Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].P(=O)([O-])[O-].[CH2:12]([Li])[CH2:13][CH2:14]C.C(O)(=O)C.[O:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>CCCCCC>[O:21]=[C:25]([C:24]1[CH:14]=[CH:13][CH:12]=[CH:22][CH:23]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: [Li]CCCC
Reactant: COP(C)(=O)OC
Reactant: C1CCOC1
Agent: O=[PH]([O-])[O-]
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)c1ccccc1)OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 29 %

Procedure:
A solution of 74.5 g (600 mmoles) dimethyl methylphosphonate (Aldrich) in 750 ml dry tetrahydrofuran was cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution was added 265 ml of 2.34 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 30 minutes at such a rate that the reaction temperature never rose above -65°. After an additional 5 minutes stirring at -78°, 41 g (300 mmole) of methyl azoate was added dropwise at a rate that kept the reaction temperature less than -70° (10 minutes). After 1 hour at -78° the reaction mixture was allowed to warm to ambient temperature, neutralized with 35 ml acetic acid and rotary evaporated to a white gel. The gelatinous material was taken up in 75 ml water, the aqueous phase extracted with 300 ml portions of ether (3x), the combined organic extracts were backwashed (50 cc H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled, b.p. 130°-5° (0.04 mm) to give 35 g (29%) dimethyl 2-oxo-2-phenylethylphosphonate (2a).
Reaction SMILES: C(N)(C)(C)C.[C:6]([NH:10][CH2:11][CH:12]([OH:25])[CH2:13][O:14][C:15]1[C:24]2[CH2:23][CH:22]=CC[C:19]=2[CH:18]=[CH:17][CH:16]=1)([CH3:9])([CH3:8])[CH3:7].[C:26]([O:29]I)(=O)[CH3:27].C(O)(=[O:33])C>[Ag]I>[CH3:7][C:6]([NH:10][CH2:11][CH:12]([OH:25])[CH2:13][O:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[CH2:27][C@@H:26]([OH:29])[C@@H:22]([OH:33])[CH2:23][C:24]=12)([CH3:9])[CH3:8]
Reactant: CC(=O)O
Reactant: CC(=O)OI
Reactant: CC(C)(C)NCC(O)COc1cccc2c1CC=CC2
Agent: [Ag]I
Solvent: CC(C)(C)N
Product: CC(C)(C)NCC(O)COc1cccc2c1C[C@H](O)[C@H](O)C2

Procedure:
Subsequently Hauck in Canadian Letters Patent 1,041,544 attempted to separate the four optical cis isomers of 2,3-cis-1,2,3,4-tetrahydro-S-[2-hydroxy-3-(tert-butylamino) propoxy]-2,3-naphthalenediol in order to determine the best of these isomers. The processes of manufacture (See pages 4, 5 and 6 of the Patent and example 4 at pages 18 and of the patent) employ water. Crystallization of isomer product is from chloroform. In Hauck's laboratory procedure resulting 1-(2,3-epoxypropoxy)-5,8-dihydronaphthalene is isolated and subsequently reacted with t-butylamine in a high pressure reactor. The resulting dl-1-(tert-butylamino)-3-(5,8-dihydronaphthyl)oxyl-2-propanol is then cis hydroxylated with wet acetic acid, silver iodide, and the resulting acetoxy iodide is hydrolysed with base and finally subjected to catalytic hydrogenation to afford crude Nadolol.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=[C:5]2[C:4](=O)[NH:3]1.P(Br)(Br)([Br:16])=O.O>C(#N)C>[Br:16][C:4]1[C:5]2[C:6](=[N:7][C:8]([S:11][CH3:12])=[N:9][CH:10]=2)[N:2]([CH3:1])[N:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: CSc1ncc2c(=O)[nH]n(C)c2n1
Solvent: O
Solvent: CC#N
Product: CSc1ncc2c(Br)nn(C)c2n1
Temperature: 5 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
1-Methyl-6-methylsulfanyl-1,2-dihydro-pyrazolo[3,4-d]pyrimidin-3-one (2.0 g, 0.01 mol) was refluxed with phosphorus oxybromide (6 g) in acetonitrile (60 mL). Water (100 mL) was then added and the reaction mixture cooled to 5° C., hold for 1 hour and filtered to give 1.6 g (61%) of pure 3-bromo-1-methyl-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine; 1H-NMR (DMSO): δ 2.61 (s, 3H), 3.96 (s, 3H), 9.00 (s, 1H), LC/MS (m/e)=260.8 (MH+), Rt=1.89 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([CH3:13])[CH:7]=1.[N:15]([O-])=O.[Na+]>C(O)(=O)C.O.[Zn]>[F:12][C:9]1[CH:10]=[CH:11][C:6]([N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:14])[NH2:15])=[CH:7][C:8]=1[CH3:13]
Reactant: COC(=O)CNc1ccc(F)c(C)c1
Reactant: O=N[O-]
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)CN(N)c1ccc(F)c(C)c1
Reaction time: 1 h
Yield: 17.4 %

