Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=1)[NH2:4].[Br:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])N>>[Br:18][C:19]1[CH:20]=[C:21]([NH:4][C:3]([C:5]2[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=2)=[N:2][OH:1])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: Nc1ccc(F)c(Br)c1
Reactant: CS(=O)(=O)NCCNc1nonc1C(N)=NO
Product: CS(=O)(=O)NCCNc1nonc1C(=NO)Nc1ccc(F)c(Br)c1

Procedure:
The title compound was prepared according to the procedure of Example 17 step E, using N′-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide and 3-bromo-4-fluoroaniline [Oakwood Products, Inc., product #013091] as the starting materials. LCMS for C12H15BrFN6O4S (M+H)+: m/z=437.0, 439.0. 1H NMR (400 MHz, DMSO-d6): δ 11.49 (s, 1H), 8.90 (s, 1H), 7.17 (m, 2H), 7.09 (dd, J=6.3, 2.5 Hz, 1H), 6.26 (t, J=6.1 Hz, 1H), 3.33 (m, 2H), 3.13 (q, J=6.0 Hz, 2H), 2.89 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([N+:21]([O-])=O)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[C:5]([F:9])=[CH:6][C:7]=1[Cl:8].C(O)C.C(O)(C)C.O.NN>O.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH2:21])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[C:5]([F:9])=[CH:6][C:7]=1[Cl:8]
Reactant: O=[N+]([O-])c1ccc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2c1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Solvent: CC(C)O
Product: Nc1ccc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2c1
Temperature: 95 °C

Procedure:
A solution of 4-[(3,4-dichloro-6-fluorophenyl)amino]-6-nitroquinazoline (709 mg, 2.076 mmol) in 140 ml of 1:9:10 water:ethanol:iso-propylalcohol was heated to reflux temperature (95° C.). Additional 60 ml of the solvents mixture was added until complete dissolution. The reaction mixture was then cooled to 65° C., and 200 μl hydrazine hydrate (4.12 mmol) and 0.5 ml Raney®Nickel (in water) were added subsequently thereto. The resulting mixture was heated up to 80–85° C., additional 0.5 ml Raney®Nickel and 50 μl of hydrazine hydrate (1.03 mmol) were added, and gentle reflux was maintained for about 15–20 minutes. Filtration and evaporation gave 4-[(3,4-dichloro-6-fluorophenyl)amino]-6-aminoquinazoline (compound 2) in 83% yield. m.p.=265° C.; MS (m/z): 323.4, 325.4 (M+); Anal. calcd.: C, 52.9; H, 2.78; N, 17.33. Found: C, 52.19; H, 2.99; N, 17.14. HPLC analysis. C-18 column, 55% acetate buffer, PH=3.8/45% acetonitrile, flow=1 ml/min; r.t=6.6 minutes.
Reaction SMILES: [O:1]=[C:2]1[NH:16][C:5]2=[CH:6][C:7]3[CH:8]=[C:9]([C:13]([OH:15])=O)[NH:10][C:11]=3[CH:12]=[C:4]2[O:3]1.[CH2:17]([O:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)C>[CH2:17]([O:24][CH:25]1[CH2:30][CH2:29][N:28]([C:13]([C:9]2[NH:10][C:11]3[CH:12]=[C:4]4[O:3][C:2](=[O:1])[NH:16][C:5]4=[CH:6][C:7]=3[CH:8]=2)=[O:15])[CH2:27][CH2:26]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(COC2CCNCC2)cc1
Reactant: O=C(O)c1cc2cc3[nH]c(=O)oc3cc2[nH]1
Solvent: CCOCC
Product: O=C(c1cc2cc3[nH]c(=O)oc3cc2[nH]1)N1CCC(OCc2ccccc2)CC1

Procedure:
The title compound is prepared from 2-oxo-1,5-dihydro-2H-oxazolo[4,5-f]indole-6-carboxylic acid and 4-benzyloxypiperidine [Tetrahedron 54, 13981, (1998)] according to the method described in Example 1/c. Mp.: 258-261° C. (diethyl ether).
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:22])[NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:14]=2)=[CH:3][CH:2]=1.[S:24]1[CH2:30][C:28](=[O:29])[N:27]([CH2:31][C:32]([OH:34])=[O:33])[C:25]1=[S:26].[Cl-].[NH4+].N>C(O)C>[CH2:19]([O:18][C:16]([C:15](=[C:30]1[S:24][C:25](=[S:26])[N:27]([CH2:31][C:32]([OH:34])=[O:33])[C:28]1=[O:29])[C:13]1[N:14]=[C:10]([NH:9][C:8]([NH:7][C:4]2[CH:5]=[CH:6][C:1]([CH3:23])=[CH:2][CH:3]=2)=[O:22])[S:11][CH:12]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccc(C)cc2)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)Nc2ccc(C)cc2)n1

