Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([CH:18](OC(C)C)[O:19][CH:20]([CH3:22])[CH3:21])([C:14]([F:17])([F:16])[CH3:15])[C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[NH:6][C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([CH2:18][O:19][CH:20]([CH3:21])[CH3:22])([C:14]([F:16])([F:17])[CH3:15])[C:4]=2[CH:3]=1
Reactant: CC(C)OC(OC(C)C)C1(C(C)(F)F)c2cc(Cl)ccc2Nc2ncccc21
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)OCC1(C(C)(F)F)c2cc(Cl)ccc2Nc2ncccc21
Reaction time: 14 h
Yield: 80.2 %

Procedure:
Method QQ: To a stirred solution of 7-chloro-5-diisopropoxymethyl-5-(1,1-difluoroethyl)-5,10-dihydrobenzo[b][1,8]naphthyridine (53) (360 mg, 0.876 mmol) in anhydrous methylene chloride (4 mL) at room temperature was added trifluoroacetic acid (8 mL) and triethylsilane (6.0 mL, 36.44 mmol). After 14 h at room temperature, the reaction mixture was concentrated in vacuo, the residue was purified by flash chromatography (30%-40% EtOAc-hexane, gradient elution) afforded 55 (248 mg, 80% yield) as a yellow solid (m.p. 148 -149° C.).
Reaction SMILES: [C:1]([N:11]1[CH2:19][C@H:17]([OH:18])[CH2:16][C@H:12]1[C:13](O)=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]>C1COCC1>[CH2:4]([O:3][C:1]([N:11]1[CH2:19][C@H:17]([OH:18])[CH2:16][C@H:12]1[CH2:13][OH:14])=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1C[C@H](O)C[C@H]1CO
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48.2 %

Procedure:
To an ice cold solution of 4.76 g (18 mmoles) of CBZ hydroxyproline (Sigma Chemical Co.) in 20 mL of dry THF was added 45 mL of a 1M solution borane-THF complex in THF (Aldrich). After stirring under argon for 15 minutes at 0°-5° C., and 4.5 h at room temperature, the mixture was quenched with 50 mL of methanol. After 30 min, the solution was concentrated. The residual colorless syrup was purified by flash chromatography (3.5×23 cm silica) using a gradient of methanol in methylene chloride. The product eluted with 10% methanol. The fractions containing pure product were stripped of solvent to give 2.18 g (46% yield) of (1) as a colorless syrup.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:12])=[C:4](Cl)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[CH2:13]([O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[CH3:14].C(N(CC)CC)C>CCO>[Cl:1][C:2]1[C:3]([Cl:12])=[C:4]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][CH2:13][CH3:14])=[CH:17][CH:18]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1
Reactant: Clc1nn2ccnc2c(Cl)c1Cl
Reactant: CCOc1ccc(N)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOc1ccc(Nc2c(Cl)c(Cl)nn3ccnc23)cc1
Temperature: 90 °C
Yield: 86 %

