Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[C:16]([O:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=1.[O:32]([C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45]O)[CH2:41][CH2:40]1)=[O:38])[C:33]([CH3:36])([CH3:35])[CH3:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:33]([O:32][C:37]([N:39]1[CH2:44][CH2:43][CH:42]([CH2:45][O:13][C:14]2[CH:15]=[C:16]([O:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:36])([CH3:34])[CH3:35]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
Diethyl azodicarboxylate (349 mg, 2.0 mmol) was added to a solution of 2-chlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl ester (600 mg, 2.0 mmol), as prepared in the preceding step, N-tert-butoxylcarbonyl-4-piperidinemethanol (430 mg, 2.0 mmol), as prepared in step (b), and triphenylphosphine (525 mg, 2.0 mmol) intetrahydrofuran (15 mL) at 0° C. The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 3 h. The reaction mixture was quenched with water (50 mL) and was extracted with ethyl acetate (3×50 mL). The organic phase was washed with saturated NaHCO3 (2×50 mL), brine (2×50 mL) and dried over Na2SO4. The solvent removed in vacuo and the residue was purified by flash column chromatography (2:1 ethyl acetate/hexane) to give the title compound as a colorless syrup (895 mg, 90%). 1H-NMR (300 MHz, CDCl3) δ 1.24 (m, 2H), 1.47 (s, 9H), 1.76 (d, 2H, J=6.6 Hz), 1.89 (m, 1H), 2.24 (s, 3H), 2.72 (t, 2H, J=2.4 Hz), 3.68 (d, 2H, J=3.2 Hz), 4.13 (m, 2H), 6.47 (t, 1H, J=2.2 Hz), 6.52 (d, 1H, J=0.7 Hz), 6.58 (d, 1 H, J=0.8 Hz), 7.38 (dd, 1H, J=0.6, 0.8 Hz), 7.61 (m, 2H), and 7.97 (dd, 1H, J=0.8, 4.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:29])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[CH:22]=3)=[CH:16][C:15]=2[F:28])=[O:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1.[OH-].[Na+]>CN(C)C=O.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:40]([CH:37]4[CH2:39][CH2:38]4)=[O:41])[CH:22]=3)=[CH:16][C:15]=2[F:28])=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)c(F)c2)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CC(=O)Nc1ccc(Oc2ccnc(NC(=O)C3CC3)c2)cc1F)Nc1ccc(F)cc1
Reaction time: 1 h
Yield: 39 %

Procedure:
N-(4-Fluorophenyl)-N′-[4-(2-aminopyridin-4-yloxy)-2-fluorophenyl]malonamide (21.3 mg) was dissolved in N,N-dimethylformamide (0.5 ml), and then triethylamine (0.030 ml) and cyclopropanecarbonyl chloride (0.010 ml) were added dropwise thereto under a nitrogen atmosphere at room temperature, followed by stirring for 1 hr. To the reaction mixture were added a 1 N aqueous solution of sodium hydroxide (1.0 ml) and methanol (1.0 ml), followed by stirring and extracting with ethyl acetate. The organic layer was concentrated under a reduced pressure to give a residue, which was purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate). Fractions containing the target compound were concentrated to give a residue, which was then dried in vacuum to provide the titled compound (9.6 mg, 39%) as white powder.
Reaction SMILES: [ClH:1].[C:2]1([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[NH2:13])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]=1>C(O)C>[ClH:1].[C:2]1([C@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[N:13]=[C:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@@H]1CCC[C@@H]1c1ccccc1
Reactant: COC1=NCCCCC1
Agent: Cl
Solvent: CCO
Product: c1ccc([C@H]2CCC[C@H]2N=C2CCCCCN2)cc1
Reaction time: 144 h

