Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]12[O:10][B:9]([C@@H:11]([NH:28][C:29]([C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[CH2:36][NH:35][CH2:34]4)=[O:30])[CH2:12][C:13]3[C:14]([O:26][CH3:27])=[C:15]([CH:23]=[CH:24][CH:25]=3)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[O:8][CH:7]1[CH2:6][CH:5]1[CH2:40][CH:3]2[C:4]1([CH3:42])[CH3:41].C([O-])([O-])=O.[K+].[K+].Br[CH2:50][CH2:51][NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56].O>CN(C=O)C>[C:55]([O:54][C:53]([NH:52][CH2:51][CH2:50][N:35]1[CH2:34][C:33]2[C:37](=[CH:38][CH:39]=[C:31]([C:29]([NH:28][C@H:11]([B:9]3[O:8][CH:7]4[C:2]([CH3:1])([CH:3]5[CH2:40][CH:5]([CH2:6]4)[C:4]5([CH3:42])[CH3:41])[O:10]3)[CH2:12][C:13]3[C:14]([O:26][CH3:27])=[C:15]([CH:23]=[CH:24][CH:25]=3)[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[O:30])[CH:32]=2)[CH2:36]1)=[O:59])([CH3:58])([CH3:57])[CH3:56]
Reactant: COc1c(C[C@H](NC(=O)c2ccc3c(c2)CNC3)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C[C@H](NC(=O)c2ccc3c(c2)CN(CCNC(=O)OC(C)(C)C)C3)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 3-((2R)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-2-(isoindoline-5-carboxamido)ethyl)-2-methoxybenzoate from Example 9 step 2 (263 mg, 0.46 mmol) in DMF (5 mL) was added K2CO3 (252 mg, 1.84 mmol) and tert-butyl 2-bromoethylcarbamate (122 mg, 0.54 mmol). The resulting reaction was stirred at room temperature overnight. Water (15 mL) was added and the aqueous phase was extracted with EtOAc. The organic phase was washed with 1N HCl, brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (Hexane/EtOAc, 2:1 to 1:2). ESI-MS m/z 718.1 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[NH2:11].[CH2:12]([OH:14])[CH3:13]>[Pd]>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([NH:11][C:12](=[O:14])[CH3:13])[CH:4]=1
Reactant: CCO
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Agent: [Pd]
Product: CC(=O)Nc1cc(N)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-fluoro-5-nitrophenylamine (2.0 g), palladium, 10 wt. % on activated carbon (0.10 g) and ethanol (20 mL) were stirred at room temperature for 2 hours under an atmosphere of hydrogen. The mixture was filtered through hyflo, washing with ethanol and the solvent removed under reduced pressure to afford title compound as a white solid, 1.7 g.
Reaction SMILES: Cl.[NH:2]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:3]1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.O1CCOCC1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>O>[CH3:7][O:6][C:4]([CH:3]1[CH2:8][CH2:9][CH2:10][CH2:11][N:2]1[S:33]([C:30]1[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=1)(=[O:35])=[O:34])=[O:5]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C1CCCCN1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)C1CCCCN1S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl pipecolinate hydrochloride (10.0 g, 55.6 mmol), triethylamine (14.1 g, 19.4 mL, 139.2 mmol, 2.5 equiv), 1,4-dioxane (75 mL), and water (75 mL) are stirred at room temperature and then p-methoxyphenylsulfonyl chloride (13.8 g, 66.8 mmol, 1.2 equiv) is added. The resulting solution is stirred at room temperature overnight. The solution is then poured into water and extracted with CH2Cl2. The combined organic extracts are dried (Na2SO4) and concentrated to an oil under reduced pressure. Purification of the oil is accomplished by chromatography on silica gel using 7/3 hexane/EtOAc as the eluent. The product is obtained as a colorless oil which solidified upon standing.
Reaction SMILES: Cl[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[SH:16][CH2:17][C:18]([OH:20])=[O:19].CN(C=O)C.[OH-].[Na+]>O>[C:18]([CH2:17][S:16][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)([OH:20])=[O:19]
Reactant: O=C(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)CS
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CSc1ccc(C(=O)c2ccccc2)cc1
Temperature: 107.5 °C
Yield: 75.2 %

