Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH:5]([OH:8])[CH2:6][F:7])=[N+:2]=[N-:3].[C:9]([N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[N+:17]([O-:19])=[O:18])#[C:10][CH3:11].C1COCC1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>[O-]S([O-])(=O)=O.[Cu+2].O.CC(O)(C)C>[F:7][CH2:6][CH:5]([OH:8])[CH2:4][N:1]1[CH:11]=[C:10]([CH2:9][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[N+:17]([O-:19])=[O:18])[N:3]=[N:2]1
Reactant: CC#Cn1ccnc1[N+](=O)[O-]
Reactant: [N-]=[N+]=NCC(O)CF
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1nccn1Cc1cn(CC(O)CF)nn1
Reaction time: 16 h
Yield: 4.2 %

Procedure:
To a vial was added fluoroazide 17 (690 mg, 5.79 mmol) and 1-propynyl-2-nitroimidazole (876 mg, 5.79 mmol). To this flask was added THF (3 mL), t-BuOH (3 mL), water (3 mL), CuSO4 (185 mg, 1.16 mmol) and sodium ascorbate (1.15 g, 5.79 mmol). After 16 hrs, the reaction was poured onto EtOAc and washed with NH4OH. The organics were combined and the material was then purified on a silica gel column using EtOAc:Hex as the eluent. The material was then further purified via recrystallization using EtOAc:Hex to afford 65 mg (4% yield) of pale yellow crystals. 1H NMR (DMSO-d6, 400 MHz), δ: 4.04 (1H, br d, J=20.4 Hz), 4.20-4.47 (4H, m), 5.53 (1H, br s), 5.66 (2H, s), 7.16, (1H, s), 7.68 (1H, s), 8.05 (1H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[N:11]1([C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:14]2[CH2:15][CH2:16][N:11]([C:17]3[N:18]=[CH:19][CH:20]=[CH:21][N:22]=3)[CH2:12][CH2:13]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCN(c3ncccn3)CC2)nc1
Temperature: 80 °C

Procedure:
To a mixture of 2-chloro-5-nitropyridine (500 mg, 3.2 mmol) and 2-piperazin-1-yl-pyrimidine (520 mg, 3.2 mmol) in DMF (15 mL) was added diisopropylethylamine (2.70 mL, 15.5 mmol). The mixture was heated in a sealed tube at 80° C. for 24 hours. The mixture was concentrated to dryness and triturated in methanol to give 2-[4-(5-nitro-pyridin-2-yl)-piperazin-1-yl]-pyrimidine. The NMR spectrum on this sample is compatible with its structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18](=[N:20][OH:21])[NH2:19])=[CH:4][CH:3]=1.Cl[C:23](=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[N:19]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[O:21][N:20]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: NC(Cc1c(-c2ccc(Cl)cc2)nc2ccccn12)=NO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)no1
Temperature: -40 °C

Procedure:
To a suspension of 2-(2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)-N′-hydroxyacetimidamide (83.3 mmol, 25.0 g) in dry CHCl3 (600 mL) was cooled to −40° C. in an ice/EtOH bath under N2 atmosphere, Py. (100.0 mmol, 8.1 mL) was added in one portion, and followed by slowly adding ethyl 2-chloro-2-oxoacetate (166.6 mmol, 18.6 mL). After that, the reaction mixture was allowed to slowly rise up to r.t., and kept stirring for 1.0 H, D, then heated to 80 C for another 2 hs. The reaction mixture was cooled to r.t. and filtered, and the filtrate was evaporated under reduced pressure to give the brown residue, which was applied to C.C.eluted by petroleum/acetone (4:1, 2:1, 1:1, and 0:1). The acetone portion was concentrated in vacuo to give the solid, which was washed with acetone for 3 times, to obtain the product, 18.0 g (58.0%), as a white solid. m/e+=383 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=O.[CH3:27][NH:28][CH3:29]>>[CH3:27][N:28]([CH2:1][C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C=O)cc(C(F)(F)F)c2)CC1
Reactant: CNC
Product: CN(C)Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared according to the method of Example 41, Step 2 using tert-butyl 4-[3-formyl-5-(trifluoromethyl)phenoxy]piperidine-1-carboxylate and dimethylamine as starting materials. LCMS (M+H)+: 403.2.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11]C)=[CH:7][CH:6]=1)=[O:4].[Cl-].[Li+]>CN(C=O)C>[F:1][C:2]([F:13])([F:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=[O:4]
Reactant: COc1ccc(C(=O)C(F)(F)F)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(O)cc1)C(F)(F)F
Temperature: 25 °C
Yield: 86.3 %

