Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1.Cl.[CH3:13][O:14][C:15](=[O:19])[CH2:16][NH:17][CH3:18].C(N(CC)CC)C.[Na+].[Cl-]>CN(C)C=O>[N:4]1[C:3]([CH2:2][N:17]([CH3:18])[CH2:16][C:15]([O:14][CH3:13])=[O:19])=[CH:11][N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: ClCc1cn2ccccc2n1
Reactant: CNCC(=O)OC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CN(C)Cc1cn2ccccc2n1
Yield: 25.9 %

Procedure:
0.303 g (1.773 mmol) of 2-(chloromethyl)imidazo[1,2-a]pyridine were dissolved in 15 ml of dimethylformamide with magnetic stirring and then 0.253 g (1.773 mmol) of sarcosine methylester hydrochloride and 0.741 ml (5.32 mmol) of triethylamine were added. The mixture was stirred at r.t. for 16 h, and then treated with 30 ml of a saturated NaCl aqueous solution. The aqueous phase was concentrated in vacuo. The residue was triturated in 75 ml of isopropanol, the salts were removed by filtration and the filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: dichloromethane/methanol, 95/5, v/v). 0.107 g (yield=26%) of methyl 2-((imidazo[1,2-a]pyridin-2-ylmethyl)(methyl)amino)acetate were obtained as a pale yellow oil. LC-MS: m/z=234 (MH+); UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.49 (d, J=6.8 Hz, 1H), 7.79 (s, 1H), 7.47 (d, J=9.0 Hz, 1H), 7.18 (ddd, J=9.0, 6.7, 1.2 Hz, 1H), 6.84 (td, J=6.7, 1.1 Hz, 1H), 3.76 (s, 2H), 3.61 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [CH:1]1([C:7]2[S:19][C:10]3[N:11]=[C:12]([CH3:18])[N:13]=[C:14](/[CH:15]=[CH:16]\[OH:17])[C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[BH4-].[Na+]>O>[CH:1]1([C:7]2[S:19][C:10]3[N:11]=[C:12]([CH3:18])[N:13]=[C:14]([CH2:15][CH2:16][OH:17])[C:9]=3[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1nc(/C=C\O)c2cc(C3CCCCC3)sc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1nc(CCO)c2cc(C3CCCCC3)sc2n1
Reaction time: 0.25 h
Yield: 72.7 %

Procedure:
To a mixture of (Z)-2-(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)ethenol (430 mg) and MeOH (10 mL) was added NaBH4 (65 mg) in small divided portions, followed by stirring for 15 minutes. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed sequentially with a saturated aqueous NH4Cl solution and brine, and dried over Na2SO4, and the residue was purified by silica gel column (hexane/EtOAc) to obtain 2-(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)ethanol (315 mg).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]3[C:19]=2[C:20](=O)[C:21]([O:23]CC)=[O:22])=[CH:6][CH:5]=1.NN.C(O)(=O)C>O.C(O)C.CO>[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]3[C:19]=2[CH2:20][C:21]([OH:23])=[O:22])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(=O)c1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CC(=O)O)cc1
Temperature: 60 °C
Yield: 96 %

Procedure:
A solution of potassium hydroxide (90% titre; 30.3 g; 0.48 mols) in water (225 mL) and ethanol (65 mL) is added with ethyl 2-(4-methylphenyl)-6-methylimidazo[1,2-a]-pyridine-3-glyoxalate (141.5 g; 0.44 mols). The suspension is refluxed to obtain a yellow-orange solution, which is concentrated to reach a temperature of 98-100° C. and added with hydrazine (51.7% titre, 27.5 g; 0.44 mols). The solution is refluxed for 14 hours, then cooled to about 60° C., added with potassium hydroxide (90% titre, 54.9 g; 0.88 mols), then distilled under atmospheric pressure to reach the inner temperature of 122÷124° C., keeping the resulting suspension under reflux until nitrogen evolution ceases. The mixture is cooled to about 100° C., diluted with water (500 mL), cooled at room temperature and filtered through Celite. The resulting clear solution is dropped in about one hour into an acetic acid solution (91 g; 1.52 mols) in methanol (500 mL). The resulting suspension is cooled to 0÷5° C., filtered and the solid is washed with water, then dried at 60° C. under vacuum to obtain 2-(4-methylphenyl)-6-methylimidazo[1,2-a]-pyridine-3-acetic acid (118.4 g, 98.5% titre, K.F. 1.4%, yield 96.5%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)=[CH:8][CH:7]=1)=[O:4].[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(C(C)C)CC)(C)C>CCOCC.ClCCl.C(OCC)(=O)C>[N:21]1([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([B:12]3[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]3)=[CH:8][CH:7]=2)=[O:4])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC1(C)OB(c2ccc(NC(=O)CCl)cc2)OC1(C)C
Reactant: C1CCNC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OB(c2ccc(NC(=O)CN3CCCC3)cc2)OC1(C)C
Temperature: 25 °C