Procedure:
A mixture of 4.0 g of cis-2-phenylcyclopentylamine hydrochloride, M.P. 205°-206° C. and 5.0 ml of O-methylcaprolactim was allowed to stand at room temperature for 6 days with occasional stirring. A few drops of ethanol were added to maintain a stirrable slurry, after which the mixture was cooled. The resulting solid was washed with ether and recrystallized from acetone/methanol to give the desired product, M.P. 181.5°-183.5° C. (dec.).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[N:13][CH:14]=2)O1.Br[C:21]1[N:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+].O1CCOCC1>O.C(Cl)Cl.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>[C:27]([C:24]1[CH:23]=[CH:22][C:21]([C:9]2[CH:14]=[N:13][C:12]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:10]=2)=[N:26][CH:25]=1)#[N:28]
Reactant: N#Cc1ccc(Br)nc1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(C#N)cn2)cn1
Yield: 23 %

Procedure:
To a microwave vial was added methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinecarboxylate (2 g, 7.60 mmol), 6-bromo-3-pyridinecarbonitrile (2.09 g, 11.40 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.62 g, 0.760 mmol), NaHCO3 (1.277 g, 15.20 mmol), 1,4-dioxane (8 ml) and water (2 ml). The mixture was microwaved for 15 min at 105° C. The resulting dark solution was diluted with water and CH2Cl2. The aqueous layer was extracted three times with CH2Cl2. The CH2Cl2 extracts were passed over a phase separator, concentrated and purified on a Biotage SP4 with a 65i column at a flow rate of 65 ml/min, 0.1% TFA eluting with 2CV water, the 0-100% ACN/Water over 10 CV. The fractions containing the product were combined and diluted with CH2Cl2 and sat. NaHCO3. The layers were separated and the aqueous layer was extracted twice with CH2Cl2, then the combined organic extracts were dried and concentrated to afford the desired product (1.0 g, 1.75 mmol) as an off white solid. LCMS (m/z): 262.0 (M+Na).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH:16]([C:18]3[CH:19]=[C:20]([N:27]([CH3:29])[CH3:28])[CH:21]=[C:22]4[C:26]=3[NH:25][N:24]=[CH:23]4)[CH3:17])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:30]([BH3-])#N.[Na+].C=O>C(#N)C.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][O:15][CH:16]([C:18]3[CH:19]=[C:20]([N:27]([CH3:28])[CH3:29])[CH:21]=[C:22]4[C:26]=3[NH:25][N:24]=[CH:23]4)[CH3:17])[CH2:13][CH2:12][N:11]([CH3:30])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: CC(OCC1(c2ccc(F)cc2)CCNCC1)c1cc(N(C)C)cc2cn[nH]c12
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(OCC1(c2ccc(F)cc2)CCN(C)CC1)c1cc(N(C)C)cc2cn[nH]c12
Reaction time: 2 h

Procedure:
To a suspension of (±)-7-(1-((4-(4-fluorophenyl)piperidin-4-yl)methoxy)ethyl)-N,N-dimethyl-1H-indazol-5-amine (101 mg, 0.255 mmol) and sodium cyanoborohydride (80 mg, 1.27 mmol) in acetonitrile (6 mL) at 0° C. was added formalin (0.053 mL). The reaction was treated with 5 drops of acetic acid and the ice bath was removed, stirring continued for 2 h. The reaction was concentrated and purified by preparative HPLC to give 78.5 mg (75%). 1H-NMR (CDCl3, 500 MHz) δ 8.17 (s, 1H), 7.90 (s, 1H), 7.38 (s, 1H), 7.23 (m, 3H), 7.10 (m, 2H), 4.66 (q, J=5.0 Hz, 1H), 3.50-3.57 (m, 2H), 3.39 (d, J=10 Hz, 1H), 3.27 (s, 6H), 3.18 (d, J=10 Hz, 1H), 2.74 (s, 3H), 2.50-2.73 (m, 4H), 2.35-2.45 (m,2H), 1.51 (d, J=5.0 Hz, 3H); Mass spec.: 411.45 (MH)+.
Reaction SMILES: Cl.O1CCOCC1.[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][NH:18][C:19]([CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[O:20])=[CH:14][CH:15]=2)[CH:10]=[N:9]1.C(=O)([O-])O.[Na+]>>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][NH:18][C:19]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[O:20])=[CH:14][CH:15]=2)[CH:10]=[N:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NCc2ccc3[nH]ncc3c2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(NCc1ccc2[nH]ncc2c1)C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8.7 %

