Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C@@H:4]([C@@H:8]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5](O)=[O:6])=[N+:2]=[N-:3].[NH2:24][C:25]1[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:26]=1[CH2:27][CH2:28][C@H:29]1[O:34][CH2:33][C@@H:32]([CH2:35][O:36][C:37](=[O:44])[NH:38][CH2:39][C:40]([F:43])([F:42])[F:41])[N:31]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:30]1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[N:1]([C@@H:4]([C@@H:8]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:5]([NH:24][C:25]1[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:26]=1[CH2:27][CH2:28][C@H:29]1[O:34][CH2:33][C@@H:32]([CH2:35][O:36][C:37](=[O:44])[NH:38][CH2:39][C:40]([F:43])([F:41])[F:42])[N:31]([C:45]([O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:46])[CH2:30]1)=[O:6])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Reactant: COc1ccc([C@@H](c2ccccc2)[C@H](N=[N+]=[N-])C(=O)O)cc1Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc([C@@H](c2ccccc2)[C@H](N=[N+]=[N-])C(=O)Nc2cccc(F)c2CC[C@@H]2CN(C(=O)OC(C)(C)C)[C@H](COC(=O)NCC(F)(F)F)CO2)cc1Cl
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
The product from step 1 (151 mg, 0.45 mmol) and the product from step 4 of Example 99 (200 mg, 0.42 mmol) were dissolved in pyridine (5 mL) and the stirred solution was cooled to −10° C. in an ice/acetone bath. To the cold solution was added POCl3 dropwise (0.04 mL, 0.45 mmol). The mixture was stirred at −10° C. for 30 min. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution (5 mL) and the mixture was allowed to warm to ambient temperature. The mixture was diluted with water (20 mL) and extracted with dichloromethane (3×15 mL). The combined dichloromethane extracts were dried (Na2SO4), filtered, and the filtrate solvents were removed in vacuo. The residue was purified on a 12 g silica gel column using a gradient elution of 0-100% EtOAc:hexanes. Fractions containing product were combined and the solvents were removed in vacuo to give the title compound as a gum. (M+H-N2)+=764.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29](C)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:33]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][C:19]([OH:22])([CH3:21])[CH3:20])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH2:33])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N
Reactant: CC(C)(O)CCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O
Product: CC(C)(O)CCOc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2ccc(F)c(F)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 459, substituting 2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3,4-difluorophenyl)-4-(2-hydroxy-2-methyl-1-propoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 300 mg, 50%). mp 181-181° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.04 (s, 6H), 1.72 (t, J=6 Hz, 2H), 4.43 (s, 1H), 4.53 (t, J=6 Hz, 2H), 7.49 (s, 2H), 7.53 (m, 1H), 7.63 (ddd, J=9 Hz, J=9 Hz, J=1.5 Hz, 1H), 7.79 (ddd, J=9 Hz, J=9 Hz, J=3 Hz, 1H), 7.83 (d, J=9 Hz, 1H), 7.95 (d, J=9 Hz, 2H), 8.19 (s, 1H); MS (DCI/NH3) m/z 466 (M+H)+. Anal. calcd. for C21H21F2N2O5S: C, 54.12; H, 4.66; N, 8.81. Found: C, 54.19; H, 4.55; N, 9.03.
Reaction SMILES: Cl.[CH:2]([O:5][C:6](=[O:10])[C@@H:7]([CH3:9])[NH2:8])([CH3:4])[CH3:3].N(C(OCC1C=CC=CC=1)=O)[C@H](C(O)=O)CC(=O)OCC1C=CC=CC=1.COC(=O)[C@H](CC1C=CC=CC=1)N[C:42](=[O:55])[C@:43]([NH2:54])([CH2:50][C:51](=[O:53])[OH:52])[NH:44][C:45](=[O:49])[CH:46]([CH3:48])[CH3:47]>>[CH:2]([O:5][C:6](=[O:10])[C@@H:7]([CH3:9])[NH:8][C:42](=[O:55])[C@:43]([NH2:54])([CH2:50][C:51](=[O:52])[OH:53])[NH:44][C:45](=[O:49])[CH:46]([CH3:48])[CH3:47])([CH3:4])[CH3:3]
Reactant: CC(C)OC(=O)[C@@H](C)N
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@](N)(CC(=O)O)NC(=O)C(C)C
Agent: Cl
Agent: O=C(C[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Product: CC(C)OC(=O)[C@@H](C)NC(=O)[C@](N)(CC(=O)O)NC(=O)C(C)C

