Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:27]=[CH:26][C:20]([O:21][CH2:22][C:23](O)=[O:24])=[C:19]([CH3:28])[CH:18]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].[CH2:33]([O:40][NH2:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:33]([O:40][NH:41][C:23](=[O:24])[CH2:22][O:21][C:20]1[CH:26]=[CH:27][C:17]([C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3](=[O:30])[C:2]([CH3:1])([CH3:31])[CH3:32])=[C:7]([CH3:29])[CH:8]=2)([CH2:13][CH3:14])[CH2:15][CH3:16])=[CH:18][C:19]=1[CH3:28])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCC(CC)(c1ccc(OCC(=O)O)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Reactant: NOCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(CC)(c1ccc(OCC(=O)NOCc2ccccc2)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a solution of acid compound 6 (27.4 mg, 0.0622 mmol) in DMF (0.1 mL) was added BnONH2, (10.5 mg, 0.0653 mmol, 1.05 equiv.), followed by iPr2NEt (33 μL, 24 mg, 0.1866 mmol, 3.0 equiv.) and HBTU (25.6 mg, 0.0684 mmol, 1.1 equiv.). After 2 h, the reaction was quenched by the addition of brine and then extracted with EtOAc (×4). The combined organic phases were stirred with triethylamine resin, dried over Na2SO4 and concentrated in vacuo to give a crude product which was subsequently purified by preparative tlc (10:90 acetone/toluene). This afforded the title compound 7 (27.7 mg, 82%)
Reaction SMILES: BrC1C=CC(C(Cl)=O)=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[Br:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([N:42]=[C:43]=[S:44])=[O:41])=[CH:36][CH:35]=1>C1(C)C=CC=CC=1.C(O)C>[Br:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]([N:42]=[C:43]=[S:44])=[O:41])=[CH:38][CH:39]=1.[Br:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([NH:42][C:43]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([O:25][C:16]3[C:15]4[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=4)[N:19]=[CH:18][CH:17]=3)=[CH:27][CH:28]=2)=[S:44])=[O:41])=[CH:36][CH:35]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccc(Br)cc1
Agent: O=C(N=C=S)c1ccc(Br)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Br)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
4-Bromo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-bromo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-bromo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (57 mg, yield 63%).
Reaction SMILES: [C:1]([NH:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C:17](=[CH:18][C:19](=O)[CH2:20][CH2:21]1)[CH2:16][CH2:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].P([C:36]#[N:37])(OCC)(OCC)=O>>[C:1]([NH:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]2[C@H:14]3[C@H:24]([CH2:25][CH2:26][C@:9]12[CH3:10])[C@:22]1([CH3:23])[C:17]([CH:18]=[C:19]([C:36]#[N:37])[CH2:20][CH2:21]1)=[CH:16][CH2:15]3)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOP(=O)(C#N)OCC
Reactant: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Product: CC(C)(C)NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C#N)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Following a procedure similar to that described in example 2(c), but using 100 mg of N-t-butyl-3-oxo-4-androstene-17β-carboxamide (prepared as described in Preparation 1), 0.2 ml of diethyl cyanophosphate and 200 mg of a boron trifluoride-diethyl ether complex, 86 mg of the title compound were obtained as a crystalline substance, melting at 198° to 200° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[F:22][C@@H:23]1[CH2:27][NH:26][C@H:25]([C:28]([NH2:30])=[O:29])[CH2:24]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:26]3[CH2:27][C@@H:23]([F:22])[CH2:24][C@H:25]3[C:28]([NH2:30])=[O:29])=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: