn2)CC1

Procedure:
Prepare by the method of example 30.2 using 2-pyridylacetonitrile (10 mmol) and 2-chloro-N-(2-chloroethyl)-N-tert-Butoxycarbonyl-ethanamine (11 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([C:14]2[C:23]3[CH2:22][CH2:21][CH2:20][C:19]4[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:18]=4[C:17]=3[N:16]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[Cl:36])[N:15]=2)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:43][NH2:44]>ClC1C=CC=CC=1.ClCCl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]([C:14]2[C:23]3[CH2:22][CH2:21][CH2:20][C:19]4[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:18]=4[C:17]=3[N:16]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[Cl:36])[N:15]=2)[NH:44][CH3:43])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=C(NS(=O)(=O)c1ccc(Cl)cc1)c1nn(-c2ccc(Cl)cc2Cl)c2c1CCCc1cc(Cl)ccc1-2
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Solvent: Clc1ccccc1
Product: CNC(=NS(=O)(=O)c1ccc(Cl)cc1)c1nn(-c2ccc(Cl)cc2Cl)c2c1CCCc1cc(Cl)ccc1-2
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
4-Chloro-N-{8-chloro-1-(2,4-dichloro-phenyl)-1,4,5,6-tetrahydro-1,2-diaza-benzo [e] azulene-3-carbonyl}-benzene-sulfonamide (2.0 g, 3.44 mmol) and PCl5 (1.56 g, 6.88 mmol) in chlorobenzene (20 mL) were refluxed at ca. 120° C. over a period of 3.0 h. The solvents were evaporated under reduced pressure to afford yellow gummy solid. The gummy solid was taken in dichloromethane (15 mL) and cooled to 0-5° C. To this cooled solution, 40% aq. monomethyl amine solution (5.0 mL) was added and stirred at ca. 29° C. over a period of 1 h. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane. The organic layer was separated, dried over anhydrous Na2SO4 and evaporated under reduced pressure to afford yellow oil. The oil was purified through column chromatography to afford 4-Chloro-N-{[8-chloro-1-(2,4-dichloro-phenyl)-1,4,5,6-tetrahydro-1,2-diaza-benzo [e] azulene-3-yl]-methylamino-methylene}-benzene sulfonamide (0.175 g, 0.294 mmol) as title compound 1, a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[NH:11][CH2:10][C@@H:9]3[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][C@@H:8]3[C:7]=2[CH:6]=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]2[NH:11][CH2:10][C@@H:9]3[CH2:13][NH:14][CH2:15][C@@H:8]3[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1NC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1NC[C@@H]1CNC[C@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (±)-cis tert-butyl 6-methoxy-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]quinoline-2(9bH)-carboxylate (25 mg, 0.082 mmol) in 4 mL methylene chloride was added 1 mL trifluoroacetic acid. The reaction was allowed to stir at ambient temperature for 2 h and then was concentrated in vacuo to afford a TFA salt. This material was free-based by partitioning between methylene chloride and aq. ammonium hydroxide. The organics were washed with brine, dried (Na2SO4) and concentrated to afford 10 mg (60%) of the title compound of Example 10. 1H NMR (CDCl3): δ 6.76-6.62 (m, 3H), 4.42 (broad s, 1H), 3.85 (s, 3H), 3.50-3.23 (overlapping m, 5H), 2.98-2.80 (m, 2H), 2.65-2.57 (m, 1H). LRMS (ESI): 205.3 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([Cl:22])=[CH:17][C:16]=2[C:23]2[N:27]([CH3:28])[C:26]([CH2:29]C)=[N:25][N:24]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32](C=O)[CH3:33]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([Cl:22])=[CH:17][C:16]=2[C:23]2[N:27]([CH3:28])[C:26]([CH2:29][N:32]([CH3:33])[CH3:31])=[N:25][N:24]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C)C=O
Reactant: CCc1nnc(-c2cc(Cl)c(F)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Product: CN(C)Cc1nnc(-c2cc(Cl)c(F)cc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A 25 mL pear-shaped flask was charged with 4-tert-butyl-N-[4-chloro-5-fluoro-2-(4-methyl-4H-[1,2,4]triazol-3-yl)-phenyl]-benzenesulfonamide (prepared according to general procedure C) (75 mg, 0.18 mmol), N,N-dimethylmethyleneiminium iodide (43 mg, 0.23 mmol), and DMF (0.44 mL). The flask was heated to 100° C. and stirred overnight. The following day, the solvent was evacuated in vacuo and the residue was purified via HPLC to afford 4-tert-butyl-N-[4-chloro-2-(5-dimethylaminomethyl-4-methyl-4H-[1,2,4]triazol-3-yl)-5-fluoro-phenyl]-benzenesulfonamide as a white powder: 1H NMR (400 MHz, CD3OD) δ 7.60 (d, 1H), 7.48-7.54 (m, 4H), 7.28 (d, 1H), 3.70 (s, 2H), 3.46 (s, 3H), 2.36 (s, 6H), 1.33 (s, 9H), MS (ES) M+H expected 480.2, found 480.1.
Reaction SMILES: ClC(N(C)C)=C(C)C.[C:9]([O:13][C:14]([NH:16][C:17]1[S:21][C:20]([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=2[F:29])=[N:19][C:18]=1[C:30](O)=[O:31])=[O:15])([CH3:12])([CH3:11])[CH3:10].[NH2:33][C:34]1[C:35]([N:43]2[CH2:48][CH2:47][CH2:46][C@H:45]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:55])([CH3:54])[CH3:53])[CH2:44]2)=[C:36]2[S:42][CH:41]=[CH:40][C:37]2=[N:38][CH:39]=1.N1C=CC=CC=1>C1COCC1>[C:9]([O:13][C:14]([NH:16][C:17]1[S:21][C:20]([C:22]2[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=2[F:29])=[N:19][C:18]=1[C:30]([NH:33][C:34]1[C:35]([N:43]2[CH2:48][CH2:47][CH2:46][C@H:45]([NH:49][C:50](=[O:56])[O:51][C:52]([CH3:53])([CH3:55])[CH3:54])[CH2:44]2)=[C:36]2[S:42][CH:41]=[CH:40][C:37]2=[N:38][CH:39]=1)=[O:31])=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3ccsc23)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CC(C)=C(Cl)N(C)C
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2ccsc2c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.9 %