Procedure:
This compound was prepared from 1.7 g D-alanine isopropyl ester hydrochloride, 3.6 g Z-Asp(OBzl) and 1.8 g N-t-butoxycarbonyl-α-aminoisobutyric acid N-hydroxysuccinimide ester in a manner similar to Example 20 (A), (C), (D) and (E). Yield: 1.2 g, m.p.: 176°-178° C.
Reaction SMILES: CS(C1C=CC(C[Cl:9])=CC=1)=O.[Cl-].[CH3:13][S:14]([C:16]1[CH:41]=[CH:40][C:19]([CH2:20][P+:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)=O>>[Cl-:9].[CH3:13][S:14][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][P+:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:40][CH:41]=1
Reactant: CS(=O)c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CS(=O)c1ccc(CCl)cc1
Agent: [Cl-]
Product: CSc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
In a similar manner, when p-methylsulfinylbenzyl chloride is used, the product is p-methylsulfinylbenzyltriphenylphosphonium chloride, melting point 258°-262°C with gasing.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][NH:15][CH3:16].CCN(C(C)C)C(C)C>CCO>[CH3:11][N:12]([CH3:17])[CH2:13][CH2:14][N:15]([CH3:16])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CNCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CN(C)CCN(C)c1ccncc1[N+](=O)[O-]

Procedure:
The method of Example 1 was followed using 4-chloro-3-nitropyridine (1.0 eq), N1,N1,N2-trimethyl ethane-1,2-diamine (2.0 eq), and DIEA (2.0 eq) in EtOH yielding N1,N1,N2-trimethyl-N2-(3-nitropyridin-4-yl)ethane-1,2-diamine which was concentrated and taken on as is. LCMS (m/z): 225.1 (MH+); LC Rt=0.574 min.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:16]>ClCCl>[N+:24]([C:21]1[CH:20]=[CH:19][C:18]([O:17][C:15]([N:11]2[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]2)=[O:16])=[CH:23][CH:22]=1)([O-:26])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Yield: 99.7 %

Procedure:
Amine preparation: to N-BOC-piperazine (500 mg) in dichloromethane (5 mL) and triethylaamine (0.41 ml) was added 4-nitrophenyl chloroformate (541 mg). After 1 hour the reaction mixture was diluted with dichloromethane, washed with brine, dried (MgSO4) and the solvent was removed in vacuo to yield piperazine-1,4-dicarboxylic acid tert-butyl ester 4-nitro-phenyl ester (940 mg).
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:8](=[O:20])[N:7]([CH3:21])[C:6]=2[S:5][C:4]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:2][C:3]2[C:11]3[C:10](=[O:12])[N:9]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:8](=[O:20])[N:7]([CH3:21])[C:6]=3[S:5][C:4]=2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][C:29]([F:32])([F:31])[F:30])[CH:23]=2)=[CH:36][CH:35]=1
Reactant: CCOC(=O)CCn1c(=O)c2c(CBr)c(-c3cccc(OC(F)(F)F)c3)sc2n(C)c1=O
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCn1c(=O)c2c(Cc3ccc(Cl)cc3)c(-c3cccc(OC(F)(F)F)c3)sc2n(C)c1=O
Temperature: 100 °C
Yield: 48.1 %