Procedure:
2,2,2-Trifluoro-1-(4-methoxy-phenyl)-ethanone (5 g, 25 mmol) was added to a solution of lithium chloride (3 g, 71 mmol) in DMF (84 mL). After the reaction mixture was refluxed for 5 days, it was cooled to room temperature and then quenched with 200 mL 1M HCl. The mixture thus formed was extracted with diethyl ether (3×100 mL). The combined organic phases were washed with H2O (3×300 mL), followed by brine (1×200 mL) and then dried over Na2SO4. The organic phase was collected by filtration and concentrated by rotary evaporation to yield yellow oil. The crude material was purified by flash column chromatography (0-25% ethyl acetate/hexanes) to yield intermediate compound (1) as a beige solid (4.1 g, 88%). 1H NMR (400 MHz, DMSO-D6): δ 11.14 (s, 1H), 7.94 (m, 2H), 6.98 (m, 2H); 19F NMR (376 MHz, CDCl3): δ −70.4.
Reaction SMILES: C([NH:4][C:5]1[C:6]([N+:14]([O-])=O)=[C:7]([B:11]([OH:13])[OH:12])[CH:8]=[CH:9][CH:10]=1)(=O)C.O[C:18]([C:21](O)([CH3:23])[CH3:22])([CH3:20])[CH3:19]>Cl.O1CCOCC1.C(O)(=O)C.[Pd]>[NH2:14][C:6]1[C:7]([B:11]2[O:12][C:21]([CH3:23])([CH3:22])[C:18]([CH3:20])([CH3:19])[O:13]2)=[CH:8][CH:9]=[CH:10][C:5]=1[NH2:4]
Reactant: CC(C)(O)C(C)(C)O
Reactant: CC(=O)Nc1cccc(B(O)O)c1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CC1(C)OB(c2cccc(N)c2N)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (3-acetamido-2-nitrophenyl)boronic acid (300 mg) in 2M aqueous hydrochloric acid solution (4 mL) was heated at 80° C. for 20 min. After cooling to room temperature, the solvent was reduced in vacuo to give a brown solid which was redissolved in 1,4-dioxane (5 mL). Pinacol (316 mg) was added and the mixture heated at 100° C. for 30 min. After cooling to room temperature the solvent was reduced in vacuo to give a beige solid which was dissolved in acetic acid (5 mL). Palladium on carbon (100 mg) was added and the mixture stirred under an atmosphere of hydrogen at 40° C. for 1 h. The reaction mixture was then filtered through Celite and the filtrate reduced in vacuo. Purification by column chromatography gave 2-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH:8]3[NH:15][CH2:16][C:17]([NH2:26])([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[CH3:18])[CH2:6]1)[CH2:12]2)=[O:4].Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH:8]3[N:15]3[CH2:16][C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)([CH3:18])[NH:26][C:28]3=[O:30])[CH2:6]1)[CH2:12]2)=[O:4]
Reactant: COC(=O)C12CC3CC(C1)C(NCC(C)(N)c1cccc(Cl)c1)C(C3)C2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C12CC3CC(C1)C(N1CC(C)(c4cccc(Cl)c4)NC1=O)C(C3)C2
Reaction time: 4 h
Yield: 118.8 %

