Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:35])[C@@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=O)=[O:26])[CH2:21]1>C(O)C.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:33][C:28]2[NH:29][C:30]([CH3:32])=[CH:31][C:27]=2[C:25]([N:22]2[CH2:23][CH2:24][C@@H:20]([N:19]([CH3:18])[CH3:35])[CH2:21]2)=[O:26])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)N2CC[C@@H](N(C)C)C2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)N2CC[C@@H](N(C)C)C2)c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3-[(3R)-3-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 4-(4-chloro-phenyl)-3-[3-[(3R)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (44.8, 38%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH:25]2[CH2:28][CH2:27][CH2:26]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][N:24]([C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH:25]2[CH2:26][CH2:27][CH2:28]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNC2CCC2)c1
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(C(=O)OCc2ccccc2)C2CCC2)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-cyclobutylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and benzyl chloroformate.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:10])[NH2:9])=[CH:4][CH:3]=1.[NH:11]([C:13]([C:15]1[S:16][CH:17]=[CH:18][C:19]=1[NH:20][C:21](=[O:31])[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=O)N>>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C:21]([NH:20][C:19]2[CH:18]=[CH:17][S:16][C:15]=2[C:13]2[NH:11][N:9]=[C:8]([C:5]3[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=3)[N:10]=2)=[O:31])=[CH:28][CH:27]=1
Reactant: N=C(N)c1ccncc1
Reactant: COc1ccc(CC(=O)Nc2ccsc2C(=O)NN)cc1
Agent: Cl
Product: COc1ccc(CC(=O)Nc2ccsc2-c2nc(-c3ccncc3)n[nH]2)cc1

Procedure:
The title compound was prepared from pyridine-4-carboximidamide hydrochloride (157 mg, 1.00 mmol) and N-(2-(hydrazinecarbonyl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide (Example 1.11.1., 204 mg, 0.668 mmol) according to the procedure described in Example 1.11.2., above. Retention time (min)=2.511, method [7], MS(ESI) 392.1 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.87 (d, J=4.5 Hz, 2H), 8.08-8.16 (m, 2H), 7.94 (d, J=5.0 Hz, 1H), 7.67-7.70 (m, 1H), 7.31 (d, J=8.6 Hz, 2H), 7.88 (d, J=8.6 Hz, 2H), 3.88 (s, 2H), 3.67 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.Br[CH2:15][CH:16]1[CH2:18][CH2:17]1>>[CH:16]1([CH2:15][O:8][C:6]2[CH:7]=[C:2]([F:1])[C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:5]=2)[CH2:18][CH2:17]1
Reactant: CCOC(=O)c1ncc(O)cc1F
Reactant: BrCC1CC1
Product: CCOC(=O)c1ncc(OCC2CC2)cc1F

Procedure:
Using ethyl 3-fluoro-5-hydroxypyridine-2-carboxylate and (bromomethyl)cyclopropane, and in the same manner as in Example 5, the title compound was obtained.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([CH:16]=O)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[NH2:18][OH:19]>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([CH:16]=[N:18][OH:19])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2ccc(C=O)o2)c(C)[nH]c1=O
Reactant: NO
Product: CCc1cc(-c2ccc(C=NO)o2)c(C)[nH]c1=O

Procedure:
Example 198 is substantially repeated except for utilizing 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl]furan-2-carbaldehyde and hydroxylamine to afford the title compound. MS: m/e=247 (M+H).
Reaction SMILES: C([O:8][C:9]1[C:10]([F:22])=[C:11]([CH2:18][C:19](=[O:21])[CH3:20])[C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=1)C1C=CC=CC=1.Br>C(OC(=O)C)(=O)C.C(O)(=O)C>[F:22][C:10]1[C:9]([OH:8])=[CH:14][CH:13]=[C:12]([N+:15]([O-:17])=[O:16])[C:11]=1[CH2:18][C:19](=[O:21])[CH3:20]
Reactant: CC(=O)Cc1c([N+](=O)[O-])ccc(OCc2ccccc2)c1F
Agent: Br
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Cc1c([N+](=O)[O-])ccc(O)c1F
Temperature: 100 °C
Yield: 79.8 %

