Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=1[CH3:7].C([O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O)(=O)C>>[OH:15][C:16]1[CH:17]=[C:18]([CH2:19][NH:1][C:2]2[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[S:9])[S:5][C:6]=2[CH3:7])[CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)Oc1cccc(C=O)c1
Reactant: COC(=S)c1cc(N)c(C)s1
Product: COC(=S)c1cc(NCc2cccc(O)c2)c(C)s1

Procedure:
Using the procedure described in Example 220, step (a), 1.6 mg (0.30 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate, 49.5 mg (0.30 mmol) of 3-acetoxybenzaldehyde, and 135 mg (2.2 equiv, 0.63 mmol) of NaHB(OAC)3 were allowed to react to give methyl 4-{[(3-hydroxyphenyl)methyl]amino}-5-methylthiothiophene-2-carboxylate. Mass spectrum (ESI, m/z): Calcd. for C14H16NO3S2, 352.07 (M+H), found, 350. 2 (imine), 352.1.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:13]=[C:14]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:15]=[CH:16][C:17]=1[C:18]([O:20]C(C)(C)C)=[O:19])=O)C1C=CC=CC=1.C([O:36][C:37](=O)[C:38]1[C:39](=[CH:50][CH:51]=[C:52]([Cl:54])[CH:53]=1)[NH:40][C:41](OC1C=CC=CC=1)=[O:42])C1C=CC=CC=1>>[Cl:54][C:52]1[CH:53]=[C:38]2[C:39](=[CH:50][CH:51]=1)[NH:40][C:41](=[O:42])[N:28]([S:25]([C:14]1[CH:13]=[C:12]([NH2:11])[C:17](=[CH:16][CH:15]=1)[C:18]([OH:20])=[O:19])(=[O:26])=[O:27])[C:37]2=[O:36]
Reactant: CC(C)(C)OC(=O)c1ccc(S(N)(=O)=O)cc1NC(=O)OCc1ccccc1
Reactant: O=C(Nc1ccc(Cl)cc1C(=O)OCc1ccccc1)Oc1ccccc1
Product: Nc1cc(S(=O)(=O)n2c(=O)[nH]c3ccc(Cl)cc3c2=O)ccc1C(=O)O
Yield: 26 %

Procedure:
From 300 mg (0.74 mmol) of 3-benzyloxycarbonylamino-4-t-butoxycarbonylbenzenesulfonamide and 310 mg (0.81 mmol) of 5-chloro-2-N-phenoxycarbonylanthranilic acid benzylester in a similar manner to Preparation Example 17, 75 mg (yield 26%: 4 steps) of the title compound was obtained. Property: colorless crystals, melting point: >200° C. (decomposition), PMR (δppm, DMSO-d6): 7.13-7.20 (2H, m), 7.56 (1H, s), 7.72 (1H, d), 7.82 (1H, s), 7.90 (1H, d), 11.68 (1H, s).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C@@H:4](O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.N1C(C)=CC=CC=1C.[C:34]([O:38][C:39](=[O:42])[NH:40][NH2:41])([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[Br:1][CH2:2][CH2:3][C@H:4]([NH:41][NH:40][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:42])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCOC(=O)[C@H](O)CCBr
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCOC(=O)[C@H](CCBr)NNC(=O)OC(C)(C)C
Reaction time: 0.08 h
Yield: 97 %

Procedure:
To a solution of ethyl (2R)-4-bromo-2-hydroxybutanoate (1.1 g, 5.2 mmol, prepared as described in J. Med. Chem. 2003, 46, 2057 or J. Am. Chem. Soc., 2004, 126, 12432 and Tetrahedron Letters 1997, 38, 4935-4938, in dry DCM (20 mL) at 0° C. was added Tf2O (1.62 g, 5.7 mmol) via syringe. After 5 min, 2,6-lutidine (0.67 g, 6.2 mmol) was added. After another 5 min, t-butylcarbazate (1.38 g, 10.4 mmol) in DCM (5 mL) was added. The solution was allowed to attain rt and stirred overnight. The solvent was evaporated and the residue was purified using flash chromatography (heptane/EtOAc 4:1, 3:1, 2:1) to give the slightly impure tert-butyl 2-[(1S)-3-bromo-1-(ethoxycarbonyl)propyl]hydrazinecarboxylate (1.65 g, 97%) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:16])[CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-:3])=[O:2].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:16][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=[N+]([O-])c1cc(O)ccc1-c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 112.3 %