Procedure:
A solution of 4-[2-amino-2-(3-chloro-phenyl)-propylamino]-adamantane-1-carboxylic acid methyl ester (7.9 g) in 40 mL DCM was cooled to −20° C. and triphosgene (3.1 g) (separately dissolved in 10 mL DCM) was added to it drop wise followed by drop wise addition of triethylamine (6.57 mL). The reaction mixture was slowly brought to RT and left at stirring for 4 h. Reaction was monitored by TLC. After completion, the reaction mixture was quenched with water and the DCM layer was separated. The aqueous layer was again extracted with DCM (2×). The combined DCM layers were dried over Na2SO4 and concentrated to afford the crude product, which was purified by column chromatography to give the desired 4-[4-(3-chloro-phenyl)-4-methyl-2-oxo-imidazolidin-1-yl] adamantane-1-carboxylic acid methyl ester (5.0 g) as a mixture of E/Z isomers as a white solid. MS (ES+): 403.4 (MH+).
Reaction SMILES: C(O)=O.[CH2:4]([O:6][CH2:7][C:8]1[CH:9]=[C:10]([NH:30][CH2:31][CH2:32][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[C:11]([CH3:29])=[C:12]([NH:14][C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[C:23](=[O:27])[NH:22][N:21]=[C:20]3Cl)=[O:16])[CH:13]=1)[CH3:5]>Cl.[Pd].CO>[CH2:4]([O:6][CH2:7][C:8]1[CH:9]=[C:10]([NH:30][CH2:31][CH2:32][N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[C:11]([CH3:29])=[C:12]([NH:14][C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[C:23](=[O:27])[NH:22][N:21]=[CH:20]3)=[O:16])[CH:13]=1)[CH3:5]
Reactant: CCOCc1cc(NCCN2CCCC2)c(C)c(NC(=O)c2ccc3c(=O)[nH]nc(Cl)c3c2)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O=CO
Product: CCOCc1cc(NCCN2CCCC2)c(C)c(NC(=O)c2ccc3c(=O)[nH]ncc3c2)c1
Reaction time: 2.5 h
Yield: 92 %

Procedure:
A mixture of 4-chloro-1-oxo-1,2-dihydro-phthalazine-6-carboxylic acid [5-ethoxymethyl-2-methyl-3-(2-pyrrolidin-1-yl-ethylamino)-phenyl]-amide formic acid salt (55 mg, 0.104 mmol), 10% wet Pd/C (catalytic), 1 drop of conc. HCl and MeOH (4 mL) was evacuated and flushed (×3) with hydrogen. The reaction was stirred under a hydrogen balloon for 2.5 h. The reaction was filtered through celite, rinsed with MeOH and concentrated to yield 1-oxo-1,2-dihydro-phthalazine-6-carboxylic acid [5-ethoxymethyl-2-methyl-3-(2-pyrrolidin-1-yl-ethylamino)-phenyl]-amide (43 mg) as a tan solid. 1H NMR (400 MHz, d6-DMSO) δ: 1.16 (t, 3H), 1.93 (m, 4H), 2.00 (s, 3H), 2.53 (m, 4H), 3.47 (m, 6H), 4.39 (s, 2H), 5.23 (bs, 1H), 6.53 (s, 1H), 6.62 (s, 1H), 8.34 (s, 2H), 8.48 (s, 1H), 8.50 (s, 1H), 10.25 (s, 1H), 12.80 (s, 1H) ppm; m/z (M+1) 450.38.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:9])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:10]1([N:13]=[C:14]=[S:15])[CH2:12][CH2:11]1.C(OCC)C>CCCCCCC>[CH2:7]([O:6][C:4](=[O:5])[C:3]([C:14](=[S:15])[NH:13][CH:10]1[CH2:12][CH2:11]1)=[C:2]([NH2:1])[CH3:9])[CH3:8]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: S=C=NC1CC1
Solvent: CCOCC
Solvent: CCCCCCC
Product: CCOC(=O)C(C(=S)NC1CC1)=C(C)N
Temperature: 100 °C
Yield: 44.9 %