Procedure:
A mixture of 6,7,8-trichloroimidazo[1,2-b]pyridazine (0.04 g, 0.18 mmol) from 1d, p-ethoxyaniline (0.025 g, 0.18 mmol) and triethylamine (0.055 mL, 0.4 mmol) were suspended in EtOH (1.0 mL) and heated to 90° C. for 2.5 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo to provide crude 6,7-dichloro-N-(4-ethoxyphenyl)imidazo[1,2-b]pyridazin-8-amine (0.05 g, 86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:25][S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)(=[O:28])=[O:27])[CH2:9][C:10]([NH:12][C@@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH:23]=C)[CH:19]=3)[CH2:14]2)=[O:11])=[CH:4][CH:3]=1.C([OH:43])(C)(C)C.C1COCC1.O.C[N+]1([O-])CCOCC1.P([O-])([O-])([O-])=O>CCOC(C)=O.O=[Os](=O)(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:25][S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=2)(=[O:27])=[O:28])[CH2:9][C:10]([NH:12][C@@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH:23]=[O:43])[CH:19]=3)[CH2:14]2)=[O:11])=[CH:4][CH:3]=1
Reactant: C=Cc1ccc2c(c1)CC[C@@H](NC(=O)C[C@@H](NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1)C2
Reactant: CC(C)(C)O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)CC[C@@H](NC(=O)C[C@@H](NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(R)-(4-fluoro-phenyl)-3-(3-trifluoromethyl-benzenesulfonylamino)-N-(6-vinyl-1,2,3,4-tetrahydro-naphthalen-2-(R)-yl)-propionamide (314 mg, 0.575 mmol) in 13 mL of a mixture solvent t-butanol/THF/water (10:2:1) was added NMO (135 mg, 1.15 mmol), followed by OsO4 (2.5% w/w in t-butanol, 175 mg, 0.017 mmol). After stirring overnight at RT, 4 mL of pH=7.2 phosphate buffer was added, followed by NaIO4 (615 mg, 2.875 mmol). After stirring for 5 h at RT, the solution was diluted with EtOAc and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness in vacuo. Flash chromatography (SiO2, EtOAc/hexane=1:1) afforded the desired compound as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][C:16]([C@@H:18]1[CH2:23][C@@H:22]2[C@@H:20]([CH2:21]2)[NH:19]1)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:24]([C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]([CH2:36][C:37](O)=[O:38])[N:28]=1)(=[O:26])[NH2:25].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>C(Cl)Cl.O>[CH2:8]([O:15][C:16]([C@@H:18]1[CH2:23][C@@H:22]2[C@@H:20]([CH2:21]2)[N:19]1[C:37](=[O:38])[CH2:36][N:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27]([C:24](=[O:26])[NH2:25])=[N:28]1)=[O:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@H]2C[C@H]2N1
Reactant: NC(=O)c1nn(CC(=O)O)c2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: NC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)OCc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester trifluoroacetate (3.9 g, 9.77 mmol), (3-carbamoyl-indazol-1-yl)-acetic acid (prepared as described in Scheme A25, 2.26 g, 9.77 mmol), HBTU (5.56 g, 14.66 mmol) in CH2Cl2 (60 mL) was added DIPEA (5.12 mL, 29.3 mmol). The reaction mixture was stirred for 48 h at RT. The reaction mixture was poured into water and extracted with CH2Cl2 (×3). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 10:0 to 0:10). Rf, TLC (EtOAc)=0.85; MS (UPLC): 436.3 [M+NH4]+, 463.2 [M+HCOO]−; tR (HPLC conditions f): 1.82 min.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[C@@H:8]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=3[S:20]([CH3:23])(=[O:22])=[O:21])[NH:7][C:6](=[O:24])[N:5]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)[C:4]=2[CH2:3]1.[H-].[Na+].[CH3:37][S:38](Cl)(=[O:40])=[O:39]>>[CH3:1][N:2]1[C:10](=[O:11])[C:9]2[C@@H:8]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=3[S:20]([CH3:23])(=[O:21])=[O:22])[N:7]([S:38]([CH3:37])(=[O:40])=[O:39])[C:6](=[O:24])[N:5]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)[C:4]=2[CH2:3]1
Reactant: CN1CC2=C(C1=O)[C@@H](c1ccc(C#N)cc1S(C)(=O)=O)NC(=O)N2c1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: CN1CC2=C(C1=O)[C@@H](c1ccc(C#N)cc1S(C)(=O)=O)N(S(C)(=O)=O)C(=O)N2c1cccc(C(F)(F)F)c1

Procedure:
Analogously to the preparation of Example 27, 4-{(4S)-6-methyl-2,5-dioxo-1-[3-(trifluoromethyl)phenyl]-2,3,4,5,6,7-hexahydro-1H-pyrrolo[3,4-d]pyrimidin-4-yl}-3-(methylsulfonyl)benzonitrile (20 mg, 41 μmol; Example 35), sodium hydride (60%, 2.3 mg, 57 μmol) and methanesulfonyl chloride (6.5 mg, 57 μmol) were reacted with one another for 2 h. The title compound was obtained as a colorless solid (1.7 mg, 7% of theory). In addition, 6.4 mg (32% of theory) of the starting material were recovered.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([C:17]4[CH2:18][CH2:19][N:20]([CH2:23][C:24]5[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=5)[CH2:21][CH:22]=4)[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1.[OH-].[Na+]>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:34][CH3:35])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([C:17]4[CH2:18][CH2:19][N:20]([CH2:23][C:24]5[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=5)[CH2:21][CH:22]=4)[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(CN2CC=C(c3cc4c(-c5cc(F)ccc5OC)ncnc4[nH]3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(F)cc1-c1ncnc2[nH]c(C3=CCN(Cc4ccc(C(=O)O)cc4)CC3)cc12
Reaction time: 12 h

