Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([CH2:19]O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)[Cl:22]>>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([CH2:19][Cl:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cc(OCc2ccccc2)c2ccccc2c1
Reactant: ClC(Cl)(Cl)Cl
Product: ClCc1cc(OCc2ccccc2)c2ccccc2c1

Procedure:
Chlorination of (4-benzyloxy-naphthalen-2-yl) [-methanol] using carbon tetrachloride analogously to Example 7(c) yielded 4-benzyloxy-2-chloromethyl-naphthalene as a colourless solid; MS: 282 (M)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9](/[CH:11]=[CH:12]/[C:13]([NH:15][S:16]([C:19]3[S:20][C:21]([Cl:25])=[C:22]([Cl:24])[CH:23]=3)(=[O:18])=[O:17])=[O:14])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:26].[H-].[Na+].[Cl:29][C:30]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:31]=1[CH2:32]Cl>CN(C=O)C>[Cl:29][C:30]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:31]=1[CH2:32][N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][C:9]=2/[CH:11]=[CH:12]/[C:13]([NH:15][S:16]([C:19]2[S:20][C:21]([Cl:25])=[C:22]([Cl:24])[CH:23]=2)(=[O:17])=[O:18])=[O:14])[C:5]([CH3:26])=[CH:6]1
Reactant: Cc1c[nH]c2c(/C=C/C(=O)NS(=O)(=O)c3cc(Cl)c(Cl)s3)cc(F)cc12
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(Cc2ccc(Cl)cc2Cl)c2c(/C=C/C(=O)NS(=O)(=O)c3cc(Cl)c(Cl)s3)cc(F)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 156.3 %

Procedure:
To a solution of 4,5-dichlorothiophene-2-sulfonic acid [(E)-3-(5-fluoro-3-methyl-1H-indol-7-yl)-acryloyl]-amide (1.025 kg, 2.37 mole) in DMF (5.1 L) at 0° C. was added NaH (60% in oil, 353 g, 8.8 mole) portionwise and the reaction mixture was allowed to stir for 30 min. 2,4-Dichlorobenzyl chloride (924 g, 1.41 mole) was added at such a rate to maintain the temperature near 0° C. After stirring about 45 min, the reaction mixture was carefully quenched with water (15 L), then diluted with 2 M HCl (9 L) and dichloromethane (10 L), which led to precipitation of the desired title product. The precipitated product was collected via vacuum filtration and the filter cake washed sequentially with water (2×2 L), and cold EtOH (2×1 L). The product was vacuum dried at 60° C. to afford 1.305 kg (93% yield) of desired product, as a solvate with DMF. The product was recrystallized from absolute EtOH to afford the pure product: 1H-NMR (400 MHz, DMSO-d6) δ 2.26 (s, 3H), 5.53 (s, 2H), 6.12 (d, 1H, J=8.4 Hz), 6.21 (d, 1H, J=15.4 Hz), 7.04 (dd, 1H, J=10.0, 2.4 Hz), 7.22 (dd, 1H, J=8.4, 2.0 Hz), 7.37 (s, 1H), 7.38 (d, 1H, J=2.0 Hz), 7.46 (dd, 1H, J=9.2, 2.4 Hz), 7.74 (d, 1H, J=15.4 Hz), 7.90 (s, 1H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23]C(=O)C4C=CC=CC=4)[CH:18]=3)[CH:14]=[CH:15][CH:16]=2)=[O:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+]>Cl.C(Cl)Cl>[NH2:23][C:19]1[CH:18]=[C:17]([C:13]2[CH:12]=[C:11]([C:9](=[O:10])[CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:16]=[CH:15][CH:14]=2)[CH:22]=[CH:21][N:20]=1
Reactant: O=C(CCN1CCOCC1)c1cccc(-c2ccnc(NC(=O)c3ccccc3)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Nc1cc(-c2cccc(C(=O)CCN3CCOCC3)c2)ccn1
Yield: 84.3 %

