Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[S:10][N:9]=[C:8]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:7]=1[C:17]#[N:18])C.S(=O)(=O)(O)[OH:21]>>[NH2:5][C:6]1[S:10][N:9]=[C:8]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:7]=1[C:17]([NH2:18])=[O:21]
Reactant: CCCCCSc1nsc(NC(=O)OCC)c1C#N
Reactant: O=S(=O)(O)O
Product: CCCCCSc1nsc(N)c1C(N)=O
Temperature: 100 °C
Yield: 100 %

Procedure:
A mixture of (4-Cyano-3-pentylsulfanyl-isothiazol-5-yl)-carbamic acid ethyl ester (2.7 g, 9.0 mmol) and concentrated sulfuric acid (5 mL) was heated to 100° C. for 6 hours. After cooling to ambient temperature, the mixture was diluted with ice water, extracted three times with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo, affording 2.2 g (100%) of 5-amino-3-pentylsulfanyl-isothiazole-4-carboxylic acid amide as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 3.26 (t, 2 H, J=7.2 Hz), 1.71 (m, 2H), 1.43-1.19 (m, 4H), 0.88 (t, 3H, J=6.8 Hz) ppm.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.C([N+]1C=CC=CC=1Br)CC.N1(C2C=CN=CC=2)CCCC1.CCN(C(C)C)C(C)C.[CH:39]1([CH2:45][CH2:46][C:47](=O)[CH:48]([CH2:66][CH:67]2[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]2)[C:49]([N:51]([CH2:57][C:58]2[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=2)[CH:52]([CH3:56])[C:53]([OH:55])=[O:54])=[O:50])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>C(Cl)Cl.CCOCC>[CH:39]1([CH2:45][CH2:46][C:47]23[O:54][C:53](=[O:55])[C:52]2([CH3:56])[N:51]([CH2:57][C:58]2[CH:63]=[CH:62][C:61]([O:64][CH3:65])=[CH:60][CH:59]=2)[C:49](=[O:50])[CH:48]3[CH2:66][CH:67]2[CH2:68][CH2:69][CH2:70][CH2:71][CH2:72]2)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: COc1ccc(CN(C(=O)C(CC2CCCCC2)C(=O)CCC2CCCCC2)C(C)C(=O)O)cc1
Agent: CCC[n+]1ccccc1Br
Agent: O=S(=O)([O-])C(F)(F)F
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: COc1ccc(CN2C(=O)C(CC3CCCCC3)C3(CCC4CCCCC4)OC(=O)C23C)cc1
Reaction time: 0.17 h

Procedure:
To a suspension of N-propyl-2-bromo pyridinium triflate (285 mg, 0.824 mmol) and 4-pyrrolidinopyridine (183 mg, 1.24 mmol) in CH2Cl2 (11.5 mL) was added Hünig's base (72 μL, 0.41 mmol) at 0° C. After stirring for 10 min, a solution of keto-acid 60 (200 mg, 0.412 mmol) in CH2Cl2 (5 mL) was added via syringe pump over 1 h at 0° C. The resulting suspension was stirred for 3 h at 0° C., at which point the volatiles were removed up to one-third under reduced pressure. The crude reaction mixture was diluted with Et2O (100 mL) and washed with aqueous NH4Cl solution and brine (each 30 mL). The organic layer were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (1:10 EtOAc/hexanes) to give a mixture of two beta-lactones (60 mg, 31%, dr 1:1.6) as a colorless oil. (±)-61 (major): Rf=0.56 (20% EtOAc/hexanes); IR (neat) 1829,1701 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.22 (d, J=8.5 Hz, 2H), 6.84 (d, J=9.0 Hz, 2H), 4.76 (d, J=15.5 Hz, 1H), 4.28 (d, J=15.0 Hz, 1H), 3.80 (s, 3H), 2.75 (t, J=7.0 Hz, 1H), 1.65-2.03 (m, 15H), 1.39 (s, 3H), 0.85-1.34 (m, 13H); 13C NMR (75 MHz, CDCl3) δ 175.0, 169.2, 159.3, 129.6, 129.4, 114.2, 86.8, 76.4, 55.4, 44.4, 42.2, 38.1, 35.0, 33.6, 33.5 (2), 33.3, 33.2, 31.7, 30.8, 26.7, 26.6, 26.3 (3), 13.0; LRMS (ESI) Calcd. for C29H41NO4 [M+H] 468, found 468. (±)-61b (minor): Rf=0.63 (20% EtOAc/hexanes); IR (neat) 1829, 1702 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.18 (d, J=8.5 Hz, 2H), 6.83 (d, J=8.5 Hz, 2H), 4.87 (d, J=15.5 Hz, 1H), 4.17 (d, J=15.5 Hz, 1H), 3.79 (s, 3H), 2.87 (dd, J=3.5, 11.0 Hz, 1H), 2.06 (br d, J=12.5 Hz, 1H), 1.46-1.87 (m, 12H), 1.14-1.42 (m, 12H), 0.79-1.10 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 174.3, 169.3, 159.0, 129.6, 128.9, 114.0, 87.2, 76.8, 55.2, 44.2, 43.8, 37.9, 37.4, 34.7, 34.5, 33.2, 33.0, 32.1, 30.4, 27.3, 26.5, 26.4, 26.2, 25.8, 12.3.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:9](OC)=[CH:8][C:4]=1[C:5]([OH:7])=O)=O.[CH3:14][NH:15][NH2:16].[CH2:17](O)C>>[CH3:17][C:9]1[CH:8]=[C:4]2[C:3]([CH:1]=[N:16][N:15]([CH3:14])[C:5]2=[O:7])=[CH:11][CH:10]=1
Reactant: CNN
Reactant: COc1ccc(C=O)c(C(=O)O)c1
Reactant: CCO
Product: Cc1ccc2cnn(C)c(=O)c2c1