Procedure:
To a solution of Example 71 (60 mg, 0.127 mmol) in 5 mL dioxane was added 6 M sodium hydroxide (212 μL, 1.270 mmol). The reaction mixture was held at 50° C. for 12 hours and then diluted with 25 mL water. The aqueous mixture was extracted with ethyl acetate (2×), and the organic fractions were discarded. The aqueous layer was diluted with an equal amount of ethyl acetate and made slightly acidic with 2.5 M hydrochloric acid. The aqueous layer was extracted with ethyl acetate (2×), and the combined organic fractions were washed with brine, dried over magnesium sulfate and concentrated to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H) 8.76 (s, 1H) 7.92 (d, J=7.93 Hz, 2H) 7.47 (d, J=8.24 Hz, 2H) 7.28-7.39 (m, 2H) 7.15-7.27 (m, 1H) 6.54 (s, 1H) 6.28 (d, J=1.53 Hz, 1H) 3.78 (s, 3H) 3.68 (s, 2H) 3.14 (s, 2H) 2.65 (t, J=5.49 Hz, 2H) 2.50 (s, 3H). MS (ESI+) m/z 459.1 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([N:23]3[CH2:27][CH2:26][CH:25]([C:28](Cl)=[O:29])[CH2:24]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:31])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[NH3:33]>ClCCl>[O:1]=[S:2]1(=[O:32])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([N:23]3[CH2:27][CH2:26][CH:25]([C:28]([NH2:33])=[O:29])[CH2:24]3)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:31])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: N
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CCC(C(=O)Cl)C3)c2c1
Solvent: ClCCl
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3CCC(C(N)=O)C3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.5 %

Procedure:
To a cooled solution of 1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidine-3-carbonyl chloride (100 mg, 0.21 mmol) in dichloromethane (20 mL) was added a saturated solution of ammonia in dichloromethane (10 mL) slowly at 0° C. After being stirred for 16 hours at room temperature, the mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford 13 mg of the desired product (yield was 13.5%). MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, CD3OD) δ ppm 8.08-8.05 (m, 2 H), 7.33-7.31 (d, J=7.6 Hz, 1 H), 7.70-7.67 (m, 2 H), 7.57-7.55 (m, 2 H), 5.85 (s, 1 H), 5.25 (s, 2 H), 4.5 (s, 2 H), 4.03-3.94 (m, 4 H), 3.71 (s, 2 H), 3.29-3.21 (m, 1 H), 2.45 (s, 3 H), 2.41-2.32 (m, 1 H), 2.31-2.21 (m, 1 H).
Reaction SMILES: [NH2:1][C@H:2]([C:15](=[O:24])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[N:25]1[C:34]2[C:33](=O)[CH2:32][CH2:31][CH2:30][C:29]=2[CH:28]=[CH:27][CH:26]=1.[BH4-].[Na+]>C(O)C.C([O-])(O)=O.[Na+]>[O:24]=[C:15]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[C@@H:2]([NH:1][CH:33]1[C:34]2[N:25]=[CH:26][CH:27]=[CH:28][C:29]=2[CH2:30][CH2:31][CH2:32]1)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C1CCCc2cccnc21
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)NCc1ccccn1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC1CCCc2cccnc21)C(=O)NCc1ccccn1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-tert-butyl 5-amino-6-oxo-6-(pyridin-2-ylmethyl-amino)hexylcarbamate, 28, (2.16 g, 6.43 mmol) in ethanol (14 mL) was added 6,7-dihydroquinolin-8(5H)-one (0.90 g, 6.12 mmol). The mixture was heated in microwave reactor at 150° C. for 13 min. After cooling the reaction to room temp., NaBH4 (0.46 g, 12.24 mmol) was added to the mixture. The reaction mixture was stirred at room temp for 1 h. The mixture was diluted with aqueous saturated NaHCO3, extracted twice with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (5% to 25% methanol/CH2Cl2) to afford the desired product 29: 1H NMR (d6-DMSO) δ 8.44 (d, J=4.4 Hz, 1H), 8.40 (m, 1H), 8.32-8.31 (m, 1H), 7.66 (t, J=7.2 Hz, 1H), 7.45 (d, J=7.6 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.20 (t, J=4.8 Hz, 1H), 7.13 (dd, J=8.0, 4.2 Hz, 1H), 6.94 (d, J=7.6 Hz, 1H), 4.32 (d, J=5.6 Hz, 2H), 3.95-3.89 (m, 1H), 3.62-3.57 (m, 1H), 2.69 (d, J=4.8 Hz, 2H), 2.61-2.56 (m, 2H), 1.99-1.95 (m, 1H), 1.89-1.83 (m, 1H), 1.63-1.28 (m, 8H), 1.35 (s, 9H); ESI+ MS: m/z (rel intensity) 468.3 (100, [M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[C:22](O)(=[O:32])[CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:24][OH:25]>>[OH:32][CH2:22][CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:24]([NH:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:3]=1)=[O:25]
Reactant: O=C(O)C(CO)c1ccccc1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)C(CO)c3ccccc3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Example 167 using (5-aminopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Preparation 95) and tropic acid to afford the title compound as a yellow solid in 7% yield, 15 mg.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22]C)[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>Br>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)C(C1(c3cccc(Cl)n3)CCC1)=NCC2
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: Oc1ccc2c(c1)C(C1(c3cccc(Cl)n3)CCC1)=NCC2
Temperature: 25 °C