Procedure:
N-(4-Fluoro-3-methylphenyl)glycine methyl ester (Intermediate 63, 7.5 g, 0.038 mol) was dissolved in a mixture of glacial acetic acid (60 ml) and water (8 ml) and the solution was cooled to ~5° C. To this was added a solution of sodium nitrite (4.3 g, 0.063 mol) in water (15 ml) at the same low temperature over 20 minutes. Stirring was continued for 1 hour and the temperature was then lowered to between -10° and 0° C. Zinc dust (15.3 g, 0.234 mol) was added at the maintained low temperature and the resulting suspension was stirred at ~0° C. for 4 hours. It was then poured into water (250 ml) and extracted with ethyl acetate (2×200 ml). The extract was washed with 8% sodium bicarbonate solution until all effervescence had ceased. It was then dried (MgSO4) and evaporated to give a brown semi-solid. This was triturated with ether/hexane (1:2, ~15 ml) to give a white solid which was filtered and washed with ice-cold ether. The liquors were evaporated to give a brown oil and this was purified by flash column chromatography on silica (Merck 9385; 225 g) eluting with ether/hexane (1:1) to give the title compound (Intermediate 64) as an orange oil (1.4 g, 17%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:14]=1[NH2:15]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:15][C:14]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:13]=1[CH3:12])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Cc1ccc(C(F)(F)F)cc1N
Product: Cc1ccc(C(F)(F)F)cc1NC(=O)c1cc(Cl)ccc1O
Yield: 73.3 %

Procedure:
Using 5-chlorosalicylic acid and 2-methyl-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[S:6][C:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)[CH:9]=1)=[O:4].I([O-])(=O)(=O)=[O:26].[Na+].O>CO>[CH3:1][NH:2][C:3]([C:5]1[S:6][C:7]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([S:16]([CH3:17])=[O:26])=[CH:14][CH:15]=2)[CH:9]=1)=[O:4]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CNC(=O)c1cc(-c2ccc(SC)cc2)c(-c2ccc(F)cc2)s1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CNC(=O)c1cc(-c2ccc(S(C)=O)cc2)c(-c2ccc(F)cc2)s1
Temperature: 0 °C
Reaction time: 48 h
Yield: 63.4 %

Procedure:
A mixture of N-methyl-5-(4-fluorophenyl)-4-[4-(methylthio)phenyl]thiophene-2-carboxamide (1.66 g), sodium periodate (1.05 g) and water (1 ml) in methanol (100 ml) was stirred at 0° C. for 2 days. The insoluble was filtered and the filtrate was evaporated. The residue was extracted with dichloromethane. The extract was washed with water, dried over magnesium sulfate and concentrated to dryness. The residue was recrystallized from ethanol to give colorless crystals of N-methyl-5-(4-fluorophenyl)-4-[4-(methylsulfinyl)phenyl]thiophene-2-carboxamide (1.1 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C@H:14]([OH:25])[CH2:15][O:16][C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>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>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C@H:14]([OH:25])[CH2:15][O:16][C@@H:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH3:18])=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1[C@H](O)CO[C@H](C)c1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4[C@H](O)CO[C@H](C)c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using dichlorobis(triphenylphosphine)palladium(II) as the catalyst and using (S)-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-((R)-1-phenyl-ethoxy)-ethanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: COC1C=CC=CC=1C1NC(=O)C2C(=CC=CC=2)N=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24].[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][CH:44]=1)[CH:40]=O>>[CH3:35][O:36][C:37]1[CH:38]=[C:39]([C:40]2[NH:25][C:23](=[O:24])[C:22]3[C:21](=[CH:29][CH:28]=[C:27]([N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH:26]=3)[N:20]=2)[CH:42]=[CH:43][CH:44]=1
Reactant: NC(=O)c1cc(N2CCCC2)ccc1N
Reactant: COc1cccc(C=O)c1
Agent: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Product: COc1cccc(-c2nc3ccc(N4CCCC4)cc3c(=O)[nH]2)c1
Yield: 38.1 %