Procedure:
3-Nitro-4-phenylphenol (215 mg, 1.0 mmol) was dissolved in N,N-dimethylformamide (5 mL) and tert-butyl 2-bromoacetate (292 mg, 1.5 mmol) was added thereto. After stirring at 80° C. for 18 hours, the reaction solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography to obtain tert-butyl 2-(3-nitro-4-phenylphenoxy)acetate (370 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[C:15]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])#[N:16].N1CCCCC1>CCO>[C:15](/[C:17](=[CH:11]/[C:10]1[CH:13]=[CH:14][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:8][CH:9]=1)/[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])#[N:16]
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Reactant: CC(C)(C)OC(=O)CC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)/C(C#N)=C\c1ccc(-c2ccccn2)cc1
Temperature: 73 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of 4-(pyridin-2-yl)-benzaldehyde (300 mg, 1.638 mmol) in EtOH (5 ml) at room temperature was added tert-butyl 2-cyanoacetate (0.281 ml, 1.965 mmol) followed by piperidine (0.016 ml, 0.164 mmol). The mixture was stirred at 73° C. overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the obtained mixture was added water and then extracted with DCM. The combined organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (silica gel, 15 to 30% EtOAc/Heptane) and gave the title compound: 350 mg (yield: 70%). LCMS (condition B): 307.2 (M+1); retention time=1.30 min.
Reaction SMILES: [OH-:1].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]>C(O)(=O)C>[OH:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]([OH:7])[CH:6]([C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[OH:3])[OH:1]
Reactant: O=Cc1ccccc1O
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Oc1ccccc1C(O)C(O)c1ccccc1O
Yield: 46 %

Procedure:
The electrolytic cell was charged with 100 milliliters of 1.5 molar aqueous sodium hydroxide and 10.0 grams (0.082 mole) of 2-hydroxybenzaldehyde (salicylaldehyde). The electrolysis was conducted at a constant current of 3.0 amperes and a temperature of 28° C to 32° C over a 1-hour period. The cathode potential was -1.67 volts versus the saturated calomel electrode. Upon completion of the electrolysis, the solution was acidified to about 6.3 by the addition of glacial acetic acid and extracted with three 100-milliliter portions of ethyl acetate. The ethyl acetate extracts were combined, washed with three 100-milliliter portions of water, and dried over anhydrous magnesium sulfate. Evaporation of the solvent in vacuo and drying of the resulting oil material in a vacuum dessicator yielded 9.3 grams (46.0 percent) of 1,2-bis(2-hydroxyphenyl)-ethane-1,2-diol (2,2'-dihydroxyhydrobenzoin) as a mixture of oil and crystals. The identity of the material was confirmed by nuclear magnetic resonance spectroscopy in pyridine-d5.
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[C:5](=[O:11])[N:4]([CH3:12])[CH:3]=1.[CH3:13][S:14]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][N:4]1[CH:3]=[C:2]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([S:14]([CH3:13])(=[O:16])=[O:15])[CH:22]=2)[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[C:5]1=[O:11]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cn1cc(Br)n2cncc2c1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cccc(S(C)(=O)=O)c2)n2cncc2c1=O
Temperature: 25 °C
Yield: 18.8 %