Procedure:
1-[1-(6-Chloropyridin-2-yl)cyclobutyl]-7-methoxy-3,4-dihydroisoquinoline (550 mg, 1.68 mmol) in 48% aqueous hydrobromic acid (3.8 ml) was heated under reflux for 4 hours. After cooling to room temperature the reaction mixture was poured on ice water. 10% aqueous sodium hydroxide solution was added until pH 8 was reached. The mixture was extracted with dichloromethane (3×). The combined organic extracts were dried (MgSO4), concentrated in vacuo and purified by flash chromatography (silica, dichloromethane, methanol). Yield: 220 mg (0.70 mmol, 42%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[H-].[Na+].[CH3:14][O:15][CH2:16]Cl.[Cl-].[NH4+]>CN(C)C=O.O>[CH3:14][O:15][CH2:16][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1
Reactant: COCCl
Reactant: O=Cc1c[nH]c2ccccc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: COCn1cc(C=O)c2ccccc21
Reaction time: 0.33 h
Yield: 20 %

Procedure:
5 g of Indol-3-aldehyde was dissolved in 40 ml of N,N-dimethylformamide, and 1.38 g of 60% sodium hydride was added under ice-cooling. The reaction solution was stirred for 20 minutes with ice-cooling, then 3.2 ml of chloromethyl methyl ether was added, and stirring was continued at room temperature for 16 hours. The reaction solution was cooled in ice, treated with water and ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was subjected to silica gel column chromatography, to give 6.1 g of the title compound (20-44% ethyl acetate-hexane)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[C:10]([N+:16]([O-])=O)[CH:9]=2)=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>C1COCC1>[NH2:16][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH:15]=[CH:14][C:11]=1[CH:12]=[O:13]
Reactant: Cc1ccc(-c2ccc(C=O)c([N+](=O)[O-])c2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(C=O)c(N)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.3 %