Procedure:
According to the preparation of 42, 26 (1.0 g, 4.9 mmol) and 3-methoxybenzaldehyde (34) (0.7 g, 4.9 mmol) were used to afford 56 (0.6 g, 40.0%) as pale yellow prism crystals.
Reaction SMILES: CCCCO[C@H:6]([CH2:9]O)CC.[C:11]([O-:24])(=[O:23])[CH2:12][CH2:13]CCCCCCCCC.[C:25]([O-:38])(=[O:37])CCCCCCCCCCC.C([Sn+2]CCCC)CCC.O=C=[N:50]C1CC(C)(C)CC(C)(CN=C=O)C1>C(O)COCCO>[C:11]([OH:24])(=[O:23])[CH:12]=[CH2:13].[NH2:50][C:25]([O:38][CH2:6][CH3:9])=[O:37]
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Reactant: CCCCCCCCCCCC(=O)[O-]
Reactant: CCCCO[C@@H](CC)CO
Agent: CCCC[Sn+2]CCCC
Solvent: OCCOCCO
Product: C=CC(=O)O
Product: CCOC(N)=O
Temperature: 70 °C
Reaction time: 5 h

Procedure:
Air was fed to a 2 L three-necked flask equipped with a stirrer, a thermometer, a condenser, and an air inlet tube, and then polytetramethylene glycol (trade name: PTG850SN, product of Hodogaya Chemical Co., Ltd.) (520.8 g), diethylene glycol (1.06 g), unsaturated fatty acid hydroxyalkyl ester-modified ε-caprolactone (trade name: FA2D, product of Daicel Chemical Industries, Ltd.) (275.2 g), p-methoxyquinone (0.5 g) serving as a polymerization inhibitor, and dibutyltin dilaurate (trade name: L101, product of Tokyo Fine Chemical Co., Ltd.) (0.3 g) serving as a catalyst were added to the flask and heated to 70° C. Thereafter, isophorone diisocyanate (trade name: Desmodur I, product of Sumika Bayer Urethane Co., Ltd.) (222 g) was uniformly added dropwise to the flask over two hours under stirring at 70 to 75° C., to thereby allow reaction to proceed. After completion of dropwise addition, reaction was allowed to proceed for about five hours and then stopped. The weight average molecular weight of the resultant product (as reduced to standard polystyrene) was determined by means of GPC(SD-8022/DP-8020/RI-8020, product of Tosoh Corporation). Thus, urethane acrylate A having a weight average molecular weight of 10,000 was produced.
Reaction SMILES: C([SiH](CC)CC)C.[S:8]1[C:12]([CH:13]([C:15]2[CH:24]=[C:23]([Br:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[O:26][CH3:27])O)=[CH:11][C:10]2[CH:28]=[CH:29][CH:30]=[CH:31][C:9]1=2.CO.O>C(Cl)Cl>[Br:25][C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([O:26][CH3:27])=[C:15]([CH2:13][C:12]2[S:8][C:9]3[CH:31]=[CH:30][CH:29]=[CH:28][C:10]=3[CH:11]=2)[CH:24]=1
Reactant: COc1c(C(O)c2cc3ccccc3s2)cc(Br)c2ccccc12
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COc1c(Cc2cc3ccccc3s2)cc(Br)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
In a nitrogen stream, triethylsilane (2.48 ml, 15.5 mmol) and a boron trifluoride-diethyl ether complex (1.08 ml, 8.54 mmol) were added dropwise to a solution of benzo[b]thiophen-2-yl-(4-bromo-1-methoxynaphthalen-2-yl)methanol (3.1 g, 7.76 mmol) in methylene chloride (60 ml) at 0° C. and the reaction mixture was stirred at room temperature for two hours, and then a 50% methanol aqueous solution (1 ml) was added and furthermore water (30 ml) was added thereto. The resulting mixture was extracted with methylene chloride, and the organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:50)] to obtain the title compound (2.38 g, 80%).
Reaction SMILES: CS[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH:11]=1)[C:6]([OH:8])=[O:7].O[O:19][S:20]([O-:22])=O.[K+].[CH3:24]O.O>>[CH3:24][S:20]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH:11]=1)[C:6]([OH:8])=[O:7])(=[O:22])=[O:19]
Reactant: O=S([O-])OO
Reactant: CSc1cc(C(=O)O)cc(N2CCCC2=O)c1
Reactant: CO
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1cc(C(=O)O)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 86 %