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared using 4.8 g of ethyl 2-(3-p-tolylureido)thiazol-4-ylglyoxylate, 2.5 g of rhodanine-3-acetic acid, 1.5 g of ammonium chloride, 1.5 ml of 20% v/v aqueous ammonia and 50 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7]([N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.[Na+].[I-:17].NCCN.N>O.[Cu]I.O1CCOCC1>[I:17][C:2]1[CH:15]=[CH:14][C:5]2[NH:6][C:7]([N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1
Reactant: [I-]
Reactant: Brc1ccc2[nH]c(N3CCCC3)nc2c1
Agent: [Cu]I
Agent: N
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: NCCN
Product: Ic1ccc2[nH]c(N3CCCC3)nc2c1
Temperature: 110 °C
Reaction time: 14 h

Procedure:
0.48 g (1.8 mmol) of 5-bromo-2-pyrrolidin-1-yl-1H-benzimidazole and 34 mg (0.18 mmol) of CuI are placed in a round flask. The reaction vessel is flushed with argon. Then 0.54 g (3.6 mmol) of NaI, 32 mg (0.36 mmol) of dimethylenediamine, and 3 mL of 1,4-dioxane are added under argon. The reaction mixture is stirred for 14 hours at 110° C. Subsequently, the cooled reaction mixture is combined with concentrated ammonia solution, diluted with water, and the precipitate formed is filtered off. The solid is stirred with methanol and again filtered. Yield: 0.3 g (53% of theoretical); C11H12IN3 (M=313.13); calc.: molpeak (M+H)+: 314; found: molpeak (M)+: 314.
Reaction SMILES: Cl.Cl.Br[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[C:17]([CH3:29])[CH:16]=1.[O:30]1[CH:34]=[CH:33][C:32](B(OC(C)C)OC(C)C)=[CH:31]1>>[O:30]1[CH:34]=[CH:33][C:32]([C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][N:8]=[C:7]3[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([CH3:29])[CH:16]=2)=[CH:31]1
Reactant: Cc1cc(Nc2ncnc3ccc(Br)cc23)ccc1OCc1ccccn1
Reactant: CC(C)OB(OC(C)C)c1ccoc1
Agent: Cl
Product: Cc1cc(Nc2ncnc3ccc(-c4ccoc4)cc23)ccc1OCc1ccccn1
Yield: 55 %