Procedure:
A 4N-hydrochloric acid/dioxane solution (2.0 ml) was added to tert-butyl 4{[(1H-indazol-5-ylmethyl)amino]carbonyl}-1-piperidinecarboxylate (160 mg, 0.446 mmol), and the resulting mixture was stirred at room temperature for 2 hours. Then, the reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The resulting residue was recrystallized from a mixture of ethanol and diethyl ether to obtain N-(1H-indazol-5-ylmethyl)-4-piperidinecarboxamide (10 mg, 9%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[N:16]([CH:23]([CH3:25])[CH3:24])[N:17]=[C:18]([CH2:20][O:21][CH3:22])[N:19]=4)=[CH:10]3)[C:6]=2[CH:26]=1>C(Cl)Cl>[CH:23]([N:16]1[C:15]([C:9]2[N:8]=[C:7]3[C:6]4[CH:26]=[CH:2][CH:3]=[CH:4][C:5]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:19][C:18]([CH2:20][O:21][CH3:22])=[N:17]1)([CH3:25])[CH3:24]
Reactant: COCc1nc(-c2cn3c(n2)-c2cc(Br)ccc2OCC3)n(C(C)C)n1
Solvent: ClCCl
Product: COCc1nc(-c2cn3c(n2)-c2ccccc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 107.5 %

Procedure:
To a suspension of 9-bromo-2-(2-isopropyl-5-methoxymethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene (0.85 g, 2.0 mmol) in IMS (20 mL) was added DCM (6 mL). The mixture was degassed with nitrogen before being treated with palladium on carbon (10% palladium, 50% water, 350 mg). The vessel was evacuated and refilled with hydrogen and stirred at RT 18 h before further catalyst was added and the reaction stirred for 72 h. The reaction was filtered then concentrated in vacuo to give 309 as a pale yellow solid (0.73 g, quantitative yield). LCMS RT=4.55 min, [M+H]+=340. 1H NMR 400 MHz (DMSO-d6) δ: 8.37 (2H, dd, J=9.88, 1.75 Hz), 7.30 (1H, ddd, J=7.93, 7.18, 1.70 Hz), 7.12-7.12 (1H, m), 7.03 (1H, dd, J=8.19, 1.22 Hz), 5.83-5.74 (1H, m), 4.48-4.47 (4H, m), 4.36 (2H, s), 3.28 (3H, s), 1.45 (6H, d, J=6.60 Hz)
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17]CC1C=CC=CC=1)=[CH:12][CH:11]=2)[C:3]([O:5][CH3:6])=[O:4]>C(O)C.[Pd]>[OH:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:7][CH:2]([CH3:1])[C:3]([O:5][CH3:6])=[O:4])=[CH:16]2
Reactant: COC(=O)C(C)Cc1cc2cc(OCc3ccccc3)ccc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C(C)Cc1cc2cc(O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.2 %

Procedure:
A mixture of methyl 2-methyl-3-[5-benzyloxyindolyl]propanoate (0.18 g, 0.56 mmol), as prepared in the preceding step, 10% palladium(0) on carbon (0.018 g) in ethanol (10 mL) was stirred at ambient temperature under hydrogen (balloon) overnight (16 h). The catalyst was removed by filtration through Celite. The filtrate was concentrated to give the title compound as a light brown oil (0.11 g, 85%) which was used directly in the next reaction.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23]([NH:30][C@@H:31]([C:35](O)=[O:36])[CH:32]([CH3:34])[CH3:33])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[C:26]([O:25][C:23](=[O:24])[NH:30][CH:31]([C:35](=[O:36])[NH:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[NH:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:32]([CH3:33])[CH3:34])([CH3:27])([CH3:29])[CH3:28]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccccc1NCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)C(NC(=O)OC(C)(C)C)C(=O)Nc1ccccc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N1-Benzyl-benzene-1,2-diamine obtained from Example 5b and triethylamine (0.19 ml, 1.35 mmol) in dry DMF (5 ml), was added Boc-D-valine (294 mg, 1.35 mmol) followed by TBTU (289 mg, 0.9 mmol). The reaction mixture was stirred at room temperature overnight. Ethyl acetate was added. The organic layer was washed with saturated NaHCO3, dried over MgSO4, filtered, and the filtrated was concentrated in vacuo. The crude material was purified by flash chromatography to yield [1-(2-Benzylaminophenylcarbamoyl)-2-methyl-propyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].S(=O)(=O)(O)O.[F:12][C:13]1[CH:27]=[CH:26][C:16]([CH:17](O)[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[F:12][C:13]1[CH:14]=[CH:15][C:16]([CH:17]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[O:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:26][CH:27]=1
Reactant: OCCCCCl
Reactant: OC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Fc1ccc(C(OCCCCCl)c2ccc(F)cc2)cc1
Yield: 75 %