Procedure:
A solution of 2-formyl-5-methoxy-benzoic acid (1.0 g, 6.10 mmol) and methyl hydrazine (0.481 mL, 1.5 eq.) in ethanol (15 mL) was stirred at 85° C. for 1.5 days. The solvent was removed and the solid was collected and washed with cold EtOH to give 7-methyl-2-methyl-2H-phthalazin-1-one (780 mg): MS m/z 191 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=O)[CH:5]=[N:6][CH:7]=1.B.C([O-])(O)=O.[Na+]>C1COCC1.O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:5]=[N:6][CH:7]=1
Reactant: O=C(Cc1cncc(Br)c1)N1CCOCC1
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1cncc(CCN2CCOCC2)c1
Temperature: 55 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
To a solution of 4-[(5-bromopyridin-3-yl)acetyl]morpholine (1.26 g, 4.40 mmol) in THF (15 mL) was added a 1M solution of borane in THF (23.2 mL, 23.2 mmol). The reaction mixture was allowed to stir at 55° C. overnight and then was allowed to cool to rt and then diluted with water (100 mL) and EtOAc (100 mL). The organic solution was separated and the aqueous solution was extracted with EtOAc (2×50 mL). The organic solutions were combined, dried over MgSO4, filtered and concentrated to give a yellow oil, which was dissolved in 1N HCl (100 mL). This solution was allowed to stir at 80° C. overnight. The reaction mixture was neutralized with sat. aq. NaHCO3 (100 mL) and then extracted with EtOAc (3×50 mL). The combined organic solutions were washed with brine, dried over MgSO4, filtered and concentrated to give 4-[2-(5-bromopyridin-3-yl)ethyl]morpholine (0.631 g, 2.33 mmol, 53%) as a light yellow oil. LCMS (FA): Rt=0.50 min, m/z=273.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1I.O1CCOCC1.[CH3:27][C:28]1([CH3:35])[C:32]([CH3:34])([CH3:33])[O:31][BH:30][O:29]1>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[B:30]1[O:31][C:32]([CH3:34])([CH3:33])[C:28]([CH3:35])([CH3:27])[O:29]1
Reactant: CC1(C)OBOC1(C)C
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(I)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
A screw-cap vial was charged with 66.15D (2.08 g, 5.39 mmol), 1,4-dioxane (20 mL), and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) DCM adduct (available from Strem) (0.220 g, 0.269 mmol). The suspension was sparged with N2, and to it were added TEA (2.25 mL, 16.2 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (available from Aldrich) (1.17 mL, 8.08 mmol). The resulting mixture was stirred overnight at 100° C. (sealed vial), cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were washed with water, 1 N HCl, and brine, dried (MgSO4), and concentrated. The crude product was twice purified by silica gel flash chromatography (0-15% EtOAc/hexane) to afford 66.56A (1.09 g, 52% yield) as a crystalline white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:3]=1[C:4]([O:6]C)=O.ClC(Cl)(O[C:17](=[O:23])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:32]1([CH2:38][CH2:39][NH2:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[I:12][C:9]1[CH:8]=[C:3]2[C:2](=[CH:11][CH:10]=1)[NH:1][C:17](=[O:23])[N:40]([CH2:39][CH2:38][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:4]2=[O:6]
Reactant: COC(=O)c1cc(I)ccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1[nH]c2ccc(I)cc2c(=O)n1CCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
To a solution (40 mL) of methyl 2-amino-5-iodobenzoate (2.3 g) in methylene chloride were added triphosgene (3.2 g) and triethylamine (3.9 g), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 2-phenylethanamine (3.0 g), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (30 mL), 60% sodium hydride (0.5 g) was added, and the mixture was stirred at 70° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (2.1 g, 65%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C:9](=[O:11])[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29].C([O-])([O-])=O.[Na+].[Na+]>CC#N.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([C:2]2[CH:3]=[C:4]3[CH2:10][C:9](=[O:11])[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]3=[N:6][CH:7]=2)[CH:23]=[C:22]([O:21][CH3:20])[C:27]=1[O:28][CH3:29]