Procedure:
To a solution of intermediate T (0.200 g, 0.677 mmol) in ether (10 mL) was added pyrrolidine (0.241 g, 3.3 mmol), diisopropylethyl amine (0.175 g, 1.3 mmol) and the reaction stirred at room temperature for 48–72 h and monitored by TLC (10% Ethyl acetate: dichloromethane). The reaction was concentrated in vacuo and purified using a 10 g prepacked silica gel column, eluting intermediate U with 10% ethyl acetate:dichloromethane, (0.145 g, 0.439 mmol, 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:15]O)=[C:6]([CH:14]=1)[O:7][CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10].S(Cl)([Cl:19])=O>C(Cl)Cl>[Cl:19][CH2:15][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:14][C:6]=1[O:7][CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C(C)Oc1cc(Cl)ccc1CO
Solvent: ClCCl
Product: COC(=O)C(C)Oc1cc(Cl)ccc1CCl
Yield: 88 %

Procedure:
By the method of Example 1, Step H, 1.0 g (0.0038 mole) of methyl 2-(5-chloro-2-hydroxymethylphenoxy)propionate and 0.5 g (0.0042 mole) of thionyl chloride were reacted in 20 mL of methylene chloride. After purification, 0.88 g of methyl 2-(2-chloromethyl-5-chlorophenoxy)propionate was isolated as a yellow liquid. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]1[CH2:16][CH2:15][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=3[C:5]=2[CH2:4]1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>>[CH3:1][N:2]([CH3:17])[CH:3]1[CH2:16][CH2:15][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([NH:14][C:18]([C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)=[O:25])=[CH:10][C:9]=3[C:5]=2[CH2:4]1
Reactant: CN(C)C1CCc2oc3ccc(N)cc3c2C1
Reactant: O=C(Cl)c1ccncc1
Product: CN(C)C1CCc2oc3ccc(NC(=O)c4ccncc4)cc3c2C1
Yield: 42.4 %

Procedure:
Beginning with 0.132 gm (0.57 mMol) of N,N-dimethyl-8-amino-1,2,3,4-tetrahydro-2-dibenzofuranamine and 0.15 gm (0.84 mMol) of isonicotinoyl chloride, 0.081 gm (42%) of the title compound were obtained by the procedure described in Example 20.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[OH-].[K+].S([O-])([O-])(=O)=O.[Na+].[Na+].[CH2:21]([CH:23]1[O:25][CH2:24]1)Cl>>[O:25]1[CH2:24][CH:23]1[CH2:21][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1
Reactant: ClCC1CO1
Reactant: O=Cc1c[nH]c2ccccc12
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: O=Cc1cn(CC2CO2)c2ccccc12
Temperature: 50 °C
Reaction time: 5 h