Procedure:
A solution of compound from Example 129, step 1 (80 mg, 0.35 mmol), (3-methylsulfonylphenyl)boronic acid (77 mg, 0.6 mmol), Na2CO3 (106 mg, 1 mmol), Pd(PPh3)2Cl2 (30.0 mg) in dioxane (3 mL) and water (0.5 mL) was stirred at 120° C. for 18 h under N2. After cooling to room temperature, the mixture was filtered, concentrated and purified by prep-HPLC to give the title compound (20.0 mg, 20%). 1H NMR (Methanol-d4 400 MHz): δ 8.70-8.65 (m, 1H), 8.30-8.20 (m, 2H), 8.16 (d, J=8.0 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.88 (t, J=8.0 Hz, 1H), 7.22 (s, 1H), 3.56 (s, 3H), 3.24 (s, 3H). LCMS (M+H)+304.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O:32][C:33]1[CH:43]=[CH:42][C:36]([CH2:37][C:38]2([NH2:41])[CH2:40][CH2:39]2)=[CH:35][CH:34]=1)C1C=CC=CC=1.FC(F)(F)C([O-])=O>>[OH:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:24])[CH2:21][NH:41][C:38]2([CH2:37][C:36]3[CH:42]=[CH:43][C:33]([OH:32])=[CH:34][CH:35]=3)[CH2:40][CH2:39]2)=[CH:11][CH:10]=1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Reactant: NC1(Cc2ccc(OCc3ccccc3)cc2)CC1
Agent: O=C([O-])C(F)(F)F
Product: O=C1COc2c(C(O)CNC3(Cc4ccc(O)cc4)CC3)ccc(O)c2N1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 253 mg (1 mmol) 1-(4-benzyloxy-benzyl)-cyclopropylamine. Yield: 20 mg (4%, trifluoroacetate); mass spectroscopy: [M+H]+=371.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:12]2[CH2:17][CH2:16][N:15]([C@@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(O)(=O)C>[C:30]1([N:11]([CH:12]2[CH2:13][CH2:14][N:15]([C@@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:16][CH2:17]2)[S:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:36](=[O:38])[CH3:37])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(S(=O)(=O)N(c2ccccc2)C2CCN([C@@H]3CCCC[C@@H]3c3ccccc3)CC2)cc1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(S(=O)(=O)N(c2ccccc2)C2CCN([C@@H]3CCCC[C@@H]3c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A solution of (+/−)-4-amino-N-phenyl-N-[cis-1-(2-phenyl-cyclohexyl)-piperidin-4-yl]-benzenesulfonamide (0.1 g, 0.2 mmol) in acetic acid (5 ml) was treated with acetic anhydride (1 ml) and stirred at room temperature for 1 h. The volatiles were evaporated and the residue was purified by flash chromatography on silica gel, eluting with dichloromethane/methanol/ammonia 110:10:1. The product was crystallised from hexane/ether, yielding the title compound (0.06 g, 59%) as a white solid, MS (ISP): m/e 532.5 (M+H+).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:11][CH2:10][C:5]2([O:9][CH2:8][CH2:7][O:6]2)[CH2:4][CH2:3]1.B1C2CCCC1CCC2.C1C[O:24]CC1>>[O:9]1[C:5]2([CH2:10][CH2:11][CH:2]([CH2:1][OH:24])[CH2:3][CH2:4]2)[O:6][CH2:7][CH2:8]1
Reactant: C1CCOC1
Reactant: C=C1CCC2(CC1)OCCO2
Agent: B1C2CCCC1CCC2
Product: OCC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
To a solution of 8-methyene-1,4-dioxa-spiro[4.5]decane (2.0 g, 13 mmol, 1.0 eq.) in THF (10 mL) at 0° C. was added dropwise 9-BBN (0.5 M in THF, 104 mL, 4.0 eq.) and the resulting mixture was stirred for 15 min and then warmed to room temperature and stirred overnight. Then NaBO4. 4H2O (32 g, 16 eq.) was introduced at 0° C. portionwise and the resulting mixture was warmed to room temperature and stirred overnight, diluted with hexanes (30 mL) and the separated aqueous phase was extracted with EtOAc. The combined organic phase was dried over over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (50% to 100% EtOAc-hexanes) to give (1,4-dioxa-spiro[4.5]dec-8-yl)-methanol (1.5 g, 67%).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11](OC)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][OH:20].[OH-].[K+]>C1COCC1.CO>[OH:20][NH:19][C:11](=[O:12])[C:10]1[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=1[C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccccc1C#Cc1ccccc1
Reactant: NO
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NO)c1ccccc1C#Cc1ccccc1
Temperature: 0 °C
Yield: 42.5 %

Procedure:
In a 100 mL round-bottomed flask was added methyl 2-(phenylethynyl)benzoate 36 (157 mg, 0.665 mmol) in THF (1.33 mL) and MeOH (1.33 mL) and the solution was cooled to 0° C. Then, a 50% aqueous solution of hydroxylamine (2195 mg, 33.2 mmol) was added followed by a 4M aqueous solution of KOH (0.33 mL, 1.329 mmol) and the resulting colorless solution was stirred at 0° C. and allowed to slowly warm to rt for 20 h. The reaction mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (2×) and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The yellow oil was crystallized in Et2O and the filtrate was evaporated and triturated again in Et2O. The solids were combined to afford title compound 37 (67 mg, 43% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.98 (s, 1H), 9.20 (s, 1H), 7.61 (d, J=7.4 Hz, 1H), 7.55-7.43 (m, 814). LRMS (ESI): (calc.) 237.25 (found) 238.2 (MH)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[C:28](B(O)O)=[CH:29][S:30][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:8][N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:28]2[C:27]([CH3:26])=[CH:31][S:30][CH:29]=2)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[C:6](=[O:25])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cscc1B(O)O
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cscc1-c1cc(CN(C)C(=O)OC(C)(C)C)cn1S(=O)(=O)c1cccnc1
Temperature: 105 °C
Reaction time: 18 h
Yield: 64.1 %