Procedure:
N-{4-[3-(3-Morpholin-4-yl-propionyl)-phenyl]-pyridin-2-yl}-benzamide (100 mg, 0.32 mmol) was dissolved in HCl (2 mL, 6 N). The mixture was irradiated with microwaves at 140° C. for 30 minutes. The mixture was diluted with DCM (20 mL) and neutralized with NaOH to pH 9. The layers were separated and the aqueous layer was washed further with DCM (2×15 mL). The combined organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated and the residue was purified to give 1-[3-(2-Amino-pyridin-4-yl)-phenyl]-3-morpholin-4-yl-propan-1-one (TFA salt) as a white solid (84 mg, 78%). MS: m/z 312.3 [MH+].
Reaction SMILES: [OH:1][NH:2][C:3]([C@@H:5]([NH:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:43])[CH2:34][NH:35]C(OC(C)(C)C)=O)=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)=[O:17])[CH2:6][NH:7]C(OC(C)(C)C)=O)=[O:4].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:35][CH2:34][C:33]([NH:32][C:29]1[CH:30]=[CH:31][C:26]([C:25]#[C:24][C:21]2[CH:22]=[CH:23][C:18]([C:16]([NH:15][C@@H:5]([CH2:6][NH2:7])[C:3]([NH:2][OH:1])=[O:4])=[O:17])=[CH:19][CH:20]=2)=[CH:27][CH:28]=1)=[O:43]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(C#Cc2ccc(C(=O)N[C@@H](CNC(=O)OC(C)(C)C)C(=O)NO)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)Nc1ccc(C#Cc2ccc(C(=O)N[C@@H](CN)C(=O)NO)cc2)cc1
Reaction time: 2 h
Yield: 104.4 %

Procedure:
To an oven-dried flask containing N-(4-{2-[4-(N-{1-(N-hydroxycarbamoyl)(1S)-2-[(tert-butoxy)carbonylamino]ethyl}carbamoyl)phenyl]ethynyl}phenyl)-2-[(tert-butoxy)carbonylamino]acetamide (6) (130 mg, 0.218 mmol) was added 1:1 TFA/CH2Cl2 (2.5 mL). The resulting pink solution was stirred for 2 h and concentrated to give a pink gum. The crude residue was rinsed with CH2Cl2 (4 mL), concentrated by rotary evaporation and dissolved in THF (2 mL) and MeOH (0.4 mL). A solution of 4 M HCl in dioxane (200 μL) was added and the resulting precipitate filtered and washed with Et2O (10 mL) to afford 90 mg of 4-({4-[(aminoacetyl)amino]phenyl}ethynyl)-N-[(1S)-1-(aminomethyl)-2-(hydroxyamino)-2-oxoethyl]benzamide as a pale tan powder.
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:9][CH2:8][CH2:7][NH:6]1)([O-:3])=[O:2].[Cl:10]/[CH:11]=[CH:12]\[CH2:13]Cl>>[Cl:10]/[CH:11]=[CH:12]\[CH2:13][N:6]1[CH2:7][CH2:8][NH:9][C:5]1=[CH:4][N+:1]([O-:3])=[O:2]
Reactant: Cl/C=C\CCl
Reactant: O=[N+]([O-])C=C1NCCN1
Product: O=[N+]([O-])C=C1NCCN1C/C=C\Cl

Procedure:
Method B, reacting 2-(nitromethylene)imidazolidine with cis-1,3-dichloropropene. Melting point: 117° - 118° .
Reaction SMILES: [CH:1]1([C:4]2(O)[CH2:7][CH:6]([C:8]3[O:12][N:11]=[C:10]([C:13]4[CH:14]=[CH:15][C:16]([CH3:31])=[C:17]([NH:19][C:20]([C:22]5[N:26]6[CH:27]=[CH:28][CH:29]=[CH:30][C:25]6=[N:24][CH:23]=5)=[O:21])[CH:18]=4)[N:9]=3)[CH2:5]2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=[O:36]>>[OH:36][CH2:2][CH2:3][CH:1]=[C:4]1[CH2:5][CH:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([CH3:31])=[C:17]([NH:19][C:20]([C:22]4[N:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]5=[N:24][CH:23]=4)=[O:21])[CH:18]=3)[N:9]=2)[CH2:7]1
Reactant: Cc1ccc(-c2noc(C3CC(O)(C4CC4)C3)n2)cc1NC(=O)c1cnc2ccccn12
Reactant: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2noc(C3CC(=CCCO)C3)n2)cc1NC(=O)c1cnc2ccccn12
Reaction time: 0.25 h