Procedure:
Method R-1: To a solution of 1-(3-benzyloxy-2-fluoro-6-nitrophenyl)-propan-2-one (3.03 g, 10 mmol) in acetic anhydride (5 mL) and acetic acid (5 mL) at room temperature was added hydrobromic acid (48% aqueous solution, 3 mL). After addition, the reaction was heated at 100° C. for 30 min and then cooled to room temperature. To this mixture was added 10 mL of hexanes with stirring. The solution was decanted and concentrated. The residue was diluted with ethyl acetate (50 mL) and washed with brine (3×20 mL). The organic layer was dried and concentrated in vacuo to provide 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (1.70 g, 80%) as a brown solid, which was used in the next step without further purification. LC/MS; (M+H)+=213.2 Method R-2: A mixture of 1-(3-benzyloxy-2-fluoro-6-nitrophenyl)-propan-2-one (65.0 g, 0.214 mol) and pyridinium chloride (60.74 g, 0.526 mol) was stirred at 180° C. for 1 hr. The reaction mixture was cooled to room temperature, diluted with 3N HCl (100 mL) and ethyl acetate (500 mL) and filtered. The aqueous layer was extracted with ethyl acetate (2×) and the combined organic layers were washed with brine, dried (MgSO4),s filtered through a pad of silica gel and concentrated in vacuo. The residue was decolorized with charcoal in methanol, filtered and concentrated in vacuo to afford 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (37 g, 81%) as a brown solid. LC/MS; (M+H)+=213.2
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1.N1C=CN=C1.[Si:18](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)CN1CCC(O)CC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)CN1CCC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.2 %

Procedure:
Treat a solution of (4-hydroxy-piperidin-1-yl)-acetic acid methyl ester (10.0 g, 57.7 mmol) and imidazole (4.71 g, 69.2 mmol) in DMF (100 mL) with t-butyl-diphenylsilyl chloride (19.04 g, 69.3 mmol) and stir for 16 hours at room temperature. Dilute the reaction with diethyl ether and wash with water. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify with a 2% methanol in CH2Cl2 to afford 17.38 g (73%) of the titled product. Rf=0.71 (9/1 CH2Cl2/methanol). ES MS (m/z): 412 (M+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][C:12]([CH3:15])([OH:14])[CH2:11][CH:10]([C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38].CCN(C(C)C)C(C)C>CN(C=O)C>[OH:14][C:12]1([CH3:15])[CH2:13][CH:8]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]2=[O:38])[CH:10]([C:16]2[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:11]1
Reactant: Cc1cccnc1C1CC(C)(O)CC(c2ncccc2C)N1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1C1CC(C)(O)CC(c2ncccc2C)N1CCCCN1C(=O)c2ccccc2C1=O
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a solution of meso-2′β,6′β-[3,4′,3″-trimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridin-4′-ol (0.2499 g, 0.84 mmol) in DMF (9 mL) was added 2-(4-bromo-butyl)-isoindole-1,3-dione (0.2605 g, 0.92 mmol), KI (0.0142 g, 0.08 mmol), and DIPEA (0.29 mL, 1.68 mmol), and stirred at 60° C. for 24 hours. The mixture was concentrated, and saturated NaHCO3 (30 mL) was added and extracted with CH2Cl2 (3×35 mL). The combined organic extracts were washed with brine (2×20 mL), dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (50:1:1 CH2Cl2—MeOH—NH4OH) provided 0.3144 g (75%) of meso-2′β,6′β-[2-[4-(4′-hydroxy-3,4′,3″-trimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′yl)-butyl]-isoindole-1,3-dione as a white solid. 1H NMR (CDCl3) δ 0.48 (s, 1H), 0.86 (s, 2H), 1.42 (s, 3H), 1.68-1.72 (m, 2H), 2.18-2.38 (m, 6H), 2.45 (s, 6H), 3.15 (t, 2H, J=6.0 Hz), 4.13 (d, 2H, J=12.0 Hz), 6.94-7.03 (m, 2H), 7.25-7.34 (m, 2H), 7.67-7.70 (m, 2H), 7.75-7.78 (m, 2H), 8.32-8.34 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14](Cl)=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.C(#N)C.[CH2:25]([OH:28])[CH:26]=[CH2:27]>C(N(CC)CC)C>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([O:28][CH2:25][CH:26]=[CH2:27])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2
Reactant: C=CCO
Reactant: CC(C(=O)Cl)c1ccc2c(=O)c3ccccc3ccc2c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCOC(=O)C(C)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
0.5 G. of 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionyl chloride is dissolved in 25 ml. of acetonitrile containing 0.5 ml. of allyl alcohol and 0.5 ml. of triethylamine. After 16 hours the mixture is evaporated to dryness and partitioned between ethyl acetate and water. The organic solution is washed, dried, passed through a short (10 g.) silica gel column, then evaporated to give allyl 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionate as an oil [nmr spectrum in deuterochloroform relative to tetramethylsilane: 1.54 (doublet, CH3), 2.84 (quartet, CH), 4.55 (doublet, OCH2), 5.1-6.0 (multiplet, CH=CH2) and 7.00 ppm (singlet, 10, 11-H); mass spectrum: 318(M+) 233,205].
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[CH:13]([OH:15])[CH3:14].CN1CC(=O)OB([C:26]2[S:30][CH:29]=[N:28][CH:27]=2)OC(=O)C1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.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>[OH:15][CH:13]([C:3]1[O:4][C:5](=[O:12])[C:6]2[C:11]([C:2]=1[C:26]1[S:30][CH:29]=[N:28][CH:27]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:14]
Reactant: CN1CC(=O)OB(c2cncs2)OC(=O)C1
Reactant: CC(O)c1oc(=O)c2ccccc2c1Br
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: [Cs+]
Solvent: CN(C)C=O
Product: CC(O)c1oc(=O)c2ccccc2c1-c1cncs1
Yield: 100.3 %

