Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].C[O-].[Na+].CO.[Cl-:14].[NH4+:15].CC(C)=O>CO>[ClH:14].[C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)(=[NH:15])[NH2:2]
Reactant: [Cl-]
Reactant: N#Cc1ccncc1
Reactant: [NH4+]
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: Cl
Product: N=C(N)c1ccncc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
4-Cyanopyridine (50.0 g) was suspended in methanol (50 mL), and 28% sodium methoxide-methanol solution (4.14 mL) was added thereto. After stirring at room temperature for 15 min, ammonium chloride (25.7 g) was added to the mixture. The mixture was stirred at room temperature for 24 hr. Acetone (200 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration to give 4-amidinopyridine hydrochloride (62.8 g) as a white solid.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:12])[N:6](C)[C:7](S)=[N:8][N:9]=1)([CH3:3])[CH3:2].[C:13]([Cl:16])([Cl:15])=O>C(OCC)(=O)C>[ClH:15].[Cl:16][C:13]1[N:6]([CH3:7])[C:5](=[O:12])[C:4]([CH:1]([CH3:3])[CH3:2])=[N:9][N:8]=1
Reactant: O=C(Cl)Cl
Reactant: CC(C)c1nnc(S)n(C)c1=O
Solvent: CCOC(C)=O
Product: CC(C)c1nnc(Cl)n(C)c1=O
Product: Cl
Temperature: 45 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
18.6 g (0.1 mole) of 6-isopropyl-3-mercapto-4-methyl-1,2,4-triazin-5(4H)-one are suspended in 100 ml of ethyl acetate. Then 10.9 g (0.11 mole) of phosgene are introduced at room temperature. The ensuing reaction is slightly exothermic. As the reaction is not yet complete, the mixture is stirred for 1 hour at 45° C. The mixture, which is still in the form of a white suspension, is then filtered. The residue is washed with absolute diethyl ether and the resultant white powder is dried in vacuo without heating, affording 20.3 g (90.8% of theory) of 3-chloro-6-isopropyl-4-methyl-1,2,4-triazin-5(4H)-one hydrochloride with a melting point of 144° C. (dec.). The compound sublimes when heated to 45° C. in a high vacuum, yielding the free chloride with a melting point of 129° C. (dec.).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11]#N.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.Cl.CC[O:32]CC>ClCCl>[I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[CH:11]=[O:32]
Reactant: CCOCC
Reactant: N#Cc1cc2c(cc1I)CCC2
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=Cc1cc2c(cc1I)CCC2
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 73 %

Procedure:
To a solution of 6-iodoindane-5-carbonitrile (36.5 mg, 0.136 mmol) in dichloromethane (1.0 mL) under N2 at −78° C. was added a solution of 1N DIBALH in toluene (272 μL, 0.272 mmol) dropwise. The reaction was stirred at −78° C. for 15 min. Keeping the temperature at −78° C., another two portions of DIBALH (100 μL each) were added until the starting material disappeared by TLC. The reaction mixture was poured into 2N HCl (45 mL) and diluted with Et2O. The mixture was stirred for 0.5 h. The Et2O layer was separated. The aqueous layer was extracted with Et2O (2×). The organic extracts were combined, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si, hexanes/EtOAc) to afford 6-iodoindane-5-carbaldehyde (27 mg, 73%). 1H NMR (500 MHz, CDCl3) δ 10.08 (s, 1H), 7.83 (s, 1H), 7.79 (s, 1H), 2.98 (t, J=7.5 Hz, 2H), 2.94 (t, J=7.5 Hz, 2H,), 2.19-2.13 (m, 2H).
Reaction SMILES: [N+]([O-])(O)=O.[CH2:5]([O:7][C:8]([C:10]1[CH:11]=[C:12]([NH:16][C:17]([NH2:19])=[NH:18])[CH:13]=[CH:14][CH:15]=1)=[O:9])[CH3:6].CN(C)[CH:22]=[CH:23][C:24]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]([Cl:32])[CH:27]=1)=O.[OH-].[Na+]>C(O)C(C)C>[CH2:5]([O:7][C:8]([C:10]1[CH:11]=[C:12]([NH:16][C:17]2[N:19]=[C:24]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([Cl:32])[CH:27]=3)[CH:23]=[CH:22][N:18]=2)[CH:13]=[CH:14][CH:15]=1)=[O:9])[CH3:6]
Reactant: CCOC(=O)c1cccc(NC(=N)N)c1
Reactant: CN(C)C=CC(=O)c1ccnc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)CO
Product: CCOC(=O)c1cccc(Nc2nccc(-c3ccnc(Cl)c3)n2)c1