Procedure:
A stirring solution of N-(5-(5-(3-cyclopropyl-3-hydroxycyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F113) (130 mg, 0.303 mmol) in trifluoroacetic acid (1 mL) was stirred at room temperature for 1.5 hours. The solvent was concentrated and dried under high vacuum. The crude product was taken in MeOH (1 mL) and a saturated solution of sodium bicarbonate (0.2 mL). The reaction mixture was stirred for 15 minutes. The crude product was extracted with ethyl acetate. The organic phase was washed with water and dried over anhydrous sodium sulfate. The solvent was concentrated to obtain the desired product N-(5-(5-(3-(3-hydroxypropylidene)cyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F32). 1H NMR (400 MHz, d6-DMSO) δ 10.04 (s, 1H), 9.48-9.45 (m, 1H), 8.59 (s, 1H), 8.08 (d, J=1.6 Hz, 1H), 7.82 (dd, J=1.6 Hz, 7.6 Hz, 1H), 7.81-7.77 (m, 1H), 7.55-7.52 (m, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.20-7.16 (m, 1H), 5.28-5.23 (m, 1H), 4.50 (s, 1H), 3.98-3.89 (m, 1H), 3.40-3.37 (m, 2H), 3.23-3.14 (m, 2H), 3.09-3.03 (m, 2H), 2.36 (s, 3H), 2.08-2.02 (m, 2H). MS m/z 430.47 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.[Li]CCCC.Cl[Si:17]([CH:20]1[C:24]2[S:25][CH:26]=[CH:27][C:23]=2[C:22]([CH3:28])=[C:21]1[CH3:29])([CH3:19])[CH3:18]>C1COCC1>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH:6][Si:17]([CH:20]2[C:24]3[S:25][CH:26]=[CH:27][C:23]=3[C:22]([CH3:28])=[C:21]2[CH3:29])([CH3:18])[CH3:19])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1N
Reactant: CC1=C(C)C([Si](C)(C)Cl)c2sccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C([Si](C)(C)Nc2c(C)cc(Br)cc2C)c2sccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, to a solution of 12.4 g (61.9 mmol) of 4-bromo-2,6-dimethylaniline in 300 ml of THF, 16.5 ml of 2.5 M (41.2 mmol) nBuLi in hexanes was added at −80° C. This mixture was warmed for ca. 2 hour to ambient temperature. Then, the resulting solution was added dropwise over ca. 1 hour, while vigorously stirring, to a solution of 10.0 g (41.2 mmol) of chloro(4,5-dimethyl-6H-cyclopenta[b]thien-6-yl)dimethylsilane in 50 ml of THF. The resulting mixture was stirred overnight at ambient temperature, and then, evaporated to dryness. To the residue, 150 ml of toluene was added. This mixture was filtered through a glass frit (G4). The filtrate was evaporated to dryness. Fractional distillation gave a yellow liquid, bp 154-156° C./0.05 mm Hg. The product crystallizes slowly at ambient temperature. Yield 8.36 g (50%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]3[O:22][CH2:23][O:24][C:17]=23)[CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClCCCl>[CH2:23]1[O:22][C:18]2[C:17](=[C:16]([CH:21]=[CH:20][CH:19]=2)[CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[O:24]1
Reactant: c1ccc(CN2CCC(CCc3cccc4c3OCO4)CC2)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: c1cc(CCC2CCNCC2)c2c(c1)OCO2
Yield: 89.5 %

Procedure:
20.3 g of 1-benzyl-4-(2,3-methylenedioxyphenethyl)piperidine was dissolved in 10 ml of 1,2-dichloroethane, 7 ml of 1-chloroethyl chloroformate was added thereto under ice-cooling, and the mixture was heated under reflux for 30 minutes. The solvent was evaporated, the resulting residue was dissolved in 100 ml of methanol, and the mixture was heated under reflux for one hour. The solvent was removed, the resulting residue was basified by adding a 5N aqueous sodium hydroxide, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by NH form silica gel column chromatography (ethyl acetate), to give 13.1 g of the title compound as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4](Br)[S:5][CH:6]=1.C([Mg]Cl)(C)C.[C:13](=O)([O:17]CC)[O:14][CH2:15][CH3:16]>C1COCC1>[CH2:15]([O:14][C:13]([C:4]1[S:5][CH:6]=[C:2]([Br:1])[N:3]=1)=[O:17])[CH3:16]
Reactant: CCOC(=O)OCC
Reactant: Brc1csc(Br)n1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(Br)cs1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 52 %