Procedure:
A mixture of 4-chloro-1-butanol (6.51 g, 60 mmol), 1 mL of concentrated sulfuric acid and 4,4′-difluorobenzhydrol (2.2 g, 10 mmol) in 50 mL of toluene was heated at reflux for 12 h. The reaction mixture was cooled, washed successively with saturated sodium bicarbonate solution (50 mL) and water (50 mL). The organic layer was dried over MgSO4, filtered and the solvent was removed by rotary evaporation. The resultant brown oil was purified on a silica gel column. Elution with 2% ethyl acetate/hexane afforded 2.33 g (7.5 mmol, 75%) of the product as a colorless oil. 1H NMR (CDCl3): δ 1.71-1.80 (2H, m), 1.84-1.93 (2H, m), 3.43 (2H, t, J=6.0), 3.52 (2H, t, J=6.4), 5.30 (1H, s) 6.95-7.02 (4H, m), 7.24-7.29 (4H, m)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][O:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH:27]=O)=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=1.[CH3:34][S:35]([CH2:38][CH2:39][NH2:40])(=[O:37])=[O:36]>>[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][O:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([C:22]4[O:26][C:25]([CH2:27][NH:40][CH2:39][CH2:38][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:24][CH:23]=4)[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)CCN
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)cc4)c3c2)o1
Product: CS(=O)(=O)CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)cc4)c3c2)o1

Procedure:
Prepared according to Procedure D from 5-(4-{4-(3-fluorobenzyloxy)anilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). 1H NMR 400 MHz (DMSO-d6) 9.40 (s, 1H); 8.67 (s, 1H); 8.30 (d, 1H); 7.86 (d, 1H); 7.75 (d, 2H); 7.43 (m, 1H); 7.30-7.21 (m, 3H); 7.15 (m, 1H); 7.07 (d, 2H); 6.80 (d, 1H); 5.15 (s, 2H); 4.40 (s, 2H); 3.65 (m, 2H); 3.40 (m, 2H); 3.11 (s, 3H); MS m/z 547 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:25]=[C:26]([F:45])[C:27]=1[N:28]1[CH2:32][C:31](=[O:33])[N:30](COCC2C=CC=CC=2)[S:29]1(=[O:44])=[O:43])[CH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[O:20][S:21]([CH3:24])(=[O:23])=[O:22])C1C=CC=CC=1>CCO.CCOC(C)=O.[Pd]>[F:45][C:26]1[CH:25]=[C:11]([CH:10]=[C:9]([OH:8])[C:27]=1[N:28]1[CH2:32][C:31](=[O:33])[NH:30][S:29]1(=[O:44])=[O:43])[CH2:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[O:20][S:21]([CH3:24])(=[O:22])=[O:23]
Reactant: Cc1ccc(OS(C)(=O)=O)c(Cc2cc(F)c(N3CC(=O)N(COCc4ccccc4)S3(=O)=O)c(OCc3ccccc3)c2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(OS(C)(=O)=O)c(Cc2cc(O)c(N3CC(=O)NS3(=O)=O)c(F)c2)c1
Reaction time: 18 h