Procedure:
4-Bromo-3-(1-hydroxyethyl)-1H-isochromen-1-one (Intermediate A2, 0.1 g, 0.372 mmol), 6-methyl-2-(thiazol-5-yl)-1,3,6,2-dioxazaborocane-4,8-dione (0.134 g, 0.56 mmol), Pd(PPh3)4 (0.021 g, 0.019 mmol) and Cs2CO3 (0.182 g, 0.56 mmol) in DMF (1 mL) were heated under microwave irradiation at 120° C. for 1 hrs and 15 min. Then, further 6-methyl-2-(thiazol-5-yl)-1,3,6,2-dioxazaborocane-4,8-dione (0.134 g, 0.56 mmol), Pd(PPh3)4 (0.021 g, 0.019 mmol) and Cs2CO3 (0.182 g, 0.56 mmol) were added and then resulting mixture was reacted for 5 hrs at 100° C. The crude product was purified via reverse phase chromatography with a Biotage C18 30 g SNAP column (Phase A, water 95%, ACN 4.9%, formic acid 0.1%; Phase B ACN 99.9%, formic acid 0.1%) to give the title compound (102 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25]([OH:27])=O)=[N:10]2)=[CH:5][CH:4]=1.[CH2:28]([NH2:31])[CH2:29][CH3:30].O>CN(C)C=O>[CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25]([NH:31][CH2:28][CH2:29][CH3:30])=[O:27])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)O)nc2n1
Reactant: CCCN
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)COC1c2ccccc2C(=O)N1c1ccc2ccc(OC)nc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.3 %

Procedure:
N,N'-Carbonyldiimidazole (1.35 g) is added to a solution of [2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyloxy]acetic acid (3 g) in anhydrous dimethylformamide (70 cc), and the mixture is stirred for 2 hours at a temperature in the region of 25° C. Propylamine (0.4 g) is then added and the mixture is stirred again for 16 hours at a temperature in the region of 25° C. The reaction mixture is then poured into water (150 cc) and the precipitate obtained is separated by filtration, washed with water, dried under reduced pressure (0.05 kPa) and recrystallized in ethanol. [2-(7-Methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyloxy]-N-propylacetamide (2.95 g), m.p. 174° C., is thereby obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10]C2C=CC(F)=C([C@]34OCC[C@H]3CSC(NC(=O)OC(C)(C)C)=N4)C=2)=[O:9])=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(NC(=O)c4ccc(Br)cn4)ccc3F)OCC[C@H]2CS1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 228.6 %