NC(=O)[C@@H]1C[C@H](F)CN1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)[C@@H]1C[C@H](F)CN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with (2S,4S)-4-fluoropyrrolidine-2-carboxamide hydrochloride (426844-23-7) in the presence of TBTU and DIEA to obtain the title compound as white solid; MS (EI): m/e=399.4 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16](O)=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[CH:3]=1.S(Cl)([Cl:22])=O>>[F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([Cl:22])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC1CCc2cc(F)cc3c(=O)c(C(=O)O)cn1c23
Product: CC1CCc2cc(F)cc3c(=O)c(C(=O)Cl)cn1c23

Procedure:
6,7Dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo[ij]-quinolizine-2-carboxylic acid (5.0 g., 0.0192 mole) is stirred with thionyl chloride (75 ml.), and the mixture is heated to its reflux temperature and maintained at reflux for about 18 hours. The mixture is evaporated to dryness, then azeotroped thrice with 50 ml. portions of benzene to provide an off-white solid, 6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H-benzo[ij]quinolizine-2-carboxylic chloride, m.p. 183°-186° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O>C(OCC)(=O)C.CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:6]2[C:7]([NH2:12])=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: O=[N+]([O-])c1ccccc1Nc1ccc(F)c(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccccc1Nc1ccc(F)c(F)c1
Reaction time: 3 h
Yield: 50.7 %

Procedure:
A solution of 3,4-difluoro-N-(2-nitrophenyl)aniline (22.76 g, 91 mmol) in 50% ethyl acetate/methanol (500 mL) was treat with palladium on carbon 10 w. % loading, matrix activated carbon support (3.07 g). The reaction mixture was placed on the Parr shaker for 3 h at 60 psi. The reaction mixture was filtered through celite and evaporated. The crude reaction product was purified by flash chromatography (SiO2, 3→50% ethyl acetate/heptane) to provided N-(3,4-difluorophenyl)benzene-1,2-diamine (10.17 g, 51%) as a brown solid: HPLC purity 99.9% at 210-370 nm, 9.4 min.; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. Ph=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:10])N)[CH:5]=[CH:6][CH:7]=1.[N:11]12[CH2:18][CH:15]([CH2:16][CH2:17]1)[C:14](=O)[CH2:13][CH2:12]2.Cl>C(O)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:13]3[CH2:12][N:11]4[CH2:18][CH:15]([CH2:16][CH2:17]4)[C:14]=3[N:8]([CH3:10])[C:4]=2[CH:3]=1
Reactant: CN(N)c1cccc(Br)c1
Reactant: O=C1CCN2CCC1C2
Agent: Cl
Solvent: CC(C)O
Product: Cn1c2c(c3ccc(Br)cc31)CN1CCC2C1
Yield: 94.7 %

Procedure:
1-(3-Bromophenyl)-1-methylhydrazine (0.48 g, 2.3 mmol) and 1-azabicyclo[3.2.1]octan-4-one (0.33 g, 2.6 mmol) were dissolved in isopropanol (3 mL), and concentrated aqueous HCl (0.75 mL) was added. The reaction mixture was heated to reflux for 18 h, concentrated and basified using 2 N NaOH. The aqueous layer was extracted with methylene chloride (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, 10%-100% solvent mixture B in ethyl acetate; solvent mixture B=80:18:2 ethyl acetate/methanol/concentrated ammonium hydroxide) to give the title compound (634 mg, 95%) as a yellow semisolid: 1H NMR (300 MHz, CDCl3) δ 7.42 (d, J=2.5 Hz, 1H), 7.20 (d, J=13.5 Hz, 1H), 7.14 (d, J=13.5 Hz, 1H), 4.40 (d, J=26.5 Hz, 1H), 3.72 (d, J=26.0 Hz, 1H), 3.63 (s, 3H), 3.34-3.25 (m, 1H), 3.20-3.17 (m, 2H), 3.17-3.13 (m, 1H), 2.97-2.92 (m, 1H), 2.87-2.76 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:16][Zn]C.CCCCCC.O>ClCCl.C(OCC)(=O)C.Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:16])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: C[Zn]C