Procedure:
14.5 g (53.7 mmol) of 3-ethoxycarbonyl-phenyl-guanidine nitrate, 11.3 g (53.7 mmol) of 3-dimethylamino-1-(2-chloro4-pyridyl)-2-propen-1-one and 2.4 g (60 mmol) of sodium hydroxide are stirred in 150 ml of isobutanol for 14 hours at 110°. After cooling, washing twice with 100 ml of ethanol each time and crystallising (tetra-hydrofuran/ethanol), N-[3-ethoxycarbonyl-phenyl]-4-(2-chloro4-pyridyl)-2-pyrimidineamine is obtained; m.p. 149°-150°, FAB-MS: 355 (M+ +H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[C:9]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[CH3:34][C:35](OC(C)=O)=[O:36]>C(Cl)Cl.O>[CH3:14][C:11]1([CH3:13])[O:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:35](=[O:36])[CH3:34])=[CH:3][CH:4]=2)=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)=[CH:18][CH:17]=2)[C:10]1=[O:15]
Reactant: CC1(C)OC(c2ccc(N)cc2)=C(c2ccc(OCc3ccc4ccccc4n3)cc2)C1=O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 26.1 %

Procedure:
To a stirred solution of 5-(4-aminophenyl)-2,2-dimethyl-4-(4-(quinolin-2-ylmethoxy)phenyl)furan-3(2H)-one (0.07 g, 0.16 mmol) in DCM (5 mL) were added Ac2O (0.018 mL, 0.19 mmol) and TEA (0.04 mL, 0.32 mmol) at 0° C. under N2 atmosphere. The reaction mixture was stirred at RT for 14 h. The reaction mixture was diluted with water and extracted with DCM (2×15 mL). Combined organic layers were washed with water (2×5 mL), brine and dried over anhydrous Na2SO4. After filtration and evaporation, the crude material was purified by silica gel column chromatography to afford N-(4-(5,5-dimethyl-4-oxo-3-(4-(quinolin-2-ylmethoxy)phenyl)-4,5-dihydrofuran-2-yl)phenyl)acetamide (20 mg, 26%), as an off white solid. 1H NMR (500 MHz, CDCl3): δ 8.22 (d, J=8.5 Hz, 1 H), 8.08 (d, J=7.9 Hz, 1H), 7.84 (d, J=8.4 Hz, 1 H), 7.74 (t, J=8.2 Hz, 1 H), 7.68 (d, J=8.2 Hz, 1 H), 7.64 (d, J=8.2 Hz, 2 H), 7.56 (t, J=8.5 Hz, 1 H), 7.48 (d, J=7.4 Hz, 2 H), 7.22 (d, J=7.5 Hz, 2 H), 7.08 (d, J=8.9 Hz, 2H), 5.42 (s, 2 H), 2.22 (s, 3 H), 1.58 (s, 6 H). MS: [M+Na]: m/z=501.3, [M+H]: m/z=479.3. HPLC: 95.9% (RT-2.32 min), Column: Acquity BEH—C-18, 50×2.1 mm, 1.7 um. Mobile Phase: 0.025% TFA in Water (A), ACN (B), Flow rate: 0.5 ml/min (Gradient).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH3:16])=[O:6]
Reactant: CO
Reactant: Cc1ccc(C(=O)O)cc1C
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C)c(C)c1