Procedure:
55 g 4-chloro benzophenone and 24 g mercaptoacetic acid are added into a 500 ml three-neck flask, and are dissolved with 350 ml DMF to obtain a solution, and then 23 g solid sodium hydroxide is added into the solution. Heating the solution to reflux (105-110° C.), and starting to cool the solution when the content of 4-chloro benzophenone detected by HPLC is less than 1%. The reaction solution is added into 500 ml water, and then water insoluble substances are extracted with 100 ml methylbenzene. Concentrated hydrochloric acid is used to regulate the pH value of the aqueous phase to 3-4, then some solid substances precipitates, filtering to obtain crude products, and the weight after drying is 58 g; the dried crude products are recrystallized in dichloroethane to obtain 52 g white crystal, with a yield of 75% and a melting point of 130-132° C. 1H-NMR data (solvent DMSO-d6): δ3.796 ppm, s, 2H; δ7.402, 7.429 ppm, d, 2H; δ7.451, 7.476, 7.501 ppm, t, 2H; δ7.567, 7.590, 7.614 ppm, t, 1H; δ7.740, 7.767 ppm, d, 2H; δ7.753, 7.775 ppm, d, 2H).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH3:10])[C:7](Cl)=[O:8])(=[O:3])[CH3:2].Cl.[NH2:12][C@H:13]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:15][S:16][CH3:17].C(N(CC)CC)C>C(Cl)Cl>[C:1]([S:4][CH2:5][CH:6]([CH3:10])[C:7]([NH:12][C@H:13]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:15][S:16][CH3:17])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(C)C(=O)Cl
Reactant: COC(=O)[C@@H](N)CCSC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCSC)NC(=O)C(C)CSC(C)=O

Procedure:
3-Acetylthio-2-methylpropanoyl chloride (3.78 ml., 25 mmole) is added dropwise over six minutes to a cold (-5°), stirred suspension of (L)-methionine, methyl ester, hydrochloride salt (4.99, 25 mmole) and triethylamine (13.94 g.) in methylene chloride (100 ml.). The mixture is stirred in the cold for three hours and then diluted with methylene chloride (100 ml.). The resulting yellow solution is washed sequentially with 10% aqueous HCl (70 ml.), saturated sodium bicarbonate (70 ml.) and brine (100 ml.), dried over sodium sulfate, and concentrated in vacuo to give (±)-N-[3-(acetylthio)-2-methyl-1-oxopropyl]-L-methionine, methyl ester.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][CH2:13][C:14](=O)[CH3:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])[NH2:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:18][C:19]1[CH:20]=[C:21]([N:22]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)=[CH:12][CH:13]=[C:14]2[CH3:15])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: CC(=O)CCC(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: Nc1ccc(F)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)c(F)c1
Yield: 90.3 %

Procedure:
A mixture of 1-(4-methylsulfonylphenyl)-1,4-pentanedione (Example 1, Step 2) (300 mg, 1.18 mmol), 3,4-difluoroaniline (0.13 ml, 1.3 mmol) and p-toluenesulfonic acid (25 mg) in toluene (80 ml) was heated to reflux for 24 hours. The reaction mixture was cooled, filtered and concentrated. The crude dark orange solid (700 mg) was purified by chromatography (silica gel, hexane/ethyl acetate, 7/3) to give 1-(3,4-difluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]-1H-pyrrole (370 mg, 90%) as a white solid: mp (DSC) 151° C. Anal Calc'd. for C18H15NSO2F2 : C, 62.24; H, 4.35; N, 4.03. Found: C, 62.08; H, 4.52; N, 4.05.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17](S(C3C=CC=CC=3)(=O)=O)[CH:16]=2)[CH:3]=1.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=3)[NH:17][CH:16]=2)[CH:3]=1
Reactant: COc1cnc2c(c1)c(-c1cc(Cl)nc(NC3CCCCC3)c1)cn2S(=O)(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cnc2[nH]cc(-c3cc(Cl)nc(NC4CCCCC4)c3)c2c1
Temperature: 50 °C
Yield: 71.5 %