Procedure:
1-Chloro-N,N,2-trimethylpropenylamine (76.1 mg, 0.570 mmol) in THF (1.0 mL) was added slowly to a solution of 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (Example 1, step 6, 76.1 mg, 0.214 mmol) in THF (0.5 mL). The mixture was stirred at room temperature for 5 h. A solution of tert-butyl [(3S)-1-(6-aminothieno[3,2-b]pyridin-7-yl)piperidin-3-yl]carbamate (62.3 mg, 0.179 mmol) in THF (2.0 mL) was then added, followed by pyridine (135.3 mg, 1.710 mmol), and the mixture was stirred at room temperature for a further 2 h. The mixture was then concentrated under reduced pressure and the residue was purified by chromatography on silica gel (0-100% EtOAc in hexanes) to afford the sub-title compound as a dark semi-solid (78.5 mg, 64%). LCMS calc. for C32H37F2N6O5S2 (M+H)+: m/z=687.2. found 687.2.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].Cl[C:7]1[N:12]=[C:11]([NH:13][C:14]2[CH:19]=[C:18]([CH:20]([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:10]=[C:9]([CH:23]2[CH2:28][CH2:27][N:26]([CH:29]3[CH2:32][O:31][CH2:30]3)[CH2:25][CH2:24]2)[CH:8]=1>>[CH2:1]([O:5][C:7]1[N:12]=[C:11]([NH:13][C:14]2[CH:19]=[C:18]([CH:20]([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:10]=[C:9]([CH:23]2[CH2:28][CH2:27][N:26]([CH:29]3[CH2:30][O:31][CH2:32]3)[CH2:25][CH2:24]2)[CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: FC(F)c1ccnc(Nc2cc(C3CCN(C4COC4)CC3)cc(Cl)n2)c1
Reactant: CCCCO
Product: CCCCOc1cc(C2CCN(C3COC3)CC2)cc(Nc2cc(C(F)F)ccn2)n1
Yield: 31 %

Procedure:
Reaction of n-butanol (3 equiv) with 6-chloro-N-(4-(difluoromethyl)pyridin-2-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-2-amine (50.0 mg, 0.127 mmol) following general Beller etherification procedure afforded the target compound as a colorless solid (17.0 mg, 31%); 1H NMR (400 MHz, DMSO) δ 9.77 (s, 1H), 8.35 (d, J=5.1 Hz, 1H), 8.22 (s, 1H), 7.19-6.86 (m, 3H), 6.18 (s, 1H), 4.57-4.51 (m, 2H), 4.48-4.42 (m, 2H), 4.25 (t, J=6.8 Hz, 2H), 3.45-3.36 (m, 1H), 2.83-2.75 (m, 2H), 2.46-2.37 (m, 1H), 1.90-1.79 (m, 2H), 1.78-1.55 (m, 6H), 1.49-1.38 (m, 2H), 0.93 (t, J=7.4 Hz, 3H); ESI-LRMS m/z [M+1]+=433.
Reaction SMILES: [C:1]1(=O)[C:9]2[CH2:8][CH:7]=[CH:6][CH2:5][C:4]=2[C:3](=[O:10])[O:2]1.O.[NH2:13][NH2:14]>C1(C)C=CC=CC=1>[C:3]1(=[O:10])[C:4]2[CH2:5][CH:6]=[CH:7][CH2:8][C:9]=2[C:1](=[O:2])[NH:14][NH:13]1
Reactant: O=C1OC(=O)C2=C1CC=CC2
Reactant: NN
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1[nH][nH]c(=O)c2c1CC=CC2