Procedure:
15.0 g of 3,4-dimethyl benzoic acid, 29.0 ml of thionyl chloride, 100 ml of methanol, and 1 ml of DMF were processed in a similar manner as in Reference Example 14-(1) to give 15.7 g of methyl 3,4-dimethylbenzoate.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:16])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[Br:17][C:18]([F:25])([F:24])[C:19](OCC)=[O:20]>CN(C)C=O.C(OCC)(=O)C.O.[Cl-].[Na+].O>[Br:17][C:18]([F:25])([F:24])[C:19]([NH:1][CH2:2][C:3]1([OH:16])[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:7][CH2:8]1)=[O:20]
Reactant: CCOC(=O)C(F)(F)Br
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CN)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(O)(CNC(=O)C(F)(F)Br)CC1
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of tert-butyl 4-(aminomethyl)-4-hydroxy-piperidine-1-carboxylate (3.00 g, 13.0 mmol) in N,N-dimethylformamide (30 mL) was added ethyl 2-bromo-2,2-difluoro-acetate (2.65 g, 13.0 mmol) and the reaction mixture stirred for 1 h under nitrogen. The reaction mixture was mixture diluted with ethyl acetate and water (25 mL) and brine (25 mL). The organic layer was dried over Na2SO4, filtered and concentrated to provide tert-butyl 4-[[(2-bromo-2,2-difluoro-acetyl)amino]methyl]-4-hydroxy-piperidine-1-carboxylate (4.98 g, 12.9 mmol, 99%). 1H NMR (400 MHz, DMSO-d6) δ 9.04 (t, J=5.9 Hz, 1H), 4.66 (s, 1H), 3.65 (d, J=12.7 Hz, 2H), 3.16 (d, J=6.1 Hz, 2H), 3.02 (s, 2H), 1.38 (m, 13H).
Reaction SMILES: [CH3:1][Li].[C:3]([C:5]1[C:9]([S:10][C:11]([F:14])([F:13])[F:12])=[C:8]([CH:15]=[O:16])[N:7]([C:17]2[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=2[Cl:28])[N:6]=1)#[N:4].Cl>C(OCC)C.[Cu]I>[C:3]([C:5]1[C:9]([S:10][C:11]([F:13])([F:12])[F:14])=[C:8]([CH:15]([OH:16])[CH3:1])[N:7]([C:17]2[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:26])([F:27])[F:25])=[CH:19][C:18]=2[Cl:28])[N:6]=1)#[N:4]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(C=O)c1SC(F)(F)F
Reactant: [Li]C
Agent: [Cu]I
Agent: Cl
Solvent: CCOCC
Product: CC(O)c1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Copper (1) iodide (6.1 g, 0.032 mol) was suspended in anhydrous diethyl ether and cooled to 0° C. Methyllithium (1.6 M in diethylether, 40 ml, 0.064 mol) was added via cannula and stirred 10 minutes. A solution of the product of Example 3 (10 g, 0.023 mol) in diethyl ether was added via cannula creating a bright yellow suspension. After 15 minutes, 10% aqueous hydrochloric acid (40 ml) was added while venting the reaction vessel. The remaining suspension was filtered through Celite® and washed with diethyl ether several times. The organic phase was washed with saturated sodium hydrogen carbonate solution, saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. Trituration from pentane provided crystals that were purified by silica gel chromatography using ethyl acetate:hexanes. The title compound was isolated as a white solid (7.56 g), m.p. about 123° C.
Reaction SMILES: [CH3:1][C:2]([CH3:17])=[CH:3][CH2:4][NH:5][C:6](=[O:16])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[N+:13]([O-:15])=[O:14].[ClH:18].[N:19]([O:21]CCC(C)C)=O>>[Cl:18][C:2]([CH3:17])([CH3:1])[C:3](=[N:19][OH:21])[CH2:4][NH:5][C:6](=[O:16])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[N+:13]([O-:15])=[O:14]
Reactant: CC(C)CCON=O
Reactant: Cl
Reactant: CC(C)=CCNC(=O)Cn1ccnc1[N+](=O)[O-]
Product: CC(C)(Cl)C(CNC(=O)Cn1ccnc1[N+](=O)[O-])=NO