Procedure:
To a solution of dibromothiazole (1 g, 4.15 mmol) in THF (15 mL) at 0° C., is added dropwise a solution of iPrMgCl in THF (2 M, 2.3 mL, 4.57 mmol, 1.10 equiv.). The reaction is stirred at 0° C. for 0.25 h. To the resulting orange solution is added via a cannula, diethyl carbonate (3 mL) in THF (5 ml). The resulting green solution is stirred further at room temperature for 0.5 h, at which point the reaction is quenched by adding saturated NH4Cl. The title compound is purified by LC using 6/4 cyclohexane/DCM as the eluent to afford 514.2 mg (52%) of the title compound as a pale yellow powdery solid.
Reaction SMILES: [Cl:1][CH2:2]/[CH:3]=[CH:4]/[CH2:5][CH2:6][C:7]([NH:9][CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:8].NC(CCCCSCC(OCC)=O)C(OCC)=O>>[Cl:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][C:7]([NH:9][CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:8]
Reactant: CCOC(=O)C(NC(=O)CC/C=C/CCl)C(=O)OCC
Agent: CCOC(=O)CSCCCCC(N)C(=O)OCC
Product: CCOC(=O)C(NC(=O)CC/C=C\CCl)C(=O)OCC

Procedure:
Diethyl 4-chlorobut-2E-enylacetamidomalonate (Chem. Eng. Data. (1970) (205), respectively, in an analogous manner to that described above for diethyl 2-amino-7-thia-nonanedioate, and used in Examples 64 to 66.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([CH3:23])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28].C[O-].[Na+].CO>>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[C:7]([CH3:23])=[N:6][C:5]=1[C:3]([NH:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[O:4]
Reactant: COC(=O)c1nc(C)c2cc(Oc3ccccc3)ccc2c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc(C(=O)NCCC(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Yield: 82.1 %

Procedure:
A mixture of 4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (120 mg, 0.39 mmol) and beta-alanine (242 mg, 2.72 mmol) in 0.5 M NaOMe/MeOH solution (4.5 mL, 2.25 mmol) was microwaved at 120° C. for 30 min. Reaction mixture was concentrated and dissolved in water (100 mL). It was acidified by 1 N HCl to pH=3-4. Gummy precipitate was collected by filtration and dissolved in EtOAc. It was dried over MgSO4, filtered and concentrated to provide the title compound 116 mg (0.32 mmol) in 81% yield. LC-MS ESI−: 365.16 (M−1)−.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)[O:14][C:12](=O)[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)=O.[F:23][C:24]1[CH:25]=[C:26]2[C:34](=[CH:35][CH:36]=1)[NH:33]C1CC(C(NC[C@@H]3OC4=C5C(=CC=C4OC3)N=C(C)C=C5)=O)CCC2=1>ClCCl>[F:23][C:24]1[CH:36]=[C:35]2[C:34](=[CH:26][CH:25]=1)[NH:33][C:8]1[CH2:7][CH2:6][CH:11]([CH:12]=[O:14])[CH2:10][C:9]2=1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](CNC(=O)C1CCc2c([nH]c4ccc(F)cc24)C1)O3
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CC1CCc2[nH]c3ccc(F)cc3c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
Dess-Martin periodinane (7.37 g, 17.4 mmol) was added portion-wise to a stirred solution/suspension of alcohol II (2.64 g, 11.8 mmole) in dichloromethane (120 mL). The alcohol completely dissolved after the Dess-Martin reagent was added. The reaction mixture was stirred at ambient temperature for 30 min, and then quenched with ethanol. The reaction mixture was diluted with ether (860 mL) and washed twice with saturated aqueous sodium bicarbonate (550 mL) followed by 5% sodium thiosulfate pentahydrate. After washing with brine and drying (MgSO4), the solvent was evaporated to give a residue which was purified by chromatography on silica gel eluting with hexane/ethyl acetate (4:1). Compound V was obtained in 47% yield (1.2 g). mp: 96-98° C. MS: [M−H]− @m/z=216.1.
Reaction SMILES: C(OC([NH:8][S:9]([N:12]([CH3:50])[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][O:21][C@H:22]1[CH2:29][N:28]2[C:30]3[CH:31]=[C:32]([C:43]([OH:45])=[O:44])[CH:33]=[CH:34][C:35]=3[C:36]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[C:27]2[C:26]2[CH:46]=[CH:47][CH:48]=[CH:49][C:25]=2[O:24][CH2:23]1)(=[O:11])=[O:10])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][S:9]([N:12]([CH3:50])[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:20][O:21][C@H:22]1[CH2:29][N:28]2[C:30]3[CH:31]=[C:32]([C:43]([OH:45])=[O:44])[CH:33]=[CH:34][C:35]=3[C:36]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[C:27]2[C:26]2[CH:46]=[CH:47][CH:48]=[CH:49][C:25]=2[O:24][CH2:23]1)(=[O:11])=[O:10]
Reactant: CN(CCN1CCCC1CO[C@@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1)S(=O)(=O)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCN1CCCC1CO[C@@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of (7S)-7-[(1-{2-[{[(tert-butoxycarbonyl)amino]sulfonyl}(methyl)amino]ethyl}-pyrrolidin-2-yl)methoxy]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid (7 mM) in DCM was treated with an excess of TFA (>100 eq). The mixture was stirred at RT for 3.5 h. Volatiles were removed in vacuo. The residue was dissolved in toluene and re-evaporated to drive off excess TFA. The material was taken on without further purification. (ES+) m/z 611 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:5]([CH2:7][CH2:8][C:9](O)=[O:10])=O.O.[NH2:17][NH2:18]>O>[OH:1][C:2]1[CH:3]=[C:4]([C:5]2[CH2:7][CH2:8][C:9](=[O:10])[NH:17][N:18]=2)[CH:12]=[CH:13][C:14]=1[CH3:15]
Reactant: NN
Reactant: Cc1ccc(C(=O)CCC(=O)O)cc1O
Solvent: O
Product: Cc1ccc(C2=NNC(=O)CC2)cc1O