Procedure:
Indole-3-carbaldehyde (5 g, 0.034 mol) was dissolved in epichlorohydrin (55 g, available from Aldrich, Milwaukee, Wis.) under mild heating. Potassium hydroxide (KOH, 4.2 g, 0.076 mol) was added to the reaction mixture in three even portions. Additionally, sodium sulphate (Na2SO4, 0.7 g) was added before every addition of KOH into the flask. After stirred for 5 hours at 50° C., the reaction mixture was filtered and epichlorohydrin was removed by vacuum distillation from the filtrate. Then the product was recrystallized from a mixture of acetone and diethyl ether in a volume ratio of 1:1 to form white crystals which were washed with diethyl ether. The yield of the product was 73% (5 g). A 1H-NMR spectrum (100 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 9.97 (s, 1H, CHO), 8.4-8.2 (m, 1H, 2-HHt), 7.38 (s, 1H, 4-HHt), 7.5-7.2 (m, 3H, 5, 6, 7-HHt), 4.65-4.42(dd, 1H, one of NCH2 protons, (HA), JAX=2.4 Hz, JAB=15.2 Hz), 4.2-3.95 (dd, 1H, another NCH2 proton, (HB), JBX=5.7 Hz,), 3.31 (m, 1H, CHO), 2.83 (t, one of OCH2 protons, (HB), JBX=4.4 Hz,) 2.51-2.4 (dd, 1H, CH2O another proton, (HA), JAX=2.4 Hz, JAB=4.6 Hz). An infrared absorption spectrum of the product was characterized by the following absorption wave numbers (KBr windows, in cm−1): ν (arene C—H) 3098, 3045; ν (CH) 2924, 2805, 2752, 2762; ν (CHO) 1646; ν (C═C in Ar) 1536, 1471, γ(Ar) 750. A mass spectrum of the product was characterized by the following ions (in m/z): 202 (100%, M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[C:4](O)[CH:3]=1.FC(F)(F)S(OC1C=CC=C2C=1C=CC(C)=N2)(=O)=O.CC1C=CC2C(=CC=CC=2[N:44]2[CH2:49][CH2:48][N:47](C(OC(C)(C)C)=O)[CH2:46][CH2:45]2)N=1.CC1C=CC2C(=CC=CC=2N2CCNCC2)N=1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[C:4]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:3]=1
Reactant: Cc1ccc2c(O)cc(Cl)cc2n1
Reactant: Cc1ccc2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc2n1
Agent: Cc1ccc2c(N3CCNCC3)cccc2n1
Agent: Cc1ccc2c(OS(=O)(=O)C(F)(F)F)cccc2n1
Product: Cc1ccc2c(N3CCNCC3)cc(Cl)cc2n1

Procedure:
The title compound was prepared from 7-chloro-5-hydroxy-2-methylquinoline (WO/0234754) using similar procedures to descriptions D1, D2 and D3.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:10]=[C:9]([CH:16]([CH3:18])[CH3:17])[C:5]=1[C:6](Cl)=[O:7])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH:16]([C:9]1[CH:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[CH:12]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[CH2:6][OH:7])([CH3:18])[CH3:17]
Reactant: CC(C)c1cc(C(C)C)c(C(=O)Cl)c(C(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)c1cc(C(C)C)c(CO)c(C(C)C)c1
Temperature: 25 °C
Yield: 3.5 %

Procedure:
A solution of 2,4,6-triisopropylbenzoyl chloride (24.96 g, 0.094 mol) in ethyl ether (150 mL) was added in portions over 1 hour to lithium aluminum hydride (3.70 g, 0.097 mol) in ethyl ether (300 mL) keeping the temperature between -15° C. and -30° C. The reaction mixture was allowed to warm to room temperature over about 1 hour. The reaction mixture was cooled to 0° C. and quenched by adding saturated aqueous sodium bisulfate solution. The layers were separated, the aqueous layer was back-extracted with ethyl acetate, the organic layers were combined and dried (magnesium sulfate), filtered, and concentrated to a white solid (21.50 g, 98% crude). An analytical sample was obtained by filtering 1.0 g through silica gel using hexanes, then 5% ethyl acetate in hexanes as eluant yielding 0.778 g of the product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](O)=[O:10])=[CH:5][CH:4]=1.S(Cl)([Cl:16])=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([Cl:16])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=CC(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc(C=CC(=O)Cl)cc1

Procedure:
100 ml of benzene was added to 17.8 grams of p-methoxycinnamic acid. 12 ml of thionyl chloride was added dropwise slowly thereto at ambient temperature. The temperature was elevated to 70° C. and the heating was continued until foaming ceased. Benzene and thionyl chloride were distilled off and the residue was dried thoroughly under reduced pressure.
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]\[CH2:11][CH2:12][O:13][N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][CH:17]=[N:18][C:19]=2[N:23]1C(=O)C2=CC=CC=C2C1=O)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].CNN>C(O)C>[CH2:7]([O:6][P:4](/[CH:9]=[CH:10]\[CH2:11][CH2:12][O:13][N:14]1[CH:22]=[N:21][C:20]2[C:15]1=[N:16][CH:17]=[N:18][C:19]=2[NH2:23])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(/C=C\CCOn1cnc2c(N3C(=O)c4ccccc4C3=O)ncnc21)OCC
Agent: CNN
Solvent: CCO
Product: CCOP(=O)(/C=C\CCOn1cnc2c(N)ncnc21)OCC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 0.1 %