Procedure:
N-(3-methyl-2-butenyl)-2-(2-nitro-1H-imidazol-1-yl)acetamide (3.4 g, 14.3 mmol) was dissolved in isoamyl nitrite (50 mL) at room temperature. The solution was cooled to 0°-5° C. in an ice-salt bath. Concentrated HCl (1.39 mL) was added dropwise. The reaction temperature was maintained between 0° to 5° C. during the addition of HCl. The reaction mixture was stirred in the ice-salt bath for 1 h, filtered, and washed with 1:2 ethanol-ether to give a white solid.
Reaction SMILES: O.[N:2]1[C:9]([Cl:10])=[N:8][C:6](Cl)=[N:5][C:3]=1[Cl:4].[CH3:11][C:12]([NH2:19])([CH3:18])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15].[OH-]>C1(C)C(C)=CC=CC=1>[Cl:10][C:9]1[N:2]=[C:3]([Cl:4])[N:5]=[C:6]([NH:19][C:12]([CH3:18])([CH3:11])[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:8]=1
Reactant: CC(C)(C)CC(C)(C)N
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(C)(C)CC(C)(C)Nc1nc(Cl)nc(Cl)n1

Procedure:
Into a flask, 20 grams of water, 50.0 grams (0.271 mole) of cyanuric chloride and 125 grams of a mixed xylene were charged and 35.9 grams (0.278 mole) of 1,1,3,3-tetramethylbutylamine was slowly and dropwise added into the mixture while keeping the temperature at 8-10° C. Then, 55.5 grams of a 20% aqueous hydroxide solution was slowly and dropwise added into the mixture while keeping the temperature at 8-10C. After the reaction was complete, the oil (organic) and water phases were separated and the water phase was separated off to obtain a xylene solution of 2,4-dichloro-6-(1,1,3,3-tetramethylbutylamino)-1,3,5-triazine.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[NH2:15][C:16]1C=CC=C[CH:17]=1.C=O>C(O)C>[O:7]1[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[CH:17]=[CH:16][NH:15]1
Reactant: Oc1ccccc1
Reactant: Nc1ccccc1
Agent: C=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: C1=Cc2ccccc2ON1
Yield: 80.5 %

Procedure:
At room temperature, phenol was dissolved in anhydrous ethanol; the pH was adjusted to 8-10; toluene, aniline and formalin were added according to the molar ratio of phenolic hydroxyl group:amine group:aldehyde group of 1:1:2. After being homogeneously stirred, the mixture was heated and refluxed, reacted for 4 h to vacuum distill off ethanol, water, toluene, and placed in a cooling unit. Butanone was added to obtain a yellowish, translucent viscous body. The viscous body was washed, purified and dried to obtain a benzoxazine intermediate having the following structural formula, wherein the yield is 80.5%.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH:1](=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]([O:17][CH2:18][CH3:19])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=Cc1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1ccccc1)C(=O)OCC

Procedure:
Into a one-liter three-necked conical flask are introduced 60 g (565.39 mmol) of benzaldehyde, 90.56 g (565.39 mmol) of diethyl malonate, 3.85 g (45.21 mmol) of piperidine, 130 ml of toluene and 2.71 g (45.16 mmol) of acetic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:15][C:16]([OH:20])([C:18]#[CH:19])[CH3:17].C(OCC)(=O)C>COCCOC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:15][C:16]([OH:20])([C:18]#[C:19][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[CH3:17]
Reactant: C#CC(C)(C)O
Reactant: Brc1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(O)C#Cc1cccnc1
Temperature: 0 °C
Yield: 40 %