Procedure:
To a solution of ethyl 3-(5-(bromomethyl)-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propanoate (100 mg, 0.187 mmol) in toluene (5 mL) was added (4-chlorophenyl)boronic acid (32.1 mg, 0.205 mmol) and aq. Cs2CO3 (1 M, 0.28 mL). The reaction was degassed under nitrogen gas (3×) then Pd(PPh3)4 (10 mg) was added. The reaction was heated at 100° C. for 18 h, cooled to RT then diluted with EA (10 mL). The organic layer was washed with brine (5 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (4:1 to 2:1) to give ethyl 3-(5-(4-chlorobenzyl)-1-methyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propanoate (51 mg, 48.1% yield) as a yellow solid. LCMS: MH+ 567 and TR=1.710 min.
Reaction SMILES: [C:1]([Si:5]([CH3:17])([CH3:16])[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)C>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[CH2:19][N:12]1[C:13]2[C:9](=[CH:8][C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:17])[CH3:16])=[CH:15][CH:14]=2)[CH:10]=[CH:11]1)[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ccc2c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 104 %

Procedure:
A suspension of 5-(tert-butyl-dimethyl-silanyloxy)-1H-indole (9.2 g, 37.2 mmol), ethyl bromoacetate (4.79 ml, 40.9 mmol) and cesium carbonate (36.4 g, 111.5 mmol) in DMF (140 ml) was stirred for 3 h at RT. Diethyl ether was added and the mixture was washed with 1N HCl and water, and dried over sodium sulfate. The ether phase was concentrated under reduced pressure to give 12.9 g (quant.) of [5-(tert-butyl-dimethyl-silanyloxy)-indol-1-yl]-acetic acid ethyl ester which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][NH2:34])[CH2:23][CH3:24])[CH3:21].C(OC(C)C)(C)C>>[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][NH:34][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2)=[O:3])[CH2:23][CH3:24])[CH3:21]
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ccccc21
Reactant: CCN(CC)CC1CCCCN1CCN
Solvent: CC(C)OC(C)C
Product: CCN(CC)CC1CCCCN1CCNC(=O)N1c2ccccc2NC(=O)c2ccccc21
Yield: 74 %

Procedure:
Prepared analogously to Example 2 from 5-(chlorocarbonyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 2-[2-[(diethylamino)methyl]-piperidin-1-yl]-ethanamine in a yield of 74% of theory. Colourless crystals, m.p. 123°-125° C. (diisopropylether).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[C:6]([O:11][CH3:12])[N:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[O:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[F-].[Cs+]>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.CO>[CH3:12][O:11][C:6]1[N:7]=[CH:8][CH:9]=[C:10]2[C:2]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[O:13][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:3][NH:4][C:5]=12
Reactant: COc1nccc2c(I)c[nH]c12
Reactant: OB(O)c1ccccc1Oc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Product: COc1nccc2c(-c3ccccc3Oc3ccccc3)c[nH]c12
Temperature: 120 °C
Yield: 38.6 %