Reactant: COc1ccc(C2(O)CCOCC2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(C2(C)CCOCC2)cc1
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of 4-(4-methoxyphenyl)tetrahydro-2H-pyran-4-ol (0.680 g, 3.27 mmol) in dichloromethane (16.0 mL) was cooled to −78° C., and titanium tetrachloride (0.720 mL, 6.53 mmol) was added dropwise thereto. After stirring the mixture for 1 hour, 1.0 mol/L dimethylzinc solution in n-hexane (13.1 mL, 13.1 mmol) was added dropwise thereto. The mixture was stirred for 2 hours, and water was added to stop the reaction. The temperature was returned to room temperature, and the mixture was diluted with ethyl acetate and 1 mol/L hydrochloric acid. The organic layer was washed with water and then with saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was then evaporated under reduced pressure, and the obtained residue was purified by column chromatography (silica gel, hexane/ethyl acetate=90/10-30/70) to obtain 0.641 g of the captioned compound (95% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH2:17]O)[CH:14]=[CH:13][C:12]=1[C:19]#[N:20])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[CH:25][C:26](=[O:60])[N:27]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]3[N:37]=[CH:38][N:39](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:40]=3)=[CH:31][N:30]=2)[CH:28]=1.CCN(C(C)C)C(C)C.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([CH2:17][N:37]2[C:36]([CH2:35][C:32]3[CH:33]=[CH:34][C:29]([N:27]4[CH:28]=[C:23]([Cl:22])[CH:24]=[CH:25][C:26]4=[O:60])=[N:30][CH:31]=3)=[CH:40][N:39]=[CH:38]2)[CH:14]=[CH:13][C:12]=1[C:19]#[N:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(CO)ccc1C#N
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOc1cc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)ccc1C#N
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled solution (-78° C.) of [2-(2-cyano-5-hydroxy-methylphenoxy)-ethyl]-carbamic acid tert-butyl ester from step 3 (248 mg, 0.85 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23, Step 5 (450 mg, 0.85 mmol) in CH2Cl2 (4.5 ml) was added DIEA (325 μl, 1.87 mmol) followed immediately by the addition of Tf2O (215 μl, 1.27 mmol). The reaction mixture stirred at -78° C. for 1 hour and was then transferred to an ice bath and stirred at 0° C. for another hour. The solvent was removed in vacuo. The residue was then dissolved in MeOH (4.5 ml) and heated to 60° C. for 4 hours. The MeOH was then removed in vacuo and the residue treated with saturated NaHCO3 and extracted with CH2Cl2. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography with 0 to 4% MeOH(NH4OH5%) in CH2Cl2 to yield the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][NH:7][C:8](=[O:19])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1)=[O:5])[CH3:2].[BH4-].[Na+].Cl>C(O)C>[CH2:1]([O:3][C:4]([CH2:6][NH:7][C:8](=[O:19])[CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][OH:18])=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CNC(=O)COc1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CNC(=O)COc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a mixture of N-(ethoxycarbonylmethyl)-2-(4-formylphenoxy)acetamide (4.6 g) and ethanol (150 ml) was added under ice cooling sodium borohydride (0.25 g), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 3% hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure gave N-(ethoxycarbonylmethyl)-2-(4-hydroxymethylphenoxy)acetamide (4.03 g).