Procedure:
3-Bromopyridine (3.0 mL, 31 mmol), triethylamine (22 mL, 160 mmol), CuI (1.2 g, 6.2 mmol), and PdCl2(PPh3)2 (1.1 g, 1.5 mmol) were combined in DME (92 mL) and cooled to 0° C. 2-Methyl-3-butyne-2-ol (9.0 mL, 93 mmol) was then added and the reaction was allowed to slowly warm to ambient temperature. The mixture was then heated to 55-60° C. for 16 h. The mixture was filtered through Celite.™., and the pad was washed thoroughly with ethyl acetate. The combined filtrates were washed with brine (3.times.100 mL), dried over MgSO4, and filtered. The solution was concentrated in vacuo, and the residue was purified by column chromatography eluting with 90:10 hexane:ethyl acetate then ethyl acetate to afford 2-methyl-4-(3-pyridinyl-)-3-butyn-2-ol (2.0 g, 40% yield) as a brown oil 1H NMR (CDCl3, 300 MHz) Δ8.76 (br s, 1H), 8.52 (br s, 1H), 7.74-7.70 (m, 1H), 4.08 (br s, 1H), 1.63 (s, 3H). MS (EI ionization) 161 (M+).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9](Br)=[CH:10][C:11]=2[N+:13]([O-:15])=[O:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:17](=[O:20])([O-])[O-].[Na+].[Na+].[CH2:23]1[CH2:27]O[CH2:25][CH2:24]1>C(OCC)(=O)C>[CH3:5][N:4]1[C@H:1]2[C@@:23]([CH3:27])([C:23]3[CH:27]=[CH:8][C:7]([C:9]4[CH:8]=[C:7]5[C:12](=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=4)[N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]5)=[CH:6][C:24]=3[CH2:25][CH2:2]2)[CH2:24][CH2:25][C:17]1=[O:20]
Reactant: C1CCOC1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)N1CCc2cc(Br)cc([N+](=O)[O-])c21
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)N1CCc2cc(-c3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)cc([N+](=O)[O-])c21
Yield: 22 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo [f]quinolin-3-one-8-boronic acid (178 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 1-acetyl-5-bromo-7-nitroindoline (185 mg, 0.65 mmol), 0.65 mL of 2M sodium carbonate and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (5% methanol/ethyl acetate eluent) to give 63 mg (22%) of the title compound a yellow solid. mp 235°-240°. FDMS: m/e=433. α[D]589 =+65.72 (c=0.99, chloroform).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:16][CH2:17][CH:18]2[CH2:20][CH2:19]2)=[C:6]([NH:8][C:9](=O)[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]([CH2:17][CH:18]3[CH2:20][CH2:19]3)[C:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:8][C:6]=2[CH:7]=1
Reactant: CC(C)(C)CC(=O)Nc1cc(Br)ccc1NCC1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)Cc1nc2cc(Br)ccc2n1CC1CC1
Temperature: 0 °C
Yield: 95.3 %

Procedure:
A mixture of N-{5-bromo-2-[(cyclopropylmethyl)amino]phenyl}-3,3-dimethylbutanamide (Step C, 11.2 g, 33.0 mmol), p-toluenesulfonic acid monohydrate (6.29 g, 33.0 mmol) and toluene (240 mL) was stirred at reflux temperature for 20 h with Dean-Stark apparatus. The mixture was cooled to 0° C. The resulting precipitate was collected by filtration and washing with small amount of ethyl acetate. The residue was dissolved in ethyl acetate (200 mL). The whole was extracted with saturated sodium hydrogen carbonate aqueous solution (100 mL). The organic layer was washed with brine (20 mL), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:1 as eluent) to give the title compound (10.1 g, 95%) as a white solid.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6]C)=[O:5].Cl.[Li+].[OH-].[CH:22]1([NH:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CO.CCN(CC)CC>[OH:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O-:6])=[O:5].[CH:29]1([NH2+:28][CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: CCCCCCCCCCCC(=O)CC(=O)OC
Reactant: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Product: C1CCC([NH2+]C2CCCCC2)CC1
Product: CCCCCCCCCCC[C@@H](O)CC(=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.8 %