Procedure:
Using an analogous procedure to that described in Example 5, 6-bromo-4-[3-methyl-4-(2-pyridylmethoxy)anilino]quinazoline dihydrochloride salt was reacted with di-isopropyl 3-furylboronate to give 6-(3-furyl)-4-[3-methyl-4-(2-pyridylmethoxy)anilino]-quinazoline in 55% yield, m.p. 206-208° C.;
Reaction SMILES: [C:1]1([C:14](O)=O)[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.OCC1C2CC3C(=CC=CC=3)C=2C=CC=1.P(Br)(Br)[Br:33].O>C1COCC1>[Br:33][CH2:14][C:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: BrP(Br)Br
Reactant: O=C(O)c1cccc2c1Cc1ccccc1-2
Agent: OCc1cccc2c1Cc1ccccc1-2
Solvent: O
Solvent: C1CCOC1
Product: BrCc1cccc2c1Cc1ccccc1-2
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
Fluorene-1-carboxylic acid was purchased from Aldrich. It was reduced as described in J. Am. Chem. Soc. 1961, 83, 417 via the methyl ester to 1-hydroxymethylfluorene 1H NMR (CDCl3): δ 4.84 ppm (CH2), 3.89 ppm (CH2). 4.1 g (21 mmol) 1-hydroxymethylfluorene dissolved in 60 ml THF was slowly added to 2.54 g PBr3 in 10 ml THF at −5° C. The orange solution was stirred for 1.5 hrs at −5° C. then stirred for 16 hrs at room temperature. This was then poured into iced water, allowed to settle and 5.1 g of 1-bromomethylfluorene was isolated on a frit as an off-white powder. 1H NMR (CDCl3): δ 4.65 ppm (CH2), 3.97 ppm (CH2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=O)[C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][N:7]([CH3:13])[C:6]=2[CH:14]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:33][CH2:34][C@@H:35]1[CH2:39][CH2:38][CH2:37][N:36]1[CH2:40][CH2:41][CH2:42][CH3:43]>O1CCCC1.CN(C)C=O>[CH2:40]([N:36]1[CH2:37][CH2:38][CH2:39][C@H:35]1[CH2:34][NH:33][C:15]([C:4]1[C:5]2[O:10][C:9]([CH3:11])([CH3:12])[CH2:8][N:7]([CH3:13])[C:6]=2[CH:14]=[C:2]([Cl:1])[CH:3]=1)=[O:17])[CH2:41][CH2:42][CH3:43]
Reactant: CN1CC(C)(C)Oc2c(C(=O)O)cc(Cl)cc21
Reactant: CCCCN1CCC[C@H]1CN
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCCCN1CCC[C@H]1CNC(=O)c1cc(Cl)cc2c1OC(C)(C)CN2C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1.03 g of 6-chloro-2,2,4-trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid in a mixed solvent of 5 ml of dimethylformamide and 10 ml of tetrahydrofuran was added 0.6 g N-methylmorpholine, and 0.55 g of isobutyl chloroformate was added dropwise thereto at -10° to -5° C. under ice-cooling. After stirring for 20 minutes at the same temperature, 0.63 g of (S)-(-)-2-aminomethyl-1-butylpyrrolidine was added at -10° to -5° C. and the mixture was stirred at room temperature for three hours. The resultant mixture was concentrated under reduced pressure, and to the residue were added an aqueous potassium carbonate solution and ethyl acetate. The organic layer was separated and washed with water and then dried over magnesium sulfate. The solvent was distilled off and the residue was recrystallized from isopropyl ether to give (S)-N-[(1-butyl-2-pyrrolidinyl)methyl]-6-chloro-2,2,4-trimethyl-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide as white crystals, melting at 110° to 112° C. [α]D =-61.7° (c=1, methanol)
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](O)([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][SH:38])=[CH:33][CH:32]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:28][C:2]1([CH3:1])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([S:38][CH2:37][C:34]3[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)([CH3:15])[CH3:16])[CH:11]=[CH:10][C:9]=2[NH:18][C:19]([C:21]2[NH:22][CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])=[CH:4][CH2:3]1
Reactant: COc1ccc(CS)cc1
Reactant: CC1(C)CC=C(c2cc(C(C)(C)O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CSC(C)(C)c2ccc(NC(=O)c3nc(C#N)c[nH]3)c(C3=CCC(C)(C)CC3)c2)cc1
Temperature: 25 °C
Yield: 55.6 %

Procedure:
To a mixture of 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-amide (as prepared in Example 14, step (d), 86 mg, 0.22 mmol) and (4-methoxy-phenyl)-methanethiol (157 μL, 1.13 mmol) in 2 mL of DCM at 0° C. was added 175 μL (2.27 mmol) of TFA. The mixture was allowed to warm to room temperature overnight, at which time it was diluted with DCM (20 mL), washed with water (1×20 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by preparative TLC on silica gel (5% methanol-CHCl3) to afford the title compound (63 mg, 54%). 1H-NMR (CDCl3; 400 MHz): δ 12.78 (br s, 1H), 9.75 (s, 1H), 8.32 (d, 1H, J=8.6 Hz), 7.75 (s, 1H), 7.51 (dd, 1H, J=7.5, 2.1 Hz), 7.41 (d, 1H, J=2.1 Hz), 7.04 (d, 2H, J=8.6 Hz), 6.75 (d, 2H, J=8.6 Hz), 5.80 (m, 1H), 3.75 (s, 3H), 3.41 (s, 2H), 2.31 (m, 2H), 2.13 (m, 2H), 1.72 (s, 6H), 1.61 (t, 2H, J=6.2 Hz), 1.12 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[CH:10]=[CH:9][C:8]=1[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16].[N:24]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:27]2[CH2:26][CH2:25][N:24]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28]2)[CH:10]=[CH:9][C:8]=1[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(c1ccc(F)cc1NCc1cc(Cl)cc(Cl)c1)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)C(F)(F)F)c(NCc3cc(Cl)cc(Cl)c3)c2)CC1
Temperature: 25 °C
Yield: 27.7 %