Procedure:
A solution of Example 178a (90.0 mg, 0.181 mmol) in dioxane (2.5 mL) was treated with 20% NaOH (0.12 mL). The reaction was heated at 50° C. for 4 hours. The solvent was evaporated and the residue was triturated with water. The solid was filtered and purified by reverse-phase HPLC as described in Example 56 to give the title compound (46.2 mg) as trifluoroacetic acid salts. 1H NMR (400 MHz, CD3OD) ppm 1.23-1.39 (m, 3H), 1.40-1.55 (m, 2H), 1.69 (m, 1H), 1.76-1.88 (m, 2H), 2.00-2.12 (m, 2H), 3.75 (m, 1H), 3.96 (s, 3H), 6.90 (d, J=1.22 Hz, 1H), 7.00 (d, J=1.53 Hz, 1H), 7.91 (d, J=2.44 Hz, 1H), 7.99 (s, 1H), 8.09 (d, J=2.75 Hz, 1H). MS (ESI+) m/z 357.5 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:11](I)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>O>[CH2:11]([O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCI
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCCCCCOc1cccc([N+](=O)[O-])c1

Procedure:
A mixture of 3-nitrophenol (57.0 g, 0.41 mol), n-hexyliodide (87.0 g, 0.41 mol), potassium carbonate (57.0 g, 0.42 mol) and ethylmethylketone (300 ml) was heated at reflux for 18 h. Water (500 ml) was added and the mixture was extracted with ethyl acetate (2×500 ml). The combined extracts were washed with 8% aqueous sodium bicarbonate (2×250 ml) and brine (250 ml) and then dried (MgSO4) and evaporated to afford a dark brown liquid. Distillation under reduced pressure gave the ether (Intermediate 66) as a mobile yellow liquid (70.3 g, 77%).
Reaction SMILES: [OH-].[Na+].[CH:3](/[C:16]1[CH:17]=[C:18]([C:21]([O:23]C)=[O:22])[NH:19][CH:20]=1)=[CH:4]\[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].S(=O)(=O)(O)O>C(O)C>[CH:3](/[C:16]1[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[NH:19][CH:20]=1)=[CH:4]\[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCC/C=C/c1c[nH]c(C(=O)OC)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCC/C=C/c1c[nH]c(C(=O)O)c1
Yield: 75 %

Procedure:
An aqueous solution (8 ml) containing 340 mg (8.0 mmol) of 95% sodium hydroxide was added to an ethanol solution (20 ml) of 1.30 g (4.3 mmol) of methyl 4-(1-trans-tridecenyl)pyrrole-2-carboxylate prepared in Example 48, and the whole was heated under reflux for 1 hour. The reaction mixture was acidified with 6N sulfuric acid and extracted with ethyl acetate. The extract was washed with an aqueous saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and treated with activated carbon. After removing the solvent under reduced pressure, the resulting residue was recrystallized from a mixed solution of hexane and tetrahydrofuran to give 940 mg (72% yield) of 4-(1-trans-tridecenyl)pyrrole-2-carboxylic acid, m.p. 161°-163° C.
Reaction SMILES: [C:1]1([S:7]([O:10][C:11]2[C:20]([Br:21])=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([CH3:22])=[N:18]3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:23]1CCOCC1>>[C:1]1([S:7]([O:10][C:11]2[C:20]([Br:21])=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([CH:22]=[O:23])=[N:18]3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1COCCO1
Reactant: Cc1ccc2ccc(OS(=O)(=O)c3ccccc3)c(Br)c2n1
Product: O=Cc1ccc2ccc(OS(=O)(=O)c3ccccc3)c(Br)c2n1
Temperature: 80 °C
Reaction time: 24 h
Yield: 91 %