Procedure:
To a solution of 3-methylsulfanyl-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid (A1) (59 mg, 0.235 mmol, 1 equiv) in MeOH/H2O (3:1, 24 ml) was added oxone (578 mg, 0.94 mol, 4 equiv). The resulting mixture was stirred at room temperature for 50 min and then concentrated in vacuo. The residue was partitioned between AcOEt and H2O and the layers separated. The organic layer was washed with H2O and brine, dried over Na2SO4 and concentrated in vacuo to give a solid which was triturated with Et2O to give 3-methanesulfonyl-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid (A5) (57 mg, 86%) as a white solid. [M+H]+=284.0, RT=2.05 min
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C@@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][C@H:9]2[CH2:17][C:18]#[N:19])=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1F.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.CCOC(C)=O>[Cl:20][C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]=1[O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH:11]([C:13]([F:16])([F:14])[F:15])[CH2:10][C@H:9]2[CH2:17][C:18]#[N:19])=[CH:6][CH:7]=1
Reactant: Fc1ccc(C(F)(F)F)cc1Cl
Reactant: N#CC[C@@H]1C[C@H](C(F)(F)F)CN1c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#CC[C@@H]1CC(C(F)(F)F)CN1c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1
Temperature: 110 °C
Yield: 87.8 %

Procedure:
2-((2S,4S)-1-(4-hydroxyphenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetonitrile (49A, 0.020 g, 0.074 mmol) and 2-chloro-1-fluoro-4-(trifluoromethyl)benzene (0.029 g, 0.15 mmol) were dissolved in DMF (0.8 mL) and cesium carbonate (0.060 g, 0.19 mmol) was added. The mixture was heated to 110° C. for 2 h. The reaction was cooled to rt and diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with water (2×), brine, dried (MgSO4) and concentrated. The crude product was purified by silica gel chromatography to provide (S)-2-(1-(4-(2-chloro-4-(trifluoromethyl)phenoxy)phenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetonitrile (0.029 g, 0.065 mmol, 87% yield) as an inseparable mixture of diastereomers which was taken on to the next step. Example 59 (off white solid, 0.002 g, 5 μmol, 15% yield) was prepared from (S)-2-(1-(4-(2-chloro-4-(trifluoromethyl)phenoxy)phenyl)-4-(trifluoromethyl)pyrrolidin-2-yl)acetonitrile following the procedure of 36C. LC-MS Anal. Calc'd for C20H16ClF6NO3 467.79. found [M+H] 468.0. 1H NMR (400 MHz, acetonitrile-d3) δ ppm 7.78-7.86 (1 H, m), 7.51 (1 H, d, J=8.59 Hz), 7.01 (2 H, d, J=8.84 Hz), 6.89 (1 H, d, J=8.59 Hz), 6.75 (2 H, d, J=9.09 Hz), 4.21-4.33 (1 H, m), 3.62 (1 H, t, J=9.35 Hz), 3.48-3.56 (1 H, m), 3.12-3.28 (1 H, m), 2.85 (1 H, dd, J=15.92, 2.78 Hz), 2.65 (1 H, dt, J=13.64, 8.59 Hz), 2.28 (1 H, dd, J=15.92, 9.85 Hz), 2.02 (1 H, ddd, J=13.58, 7.89, 5.81 Hz). Analytical HPLC: RT=11.2 min, HI: 99.0%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)=[N:2]1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(O)C>[CH2:12]([N:9]1[CH2:10][CH:11]=[C:6]([C:3]2[CH:4]=[CH:5][NH:1][N:2]=2)[CH2:7][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1cc(-c2cc[nH]n2)ccn1
Reactant: BrCc1ccccc1
Solvent: CC(C)O
Product: C1=C(c2cc[nH]n2)CCN(Cc2ccccc2)C1
Reaction time: 0.5 h