Procedure:
To a solution of methanesulfonic acid 2-[3-benzyloxy-4-(5-benzyloxymethyl-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-5-fluorobenzyl]-4-methylphenyl ester (85 mg) in EtOH (3 mL) and EtOAc (6 mL) is added 5% Pd/C (75 mg) and the mixture is hydrogenated at 1 atm for 18 h. The catalyst is filtered and washed with EtOH (3×). Solvent is evaporated to near dryness before water and acetonitile is added to form a solution. It is then lyophilized to give the title compound: MS (M−H)−=443.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)=[CH:10][N:4]2[N:3]=1.[Br:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30].N1C=CC=CC=1>CC#N>[Br:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:20])([CH3:21])[CH3:22])[CH:16]=3)=[CH:10][N:4]2[N:3]=1)=[O:30]
Reactant: O=C(Cl)c1cccc(Br)c1
Reactant: Cc1ccc(-c2cn3nc(N)ccc3n2)cc1NC(=O)C(C)(C)C
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1ccc(-c2cn3nc(NC(=O)c4cccc(Br)c4)ccc3n2)cc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.8 %

Procedure:
An 8-mL vial is charged with N-[5-(6-aminoimidazo[2,1-f]pyridazin-2-yl)-2-methyl-phenyl]-2,2-dimethyl-propanamide (0.097 g, 0.3 mmol), 3-bromobenzoyl chloride (0.059 mL, 0.45 mmol), pyridine (0.073 mL), and MeCN (1.0 mL). The mixture is stirred at room temperature for 16 hours, concentrated onto celite and purified by silica gel chromatography (0-100% 1:0.1 EtOAc:MeOH in CH2Cl2) to give the title compound (0.065 g). LCMS (m/z)=506.4 and 508.4 [M+H]+, tR=2.96 min.
Reaction SMILES: FC1C=CC=CC=1C(Cl)=O.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](Cl)=[O:17].[NH2:19][C:20]1[CH:21]=[C:22]([CH:33]=[CH:34][N:35]=1)[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>>[CH2:26]([NH:25][C:23](=[O:24])[C:22]1[CH:33]=[CH:34][N:35]=[C:20]([NH:19][C:16]([C:12]2[S:11][CH:15]=[CH:14][CH:13]=2)=[O:17])[CH:21]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1cccs1
Reactant: Nc1cc(C(=O)NCc2ccccc2)ccn1
Agent: O=C(Cl)c1ccccc1F
Product: O=C(NCc1ccccc1)c1ccnc(NC(=O)c2cccs2)c1
Yield: 73 %

Procedure:
Following the procedure as describe in Example 6, making variations as required to replace 2-fluorobenzoyl chloride with thiophene-2-carbonyl chloride to react with 2-amino-N-benzylisonicotinamide, N-benzyl-2-(thiophene-2-carboxamido)isonicotinamide was obtained as a colorless solid in 73% yield: mp 160-162° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 11.07 (s, 1H), 9.32 (t, J=5.7 Hz, 1H), 8.53-8.47 (m, 2H), 8.23-8.22 (m, 1H), 7.87 (d, J=5.0 Hz, 1H), 7.58-7.48 (m, 1H), 7.31-7.37 (m, 6H), 4.46 (d, J=5.9 Hz, 2H); MS (ES+) m/z 338.5 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12][CH2:13][OH:14])[CH:6]=[CH:5]2.[N:15]1[NH:16][C:17](=[O:21])[CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1.[Cu]>[OH:14][CH2:13][CH2:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([N:16]1[C:17](=[O:21])[CH:18]=[CH:19][CH:20]=[N:15]1)[CH:11]=[CH:10]2
Reactant: OCCc1ccc2cc(Br)ccc2c1
Reactant: O=c1cccn[nH]1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=c1cccnn1-c1ccc2cc(CCO)ccc2c1
Temperature: 25 °C
Yield: 54.2 %