Procedure:
Into a solution of 4-(4-methylphenyl)-2-nitrobenzaldehyde (590 mg) in THF (50 ml) was added a solution of sodium hydrosulfite (2.66 g)/water (25 ml). After being stirred at room temperature for 10 minutes, the reaction mixture was extracted with ethyl acetate, and the extract was washed with an aqueous solution of sodium chloride. The extract was dried (anhydrous magnesium sulfate) and was then concentrated to obtain 2-amino-4-(4-methylphenyl)benzaldehyde (0.26 g) as a light brown powder.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:9]=[N:10][CH:11]=[N:12][CH:13]=1.F[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1.Cl>CS(C)=O>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[N:12][CH:13]=2)=[CH:16][CH:17]=1)#[N:20]
Reactant: Nc1cncnc1
Reactant: N#Cc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Nc2cncnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
To 20 ml of dimethyl sulfoxide was added 2.8 g of potassium tert-butoxide. After stirring at room temperature for 30 minutes, 1.9 g of 5-aminopyrimidine was added thereto, followed by stirring at room temperature for 30 minutes. To the solution was added 1.21 g of 4-fluorobenzonitrile, and the mixture was stirred at room temperature for 30 minutes and then at 50° C. for 30 minutes. The reaction mixture was poured into ice-water, neutralized with hydrochloric acid. The resulting crystals were collected by filtration and dissolved in acetone. Any insoluble matter was removed by filtration, and the solvent was removed by distillation. The resulting crystals were washed with ethyl ether to obtain 1.04 g of 5-[(4-cyanophenyl)amino]pyrimidine.
Reaction SMILES: [CH:1]1([C:4](N)=O)[CH2:3][CH2:2]1.F[B-](F)(F)F.C([O+](CC)CC)C.[NH2:19][C:20]1[C:21]([NH:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([CH2:36][C:37]#[N:38])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[CH:1]1([C:4]2[N:29]([C@H:30]3[CH2:31][CH2:32][C@H:33]([CH2:36][C:37]#[N:38])[CH2:34][CH2:35]3)[C:21]3=[C:22]4[S:28][CH:27]=[CH:26][C:23]4=[N:24][CH:25]=[C:20]3[N:19]=2)[CH2:3][CH2:2]1
Reactant: N#CC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Reactant: NC(=O)C1CC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: N#CC[C@H]1CC[C@H](n2c(C3CC3)nc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of cyclopropanecarboxamide (65.0 mg, 0.764 mmol) and triethyloxonium tetrafluoroborate (145 mg, 0.763 mmol) in tetrahydrofuran (0.4 mL) was stirred at room temperature for 1 h and then concentrated. A mixture of {trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}acetonitrile (22 mg, 0.077 mmol), and the above made reagent in ethanol (0.70 mL) was heated at reflux for 2 h. The mixture was purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (2.5 mg, 9.7%). LCMS calculated for C19H21N4S (M+H)+: m/z=337.1. Found: 337.0.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[C:11]([NH:14][C@@H:15]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16](O)=[O:17])(=[O:13])[CH3:12].CCN=C=NCCCN(C)C.Cl.[NH2:38][C@@H:39]([CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([N:55]2[CH2:59][C:58](=[O:60])[N:57]([CH2:61][C:62]3[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][CH:63]=3)[S:56]2(=[O:71])=[O:70])[CH:50]=1)[C:40]([NH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:41]>C(Cl)Cl>[C:11]([NH:14][C@@H:15]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:16]([NH:38][C@H:39]([C:40](=[O:41])[NH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([N:55]2[CH2:59][C:58](=[O:60])[N:57]([CH2:61][C:62]3[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][CH:63]=3)[S:56]2(=[O:70])=[O:71])[CH:50]=1)=[O:17])(=[O:13])[CH3:12]
Reactant: CCCCCNC(=O)[C@@H](N)Cc1cccc(N2CC(=O)N(Cc3ccc(OC)cc3)S2(=O)=O)c1
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCCCNC(=O)[C@H](Cc1cccc(N2CC(=O)N(Cc3ccc(OC)cc3)S2(=O)=O)c1)NC(=O)[C@H](Cc1ccccc1)NC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HOBt (40.5 mg, 0.264 mmol), (S)-2-acetylamino-3-phenyl-propionic acid (54.7 mg, 0.264 mmol) and EDCl (50.6 mg, 0.264 mmol) are added to a solution of the title G compound, (S)-2-amino-3-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-N-pentyl-propionamide (129 mg, 0.264 mmol) in CH2Cl2 (5 mL) and stirred at RT for 2 h. The reaction is concentrated and the product is taken up in EtOAc, washed with 1N aqueous HCl, saturated aqueous NaHCO3 and brine, dried over magnesium sulfate, filtered and concentrated to yield (S)-2-acetylamino-N-((S)-2-{3-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-1-pentylcarbamoyl-ethyl)-3-phenyl-propionamide as a white solid: [M+1]+=678.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[CH2:12]([N:19]1[CH:27]=[C:26]2[C:21]([CH:22]=[C:23](B3OC(C)(C)C(C)(C)O3)[CH:24]=[CH:25]2)=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:12]([N:19]1[CH:27]=[C:26]2[C:21]([CH:22]=[C:23]([C:2]3[CH:3]=[CH:4][N:5]4[C:10]=3[C:9]([NH2:11])=[N:8][CH:7]=[N:6]4)[CH:24]=[CH:25]2)=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ncnn2ccc(Br)c12
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnn2ccc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 110 °C
Yield: 75 %

Procedure:
To a stirred degassed mixture 5-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine (500 mg, 2.35 mmol), Intermediate C (1.18 g, 3.52 mmol), Na2CO3 (746 mg, 7.04 mmol) and H2O (3.5 mL) in DMF (18 mL) was added tetrakis(triphenylphosphine)palladium(0) (271 mg, 0.24 mmol). The reaction was heated at 110° C. for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (50 mL) and H2O (50 mL). The layers were separated and the aqueous was further extracted with ethyl acetate (1×50 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to dryness. The crude material was purified via ISCO® chromatography using 3:1 ethyl acetate/hexanes to afford 600 mg (75%) of the desired product, which contained trace impurities. ES-MS ink 341.23 [M+H]+, HPLC RT (min) 2.91.