Procedure:
To a solution of tert-butyl (4aR,7aR)-7a-(5-(5-bromopicolinamido)-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-ylcarbamate (12 mg) in dichloromethane (0.43 mL) was added TFA (67 μL) and the reaction mixture was stirred at rt for 2 h. The reaction mixture was subjected directly to preparative TLC eluting with 90% CH2Cl2/9% MeOH/1% NH4OH to give N-(3- (4aS,7aS)-2-amino-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-7a-yl)-4-fluorophenyl)-5-bromopicolinamide as a white foam (10 mg). 1H NMR (500 MHz, CDCl3) δ 9.89 (1H, s), 8.70 (1H, d, J=2.0 Hz), 8.20 (1H, d, J=8.5 Hz), 8.06 (1H, dd, J=2.0, 8.06 Hz), 8.0 (1H, m), 7.75 (1H, m), 7.09 (1H, m), 4.13 (2H, m), 3.22 (1H, m), 3.02 (1H, m), 2.89 (1H, m), and 2.22 (2H, q, J=7.5 Hz). MS: 453.3 (M+H)+. Retention time: 22.49 chiralcel OJ-H 4.6×100 mm, flow rate: 2 mL/min) eluting with 30% B (A: 0.1% Et2NH/Heptane; B: ethanol); Retention time: 12.54 chiralcel OD-H 4.6×100 mm, flow rate: 2 mL/min) eluting with 30% B (A: 0.1% Et2NH/Heptane; B: ethanol).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[S:12][N:11]=[N:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=O.O.[NH2:15][NH2:16]>O>[S:12]1[C:13]2[C:5]([C:3]([NH:15][NH2:16])=[O:2])=[CH:6][CH:7]=[CH:8][C:9]=2[N:10]=[N:11]1
Reactant: COC(=O)c1cccc2nnsc12
Reactant: NN
Solvent: O
Product: NNC(=O)c1cccc2nnsc12
Reaction time: 6 h
Yield: 90.7 %

Procedure:
9.7 g of 7-methoxycarbonylbenzo-1,2,3-thiadiazole are reacted for 19 hours with 4.8 g of hydrazine hydrate in 30 ml of water at 50° C. and then for a further 6 hours at 80°-90° C. The suspension is cooled slightly, filtered while hot and washed with water to give 8.8 g of white crystals having a melting point of 270°-272° C.
Reaction SMILES: [H-].[Na+].I[CH2:4][CH3:5].[C:6]([C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:14]2)=[CH:10][CH:9]=1)#[N:7]>CN(C)C=O.O>[C:6]([C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:14]2[CH2:4][CH3:5])=[CH:10][CH:9]=1)#[N:7]
Reactant: CCI
Reactant: CCOC(=O)c1cc2ccc(C#N)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(C#N)cc2n1CC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 1 l flask, 23.5 g of ethyl 6-cyanoindole-2-carboxylate was dissolved in 300 ml of dimethylformamide, and 6.6 g of 60% NaH was slowly added thereto at 0° C. 17.6 ml of iodoethane was then added thereto at −10˜0° C. and the mixture was stirred for 2 hours at room temperature. The reaction solution was cooled and, after adding ice, diluted with water and then extracted three times with ethyl acetate. The organic extracts were combined, dried over MgSO4 and then evaporated. The residue was purified with silica gel column chromatography [eluent: ethyl acetate/n-hexane(1:3)]. The fractions containing the desired product were combined and then evaporated to obtain 26.2 g of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][C:12]([CH2:16]O)([CH2:14]O)[CH3:13]>>[Br:1][C:2]1[CH:3]=[C:4]([B:8]2[O:10][CH2:13][C:12]([CH3:16])([CH3:14])[CH2:11][O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: CC(C)(CO)CO
Product: CC1(C)COB(c2cccc(Br)c2)OC1
Yield: 86 %

Procedure:
The title compound (86%, crystals) was prepared from 3-bromophenylboronic acid and neopentylglycol.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[C:40]1[N:41]=[C:42]([CH2:65][CH3:66])[C:43]([NH:48][C@H:49]2[C@@H:53]([OH:54])[CH2:52][N:51]([C:55]([O:57][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[O:56])[CH2:50]2)=[N:44][C:45]=1[CH2:46][CH3:47].[F:67][CH2:68][CH2:69]Br>>[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[C:40]1[N:41]=[C:42]([CH2:65][CH3:66])[C:43]([NH:48][C@H:49]2[C@@H:53]([O:54][CH2:69][CH2:68][F:67])[CH2:52][N:51]([C:55]([O:57][CH2:58][C:59]3[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=3)=[O:56])[CH2:50]2)=[N:44][C:45]=1[CH2:46][CH3:47]
Reactant: FCCBr
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Agent: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1OCCF