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (4-methyl-3-thienyl)boronic acid (198 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 200 mg, 64%). More specifically, a suspension of tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (4-methyl-3-thienyl)boronic acid (198 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg) in 1,2-dimethoxyethane (10 mL) and water (7.5 mL) was stirred at 105° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:1) to give the title compound as a pale-yellow oil (yield 200 mg, 64%).
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([F:17])[CH:9]=2)=[CH:5][CH:4]=1)#[N:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:49][C@@H:50]1[CH2:54][CH2:53][CH2:52][N:51]1[CH2:55][C@@H:56]1[CH2:60][CH2:59][CH2:58][NH:57]1>CN(C=O)C>[F:17][C:10]1[CH:9]=[C:8]([C:6]2[S:7][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH:16]=[CH:15][C:11]=1[C:12]([N:57]1[CH2:58][CH2:59][CH2:60][C@H:56]1[CH2:55][N:51]1[CH2:52][CH2:53][CH2:54][C@H:50]1[CH3:49])=[O:14]
Reactant: N#Cc1ccc(-c2ccc(C(=O)O)c(F)c2)s1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2ccc(C#N)s2)cc1F
Yield: 12.6 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure D in 6 mL DMF using 4-(5-cyano-thiophen-2-yl)-2-fluoro-benzoic acid (181 mg, 0.73 mmol), EDC-HCl (210 mg, 1.1 mmol), HOBt (149 mg, 1.1 mmol), DIEA (0.31 mL, 1.8 mmol) and 2-(R)-Methyl-1-(2-(S)-pyrrolidinylmethyl)pyrrolidine (101 mg, 0.60 mmol) to give the title compound (30 mg, 12% yield). MS (ES+) 398.3 (M+H)+
Reaction SMILES: Br[Zn][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:9][C:10]1[C:11](=[O:18])[CH:12]=[C:13]([Cl:17])[C:14](=[O:16])[CH:15]=1.Cl.C(OCC)(=O)C>C1COCC1>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][C:14]1([OH:16])[CH:15]=[C:10]([Cl:9])[C:11](=[O:18])[CH:12]=[C:13]1[Cl:17])[CH3:8]
Reactant: CCOC(=O)C[Zn]Br
Reactant: O=C1C=C(Cl)C(=O)C=C1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC1(O)C=C(Cl)C(=O)C=C1Cl
Yield: 92 %