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[C:11](OCC)=[O:12].[Cl-].[Ca+2].[Cl-].[BH4-].[Na+].[Cl-].[NH4+]>O1CCCC1.[O-2].[O-2].[Mn+4].C(O)C>[CH3:1][C:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[S:4][C:3]=1[CH:11]=[O:12]
Reactant: CCOC(=O)c1sc2cccnc2c1C
Agent: [Mn+4]
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C=O)sc2cccnc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.2 %

Procedure:
To a mixture of ethyl 3-methylthieno[3,2-b]pyridine-2-carboxylate (3.00 g) synthesized above, calcium chloride (3.02 g), ethanol (30 mL) and tetrahydrofuran (30 mL) was added sodium borohydride (2.06 g) at 0° C., and the mixture was stirred at room temperature for 5 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a white solid. To a solution (50 mL) of the obtained solid in tetrahydrofuran was added active manganese dioxide (12.2 g), and the mixture was stirred at 50° C. overnight. Manganese dioxide was filtered off, and the filtrate was concentrated under reduced pressure to give the title object compound (2.24 g, 93%) as a white solid.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[CH:4][N:3]=1.[NH3:20]>CO>[NH2:20][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N
Reactant: O=[N+]([O-])c1c(OCCc2ccccc2)ccnc1F
Solvent: CO
Product: Nc1nccc(OCCc2ccccc2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.02 g of 2-fluoro-4-(2-phenylethoxy)-3-nitropyridine (starting material K3) are dissolved in 10 ml of a 5M solution of ammonia in methanol and stirred at ambient temperature for 16 hours. The solvent is distilled off and the residue is chromatographed on silica gel (dichloromethane/petroleum ether 4:1+1% triethylamine). Concentration of the pure fractions and drying in vacuo gives 1.16 g of the title compound as a yellow solid of m.p. 131–132° C. The mass spectrum shows the molecular peak MH+ at 260.0 Da.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][CH2:5][C:6]1[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=1[C:8]#[N:9].[Cl-].[Ca+2].[Cl-]>C(O)C.O>[NH2:18][C:16]1[CH:15]=[CH:14][C:3]([O:4][CH2:5][C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]#[N:9])=[C:2]([Cl:1])[CH:17]=1
Reactant: N#Cc1ccccc1COc1ccc([N+](=O)[O-])cc1Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: N#Cc1ccccc1COc1ccc(N)cc1Cl
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
To a solution of 2-[(2-chloro-4-nitrophenoxy)methyl]benzonitrile (2.0 g) in ethanol/water (9:1, 40 mL) was added calcium chloride (90%, 427 mg), and the mixture was stirred at 100° C. for 10 min. Reduced iron (90%, 2.6 g) was added at room temperature, and the mixture was stirred at 100° C. for 3 hrs. After the completion of the reaction, the reaction mixture was filtered (celite), and the filtrate was concentrated under reduced pressure. Water was added to the residue and the mixture was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate:methylene chloride=2:1:1) to give the title compound (1.2 g) as a white solid.
Reaction SMILES: Cl.Cl.[C:3]([O:7][C:8]([N:10]([C@@H:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[C:11]1[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:38])=[CH:33][CH:32]=1.C1COCC1>CCN(CC)CC>[C:37]([C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:26]2[CH2:27][CH2:28][C@@H:24]([N:10]([C:8]([O:7][C:3]([CH3:4])([CH3:5])[CH3:6])=[O:9])[C:11]3[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=3)[CH2:25]2)=[CH:36][CH:35]=1)(=[O:38])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCNC2)nc1
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(N(C(=O)OC(C)(C)C)[C@@H]2CCN(Cc3ccc(C(=O)c4ccccc4)cc3)C2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a mixture of ethyl (2E)-3-(6-{(tert-butoxycarbonyl)[(3R)-3-pyrrolidinyl]amino}-3-pyridyl)acrylate dihydrochloride (150 mg), [4-(bromomethyl)phenyl](phenyl)methanone (143 mg), and THF (3.5 mL) was added Et3N (0.168 mL). After stirring for 2 hours at room temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-{6-[[(3R)-1-(4-benzoylbenzyl)-3-pyrrolidinyl](tert-butoxycarbonyl)amino]-3-pyridyl}acrylate (149 mg)
Reaction SMILES: [CH2:1]([C:8]1[NH:12][N:11]=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:13]1([C:19](Cl)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:12]2[C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:9][N:10]=[N:11]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(Cc2nnn[nH]2)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: c1ccc(Cc2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
Prepared from 5-benzyl-1H-tetrazole and triphenylmethyl-chloride.