Procedure:
To a hot (80° C.) solution of 4-(1H-pyrazol-3-yl)pyridine (9.6 g) in 2-propanol (60 mL) was added benzyl bromide (20 mL, 2.5 equiv.) and the resulting mixture was heated at reflux for 10 minutes. After cooling in an ice bath, the precipitate was filtered and washed with more 2-propanol and air dried. The solid was suspended in ethanol at 0° C. and sodium borohydride (13 g) was added in several portions over 30 minutes, and the mixture was stirred for an additional 30 minutes. The reaction was quenched by the careful addition of water, the ethanol was removed by evaporation, and the residue was partitioned between dichloromethane and water. The organic layer was dried over MgSO4, filtrated and evaporated to give 1-benzyl-4-(1H-pyrazol-3-yl)-1,2,3,6-tetrahydropyridine (16 g)
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:3]=1.N[C:14]1[N:18]([CH2:19][CH3:20])[N:17]=[CH:16][CH:15]=1.[CH2:21](NN)[CH3:22].O.NN>>[CH2:19]([N:18]1[C:14]2[C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][NH:6][C:2]=3[N:1]=[C:8]3[CH2:9][CH2:10][C:22]4[CH:21]=[CH:7][CH:4]=[CH:3][C:2]=4[C:16]([C:15]=23)=[N:17]1)[CH3:20]
Reactant: CCn1nccc1N
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Reactant: CCNN
Agent: NN
Solvent: O
Product: CCn1nc2c3c(nc4[nH]nc(-c5ccccc5)c4c31)CCc1ccccc1-2

Procedure:
By substituting 5-amino-3-phenylpyrazole for the 5-amino-1-ethylpyrazole in part a of Example 1 and continuing as in that Example but substituting ethylhydrazine for the hydrazine hydrate in part e, 2-ethyl-2,5,7,8-tetrahydro-3-phenyl-1,2,4,5,6-pentaazabenzo[6,7]cyclohepta[1,2,3-cd]-as-indacene is obtained.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9](=[O:23])[C:10](=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12].CO[C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1.O>CN(C=O)C>[CH3:14][O:13][C:11](=[O:12])[C:10](=[CH:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:30][C:29]2[CH:32]=[CH:33][CH:26]=[C:27]([O:4][CH3:1])[CH:28]=2)=[CH:20][CH:21]=1)[C:9]([O:8][CH3:7])=[O:23]
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)C(=Cc1ccc(O)cc1)C(=O)OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(=Cc1ccc(OCc2cccc(OC)c2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
K2CO3 was added to a solution of 4-hydroxybenzylidene-malonic acid dimethyl ester (6.95 mmol) and 4-methyoxybenzyl chloride (7.64 mmol) in DMF (15 ml). It was stirred at room temperature overnight. The reaction was poured into water, and the product was extracted with ethyl acetate twice. The organic layer was washed with water and saturated brine, dried over Na2SO4, and concentrated in vacuo. The resulting residue was purified using silica gel column chromatography (hexane/ethyl acetate=2/1) to give compound 33.1 as a white solid (3.2 mmol).
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24][NH2:25]>>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6]1=[CH:17][C:2]([NH:25][CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[C:21]([O:20][CH3:19])[CH:22]=3)=[N:3][C:4](=[O:18])[N:5]1[CH2:14][CH2:13]2
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Reactant: COc1cccc(CN)c1
Product: COc1cccc(CNc2cc3n(c(=O)n2)CCc2cc(OC)ccc2-3)c1