Procedure:
A mixture of 1-(2-(3,5-dichlorobenzylamino)-4-fluorophenyl)-2,2,2-trifluoroethanone (0.78 g, 2.1 mmol), t-butyl piperazine-1-carboxylate (0.41 g, 2.2 mmol), N,N-diisopropylethylamine (0.8 mL, 4.4 mmol) and acetonitrile (10 mL) was heated at reflux for 18 h, cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate; this solution was washed with water, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 10% ethyl acetate in hexanes as eluent to yield the title compounds as a yellow solid (0.31 g, 28%). 1H NMR (400 MHz, CDCl3): δ 9.38 (br, 1 H), 7.67 (d, 1 H), 7.31 (s, 1 H), 7.21 (s, 2 H), 6.13 (dd, 1 H), 5.70 (d, 1 H), 4.42 (d, 2 H), 3.54 (m, 4 H), 3.38 (m, 4 H), 1.49 (s, 9 H). MS (ESI) m/z: Calculated: 531; Observed: 532 (M+H+).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:24])[C:9]2[C:17]3[C:12](=NC=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[NH:11][CH:10]=2)=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[OH:26].O.[CH3:28][N:29](C)C=O>O1CCCC1>[F:1][C:2]1[C:3]([OH:26])=[CH:4][CH:5]=[C:6]([F:25])[C:7]=1[C:8]([C:9]1[C:28]2[N:29]=[C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:16]=[CH:17][C:12]=2[NH:11][CH:10]=1)=[O:24]
Reactant: Oc1ccc(F)c(C(O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1F
Reactant: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1c(F)ccc(O)c1F)c1c[nH]c2ccc(-c3cccnc3)nc12
Temperature: 25 °C
Reaction time: 50 h

Procedure:
To 2,4-difluoro-3-[hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenol (P-0009, 45.0 mg, 1.27 mmol) in tetrahydrofuran (15 mL) and N,N-dimethylformamide (5 mL) was added dichlorodicyanoquinone (87 mg, 3.8 mmol). The reaction was stirred at room temperature for 50 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The desired compound was isolated by silica eel column chromatography eluting with 5% methanol in methylene chloride to give a white solid (P-0066, 7 mg, 15.6%). MS(ESI) [M+H+]+=352.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[I:8][CH2:9][CH2:10][CH2:11][CH2:12]I>O1CCOCC1>[I-:8].[CH2:9]([N+:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH2:10][CH2:11][CH2:12][N+:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1.[I-:8]
Reactant: ICCCCI
Reactant: Cc1ccncc1
Solvent: C1COCCO1
Product: Cc1cc[n+](CCCC[n+]2ccc(C)cc2)cc1
Product: [I-]
Yield: 91 %

Procedure:
A mixture of 4-methylpyridine (1.02 g) and 1,4-diiodobutane (1.55 g) in 5 mL of dioxane was refluxed for 8 hours. The obtained salt was precipitated with diethyl ether and filtered. The precipitate was washed with ether and dried under vacuum to provide Compound 5 in 91% yield. This product was used without any further purification. The structure of Compound 5 is given below:
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH:7]=O.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH2:7][N:16]1[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]1
Reactant: Cc1c(C=O)sc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(CN2CCN(C(=O)OC(C)(C)C)CC2)sc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-methylbenzo[b]thiophene-2-carbaldehyde (0.029 mol) in dry DCM (100 mL) is added t-butyl piperazine-1-carboxylate (0.0319 mol), and the mixture is stirred at RT for 1 h. 0.042 Mol of NaBH(OAc)3 is added in portions, and the reaction mixture is stirred overnight at RT. The resulting solution is concentrated under vacuum, and the residue is partitioned between DCM and aqueous sodium bicarbonate solution. The organic phase is separated, washed with water, dried (MgSO4) and evaporated in vacuo. The residue is purified by column chromatography on silica gel by eluting with DCM/MeOH (9/1) to afford t-butyl 4-((3-methylbenzo[b]thiophen-2-yl)methyl)piperazine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][C:6]1[N:7]=[C:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[S:9][C:10]=1[CH2:11]O.CC(C)(O)[C:25]#[N:26].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][C:6]1[N:7]=[C:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[S:9][C:10]=1[CH2:11][C:25]#[N:26]
Reactant: CC(C)(O)C#N
Reactant: OCc1sc(N2CCOCC2)nc1Cc1ccc(Cl)c(Cl)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: N#CCc1sc(N2CCOCC2)nc1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.2 %