Procedure:
A mixture of 2.03 ml of ethyl 3-aminocrotonate (16 mmol) and 1.59 g of cyclopropyl iso-thiocyanate (16 mmol) was heated to 100° C. for 5 h. The reaction mixture was then cooled to 0° C. and diethyl ether (5 ml) and a small amount of heptane were added. An oily precipitate formed and after 5 min the solvents were decanted off. The remaining residue was triturated with a small amount of diethyl ether at 0° C. The precipitate was then filtered off and dried to give 1.64 g (45%) of 3-amino-2-cyclopropylthiocarbamoyl-but-2-enoic acid ethyl ester as a yellow solid. 1HNMR (DMSO-d6, 300 MHz): δ 0.60 (m, 2H), 0.76 (m, 2H), 1.11 (t, J=7.1 Hz, 3H), 1.90 (s, 3H), 3.28 (m, 1H), 3.97 (q, J=7.1 Hz, 2H), 7.24 (br s, 1H), 8.21 (br s, 1H), 9.79 (d, J=5.5 Hz, 1H).
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[Br:12][C:13]1[CH:14]=[C:15](/[CH:19]=[CH:20]/[C:21](O)=[O:22])[CH:16]=[CH:17][CH:18]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:21](=[O:22])/[CH:20]=[CH:19]/[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Br:12])[CH:14]=1)[CH2:4]2
Reactant: O=C(O)/C=C/c1cccc(Br)c1
Reactant: N[C@H]1CN2CCC1CC2
Agent: Cl
Product: O=C(/C=C/c1cccc(Br)c1)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(3-bromophenyl)propenoic acid; the compound was purified by chromatography on silica gel using ammoniated methanol/chloroform mixtures as the eluent; MS (ES+) 335, 337 (MH+).
Reaction SMILES: Cl[S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(N(CC)CC)C>C(Cl)Cl>[O:19]1[CH2:20][CH2:21][N:16]([S:2]([C:5]2[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)(=[O:4])=[O:3])[CH2:17][CH2:18]1
Reactant: C1COCCN1
Reactant: COC(=O)Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(S(=O)(=O)N2CCOCC2)cc1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
Methyl 2-(4-chlorosulfonylphenyl)acetate (2.0 g, 8.04 mmol) was taken in dry DCM (50 mL) under argon atmosphere and cooled to 0-5° C., morpholine (0.77 mL, 8.84 mmol) followed by triethylamine (1.16 mL, 8.84 mmol) was added dropwise to the mixture at 0-5° C. Reaction mixture was then brought to room temperature and stirred for additional 2 hours. Reaction mixture was washed with water followed by brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product, which was purified by column chromatography using 14-20% ethyl acetate in hexane as eluent to give Methyl 2-(4-morpholinosulfonylphenyl)acetate (1.5 g).
Reaction SMILES: C([O:5][C:6](=O)/[C:7](=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]2)=[C:22]([O:32][CH3:33])[CH:21]=1)/[CH2:8][CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[CH2:11][N:10]1[CH2:9][CH2:8]/[C:7](=[CH:19]\[C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]3)=[C:22]([O:32][CH3:33])[CH:21]=2)/[C:6]1=[O:5]
Reactant: COc1cc(/C=C(\CCNCc2cccc(F)c2)C(=O)OC(C)(C)C)ccc1-n1cnc(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(/C=C2\CCN(Cc3cccc(F)c3)C2=O)ccc1-n1cnc(C)c1
Yield: 60.8 %