Procedure:
A stirred suspension of 3-(3-hydroxy-4-methylbenzoyl)propionic acid (6.75 g, 0.032 mole) in water (40 ml) was treated with hydrazine hydrate (2.4 ml, 0.048 mole) and heated under reflux for one hour. The mixture was diluted with water (50 ml) and cooled. The product (6.36 g, 96%, m.p. 215°-218° C) was collected, washed with water and crystallised from ethanol to give pure 6-(3-hydroxy-4-methylphenyl)-4,5-dihydro-3(2H)-pyridazinone, m.p. 216°-218° C. (Found: C, 64.80; H, 5.94; N, 13.52; M+, 204. C11H12N2O2 requires: C, 64.69; H, 5.92; N, 13.72%; M, 204).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C=O)C>[CH2:11]([O:8][C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[CH:5][N:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ncccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cccnc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
3-bromo-2-hydroxypyridine (1.74 g, 10 mmol) was added to a suspension of NaH (440 mg of 60% dispersion in mineral oil, 11 mmol) in DMF (10 mL), and the resultant mixture was stirred at rt for 30 min. Benzyl bromide (1.3 mL, 11 mmol) was then added, and the reaction was stirred at rt overnight. It was then quenched by the addition of water, and the product extracted with ethyl acetate (2×50 mL). The extracts were combined, washed with 1N HCl solution, then dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography using hexanes to 100% ethyl acetate in hexanes as eluent to give the title compound as a colorless thick oil, (1.37 g, 52% yield). MS m/z 264, 266(MH+); 1H NMR (500 MHz, CDCl3) δ ppm 5.17 (s, 2 H) 6.05 (t, J=7.02 Hz, 1 H) 7.27–7.88 (m, 6 H) 7.70 (dd, J=7.17, 1.98 Hz, 1 H)
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[N:9][C:8]=2[CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NN>CO.C(OCC)(=O)C>[C:1]1([C:7]2[S:11][CH:10]=[N:9][C:8]=2[CH2:12][NH2:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ncsc1-c1ccccc1
Agent: NN
Solvent: CO
Solvent: CCOC(C)=O
Product: NCc1ncsc1-c1ccccc1
Reaction time: 8 h
Yield: 85.4 %