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting benzyl (3R,4S)-3-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-4-hydroxypyrrolidine-1-carboxylate and 2-fluoro-1-bromo ethane, and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ) 7.49, 7.41-7.25, 5.18, 4.81, 4.67, 4.55, 4.17, 4.06, 3.80-3.62, 3.39-3.29, 2.69, 2.47, 1.28, 1.15; IR (diffuse reflectance) 2971, 2386 (w), 2350 (w), 2338 (w), 2039 (w), 2014 (w), 1710 (s), 1699 (s,b), 1569, 1499, 1467 (s), 1450, 1428, 1420, 1397, cm−1; HRMS (FAB) calcd for C28H31Cl2FN4O3+H 561.1835, found 561.1808.
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].Br[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O>CN(C)C=O>[N+:1]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH3:6])([O-:3])=[O:2]
Reactant: CCCCCCCCCCCCCBr
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCC[N+](=O)[O-]
Reaction time: 6 h

Procedure:
To a stirred, room temperature suspension of sodium nitrite (227 g, 3.29 mol) in dimethylformamide (3.8 L) was added 1-bromotridecane (514.51 g, 1.95435 mol), and the mixture was stirred for 6 hours. The mixture was poured into cold water (8 L) and extracted with petroleum ether (2×2 L). The organic layer was washed with water (2 n), saturated sodium chloride, dried (MgSO4), and rotoevaporated to a yellow oil. The oil was distilled in vacuo to give another oil; yield 171.9 g, bp 101°-120° C. (0.2 mm Hg). The oil was chromatographed on silica gel (3.0 kg, 230-400 mesh) using ether/ethyl acetate (100:1, 4×2 L; 80:1, 4×2 L; 50:1, 7×2 L) to give a clear colorless oil; yield 109.8 g (24.5%).
Reaction SMILES: [NH2:1][CH:2]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:31])([F:30])[CH:27]([F:29])[F:28])[CH:20]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[OH:4].[C:32]1([C:43](O)=[O:44])[CH:33]=[CH:34][CH:35]=[C:36]2[CH2:42][CH2:41][CH2:40][CH:39]=[CH:38][C:37]=12.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[OH:4][CH:3]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:9][CH:10]=1)[CH:2]([NH:1][C:43]([C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[CH2:42][CH2:41][CH2:40][CH:39]=[CH:38][C:37]=12)=[O:44])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:30])([F:31])[CH:27]([F:28])[F:29])[CH:20]=1
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Oc2ccccc2)cc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-(phenyloxy)phenyl)-3-(3-((1,1,2,2-tetrafluoroethyl)oxy)phenyl)-1-propanol (300 mg, 0.69 mmol) in acetonitrile (16 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (130 mg, 0.69 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (198 mg, 1.03 mmol) and 1-hydroxy-1H-benzotriazole (106 mg, 0.69 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (285 mg, 68%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:14][CH:15]([C:20]23OCC(C)(C[O:25]2)C[O:21]3)[CH2:16][CH:17]([CH3:19])[CH3:18])[C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.Cl>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:14][C@@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:20]([OH:25])=[O:21])[C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: CC(C)CC(NC(c1ccc(Br)cc1)c1nccs1)C12OCC(C)(CO1)CO2
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@H](N[C@@H](c1ccc(Br)cc1)c1nccs1)C(=O)O
Reaction time: 2 h

Procedure:
To a solution of [(4-bromo-phenyl)-thiazol-2-yl-methyl]-[3-methyl-1-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-butyl]-amine (500 mg, 1.06 mmol) in THF (20 mL) and water (18 mL), was added 1N HCl (3.5 mL). The reaction mixture was stirred for 2 h. After checking the TLC for the disappearance of the starting material, Li(OH).H2O (280.2 mg, 6.3 eq.) was added and stirred at room temperature for 2 h. Then 1N HCl was added to adjust the pH 4-6, and the product was extracted with BOAC and the organic layer dried over MgSO4. The solvent was evaporated to yield (2S)-2-{(S)-[(4-bromophenyl)-thiazol-2-yl-methyl]-amino}-4-methylpentanoic acid as a yellow solid.