Procedure:
A mixture of (Z)-9-[4-(diethoxyphosphoryl)but-3-enyloxy]-6-phthalimidopurine (305 mg, 647 mmol) and methylhydrazine (31.3 mg, 679 μmol) in ethanol (7 ml) was stirred at room temperature for 1.5 hr. The solvent was removed and the residue was purified by column chromatography on silica gel eluting with dichloromethane-methanol (19:1, 9:1) to afford (Z)-9-[4-(diethoxyphosphoryl)but-3-enyloxy]adenine as a colourless gum (177 mg, 80%); λmax (EtOH) 260 (13,045) nm; υmax (KBr) 3320, 3175, 2980, 1645, 1595, 1325, 1295 and 1240 cm-1 ; δH [(CD3)2SO] 1.22 (6H, t, J 7 Hz, CH3), 2.95 (2H, m, CH2), 3.97 (4H, pseudo qu, J 7 Hz, CH2CH3), 4.46 (2H, t, CH2O ), 5.85 (1H, dd, J 14 Hz and 20 Hz, PCH=CH), 6.65 (1H, ddt, J 7 Hz, 14 Hz and 52Hz, PCH=CH), 7.38 (2H, br.s, NH2), 8.15 (1H, s, H-2/H-8), 8.41 (1H, s, H-2/H-8) (Found: C, 45.30; H, 5.92; N, 20.17%; M+ 341.1253. C13H20N5O4P. 0.3H2O requires C, 45.03; H, 5.96; N, 20.20%; M+ 341.1253).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Cl:12][C:13]1[CH:14]=[C:15]([C:20]#[C:21][CH2:22][OH:23])[CH:16]=[CH:17][C:18]=1[Cl:19].CCCCCCC.C(OCC)(=O)C.C(O)C#C>ClCCl>[Cl:12][C:13]1[CH:14]=[C:15]([C:20]#[C:21][CH:22]=[O:23])[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: OCC#Cc1ccc(Cl)c(Cl)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: C#CCO
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCCC
Product: O=CC#Cc1ccc(Cl)c(Cl)c1
Yield: 48.9 %

Procedure:
Pyridinium chlorochromate (24.23 g; 112.4 mmol; 2 eq) was added to a stirred solution of 3-(3,4-dichlorophenyl)prop-2-yn-1-ol (11.3 g; 56.2 mmol) in dichloromethane (225 mL) at room temperature. The mixture was stirred for 3.5 h until TLC (2:1 heptane/ethyl acetate) indicated the disappearance of the starting propargyl alcohol. The mixture was then filtered through a bed of celite, and the filter cake was rinsed with dichloromethane (150 mL). The dichloromethane was concentrated using a rotary evaporator to give the desired product (5.48 g; 27.5 mmol; 49%) which was used in the next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.20 (d, 1H) 7.31 (d, 1H) 7.51 (s, 1H) 9.43 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH3:36][CH:37]([CH3:45])[CH2:38][CH2:39][CH:40]=[CH:41]B(O)O>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([CH:41]=[CH:40][CH2:39][CH2:38][CH:37]([CH3:45])[CH3:36])=[CH:35][CH:34]=2)[N:8]([C:20]2[CH:21]=[C:22]([N:26]3[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]3)[CH:23]=[CH:24][CH:25]=2)[CH:9]=1
Reactant: CC(C)CCC=CB(O)O
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Product: CC(C)CCC=Cc1ccc(Cc2nc(-c3ccc(Cl)cc3Cl)cn2-c2cccc(N3CC(=O)NS3(=O)=O)c2)cc1