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 3-methoxy-benzylamine as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 7.95 (t, 1H), 7.65 (d, 1H), 7.25 (t, 1H), 7.00-6.85 (4H), 6.82 (dd, 1H), 6.19 (s, 1H), 4.50 (d, 2H), 3.92 (t, 2H), 3.82 (s, 3H), 3.74 (s, 3H) and 2.92 (t, 2H); MS (ESI) (M+H)+ 364.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[C:13](OC)(=[O:20])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].CO>CCCCCCC.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:13]([O:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([OH:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)(=[O:20])[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Reactant: COC(=O)CCC(=O)OC
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCCCCCC
Solvent: CO
Product: COC(=O)CCC(=O)OC1CC(C)(C)N(O)C(C)(C)C1

Procedure:
A solution of 6.0 g (35 mmol) of 1-oxyl-2,2,6,6-tetramethyl-4-hydroxypiperidine and 11.4 g (78 mmol) dimethyl succinate in 60 mL of heptane is brought to reflux. 0.05 mL of tetraisopropyl orthotitanate is added and the reaction mixture is refluxed for 16 hours while the evolved methanol is trapped in a Dean-Stark trap. The reaction mixture is then concentrated and the title compound is isolated as a red oil after column chromatography and melts at 76° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])=[CH:28][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[C:14]([CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])[CH:15]=1)=[O:9])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].C(Cl)(Cl)Cl.Cl>C(O)C.O>[CH2:1]([O:5][C:6]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])=[CH:28][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[C:14]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:15]=1)=[O:9])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)CCc1cc(C(=O)c2cc(OCC(C)C)ccc2OCC(C)C)ccc1OCC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: O
Product: CC(C)COc1ccc(OCC(C)C)c(C(=O)c2ccc(OCC(C)C)c(CCC(=O)O)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
In 26 ml of ethanol is dissolved 5.2 g of ethyl 3-[5-(2,5-diisobutoxybenzoyl)-2-isobutoxyphenyl]-propanoate. After adding 6 ml of 5 mol/L aqueous solution of sodium hydroxide, the mixture is stirred at ambient temperature for 30 minutes. Chloroform and water are added to the reaction mixture, pH is adjusted to 2 with 6 mol/L hydrochloric acid, and the organic layer is separated. The organic layer is washed with water and saturated aqueous solution of sodium chloride successively, and the solvent is distilled off from the reaction mixture under reduced pressure. Thus, 4.9 g of 3-[5-(2,5-diisobutoxybenzoyl)-2-isobutoxyphenyl]-propanoic acid is obtained as a yellow solid product.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[CH2:13][CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][CH2:17][C:5]1=2.C(C(O)=O)(F)(F)F.C(Cl)[Cl:33]>>[ClH:33].[ClH:33].[CH2:13]1[C:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[N:4]([CH2:3][CH2:2][NH2:1])[C:5]=2[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCN)c3ccccc23)CC1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NCCn1c2c(c3ccccc31)CCNCC2
Reaction time: 4 h

Procedure:
tert-Butyl 6-(2-aminoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0336 g, 0.102 mmol) was dissolved in CH2Cl2 (2 mL) at rt. CF3CO2H (1 mL) was added and the reaction mixture was stirred for 4 h. The reaction mixture was concentrated and the residue was taken up in EtOAc (2 mL). HCl in Et2O (1 N) and MeOH were added and the mixture was concentrated to give crude 2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethanamine dihydrochloride (0.0339 g). 1H NMR (300 MHz, DMF-d7) δ 3.48-3.51, 3.53-3.59, 3.65-3.70, 3.75-3.79, 4.94, 7.27, 7.35, 7.72, 7.91; MS (ESI+) for C14H19N3 m/z 230.2 (M+H)+.