Procedure:
A mixture of SeO2 (500 mg, 4.51 mmol) and 1,4-dioxane (10 mL) was heated to over 80° C. 8-Bromo-2-methylquinolin-7-yl benzenesulfonate (15, 1.70 g, 4.49 mmol) in 1,4-dioxane (5 mL) was added. After stirring at 80° C. for 24 h, the reaction was cooled and vacuum filtered. The filtrate was collected and concentrated to yield a yellow solid. Purification by SiO2 column chromatography (CHCl3) gave 16 as a white solid (1.60 g, 4.08 mmol, 91% yield). 1H NMR (500 MHz, CDCl3) δ 10.25 (s, 1H), 8.37 (d, 1H, J=7.5 Hz), 8.09 (d, 1H, J=8.5 Hz), 7.99 (d, 2H, J=7.0 Hz), 7.91 (d, 1H, J=9.0 Hz), 7.79 (d, 1H, J=9.0 Hz), 7.72 (t, 1H, J=7.5 Hz), 7.57 (t, 2H, J=8.0 Hz). 13C NMR (500 MHz, CDCl3) δ 193.33, 153.80, 149.08, 146.10, 138.35, 135.82, 135.17, 129.79, 129.66, 128.99, 128.37, 125.61, 119.93, 118.51.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:14][N:13]([CH2:15][CH2:16][C:17]([NH:19]C2C=CC=CC=2)=[O:18])[C:12](=[O:26])[CH2:11][N:10]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)(=[O:29])=[O:28])[C:9]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC=CC=1.[CH2:45](N)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH2:45]([NH:19][C:17](=[O:18])[CH2:16][CH2:15][N:13]1[CH2:14][CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9](=[O:37])[N:10]([S:27]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)(=[O:28])=[O:29])[CH2:11][C:12]1=[O:26])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: O=C(CCN1CC(Cc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(Cl)cc2)CC1=O)Nc1ccccc1
Reactant: NCc1ccccc1
Solvent: Nc1ccccc1
Product: O=C(CCN1CC(Cc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(Cl)cc2)CC1=O)NCc1ccccc1

Procedure:
Instead of the starting material compound of Example 273, that is, aniline, benzylamine was used for the similar procedure as in Example 273 to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@@H:12]2[CH2:15][C@H:14]([C:16]3[N:20]4[C:21]5[CH:27]=[CH:26][N:25]([S:28]([C:31]6[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=6)(=[O:30])=[O:29])[C:22]=5[N:23]=[CH:24][C:19]4=[N:18][N:17]=3)[C:13]2([CH3:39])[CH3:38])(=[O:10])=[O:9])=[N:6][CH:7]=1.[C:40]([NH:43][C@@H]1C[C@H](C(O)=O)C1(C)C)(=O)C.CCN(C(C)C)C(C)C.BrC1C=CC(S(Cl)(=O)=O)=NC=1.C([Zn]C#N)#N>CN(C=O)C.[OH-].[Na+].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.C(Cl)CCl>[C:40]([C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@@H:12]2[CH2:15][C@H:14]([C:16]3[N:20]4[C:21]5[CH:27]=[CH:26][N:25]([S:28]([C:31]6[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=6)(=[O:30])=[O:29])[C:22]=5[N:23]=[CH:24][C:19]4=[N:18][N:17]=3)[C:13]2([CH3:39])[CH3:38])(=[O:9])=[O:10])=[N:6][CH:7]=1)#[N:43]
Reactant: CC(=O)N[C@@H]1C[C@H](C(=O)O)C1(C)C
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@H]4C[C@@H](NS(=O)(=O)c5ccc(Br)cn5)C4(C)C)n23)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#C[Zn]C#N
Agent: O=S(=O)(Cl)c1ccc(Br)cn1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc([C@H]4C[C@@H](NS(=O)(=O)c5ccc(C#N)cn5)C4(C)C)n23)cc1
Temperature: 80 °C
Yield: 14 %