Reactant: C[Si](C)(C)CCOCN1C(=O)Cc2cc(Br)cnc21
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(-c2cnc3c(c2)CC(=O)N3COCC[Si](C)(C)C)cc(OC)c1OC
Temperature: 80 °C
Yield: 59.5 %

Procedure:
To a solution of 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (0.85 g, 2.5 mmol) in CH3CN (5 mL) was added 3,4,5-trimethoxyphenylboronic acid (525 mg, 2.5 mmol), bis(triphenylphosphine)-palladium(II) dichloride (250 mg, 0.35 mmol), and 1 M Na2CO3 (5 mL). The resulting mixture was de-gassed with Ar for 10 min, after which it was heated at 80° C. for 2 hr. The reaction mixture was partitioned between EtOAc and H2O, and the organic layer was separated, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with 3:1 EtOAc:Hexanes to yield the title compound (640 mg, 60%). HPLC retention time: 2.51 minutes; MS ESI (m/z): 431.4 (M+1)+, calc. 430.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[C-:13]#[N:14].[K+].[Cl-].[NH4+:17]>CO.O>[NH2:17][C:9]1([C:13]#[N:14])[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=2)[CH2:10]1
Reactant: [NH4+]
Reactant: [C-]#N
Reactant: O=C1CCc2cccc(Cl)c2C1
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: N#CC1(N)CCc2cccc(Cl)c2C1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
To a vigorously stirred solution, maintained under nitrogen, containing 277 mmol of 8-chloro-3,4-dihydro-2(1H)-naphthalenone in 350 ml of methanol and 170 ml of water are successively added 282 mmol of potassium cyanide and 290 mmol of ammonium chloride. After stirring for 48 hours at 20° C., the mixture is concentrated. The residue is taken up in ethyl acetate. This organic phase is washed with water and extracted with 1N hydrochloric acid. The acidic phases are basified with 35% sodium hydroxide and extracted with ethyl acetate. The expected product is obtained, in solid form, after drying and evaporating the organic phases.
Reaction SMILES: Br[C:2]1[C:3](=[O:32])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:59][C:60]1[CH:61]=[C:62](B(O)O)[CH:63]=[CH:64][C:65]=1[O:66][CH3:67]>>[F:59][C:60]1[CH:61]=[C:62]([C:2]2[C:3](=[O:32])[C:4]3[C:9]([C:10]=2[C:11]2[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([F:17])[CH:16]=2)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:29])=[O:30])[CH2:26][CH2:27]2)[CH:5]=3)[CH:63]=[CH:64][C:65]=1[O:66][CH3:67]
Reactant: COc1ccc(B(O)O)cc1F
Reactant: CS(=O)(=O)N1CCN(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCN4CCN(S(C)(=O)=O)CC4)cc3C2=O)cc1F
Yield: 71 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-{2-[4-(methylsulfonyl)piperazin-1-yl]ethoxy}-1H-inden-1-one obtained in Step 1 of Example 96 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 3-fluoro-4-methoxyphenylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (EtOAc/CH2Cl2=1:1) to obtain the title compound (71%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:16])[CH3:15])=[CH:10][CH:9]=1.[Cl:17][C:18]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.CCO.[OH-].[Na+]>CO>[Cl:17][C:18]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[CH:15][C:14]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:9][CH:10]=1)=[O:16]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: CC(=O)c1ccc(OC2CCCCO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: O=C(C=Cc1cccc(Cl)c1Cl)c1ccc(OC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
4′-Tetrahydropyranyloxy-acetophenone (1.98 g, 9.0 mmol),ii 2,3-dichlorobenzaldehyde (1.93 g, 11.0 mmol), EtOH (15 mL), and MeOH (15 mL) were combined in a 100 mL round bottom flask with a stir bar. After all of the reactants were dissolved, 50% (w/v) aq. NaOH (1.0 mL, 19 mmol) was added. The flask was stoppered and stirred at room temperature for 8 h. The resulting white precipitate was filtered, washed with EtOH (1 mL, 3×), and allowed to air dry to afford 2.95 g of THP-4Al as a white powder (87% yield). The product was used without further purification. TLC: Rf=0.40 (hexane/EtOAc 4:1); Melting point: 116-118° C.; 1H NMR: (300 MHz, Acetone-d6) δ 8.15, 7.18 (AA′XX′ peak, Jaa′=Jxx′=2.5, Jax=8.4, Jax′=0.4 Hz, 2H), 8.13 (d, J=16 Hz, 1H), 8.04 (dd, J=7.9, 1.4 Hz, 1H), 7.89 (d, J=16 Hz, 1H), 7.64 (dd, J=7.9, 1.4 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 5.61 (t, J=3.0 Hz, 1H), 3.82 (ddd, J=11.5, 8.4, 2.6 Hz, 1H), 3.61 (dtd, J=11.5, 4.0, 1.3 Hz, 1H), 1.86 (m, 3H), 1.66 (m, 3H); 13C NMR: (75 MHz, DMSO-d6) δ 187.23, 161.54, 138.27, 136.06, 133.45, 132.73, 131.77, 131.48, 130.95, 128.36, 126.93, 126.31, 116.38, 96.22, 61.89, 30.14, 25.13, 18.67; IR (ATR): 2964, 1656, 1608, 1595, 1573, 1556, 1507, 1455, 1425, 1411, 1372, 1326, 1314, 1248, 1222, 1205, 1173, 1155, 1121, 1106, 1035, 1020, 961 cm−1; ESI-MS: expected, 376.1; observed, m/z 376.9 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[N:16][N:17]([C:18]4[N:23]=[C:22]([N:24]5[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]5)[CH:21]=[CH:20][CH:19]=4)[C:11]=3[CH:10]=2)=[N:6][C:7]=1[CH3:8].Cl>CO.O1CCOCC1>[N:24]1([C:22]2[N:23]=[C:18]([N:17]3[C:11]4[CH:10]=[C:9]([C:5]5[N:6]=[C:7]([CH3:8])[C:2]([NH2:1])=[N:3][CH:4]=5)[N:14]=[CH:13][C:12]=4[CH:15]=[N:16]3)[CH:19]=[CH:20][CH:21]=2)[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1
Reactant: Cc1nc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCN(C(=O)OC(C)(C)C)CC3)n2)cnc1N
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1nc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCNCC3)n2)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.3 %

Procedure:
To a solution of tert-butyl 4-[6-[6-(5-amino-6-methyl-pyrazin-2-yl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-1,4-diazepane-1-carboxylate (0.2293 mmol; 115 mg) in Methanol (10 mL) was added hydrochloric acid, 4.0 M in 1,4-Dioxane (5 mL). The resulting mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 208 as an off-white solid (4.0 mg, 4.3%). MS (ESI) m/z: 402.1 [M+H]+
Reaction SMILES: [C:1]([C:4]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:3])[NH2:2].[CH2:24](Br)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:4]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:7]1)(=[O:3])[NH2:2]
Reactant: NC(=O)C(CC1CCNCC1)(c1ccccc1)c1ccccc1
Reactant: BrCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)C(CC1CCN(CCc2ccccc2)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 48.7 %

Procedure:
A mixture of 4-(2-carbamoyl-2,2-diphenylethyl)piperidine (300 mg, 0.97 mmol) (Preparation 3), phenethyl bromide (198 mg, 1.07 mmol) and potassium carbonate (400 mg) in acetonitrile (10 ml) was heated under reflux for 6 hours, allowed to cool to room temperature and evaporated. The residue was partitioned between dichloromethane and 10% aqueous potassium carbonate solution and the aqueous layer was extracted twice into dichloromethane. The combined organic layers were dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica using dichloromethane plus 0-10% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound (195 mg, 49%) as a colourless foam, which was characterised as a hydrate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[CH:17]=[C:18]([CH:31]=[C:32]([C:35]([O:37][CH3:38])=[O:36])[C:33]=2[CH3:34])[O:19][CH:20]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21]2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:39](=O)[CH3:40].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][CH:12]([N:15]([CH2:39][CH3:40])[C:16]2[CH:17]=[C:18]([CH:31]=[C:32]([C:35]([O:37][CH3:38])=[O:36])[C:33]=2[CH3:34])[O:19][CH:20]2[CH2:21][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:23]2)[CH2:13][CH2:14]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC=O
Reactant: COC(=O)c1cc(OC2CN(C(=O)OC(C)(C)C)C2)cc(NC2CCC(NC(=O)OC(C)(C)C)CC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN(c1cc(OC2CN(C(=O)OC(C)(C)C)C2)cc(C(=O)OC)c1C)C1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of tert-butyl 3-(3-((4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-5-(methoxycarbonyl)-4-methylphenoxy)azetidine-1-carboxylate (0.90 g, 1.69 mmol) and acetaldehyde (0.22 g, 5.06 mmol) in dichloroethane (10 mL), was added acetic acid (0.61 g, 10 mmol) and the reaction stirred at room temperature for 20 minutes. Then sodium triacetoxyborohydride (1.07 g, 5.05 mmol) was added at 0° C. and the reaction was stirred at room temperature for 2 h. On completion, the reaction was quenched with aqueous sodium bicarbonate, the organic phase separated and the aqueous phase extracted with dichloromethane. The combined organic layers were washed with water, dried, concentrated under reduced pressure giving the title compound which was used without further purification (0.85 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][N:12]=[N:11][N:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][F:23]>C(#N)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][N:12]([CH2:21][CH2:22][F:23])[NH:11][N:10]=1