Procedure:
To a solution of (4-(3,4-dichlorobenzyl)-2-morpholinothiazol-5-yl)methanol (1.19 g, 3.31 mmol) in THF (58.6 mL) was added acetone cyanohydrin (0.454 mL, 4.97 mmol), 1,1′-(azodicarbonyl)dipiperidine (1.67 g, 6.62 mmol) and tributylphosphine (1.65 mL, 6.62 mmol) and the reaction was stirred for 3 hours at room temperature. The reaction was concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/DCM=0/100→20/80) to give 551 mg (45% yield) of the title compound as a beige solid. LC/MS (FA) ES+ 368, 370. NMR (400 MHz, CDCl3) δ: 7.35 (d, 1H, J=6.0 Hz), 7.32 (d, 1H, J=2.0 Hz), 7.07 (dd, 1H, J=6.0, 2.0 Hz), 3.82 (s, 2H), 3.80-3.77 (m, 4H), 3.66 (s, 2H), 3.42-3.40 (m, 4H).
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7](O)=[O:8])(=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:48][CH2:49][C:50]1[C:51](=[O:76])[N:52]([CH2:60][C:61]2[CH:66]=[CH:65][C:64]([C:67]3[C:68]([C:73]([OH:75])=[O:74])=[CH:69][CH:70]=[CH:71][CH:72]=3)=[CH:63][CH:62]=2)[C:53]([CH2:56][CH2:57][CH2:58][CH3:59])=[CH:54][CH:55]=1>CN(C=O)C>[CH2:56]([C:53]1[N:52]([CH2:60][C:61]2[CH:62]=[CH:63][C:64]([C:67]3[C:68]([C:73]([OH:75])=[O:74])=[CH:69][CH:70]=[CH:71][CH:72]=3)=[CH:65][CH:66]=2)[C:51](=[O:76])[C:50]([CH2:49][NH:48][C:7](=[O:8])[CH:6]([CH2:5][SH:4])[CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:55][CH:54]=1)[CH2:57][CH2:58][CH3:59]
Reactant: CCCCc1ccc(CN)c(=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: CC(=O)SCC(CC(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCc1ccc(CNC(=O)C(CS)CC(C)C)c(=O)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 140 %

Procedure:
2-Acetylsulfanylmethyl-4-methyl-pentanoic acid (24 mg, 1.1 eq) and HATU (44 mg, 1.1 eq) were dissolved in DMF (2 mL). DIPEA (740 μL, 4 eq) was added, and the mixture was stirred at room temperature for 15 minutes. 4′-(3-Aminomethyl-6-butyl-2-oxo-2H-pyridin-1-ylmethyl)biphenyl-2-carboxylic acid HCl (45 mg, 0.1 mmol) was added, and the solution was stirred at room temperature for 4 hours. The reaction was quenched with water (8 mL) and concentrated HCl (3 drops), and the mixture extracted with EtOAc (10 mL). The organic layer was dried over Na2SO4, and evaporated. The residue was dissolved in MeOH (1 mL) and 1M NaOH (3 mL). The solution was stirred under nitrogen for 20 minutes, and the reaction was then quenched with acetic acid (2 mL). The MeOH was evaporated, and the aqueous component extracted with EtOAc (10 mL). The solvent was evaporated and the residue purified by reverse phase chromatography to afford the title compound (7.5 mg, 140 μmol). MS m/z: [M+H+] calcd for C31H39N2O4S, 535.7. found 535.2.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25](=[O:57])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C@@H:34]2[C@@H:37]([S:38]SC3C([N+]([O-])=O)=CC=CN=3)[C:36](=[O:49])[N:35]2[C:50]2[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=2)=[CH:30][CH:29]=1)([CH3:23])([CH3:22])[CH3:21].CCN(CC)CC.Br[CH2:66][C:67]([C:69]1[CH:77]=[CH:76][C:72]2[CH2:73][CH2:74][O:75][C:71]=2[CH:70]=1)=[O:68]>CC(C)=O.O>[C:20]([O:24][C:25](=[O:57])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C@@H:34]2[C@@H:37]([S:38][CH2:66][C:67]([C:69]3[CH:77]=[CH:76][C:72]4[CH2:73][CH2:74][O:75][C:71]=4[CH:70]=3)=[O:68])[C:36](=[O:49])[N:35]2[C:50]2[CH:55]=[CH:54][C:53]([F:56])=[CH:52][CH:51]=2)=[CH:30][CH:29]=1)([CH3:21])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)COc1ccc([C@@H]2[C@@H](SSc3ncccc3[N+](=O)[O-])C(=O)N2c2ccc(F)cc2)cc1
Reactant: O=C(CBr)c1ccc2c(c1)OCC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc4c(c3)OCC4)C(=O)N2c2ccc(F)cc2)cc1
Reaction time: 0.25 h