Procedure:
To a solution of 5-bromo-N-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclobutyl)pyridine-2-sulfonamide (0.69 g, 1.1 mmol, prepared using A from (1S,3R)-3-acetamido-2,2-dimethylcyclobutanecarboxylic acid [Tetrahedron: Asymmetry 2008, 19, 302-308] and Preparation #9 with EDC, C with DIEA, JJ, N from 5-bromopyridine-2-sulfonyl chloride [Chem Impex]) in degassed DMF (1.5 mL) was added dicyanozinc (0.321 g, 2.74 mmol) followed by Pd(Ph3P)4 (0.063 g, 0.055 mmol, Strem). The reaction was heated at about 80° C. for about 16 h under a nitrogen atmosphere. The reaction mixture was allowed to cool to ambient temperature before it was diluted with aqueous NaOH (1N, 10 mL) and extracted with EtOAc (25 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The product was purified by silica gel chromatography (12 g) eluting with a gradient of 1-10% MeOH in DCM to give 5-cyano-N-((1R,3S)-2,2-dimethyl-3-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclobutyl)pyridine-2-sulfonamide (0.09 g, 14%) as a tan solid: LC/MS (Table 2, Method a) Rt=2.14 min; MS m/z: 577 (M+H)+.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:37]=[CH:36][C:12]([C:13]([NH:15][CH:16]([CH2:34][CH3:35])[C:17]([CH3:33])([CH3:32])[C:18]([N:20]3[CH2:25][CH2:24][CH:23]([CH2:26][C:27]([O:29]CC)=[O:28])[CH2:22][CH2:21]3)=[O:19])=[O:14])=[CH:11][CH:10]=2)=[NH:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+].C(O)(=O)C>C(O)C>[N:1]1([C:7]([C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:15][CH:16]([CH2:34][CH3:35])[C:17]([CH3:32])([CH3:33])[C:18]([N:20]3[CH2:25][CH2:24][CH:23]([CH2:26][C:27]([OH:29])=[O:28])[CH2:22][CH2:21]3)=[O:19])=[O:14])=[CH:36][CH:37]=2)=[NH:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC1CCN(C(=O)C(C)(C)C(CC)NC(=O)c2ccc(C(=N)N3CCOCC3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CCC(NC(=O)c1ccc(C(=N)N2CCOCC2)cc1)C(C)(C)C(=O)N1CCC(CC(=O)O)CC1
Reaction time: 3 h
Yield: 0.1 %

Procedure:
Ethyl N-(N-(4-(4-morpholinoimidoyl)benzoyl)-β-ethyl-α,α-dimethyl-β-alanyl)-4-piperidineacetate (28 mg, 54.4 mmol) as prepared in Example 43 was dissolved in ethanol (10 ml). To the resulting solution was added a 4N aqueous solution of NaOH (3 ml) under cooling with ice and the mixture was stirred for 3 hours. The mixture was neutralized with acetic acid under cooling with ice. After the ethanol was distilled off, the residue was dissolved in water and purified with a high performance liquid chromatography (HPLC) [column: ODS 5C18 (μ bondasphere, φ 19×150 mm), mobile phase: (A) 0.1% TFA, (B) 100% CH3CN/0.1% TFA, gradient: (A):(B)=76:24-74:26, 6 minutes, flow rate: 17 ml/min]. The desired fractions were collected and lyophilized to yield the titled compound (20.3 mg, 77%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[F:28])[C:22](O)=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].ClC(OCC(C)C)=O.[CH3:38][N:39]1CCOCC1.CN>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[F:28])[C:22]([NH:39][CH3:38])=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cc(C(=O)O)ccc1F
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: CN
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(F)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoic acid (1 g, 2.1 mmol) in N,N-dimethylformamide (20 mL) was cooled to −10 C. Isobutyl chloroformate (0.27 mL, 2.1 mmol) and N-methyl morpholine (0.23 mL, 2.1 mmol) were added to the reaction vessel. After stirring at −10 C for 20 minutes, a solution of N-methyl amine (2.1 mL, 4.2 mmol, 2 M in THF) was added and the reaction mixture was warmed to room temperature as it stirred for 18 hours. The reaction mixture was concentrated in vacuo, suspended in water, filtered and washed with water, ethyl acetate and diethyl ether. 1H NMR (400 MHz, CD3OD) δ 8.03 (dddd, J=3.0, 6.4, 9.2 and 11.6 Hz, 1H), 7.81 (dd, J 3.0 and (0.2 Hz, 1H), 7.66 (q, J=10.4 Hz, 1H), 7.47 (t, J=12 Hz, 1H), 7.06 (t, J=12 Hz, 2H), 6.67 (s, 1H), 5.38 (s, 2H), 2.91 (s, 3H), 2.10 (s, 3H) ppm. 19F NMR (400 MHz, CD3OD) δ−111.50 (1 F), −115.97 (1 F), −120.16 ppm. ES-HRMS m/z 481.0346 (M+H calcd for C21H17BrF3N2O3 requires 481.0369).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[N:11]([CH3:17])[C:10]=1[C:18]([NH:20][CH3:21])=[O:19])C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[N:11]([CH3:17])[C:10]=1[C:18]([NH:20][CH3:21])=[O:19]
Reactant: [H][H]
Reactant: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(C)n1C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CNC(=O)c1c(O)c(=O)cc(C)n1C
Yield: 100.4 %