Procedure:
A solution of methyl 3-oxotetradecanoate (19 g, 0.074 mol) in MeOH (100 mL) was degassed by sparging with argon (15 min). [(R)-Ru(Binap)Cl]2.NEt3 catalyst (0.187 g, 0.111 mmol) and 2 N aqueous HCl (0.5 mL) were added and the resulting mixture was hydrogenated at 60 psig and 40-50° C. for 18 h. The reaction was diluted with hexanes (250 mL), filtered through a short column of silica gel, and concentrated. The crude product was dissolved in tetrahydrofuran (THF; 200 mL), treated 2.4 N aqueous LiOH (83 mL, 0.2 mol) and stirred vigorously at room temperature for 4 h. The resulting slurry was partitioned between ether (200 mL) and 1 N aqueous HCl (200 mL) and the layers separated. The aqueous layer was extracted with ether (100 mL) and the combined ethereal extracts were dried (Na2SO4) and concentrated. The crude hydroxy acid was dissolved in hot acetonitrile (250 mL), treated with dicyclohexylamine (DCHA; 17 ml, 0.085 mol) and stirred at 60° C. for 1 h. The product that crystallized upon cooling was collected and recrystallized from acetonitrile (650 mL) to yield 28.6 g (91%) of dicyclohexylammonium (R)-3-hydroxytetradecanoate as a colorless solid: mp 94-95° C.; 1H NMR (CDCl3) δ 0.88 (˜t, 3 H, J˜6.5 Hz), 1.05-1.58 (m, 24 H), 1.65 (m, 2 H), 1.80 (m, 4 H), 2.01 (br d, 4 H) 2.18 (dd, 1 H, J=15.7, 9.4 Hz), 2.36 (dd, 1 H, J=15.7, 2.6 Hz), 2.94 (m, 2 H), 3.84 (m, 1 H)
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:12][O:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15]>C(OCC)C>[S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)([O-:16])(=[O:15])=[O:13].[CH3:12][N+:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[S:4][C:3]=1[S:2][CH3:1]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CSc1nc2ccccc2s1
Solvent: CCOCC
Product: CSc1sc2ccccc2[n+]1C
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 116.2 %

Procedure:
A mixture of 2-methylthio-benzothiazole (18.4 g, 0.1 mol) and methyl-p-toluenesulfonate (76 mL, 0.5 mol) was heated to a temperature between 120° C. to 145° C. for 1 hour. After cooling to room temperature diethyl ether (200 mL) was added. The resulting solid was triturated with diethyl ether and isolated by filtration to give the crude product (42.7 g, quantitative). 1H-NMR (300 MHz, CDCl3): δ 8.12 (d, 1H), 7.92 (d, 1H), 7.62 (d, 3H), 7.3 (t, 1H), 7.02 (d, 2H), 4.05 (s, 3H); 3.0 (s, 3H), 2.23 (3, 3H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[O:13][CH2:12][CH2:11][NH:10][CH2:9]1.C(N(CC)CC)C.Cl[C:22]1[N:27]=[C:26]([NH2:28])[C:25]([N+:29]([O-:31])=[O:30])=[CH:24][CH:23]=1.C(OCC)(=O)C>CS(C)=O>[N+:29]([C:25]1[C:26]([NH2:28])=[N:27][C:22]([N:10]2[CH2:11][CH2:12][O:13][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)[CH2:9]2)=[CH:23][CH:24]=1)([O-:31])=[O:30]
Reactant: c1ccc(C2CNCCO2)nc1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Nc1nc(N2CCOC(c3ccccn3)C2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 18 h
Yield: 70.5 %

Procedure:
To a solution of 2-(pyridin-2-yl)morpholine hydrochloride (1000 mg, 4.22 mmol) and triethylamine (1.3 mL, 9.3 mmol) in dimethylsulfoxide (10 mL) was added 6-chloro-3-nitropyridin-2-amine (734 mg, 4.23 mmol). The reaction mixture was stirred at 100° C. for 18 h. The reaction mixture was cooled to room temperature. Ethyl acetate was added and the mixture was washed with water (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL×2). The combined organics were washed with brine (20 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via flash chromatography (40-100% ethyl acetate in heptanes) to afford the title compound (0.897 g, 70%). 1H NMR (400 MHz, CDCl3) δ 3.08 (s, 1H), 3.18-3.29 (m, 1H), 3.83 (s, 1H), 4.20 (s, 1H), 4.41 (d, 1H), 4.63 (dd, 1H), 4.67-4.80 (m, 1H), 6.18 (s, 1H), 7.23-7.26 (m, 1H), 7.54 (s, 1H), 7.75 (s, 1H), 8.22 (s, 1H), 8.60 (s, 1H).