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using 5-methyl-1-hexenylboronic acid (43 mg, 0.3 mmol) to give 5-(3-{4-(2,4-dichloro-phenyl)-2-[4-(5-methyl-hex-1-enyl)-benzyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]C1.Cl.Cl.Cl.N1(CCN2CCC(N)CC2)CCCCC1>>[N:1]1([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16][C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:24]=[CH:23][CH:22]=4)=[O:18])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12
Agent: Cl
Agent: NC1CCN(CCN2CCCCC2)CC1
Product: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCC4)CC3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see Example 8) and amine 1.
Reaction SMILES: O=[O+][O-].[CH3:4][O:5][C:6]1[C:11]([CH:12]=CC)=[CH:10][CH:9]=[CH:8][C:7]=1[O:15][C:16]1[C:17]([CH3:22])=[CH:18][CH:19]=[CH:20][CH:21]=1.C(O)(=[O:25])C>C(OCC)(=O)C>[CH3:4][O:5][C:6]1[C:7]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:8][CH:9]=[CH:10][C:11]=1[CH:12]=[O:25]
Reactant: CC(=O)O
Reactant: CC=Cc1cccc(Oc2ccccc2C)c1OC
Agent: O=[O+][O-]
Solvent: CCOC(C)=O
Product: COc1c(C=O)cccc1Oc1ccccc1C

Procedure:
Ozone gas was introduced to a solution of o-tolyl 2-methoxy-3-(1-propenyl)phenyl ether (30 g) in a mixture of ethyl acetate (200 ml) and glacial acetic acid (10 ml) with stirring under cooling for an hour. The reaction mixture was treated in a similar manner to that of Example 4-(3) to give oily 2-methoxy-3-(o-tolyloxy)benzaldehyde (28 g)
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[OH:22].C(N(CC)CC)C.[CH2:30]([OH:34])[CH2:31][C:32]#[CH:33]>CN(C)C=O.ClCCl.O>[N:16]1([C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[CH:5]=[CH:4][C:3]4[O:22][C:32]([CH2:31][CH2:30][OH:34])=[CH:33][C:2]=4[CH:7]=3)=[N:9][CH:10]=2)=[O:15])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: C#CCCO
Reactant: O=C(c1ccc(-c2ccc(O)c(I)c2)nc1)N1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(c1ccc(-c2ccc3oc(CCO)cc3c2)nc1)N1CCOCC1
Temperature: 65 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a solution of Example 44C (2.85 g, 6.95 mmol), triethylamine (2.4 mL, 17.4 mmol), and 3-butyn-1-ol (0.73 g, 10.4 mmol) in dimethylformamide (15 mL) at 20° C. was added cuprous iodide (0.2 g, 1.0 mmol) and bis-triphenylphosphine palladium dichloride (0.24 g, 0.35 mmol). The mixture was stirred for one hour, then heated to 65° C. for 16 hours. The reaction was cooled to 23° C., diluted with dichloromethane (200 mL) and water (100 mL). The mixture was stirred with Celite then filtered. The filtrate was washed with water (1×50 mL), the organic phase separated, dried (Na2SO4), filtered and concentrated under reduced pressure to give a tan foam. The residue was chromatographed on silica using 5% methanol in dichloromethane to give the titled compound as a yellow solid (1.83 g, 75%/). MS (DCI) m/z 353 (M+H)+;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][C:17]3[C:16]4[CH2:15][C:14]([CH3:21])([CH3:20])[CH2:13][C:12]=4[S:11][C:10]=3[C:9]2=[O:22])[C:3]=1[CH:23]=[O:24].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:19][CH2:18][C:17]3[C:16]4[CH2:15][C:14]([CH3:20])([CH3:21])[CH2:13][C:12]=4[S:11][C:10]=3[C:9]2=[O:22])[C:3]=1[CH2:23][OH:24]
Reactant: CC1(C)Cc2sc3c(c2C1)CCN(c1nccc(Cl)c1C=O)C3=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)Cc2sc3c(c2C1)CCN(c1nccc(Cl)c1CO)C3=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
A mixture of 4-chloro-2-{4,4-dimethyl-9-oxo-7-thia-10-azatricyclo[6.4.0.02,6]dodeca-1(8),2(6)-dien-10-yl}pyridine-3-carbaldehyde 109a (1.2 g, 3.3 mmol), NaBH4 (228 mg, 6.0 mmol), and methanol (10 mL) was stirred at 0° C. for 0.5 h. Then the reaction mixture was quenched with water (10 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (2×15 mL). The combined dichloromethane extract was concentrated under reduced pressure to afford 330a as a pale yellow solid (1.0 g, 84%). MS-ESI: [M+H]+ 362.9
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[C:3](=[O:13])[C:4]1[C:9]([C:10]2=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:14][CH2:15][O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18]>C(O)C>[OH:1][C:11]1[C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:13])[C:2]=1[N:22]1[CH2:21][CH2:20][N:19]([C:17]([O:16][CH2:15][CH3:14])=[O:18])[CH2:24][CH2:23]1
Reactant: O=C1c2ccccc2C(=O)C2OC12
Reactant: CCOC(=O)N1CCNCC1
Solvent: CCO
Product: CCOC(=O)N1CCN(C2=C(O)C(=O)c3ccccc3C2=O)CC1
Reaction time: 24 h
Yield: 44.9 %