Procedure:
Pd(OH)2 on charcoal (0.2 g) was added to a solution of 3-(benzyloxy)-N,1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide (1.25 g, 4.366 mmol) in ethanol (120 ml) under nitrogen. The mixture was hydrogenated at 50 psi hydrogen for 4 hrs. The Pd(OH)2 was removed by filtration through Celite and the Celite cake was washed with ethanol (3×25 ml). The Celite cake was further stirred with ethanol (100 ml). and then filtered through Celite. The combined ethanol filtrate was evaporated to give a solid (0.86 g, quantitative yield). Melting point: >250° C. H-NMR (CDCl3: DMSO-d6 [2:11]) δ: 1.81 (s, 3H, Me), 2.34 (d, 3H, NHMe), 3.01 (s, 3H, NMe), 5.67 (s, 1H, CH), 7.88 (s, 1H, NH). Elemental Analysis: Calc. C 55.09; H 6.6; N 14.28. Found. C 54.67; H 6.31; N 14.12.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11](=O)[CH2:10][CH2:9][C:4]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:3]1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][CH:11]2[CH2:10][CH2:9][C:4]3([O:8][CH2:7][CH2:6][O:5]3)[CH2:3][C:2]2([CH3:13])[CH3:1])=[CH:18][CH:17]=1
Reactant: CC1(C)CC2(CCC1=O)OCCO2
Reactant: COc1ccc(CN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CNC2CCC3(CC2(C)C)OCCO3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
7,7-Dimethyl-1,4-dioxaspiro[4.5]decan-8-one (2.8 g, 15.217 mmol, 1 eq) and 4-methoxy-benzylamine (2.08 g, 15.217 mmol, 1 eq) were dissolved in dichloromethane (100 ml) and stirred for 3 h at RT. Na(OAc)3BH (9.67 g, 45.65 mmol, 3 eq) was added in portions at 0° C., and stirring was carried out for 20 h at RT. The reaction solution was diluted with dichloromethane (100 ml), washed with water (100 ml) and sat. NaCl solution (100 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (Alox neutral, 10% ethyl acetate in hexane). Yield: 46% (2.13 g, 6.98 mmol).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][O:11][CH2:12]Cl.ClCCl.[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[OH:26])[CH:21]=[O:22]>O>[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH2:10][O:11][CH3:12])[CH:21]=[O:22]
Reactant: COCCl
Reactant: O=Cc1ccc(O)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: COCOc1ccc(C=O)cc1F
Temperature: 25 °C
Reaction time: 11 h

Procedure:
N,N-diisopropylethylamine (23.7 ml) and chloromethyl methyl ether (7.76 ml) were added to a dichloromethane (130 ml) solution of 3-fluoro-4-hydroxybenzaldehyde (13 g) under cooling on ice, and the obtained mixture was stirred at room temperature for 11 hours. Water was added to the reaction solution, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=19:1 to 7:3), so as to obtain the title compound (17.4 g).
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].C1C=CC2N(O)N=NC=2C=1.[NH2:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:10])=[CH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Reactant: NCCN1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CC#N
Product: [N-]=[N+]=Nc1ccc(C(=O)NCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Azidobenzoic acid (858 mg, 5.15 mmol), HOBt (704 mg, 5.15 mmol, 1.0 eq.) and N-(2-aminoethyl)piperidine (0.788 ml, 5.41 mmol, 1.05 eq.) were dissolved in acetonitrile (6 ml) and DMF (6 ml), WSC (1.21 g, 6.19 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (50 ml) and washed with 5% aqueous sodium carbonate solution and saturated brine. The aqueous layers were each extracted with ethyl acetate (30 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated at 30° C. or below to give the title compound as a pale-yellow oil.