Reaction SMILES: C(N)(C)C.[CH2:5]([NH2:8])[CH2:6][CH3:7].C(N[C:13]1[C:26]2[C:25](=[O:27])[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:28])[CH:23]=3)[C:18](=[O:29])[C:17]=2[CH:16]=[CH:15][CH:14]=1)CC>>[CH2:5]([NH:8][C:16]1[C:17]2[C:18](=[O:29])[C:19]3[C:24](=[CH:23][C:22]([Cl:28])=[CH:21][CH:20]=3)[C:25](=[O:27])[C:26]=2[CH:13]=[CH:14][CH:15]=1)[CH2:6][CH3:7]
Reactant: CCCNc1cccc2c1C(=O)c1cc(Cl)ccc1C2=O
Reactant: CCCN
Solvent: CC(C)N
Product: CCCNc1cccc2c1C(=O)c1ccc(Cl)cc1C2=O

Procedure:
If the procedure indicated is followed but isopropylamine is replaced by propylamine, 22 g of 1-propylamino-7-chloroanthraquinone are obtained. The nitrobenzene/methanol mother liquor is concentrated and the residue is treated with methanol and with a little nitrobenzene. After working up, 8 g of 1-propylamino-6-chloroanthraquinone are obtained.
Reaction SMILES: [CH3:1][S:2]([CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([O:25]C(=O)C)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])(=[O:4])=[O:3].[OH-].[Na+]>CO>[CH3:1][S:2]([CH:5]([CH2:16][CH2:17][CH2:18][CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=[O:3])=[O:4]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OC)S(C)(=O)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCC(O)CCCC(CCCCCCC(=O)O)S(C)(=O)=O
Yield: 92.5 %

Procedure:
A solution of methyl 8-methylsulfonyl-12-acetoxyheptadecanoate (29.4 g., 0.07 mole) and 20% aqueous sodium hydroxide (70 ml.) in methanol (70 ml.) is stirred at room temperature for 17 hours. The resulting solution is evaporated in vacuo at ~100° C. to an oily residue which is dissolved in water. The aqueous solution is extracted with ether and the organic extract discarded. Then, the aqueous phase is acidified to Congo Red with 6N hydrochloric acid and extracted with ether. The organic extract is washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo at ~100° C. providing crude title compound as a viscous oil (23.6 g., 93%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[Cl-].[NH4+]>C(O)(C)C.O.CCOC(C)=O.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: O
Product: Nc1cc(Br)cnc1N
Temperature: 90 °C
Yield: 94.7 %

Procedure:
5-Bromo-3-nitropyridin-2-amine (3 g) was dissolved in isopropyl alcohol (56 mL) and water (28 mL). Ammonium chloride (1.47 g, 2 eq) was added followed by iron powder (2.31 g, 3 eq). The reaction was heated to 90° C. for 45 minutes. The solution was then cooled, and diluted with EtOAc, filtered, and the layers were separated. The organic layer was then washed with brine, dried over sodium sulfate, and concentrated delivering product as a solid (2.45 g, 95% yield). 1H-NMR (300 MHz, DMSO-d6) δ 7.25 (d, 1H), 6.77 (d, 1H), 5.70-5.40 (bs, 2H), 5.20-4.80 (bs, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20]>O>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:19]([O-:21])=[O:20])[CH:27]=3)[CH:15]=[CH:16][C:11]=2[NH:10][C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: O=c1[nH]c2ccc(Br)cc2n1Cc1ccccc1
Solvent: O
Product: O=c1[nH]c2ccc(-c3cccc([N+](=O)[O-])c3)cc2n1Cc1ccccc1

Procedure:
Prepared from 1-benzyl-6-bromo-1,3-dihydro-benzoimidazol-2-one and 3-nitro-phenyl boronic acid in the same fashion as that of Example 5. White solid: mp 202-203° C.; 1H-NMR (DMSO-d6) δ11.2 (s, 1H), 8.38 (t, 1H, J=1.97 Hz), 8.15 (dd, 1H, J=7.83, 1.97 Hz), 8.80 (d, 1H, J=7.83 Hz), 7.72 (t, 1H, J=7.83 Hz), 7.56 (bs, 1H), 7.43-7.22 (m, 6H), 7.13 (d, 1H, J=7.83 Hz), 5.1 (s, 2H); MS (ES) m/z 344([M−H]−, 100%); Anal. Calc. For C20H15N3O3.0.25 H2O: C, 68.66; H, 4.46; N, 12.01. Found: C, 68.42; H, 4.44; N, 11.77.