Procedure:
A mixture of 3-iodo-7-methoxy-1H-pyrrolo[2,3-c]pyridine (0.274 g, 1.0 mmol), 2-phenoxyphenylboronic acid (0.278 g, 1.3 mmol, 1.3 equivalents), Pd(PPh3)4 (0.058 g, 0.05 mmol), and cesium fluoride (0.456 g, 3 mmol) in dimethxoyethane (3 mL) and methanol (1.5 mL) was heated under microwave conditions (120° C., 30 minutes). The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 30% ethyl acetate/hexanes) to give the title compound (0.122 g, 38.6% yield).
Reaction SMILES: C(O[C:6]([N:8](C)[C@@H:9]([CH2:13][C:14](C)(C)[CH3:15])[C:10](O)=[O:11])=O)(C)(C)C.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)=[CH:23][CH:22]=1.FC(F)(F)C1N=C(N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=CC=1>>[CH3:6][NH:8][C@H:9]([C:10]([NH:35][C@@H:32]1[C@@H:30]2[C@@H:29]([CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:36])[F:37])=[CH:26][CH:25]=3)[CH2:31]2)[CH2:34][CH2:33]1)=[O:11])[CH2:13][CH2:14][CH3:15]
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cc3)C[C@@H]21
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Agent: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Product: CCC[C@H](NC)C(=O)N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting (S)-N-(tert-butoxycarbonyl)-N-methyl-L-norvaline for (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid and (3aR,4S,6aS)-2-[4-(trifluoromethyl)phenyl]octahydrocyclopenta[c]pyrrol-4-amine from Example 607 for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 587: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.27 (d, J=7.4, 1H), 7.58 (d, J=8.3, 2H), 6.63 (d, J=8.7, 2H), 4.40 (dd, J=6.7, 5.4, 1H), 3.55 (dd, J=10.2, 3.1, 1H), 3.38 (dd, J=10.0, 7.6, 1H), 3.22 (ddd, J=10.5, 8.4, 7.0, 2H), 3.02 (dd, J=9.9, 3.7, 1H), 2.78-2.66 (m, 2H), 2.45 (s, 3H), 2.21-2.01 (m, 2H), 1.95 (ddd, J=12.9, 7.9, 2.7, 1H), 1.88-1.79 (m, 1H), 1.77-1.63 (m, 2H), 1.58-1.46 (m, 2H), 1.42-1.32 (m, 1H), 0.87 (t, J=7.4, 3H); MS (ESI+) m/z 384 (M+H)+.
Reaction SMILES: [CH3:1][NH2:2].O.[Br:4][CH:5]([CH2:9][CH2:10][Br:11])[C:6](Br)=[O:7]>C(Cl)(Cl)Cl>[CH3:1][NH:2][C:6](=[O:7])[CH:5]([Br:4])[CH2:9][CH2:10][Br:11]
Reactant: O=C(Br)C(Br)CCBr
Reactant: CN
Solvent: ClC(Cl)Cl
Solvent: O
Product: CNC(=O)C(Br)CCBr
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
A solution mixture consisting of 40% aqueous methylamine solution (7.9 g, 0.10 mol, manufactured by JUNSEI CHEMICAL CO., LTD.) and water (3.3 g) was cooled to not more than 10° C. To the solution mixture, 2,4-dibromobutyric acid bromide (38 g, 0.12 mol) was added dropwise over a period of 15 minutes while keeping the temperature at not more than 10° C. After the completion of the dropwise addition, the mixture was heated to 30° C. and stirred for 30 minutes. The reaction liquid was combined with 50 g of chloroform, and the organic phase was extracted. The organic phase was separated and dried over magnesium sulfate, and the magnesium sulfate was filtered out. The organic phase obtained was concentrated to afford a crude crystal, which was then washed with a 1:1 solution of diethyl ether and hexane to give N-methyl-2,4-dibromobutyric acid amide (21.4 g, 0.083 mol, mp: 54° C., yield: 69%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([CH2:43][CH2:44][CH2:45][S:46]([CH3:49])(=[O:48])=[O:47])=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:42][C:41]1[CH:40]=[C:39]([CH2:43][CH2:44][CH2:45][S:46]([CH3:49])(=[O:47])=[O:48])[CH:38]=[C:37]([CH3:50])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(CCCS(C)(=O)=O)cc(C)c1Br
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(CCCS(C)(=O)=O)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 2-bromo-1,3-dimethyl-5-(3-(methylsulfonyl)propyl)benzene following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.66 min; Mass spectrum (ESI+): m/z=567 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][N:32]=2)[CH:28]=O)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][N:32]=[C:25]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:26]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccnc(N2CCCC2)c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccnc(N2CCCC2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 2-(pyrrolidin-1-yl)isonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.58 min.; [M+H]+: 396.07 g/mol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C@H:11]([NH:15][C:16]([O:18][CH2:19][CH:20]1[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CC1C=C(C)C=C(C)N=1.[NH:66]1[CH2:71][CH2:70][O:69][CH2:68][CH2:67]1.[Cl-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C@H:11]([NH:15][C:16]([O:18][CH2:19][CH:20]1[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[C:12]([N:66]1[CH2:71][CH2:70][O:69][CH2:68][CH2:67]1)=[O:14])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: CC(C)(C)OC(=O)NCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.1 %