Procedure:
Under nitrogen atmosphere, 6 mL of THF was added to 1.22 g (2 mmol, 0.6 equivalent) of (BrZnCH2COOEt.THF)2. Under argon atmosphere, a solution of 0.59 g (3.33 mmol) of 2,5-dichloro-p-benzoquinone in 6.5 mL of THF was added dropwise while stirring at 0˜5° C. The mixture was stirred at 20˜25° C. 5 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 25 mL of ethyl acetate, and the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. After concentration under reduced pressure, purification with silica gel column (developing solvent; ethyl acetate/n-hexane=1/3, 1/2) afforded 0.81 g of the desired product (yield 92%).
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[N:11]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[N:3]=[C:4]([CH3:10])[CH:5]=[C:6]2[CH:9]=[N:11][NH:8][C:7]=12
Reactant: O=N[O-]
Reactant: Cc1cc(C)c(N)c(Br)n1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc2cn[nH]c2c(Br)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-bromo-4,6-dimethylpyridin-3-amine [104829-98-3] (4.00 g, 19.9 mmol) in acetic acid (300 mL) was treated with a solution of sodium nitrite (1.37 g, 19.9 mmol) in water (2.5 mL). The reaction mixture was stirred at RT for 15 min and was then allowed to stand at ambient temperature for 24 h. An additional solution of sodium nitrite (500 mg, 7.25 mmol) in water (1 mL) was added to the mixture which was allowed to stand at RT for 16 h. Acetic acid was evaporated under reduced pressure and the residual aqueous solution was partitioned between EtOAc and sat. aq. NaHCO3. The precipitate was filtered off, washed and discarded. The combined filtrates were washed with water and brine, then dried (Phase separator) and concentrated under vacuum to give 7-bromo-5-methyl-1H-pyrazolo[3,4-c]pyridine as a solid. MS (LC-MS): 212 [M+H]+, tR (HPLC conditions k): 2.49 min.
Reaction SMILES: [N:1]([C:38]([CH2:40][O:41][CH2:42][C:43]([OH:45])=O)=[O:39])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(Cl)Cl.[NH2:49][CH2:50][C:51]([NH:53][CH2:54][C:55]([NH:57][CH2:58][C:59]([O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:60])=[O:56])=[O:52].CC1C=CC(S(O)(=O)=O)=CC=1>CCN(CC)CC>[N:1]([C:38]([CH2:40][O:41][CH2:42][C:43]([NH:49][CH2:50][C:51]([NH:53][CH2:54][C:55]([NH:57][CH2:58][C:59]([O:61][CH2:62][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1)=[O:60])=[O:56])=[O:52])=[O:45])=[O:39])([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: NCC(=O)NCC(=O)NCC(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COCC(=O)NCC(=O)NCC(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of (C18H37)2NCOCH2OCH2COOH (1.0 g, 1.5 mmol) in CH2Cl2 (30 mL) 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.31 g, 1.6 mmol) was added and the reaction was stirred at room temperature. After 0.5 h Gly-Gly-Gly-OCH2Ph.TsOH (0.66 g, 1.5 mmol) and Et3N (0.6 mL) were added and the mixture was stirred overnight. The reaction mixture was then washed with water (20 mL), 0.5 N HCl (20 mL), water (20 mL), 10% aqueous Na2CO3 (20 mL), brine (20 mL), and then dried over MgSO4. The solvent was evaporated and the residue was crystallized form MeOH to yield (C18H37)2NCOCH2OCH2CO-Gly-Gly-Gly-OCH2Ph as a deliquescent white solid (1.26 g, 89%), mp 41–42° C. 1H-NMR (300 MHz, δ, CDCl3) 0.86 (6H, t, J=6.9 Hz), 1.24 (64H, m), 1.49 (4H, bs), 3.04 (2H, t, J=7.5 Hz), 3.24 (2H, t, J=7.5 Hz), 3.95–4.05 (6H, m), 4.09 (2H, s), 4.29 (2H, s), 5.12 (2H, s), 7.23 (1H, t, J=6.0 Hz), 7.30–7.35 (5H, m), 7.93 (1H, t, J=5.7 Hz), 8.27 (1H, t, J=5.7 Hz). 13C-NMR (75 MHz, δ, CDCl3): 13.9, 22.5, 26.7, 26.9, 27.4, 28.6, 29.2, 29.3, 29.6, 31.8, 41.0, 42.9, 46.3, 46.7, 66.9, 69.6, 71.7, 128.2, 128.4, 128.6, 135.3, 168.6, 169.7, 169.8, 170.0, 171.5. IR (KBr, cm−1): 1749 (CO), 1651 (CO).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([NH2:15])=[C:4]([NH:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH:3]=1.C(N(CC)CC)C.[CH2:36]([O:38][CH2:39][C:40](Cl)=[O:41])[CH3:37]>ClCCl>[CH2:36]([O:38][CH2:39][C:40]([NH:15][C:5]1[C:6]([O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:7][C:2]([CH3:1])=[CH:3][C:4]=1[NH:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)=[O:41])[CH3:37]
Reactant: Cc1cc(NCCOCCCc2cccnc2)c(N)c(Oc2ccccc2)n1
Reactant: CCOCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCC(=O)Nc1c(NCCOCCCc2cccnc2)cc(C)nc1Oc1ccccc1
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
Under a nitrogen atmosphere, a solution of 6-methyl-2-phenoxy-N4-{2-[3-(pyridin-3-yl)propoxy]ethyl}pyridine-3,4-diamine (5.2 g, 14 mmol), anhydrous dichloromethane (40 mL), and anhydrous triethylamine (2.3 mL, 16.5 mmol) was cooled to 5° C. A solution of ethoxyacetyl chloride (1.77 g, 14.4 mmol) in dichloromethane (10 mL) was then added over a period of ten minutes, and the reaction was stirred for 30 minutes. The reaction mixture was diluted with dichloromethane (25 mL), washed with aqueous saturated sodium bicarbonate (3×) and brine (3×), dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 5.8 g of 2-ethoxy-N-(6-methyl-2-phenoxy-4-{2-[3-(pyridin-3-yl)propoxy]ethylamino}pyridin-3-yl)acetamide as an oil.