Reactant: FCCBr
Reactant: Clc1cccc(-c2nnn[nH]2)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FCCN1NN=C(c2cccc(Cl)c2Cl)N1
Reaction time: 0.25 h
Yield: 65.4 %

Procedure:
To 100 mL of acetonitrile was added 5 g of 5-(2,3-dichlorophenyl)-1H-tetrazole (Lancester Synthesis Inc., Windham, N.H.) followed by 2.5 g of potassium carbonate. After stirring for 15 min, 5 g of 1-bromo-2-fluoroethane was added dropwise. After the addition, the resulting mixture was then heated to reflux for 3 hours and then filtered. The solvent was then evaporated under reduced pressure leaving 4 g of 5-(2,3-dichlorophenyl)-2-(2-fluoroethyl)-1H-tetrazole as an oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26])#[N:21]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:25]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:26])#[N:21]
Reactant: COc1ccc(C(=O)Cl)cc1C#N
Reactant: c1ccc2c(c1)NCS2
Agent: C=O
Agent: Nc1ccccc1S
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CSc3ccccc32)cc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (1.89 g) and 37% formalin (1.25 mL) in the same manner as in Example 1 was dissolved in chloroform (20 mL), and triethylamine (2.08 mL) and 3-cyano-4-methoxybenzoyl chloride were added to the solution, and then the mixture was stirred at room temperature for 2 hours. The organic solvent was distilled off under reduced pressure and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (e).
Reaction SMILES: [C:1](=[O:18])([O:12][CH2:13][C:14]([NH:16][CH3:17])=[O:15])OC1C=CC([N+]([O-])=O)=CC=1.[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>ClCCCl>[N:19]1([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH2:23][N:22]([C:1]([O:12][CH2:13][C:14]([NH:16][CH3:17])=[O:15])=[O:18])[CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CNC(=O)COC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCCl
Product: CNC(=O)COC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
A solution, cooled to 0° C., of 1.1 g (3 mmol) of 4-nitrophenyl 2-(methylamino)-2-oxoethyl carbonate, prepared in step 3.1., in 10 ml of 1,2-dichloroethane is admixed dropwise at about 0° C. with a solution of 0.53 g (2.85 mmol) of 1,1-dimethylethyl piperazine-1-carboxylate in 5 ml of 1,2-dichloroethane. Stirring is continued at 0° C. for 1 hour, then at ambient temperature for 3 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:20]([O:23][C@@H:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:19][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14](O)=[O:15])=[CH:11][CH:12]=2)[C:7]([CH3:17])=[C:6]1[CH3:18].Cl.[CH:31]([C:34]1[CH:35]=[C:36]([C@@H:40]([NH2:42])[CH3:41])[CH:37]=[CH:38][CH:39]=1)([CH3:33])[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCN(C(C)C)C(C)C>[Cl:1][C:2]1[CH:22]=[CH:21][C:20]([O:23][C@@H:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:19][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14](=[O:15])[NH:42][C@H:40]([C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([CH:31]([CH3:33])[CH3:32])[CH:35]=3)[CH3:41])=[CH:11][CH:12]=2)[C:7]([CH3:17])=[C:6]1[CH3:18]
Reactant: COC(=O)[C@H](C)Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)Oc1ccc(Cl)c(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1
Reaction time: 15 h

Procedure:
The (S)-1-(2-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid (71 mg, 0.17 mmol), the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride (53 mg, 0.27 mmol) and HATU (88 mg, 0.23 mmol) were dissolved in DMF (3 mL) and DIEA (0.15 mL). It was stirred for 15 h. The solution was filtered and purified by preparative HPLC.