Procedure:
(S)-4-tert-Butoxycarbonylamino-2-(9H-fluoren-9-ylmethoxycarbonylamino)butyric acid (150 mg, 0.341 mmol) was dissolved in N,N-dimethylformamide (1.0 ml), and then 2-3H-1,2,3-triazolo[4,5-b]pyridin-3-ol (51 mg, 0.377 mmol), O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (148 mg, 0.377 mmol),2,4,6-trimethylpyridine (91 μl), and morpholine (45 μl, 0.512 mol) were added thereto at room temperature. After the mixture was stirred at room temperature for 16 hours, a saturated aqueous sodium chloride solution (20 ml) was added to stop the reaction. The mixture was extracted three times with ethyl acetate (20 ml). The ethyl acetate extraction solutions were combined together, and sequentially washed with a saturated aqueous sodium bicarbonate solution (20 ml) and a saturated aqueous sodium chloride solution (20 ml). The washed ethyl acetate solution was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=1:1) to yield [(S)-3-(9H-fluoren-9-ylmethoxycarbonylamino)-4-morpholin-4-yl-4-oxobutyl]carbamic acid tert-butyl ester (172.2 mg) as a white amorphous material.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[F:32][C:33]1[CH:57]=[CH:56][CH:55]=[CH:54][C:34]=1[O:35][C:36]1[N:41]=[C:40]2[O:42][C:43]([C:45]3[CH:50]=[C:49]([CH3:51])[C:48]([OH:52])=[C:47]([CH3:53])[CH:46]=3)=[N:44][C:39]2=[CH:38][CH:37]=1.O[C:59]([CH3:68])([CH3:67])[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61]>O1CCCC1.C(N(CC)CC)C>[F:32][C:33]1[CH:57]=[CH:56][CH:55]=[CH:54][C:34]=1[O:35][C:36]1[N:41]=[C:40]2[O:42][C:43]([C:45]3[CH:50]=[C:49]([CH3:51])[C:48]([O:52][C:59]([CH3:68])([CH3:67])[C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])=[C:47]([CH3:53])[CH:46]=3)=[N:44][C:39]2=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)O
Reactant: Cc1cc(-c2nc3ccc(Oc4ccccc4F)nc3o2)cc(C)c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(-c2nc3ccc(Oc4ccccc4F)nc3o2)cc(C)c1OC(C)(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
With ice cooling, 72 mg of triphenylphosphine were dissolved in 1 ml of dry tetrahydrofuran, and 47 mg of diethyl azodicarboxylate were added. After 15 min, 80 mg of 4-[5-(2-fluorophenoxy)oxazolo[5,4-b]pyridin-2-yl]-2,6-dimethylphenol were added, followed by 32 μl of triethylamine and 44 mg of tert-butyl alpha-hydroxyisobutyrate. The reaction mixture was then stirred at room temperature for 16 hours, and another 72 mg of triphenylphosphine and 47 mg of diethyl azodicarboxylate were added with ice cooling. After a further 4 h at room temperature, the reaction was concentrated and purified by preparative HPLC. This gave 60 mg (53%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])=[CH:4][C:3]=1[S:21][C:22]1[N:26]([CH3:27])N=[N:24][N:23]=1.ClC1C(=O)C2C(=CC=CC=2)C(=O)C=1NC1C=CC(S(NC2C=CC=C(OC)C=2)(=O)=O)=CC=1>>[NH:23]1[C:22]([S:21][C:3]2[CH:4]=[C:5]([NH:12][S:13]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)(=[O:15])=[O:14])[C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=3)=[N:26][CH:27]=[N:24]1
Reactant: Cn1nnnc1Sc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Agent: COc1cccc(NS(=O)(=O)c2ccc(NC3=C(Cl)C(=O)c4ccccc4C3=O)cc2)c1
Product: O=S(=O)(Nc1cc(Sc2ncn[nH]2)c(O)c2ccccc12)c1cccs1

Procedure:
5.2.48 N-(3-(1H-1,2,4-triazol-5-ylthio)-4-hydroxynaphthalen-1-yl)thiophene-2-sulfonamide (14e) was prepared according to the procedure for 14d except using (E)-N-(3-(1H-1,2,4-triazol-5-ylthio)-4-oxonaphthalen-1(4H)-ylidene)thiophene-2-sulfonamide (13e), which afforded the title compound 20 mg (100%) as a white solid, m.p.: 180° C. (dec.).