Procedure:
Triphenyl phosphine (50 mg, 0.191 mmol) was added to a solution of {4-[(2R,3R)-1-(4-fluoro-phenyl)-3-(3-nitro-pyridin-2-yldisulfanyl)-4-oxo-azetidin-2-yl]-phenoxy}-acetic acid tert-butyl ester (100 mg, 0.179 mmol) in acetone/water (3 mL/0.5 mL) at room temperature. The mixture was stirred for 15 min. The solvent was removed under reduced pressure and the residue was dissolved in DCM (3 mL). Et3N (75 μL, 0.534 mmol) and 2-bromo-1-(2,3-dihydro-benzofuran-6-yl)-ethanone (91 mg, 0.377 mmol) were added and the solution was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC using a gradient of 40-80% MeCN in a 0.1M ammonium acetate buffer as eluent. The pure fractions were pooled and most of the MeCN was removed under reduced pressure. The residue was extracted with EtOAc and the organic layer was washed with brine, dried over MgSO4 and concentrated. The title compound was obtained.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[OH-].[Na+].N(C(OC(C)(C)C)=O)[C@H](C(O)=O)CC1C=CC(O)=CC=1>>[NH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:1])[CH:7]=1)[OH:5]
Reactant: NCC(O)c1ccccc1
Reactant: Cl
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: NC[C@H](O)c1cccc(Cl)c1

Procedure:
To 15 ml of 1N aqueous solution of hydrochloric acid was added 3.38 g of the concentrate of the reaction products containing 15.0 mmol of 2-amino-1-phenylethanol obtained in the same manner as in Example 295. The resultant solution was added with 7.5 ml of 1N sodium hydroxide solution containing 2.10 g of Boc-L-Tyr (7.5 mmol) with stirring slowly to precipitate or crystallize crystals. The crystals were isolated by filtration to give 2.49 g (5.5 mmol) of (R)-2-amino-1-(3-chlorophenyl)ethanol.Boc-L-Tyr salt. The yield relative to (R)-2-amino-1-(3-chlorophenyl)ethanol in the concentrate was 73.4%.
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][C:4]1[O:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]=1.Cl.Cl.[NH:18]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[NH2:19].C([O-])(=O)C.[Na+]>C(O)C>[CH3:15][C:2]1[CH:3]=[C:4]([NH:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:9])=[O:10])[N:18]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:19]=1
Reactant: NNc1cccnc1
Reactant: CC(=O)Cc1nc2ccccc2c(=O)o1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Nc2ccccc2C(=O)O)n(-c2cccnc2)n1
Temperature: 25 °C
Yield: 68.6 %

Procedure:
A solution of 2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one (10.2 g, 50.0 mmol), 3-hydrazinopyridine dihydrochloride (9.10 g, 50.0 mmol) and sodium acetate (9.84 g, 120 mmol) in ethanol (100 mL) was heated under reflux for 1 hour. The solution was cooled to room temperature and concentrated under reduced pressure. The residue was poured into water, and organic matter was extracted with a mixture of chloroform/methanol. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvents were evaporated under reduced pressure. The residue thus obtained was crystallized from ethyl acetate/diethylether/hexane to give the title compound (10.1 g, 69% yield).