Procedure:
A mixture of the product from Example 31E (500 mg, 1.87 mmol), 2H-pyridazin-3-one (180 mg, 1.87 mmol), copper powder (120 mg, 1.87 mmol), and K2CO3 (775 mg, 5.61 mmol, 3 equiv.) in pyridine (75 mL) was stirred at reflux under a dry nitrogen atmosphere for 20 hr. The reaction mixture was cooled to room temperature then concentrated under reduced pressure. Residual pyridine was removed by repeated evaporation with toluene. The residue was partitioned between ethyl acetate (350 mL) and saturated aqueous Na2CO3. The organic layer was washed twice with aqueous NH4OH, dried (MgSO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (75:25 ethyl acetate/hexane) to provide the title compound (270 mg, 54% yield). 1H NMR (CDCl3, 300 MHz) δ 8.11 (d, J=2 Hz, 1H), 7.97-7.93 (m, 1H), 7.88 (t, J=9 Hz, 2H), 7.75-7.68 (m, 2H), 7.41 (dd, J=2, 12 Hz, 1H), 7.31-7.24 (m, 1H), 7.10 (dd, J=2, 12 Hz, 1H), 3.97 (t, J=6 Hz, 2H), 3.06 (t, J=6 Hz, 2H). MS (DCl-NH3) [M+H]+ at 267, [M+NH4]+ at 284.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:47][C@@H:48]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:49]1[CH:50]=[C:51]([P:55]([CH3:60])(=[O:59])[O:56][CH2:57][CH3:58])[CH:52]=[CH:53][CH:54]=1>CC#N>[OH:1][C:2]1[C:7]([C:8]([NH:47][C@@H:48]([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:49]2[CH:50]=[C:51]([P:55]([CH3:60])(=[O:59])[O:56][CH2:57][CH3:58])[CH:52]=[CH:53][CH:54]=2)=[O:10])=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1
Reactant: CCOP(C)(=O)c1cccc([C@@H](N)c2ccccc2)c1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOP(C)(=O)c1cccc([C@@H](NC(=O)c2cnc(-n3cccn3)nc2O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 8-b, (12.3 g, 40 mmol) and Et3N (11 g, 109 mmol) in MeCN (200 ml) was added HATU (16.6 g, 43.8 mmol). The mixture was stirred for 10 min at room temperature and then ethyl 3-((S)-amino(phenyl)methyl)phenyl(methyl)phosphinate, 25-d, (10.55 g, 36.5 mmol) was added. The resulting mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under vacuum and the residue was taken into ethyl acetate followed by washing with saturated NH4Cl. The organic layer was dried over sodium sulfate and concentrated under vacuum to provide the crude product, 25-e, (33 g) as red oil. The crude product was used for the next step directly.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([N:11]1C(=O)C3C(=CC=CC=3)C1=O)[C@@H:6]([O:22][CH3:23])[CH2:5]2.C(O)C.NN>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([NH2:11])[C@@H:6]([O:22][CH3:23])[CH2:5]2
Reactant: CO[C@H]1Cc2cc(Cl)ccc2[C@H]1N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Product: CO[C@H]1Cc2cc(Cl)ccc2[C@H]1N
Temperature: 90 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To a suspension of 2-[(1R,2S)-5-chloro-2-methoxy-2,3-dihydro-1H-inden-1-yl]-1H-isoindole-1,3(2H)-dione (7) (25.8 g, 0.0787 mol) in ethanol (260 mL, 4.4 mol) was added hydrazine (4.94 mL, 0.157 mol), and the flask was affixed with a reflux condenser and heated to a bath temperature of 90° C. A precipitate began to form after several minutes of stirring and after 1 hour of heating the mixture had become a thick slurry/solid. The reaction was cooled to room temperature and the solid reaction byproducts were filtered and washed with CH2Cl2 (˜300 mL). The volatiles were removed from the filtrate in vacuo, and the residue was suspended in CH2Cl2 (250 mL), at which point the solid byproducts were again removed by filtration. The volatiles were removed in vacuo, and the residue was again suspended in CH2Cl2 (˜50 mL). The solid byproducts were removed a final time by filtration to afford (1R,2S)-5-chloro-2-methoxyindan-1-amine (15.5 g, 99%) as a red/orange waxy solid. LCMS: (FA) ES+ molecular ion 198, major ionization 181; 1H NMR (400 MHz, DMSO) δ 7.30 (d, J=7.9, 1H), 7.25-7.16 (m, 2H), 4.14 (d, J=4.9, 1H), 3.89 (td, J=2.8, 4.9, 1H), 3.29 (s, 3H), 2.89 (ddd, J=3.8, 16.4, 21.3, 2H), 2.04 (s, 2H). Chiral HPLC (Chiralpak AD 4.6×250 column eluted with 95/5/0.1% hexane/EtOH/DEA @ 1.0 ml/min-30 min run) showed an ee of >99%.