Procedure:
Prepare a cold (0° C.) solution of 2-(5-phenylthiazol-4-ylmethyl)isoindole-1,3-dione (260 mg, 0.8 mmol) in methanol (15 mL). Add hydrazine (0.05 mL, 1.6 mmol). Warm the reaction to room temperature and stir overnight. Concentrate the reaction in vacuo. Dissolve the residue in ethyl acetate (25 mL) and filter to remove solids. Concentrate the filtrate in vacuo to an oil. Chromatograph (silica gel, 93:6:1 CHCl3/MeOH/concentrated NH4OH) to afford the title compound (130 mg). 1H NMR (CDCl3) δ 8.75 (s, 1H), 7.39-7.49 (m, 5H), 4.00 (s, 2H), 1.62 (br s, 2H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(Cl)Cl.FC(F)(F)C(O)=O>>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([C:8]2([NH2:7])[CH2:11][CH2:10][CH2:9]2)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(C2(NC(=O)OC(C)(C)C)CCC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(C2(N)CCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 1-neck round-bottom flask, [1-(3-Methoxy-phenyl)-cyclobutyl]-carbamic acid tert-butyl ester (4.20 g, 15.1 mmol), Methylene chloride (25 mL, 390 mmol), and Trifluoroacetic Acid (5 mL, 60 mmol) were added. The reaction was stirred at room temperature overnight. The reaction was partitioned with Saturated NaHCO3 and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum to give 1-(3-Methoxy-phenyl)-cyclobutylamine as an oil (2.60, 96%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[CH2:6][NH:7][C:8](=[O:27])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[CH:18]=[CH:17][C:16]=2[NH2:26])[CH:10]=1.[CH3:33][N:34]([CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)[C:35]([C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](O)=[O:41])=[O:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:22]([N:21]([CH2:24][CH3:25])[C:19]1[CH:18]=[CH:17][C:16]([NH:26][C:40](=[O:41])[C:39]2[CH:43]=[CH:44][CH:45]=[C:37]([C:35]([N:34]([CH3:33])[CH2:46][CH2:47][N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[O:36])[CH:38]=2)=[C:15]([C:11]2[CH:10]=[C:9]([C:8](=[O:27])[NH:7][CH2:6][C:5]3[CH:28]=[CH:29][CH:30]=[C:3]([C:2]([F:31])([F:1])[F:32])[CH:4]=3)[CH:14]=[CH:13][N:12]=2)[CH:20]=1)[CH3:23]
Reactant: CCN(CC)c1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCOCC3)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 13.6 %

Procedure:
A mixture of 80 mg of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-(diethylamino)phenyl)isonicotinamide, 64 mg of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid, 83 mg of HATU, and 190 μL of diisopropylethylamine in 0.5 mL of DMF was stirred at 60° C. for 2 h. The product was isolated by reverse phase chromatography eluting with 0.05% TFA in a water/acetonitrile gradient. This procedure gave 17.6 mg of product. 1H NMR (400 MHz, CD3OD, ppm): δ 9.54 (t, J=5.9 Hz, 1H), 8.98 (dd, J=5.2, 0.6 Hz, 1H), 8.88 (d, J=9.0 Hz, 1H), 8.49 (s, 1H), 8.26 (d, J=2.6 Hz, 1H), 8.20 (s, 1H), 8.16-8.10 (m, 1H), 7.90 (dd, J=5.2, 1.5 Hz, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.75-7.63 (m, 4H), 7.63-7.50 (m, 2H), 4.74-4.67 (m, 2H), 4.21-4.03 (m, 2H), 3.99 (t, J=5.7 Hz, 2H), 3.90-3.69 (m, 4H), 3.76 (q, J=7.2 Hz, 4H), 3.54 (t, J=5.9 Hz, 2H), 3.34-3.18 (m, 2H), 3.10 (s, 3H), 1.22 (t, J=7.2 Hz, 6H). MS (ESI, m/z) 717.24 [M+H]+.
Reaction SMILES: Cl.[F:2][C:3]([F:8])([F:7])[C@@H:4]([NH2:6])[CH3:5].[Br:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][C:11]=1[F:19].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH:6][C@@H:4]([CH3:5])[C:3]([F:8])([F:7])[F:2])=[O:15])=[CH:12][C:11]=1[F:19]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Reactant: C[C@H](N)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1ccc(Br)c(F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2S)-1,1,1-Trifluoropropan-2-amine hydrochloride (0.068 g, 0.46 mmol) (ACS Scientific Inc., Cat. #2-01-6) was added to a mixture of 4-bromo-3-fluorobenzoic acid (0.100 g, 0.457 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.26 g, 0.68 mmol) in methylene chloride (2.50 mL), followed by N,N-diisopropylethylamine (0.16 mL, 0.91 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was worked up with aqueous NaHCO3, and extracted with methylene chloride (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-20%) to afford the desired product. LCMS (M+H)+: m/z=314.0/316.0.