Procedure:
To a methylene chloride (0.5 mL) solution of (E)-4-(3-fluorobenzylamino)-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]butyric acid tert-butyl ester (4.50 mg), trifluoroacetic acid (500 μL) was added. After agitating reaction solution at room temperature for 1.5 hours and agitating that materials disappeared, reaction solution was concentrated under reduced pressure as it was. The residue was dissolved in DMF (0.5 mL), IPEA (17.0 μL), EDC (5.58 mg), and HOBT (3.93 mg) were added to the reaction solution one by one, and the reaction solution was agitated at room temperature for 1.5 hours. After confirming disappearance of the starting materials, water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (elution solvent:ethyl acetate→ethyl acetate:ethanol=20:1), and 2.30 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[O:9][C:10]1[C:15]2[C:16]([O:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[N:17][O:18][C:14]=2[CH:13]=[CH:12][CH:11]=1.[CH3:34]I.O>O1CCCC1>[CH3:34][O:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[O:9][C:10]1[C:15]2[C:16]([O:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[N:17][O:18][C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(O[C@@H]4CCC[C@H]4O)c23)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H]1CCC[C@H]1Oc1cccc2onc(OCC3CCN(C(=O)OC(C)(C)C)CC3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
To a suspension of sodium hydride (60% oil dispersion 11 mg, 0.277 mmol) in tetrahydrofuran (5.0 mL) was added a solution of tert-butyl 4-{[(4-{[trans-2-hydroxycyclopentyl]oxy}-1,2-benzisoxazol-3-yl)oxy]methyl}piperidine-1-carboxylate (80 mg, 0.185 mmol, EXAMPLE 32, Step 1) in tetrahydrofuran (2.0 mL) at 0° C. under nitrogen. After being stirred at 0° C. for 30 min, methyliodide (14 μL, 0.222 mmol) was added to the mixture. The mixture was stirred at 0° C. for 3 h, water was added to the mixture. The mixture was extracted with ethyl acetate (30 mL×2) and washed with brine. The extracts were combined and dried over sodium sulfate and concentrated in vacuo to give an oil. The residual oil was purified by silica gel column chromatography (hexane/ethyl acetate 5:1 to 4:1) to give 78 mg (94%) of the title compound as a colorless viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH:7]=[CH:8][NH:9]2)=[N:4][CH:3]=1.O=P(Cl)(Cl)[Cl:15].[OH-].[Na+].C(Cl)Cl.CO.[NH4+].[OH-]>C(Cl)Cl>[Cl:15][C:6]1[CH:7]=[CH:8][N:9]=[C:10]2[C:5]=1[N:4]=[CH:3][C:2]([F:1])=[CH:11]2
Reactant: O=c1cc[nH]c2cc(F)cnc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: Fc1cnc2c(Cl)ccnc2c1
Temperature: 110 °C
Reaction time: 16 h
Yield: 64.3 %

Procedure:
A pressure resistant vial was charged with 7-fluoro-1,5-naphthyridin-4(1H)-one (600 mg, 3.66 mmol) and POCl3 (6.8 mL, 73.1 mmol). Vessel sealed and stirred at 110° C. for 16 hrs. Reaction mixture was cooled to room temperature and poured onto ice while stirring vigorously. While keeping reaction mixture at 0° C., it was basified to pH˜8 with 6N NaOH. Product extracted with dichloromethane. Organic layer collected, dried over sodium sulfate and concentrated to afford desired material. This was passed through a silica plug in 1-5% (90:10:1 DCM/MeOH/NH4OH)/DCM to afford 8-chloro-3-fluoro-1,5-naphthyridine (430 mg, 64% yield) as a tan solid. MS [M+H]=182.9. Calc'd for C8H4ClFN2=182.58
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@@H:9]([C@H:15]([OH:18])[CH2:16][CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11])C1C=CC=CC=1>CCO.[Pd]>[NH2:8][C@@H:9]([C@H:15]([OH:18])[CH2:16][CH3:17])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)[C@H]([C@H](O)CC)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@@H](N)[C@H](O)CC