Procedure:
A suspension of isobenzofuran-1,3(4H,7H)-dione (4.2 g, 28 mmol) in 45 mL toluene was heated at reflux and charged with hydrazine hydrate (1.63 mL, 33.6 mmol) dropwisely in a round bottom flask equipped with a condenser. The reaction mixture was heated at reflux for 2 h. The mixture was filtered to afford the titled compound a white solid (4.2 g, yield: 91%).
Reaction SMILES: N([O-])=O.[Na+].[OH:5][CH2:6][C:7]1[N:11]([CH2:12][C:13]#[CH:14])[C:10](S)=[N:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>O>[OH:5][CH2:6][C:7]1[N:11]([CH2:12][C:13]#[CH:14])[CH:10]=[N:9][CH:8]=1
Reactant: C#CCn1c(CO)cnc1S
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: C#CCn1cncc1CO
Reaction time: 1 h
Yield: 41.8 %

Procedure:
To 5.0M nitric: acid (134 ml) was added sodium nitrite (411 mg), and 5-hydroxymethyl-2-mercapto-1-(2-propyn-1-yl)imidazole (25.0 g) was added by portions to the mixture. After the mixture was allowed to be at room temperature and stirred for 1 hour, water (60 ml) was added to the mixture. The mixture was neutralized with potassium carbonate at 0° C. and the solvent was distilled off under reduced pressure. Ethanol was added to the mixture, the insolubles were filtered off, and the solvent was distilled off under reduced pressure. To the obtained residue was added methanol-ethyl acetate, and basic silica gel was added to the mixture. This mixture was purified by basic silica gel column chromatography (methanol:ethyl acetate=1:8), and the obtained solid was recrystalized from hexane-ethyl acetate, to give 5-hydroxymethyl-1-(2-propyn-1-yl)imidazole (8.46 g) as yellow crystals.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH:7]=[CH:6][C@@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH2:15][CH2:16][O:17][CH3:18])[C:3]1=[O:19].[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29]([NH:31][C@H:32]([C:34](O)=[O:35])[CH3:33])=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29]([NH:31][C@H:32]([C:34]([NH:1][C@H:2]2[CH2:8][CH:7]=[CH:6][C@@H:5]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:4]([CH2:15][CH2:16][O:17][CH3:18])[C:3]2=[O:19])=[O:35])[CH3:33])=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COCCN1C(=O)[C@@H](N)CC=C[C@H]1c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COCCN1C(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc2cc(F)cc(F)c2)CC=C[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
To a solution of (3S,7S)-3-amino-1-(2-methoxyethyl)-7-phenyl-1,3,4,7-tetrahydro-2H-azepin-2-one (6d) (55 mg) in DCM (4 mL) at 0° C. under N2 was added N-[(3,5-difluorophenyl)acetyl]-L-alanine (51 mg), HOBt-hydrate (71 mg), EDAC.HCl (61 mg) and N-methyl morpholine (34 mg). The reaction mixture was stirred 1 h at 0° C. and 3 h at RT, then diluted with 30% hexanes/EtOAc (100 mL). The organic phase was consecutively washed with H2O, 0.2 N HCl, saturated NaHCO3, and brine, dried (Na2SO4), filtered and evaporated. The crude product was purified by flash chromatography (1%-2% MeOH/DCM) to afford a white solid (82 mg, 80%).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:8][C:9]=1[NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[OH-].[K+]>C(O)C.O.Cl>[C:14]([O:13][C:11]([NH:10][C:9]1[CH:8]=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(-c2ccc(Cl)cc2)sc1C(=O)O

Procedure:
A solution of 1a (1.37 g, 3.73 mmol) in ethanol (20 mL) was mixed with KOH (627 mg, 11.2 mmol) in water (20 mL). The resultant mixture was heated at 60° C. for 1 h, diluted with HCl (50 mL, 1N) and extracted with ethyl acetate (60 mL, 3×). The combined organic phases were dried over MgSO4, filtered, and concentrated to afford compound 1b as a yellow solid.