Procedure:
A mixture of 1.174 g of 2,3-epoxy-2, 3-dihydro-1,4-naphthoquinone, 1.58 g of ethyl-N-piperazinocarboxylate and 100 ml of absolute ethanol was stirred for 24 hours, then evaporated. The residue was chromatographed on silica gel, eluting with 5% methanol in chloroform, giving 1.0 g of the desired product, mp 115°-118° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[C:18](=[O:20])[CH3:19].C(N(CC)CC)C.[C:28](Cl)(=[O:32])[CH:29]([CH3:31])[CH3:30].O>ClCCl.CN(C)C1C=CN=CC=1>[C:18]([C:3]1[CH:4]=[CH:5][C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:7][C:2]=1[O:1][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])(=[O:20])[CH3:19]
Reactant: COc1ccc(COc2ccc(C(C)=O)c(O)c2)cc1
Reactant: CC(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(COc2ccc(C(C)=O)c(OC(=O)C(C)C)c2)cc1
Temperature: 0 °C

Procedure:
1-[2-Hydroxy-4-(4-methoxy-benzyloxy)-phenyl]-ethanone (9.11 g, 0.034 mol) is dissolved in dry dichloromethane (120 ml) under an atmosphere of dry argon. Triethylamine (5.14 ml, 0.037 mol) and 4-dimethylaminopyridine (0.204 g, 1.67 mmol) are added, and the mixture is cooled to 0° C. using an ice-water bath. Isobutyryl chloride (3.89 ml, 0.037 mol) is then added dropwise, and the mixture is stirred while warming to room temperature. The mixture is poured into water (100 ml), and the dichloromethane layer is separated, washed with saturated brine (100 ml), dried (MgSO4), treated with activated charcoal (300 mg), filtered and evaporated to give a pale pink solid.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][N:14]1[C:18]2=[C:19]3[CH:25]=[CH:24][N:23]([S:26]([C:29]4[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[C:20]3=[N:21][CH:22]=[C:17]2[CH2:16][CH2:15]1.[I:36]I.CC(O)=O.[NH4+].[Cl-]>C1COCC1.O.C([O-])(O)=O.[Na+].C(Cl)Cl>[I:36][C:24]1[N:23]([S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:20]2=[N:21][CH:22]=[C:17]3[CH2:16][CH2:15][N:14]([CH3:13])[C:18]3=[C:19]2[CH:25]=1
Reactant: II
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c4c(cnc32)CCN4C)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3c4c(cnc32)CCN4C)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
Diisopropylamine (0.29 mL, 2.0 mmol) in THF (5 mL) was cooled to about −70° C. then treated with n-BuLi (1.6 M in hexanes, 1.1 mL, 1.8 mmol) keeping the internal temperature of the reaction at about −60 to −70° C. After about 15 min the mixture was warmed to about 20° C. The mixture was added slowly to the 1-methyl-6-tosyl-1,2,3,6-tetrahydrodipyrrolo[2,3-b:2′,3′-d]pyridine (0.300 g, 0.916 mmol) in THF (5.0 mL) at about −60° C. to −70° C. The mixture was stirred at about −70° C. for about 1 h then iodine (0.27 g, 1.1 mmol) in THF (2 mL) was added keeping the temperature of the mixture at about −65 to −70° C. The mixture was stirred for about 1 h at about −70° C. then AcOH (0.16 mL, 2.8 mmol) and about 1 mL saturated aqueous NH4Cl were added. The mixture was warmed to rt then diluted with water (10 mL), saturated aqueous NaHCO3 (5 mL) and DCM (50 mL). The layers were separated then the aqueous layer was extracted with DCM (15 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The material was triturated in EtOAc (8 mL) then filtered and washed with EtOAc (2 mL) to give the title compound (0.24 g, 58%): LC/MS (Table 2, Method a) Rt=2.52 min; MS m/z 454 (M+H)+.