Procedure:
In a pear flask, at rt, ethyl (2S*,3R*)-2-(dibenzylamino)-3-hydroxy-pentanoate (0.165 g, 0.48 mmol) was dissolved in EtOH (12 mL) and passed through the H-Cube® hydrogenator flow reactor, using 10% Pd/C as catalyst [flow:1.0 mL/min; P=1.0 bar, T=70° C.]. After evaporation of the solvent, the title compound was obtained as yellowish oil and used without further purification in the following step. MS (ESI) m/z: 162 [M−H]+.
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12]N)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].Cl.[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1>S(=O)(=O)(O)O.O1CCOCC1>[C:2]([C:6]1[CH:11]=[CH:10][C:9]2[NH:12][C:19]3[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][C:18]=3[C:8]=2[CH:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1ccc(NN)cc1
Reactant: CN1CCC(=O)CC1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CN1CCc2[nH]c3ccc(C(C)(C)C)cc3c2C1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
(4-tert-Butylphenyl)hydrazine hydrochloride (1 equiv.) is taken in 7% sulfuric acid in 1,4-dioxane. 1-Methylpiperidin-4-one hydrochloride (0.76-1.4 equiv.) is added and the contents are stirred at 80° C. for 3 h. The reaction is monitored by TLC and LCMS. After completion of the reaction, the reaction mixture is concentrated and then quenched with aq. NaHCO3 solution, followed by extracted with EtOAc. The organic layer is dried over anhydrous sodium sulfate, evaporated to dryness and purified by column chromatography (5% MeOH-DCM) to afford 8-tert-butyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][CH2:4][Mg]Cl.[F:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[C:18]1[C:19]([CH:34]=[O:35])=[CH:20][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[CH:22][CH:23]=1.[Cl-].[NH4+]>C1COCC1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[CH:20][C:19]=1[CH:34]([OH:35])[CH2:4][CH2:3][C:2]([CH3:8])([CH3:7])[CH3:1]
Reactant: CC(C)(C)CC[Mg]Cl
Reactant: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C=O)c2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(-c3cc(OC)ccc3F)c(C(O)CCC(C)(C)C)c2)cc1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
A solution of (3,3-dimethylbutyl)magnesium chloride in THF (0.50 M, 13.1 mL) was added to a solution of 2′-fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)-[1,1′-biphenyl]-2-carbaldehyde (800 mg) in THF (15 mL) at 0° C., and the mixture was stirred at 0° C. for 50 min. To the reaction mixture was added saturated aqueous ammonium chloride solution at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (788 mg) as a pale-yellow oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5][C:4]2[CH:13]=[C:14]([CH2:17][C:18]([OH:20])=[O:19])[CH:15]=[CH:16][C:3]1=2.[CH2:21](O)[CH3:22]>Cl>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5][C:4]2[CH:13]=[C:14]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:15]=[CH:16][C:3]1=2
Reactant: CCO
Reactant: O=C(O)Cc1ccc2c(c1)Cc1ccccc1CC2=O
Agent: Cl
Product: CCOC(=O)Cc1ccc2c(c1)Cc1ccccc1CC2=O

Procedure:
In 3 ml of a 12% ethanol solution of hydrogen chloride was dissolved 0.14 g of 10,11-dihydro-11-oxo-5H-dibenzo[a,d]cycloheptene-3-acetic acid obtained in Example 3. The solution was heated under reflux for 30 minutes with stirring. After the reaction, the reaction mixture was cooled, and the solvent was distilled off. Water was added to the residue, and the mixture was extracted with ether. The ethereal layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. Then, the ether was distilled off. The residue was chromatographed on a silica gel column using benzene as an eluent. From the eluate, 0.12 g of ethyl 10,11-dihydro-11-oxo-5H-dibenzo[a,d]cycloheptene-3-acetate was obtained as a slightly yellow oily substance.
Reaction SMILES: CC(C)(OC([NH:7][C@H:8]([C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25])[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=O)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:18]1([CH2:17][O:16][C:14]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]([C:24]([N:26]2[CH2:27][CH2:28][N:29]([C:32]3[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=3)[CH2:30][CH2:31]2)=[O:25])[NH2:7])=[O:15])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCN(c2ccncc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 24.2 g (46 mmol) of 1-[N2-(1,1-dimethylethoxycarbonyl)-N6-(phenylmethoxycarbonyl)-L-lysyl]-4-(4-pyridinyl)piperazine and 150 ml of methylene chloride were added 50 ml of trifluoroacetic acid and the reaction mixture was stirred overnight at room temperature. The reaction mixture was neutralised by the addition of saturated aqueous sodium hydrogen carbonate solution, the organic phase was dried and evaporated down in vacuo. 12 g (62% of theory) of the desired compound were obtained as a colourless oil.