Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:7]([CH3:8])=[C:6]([I:9])[C:5]([CH3:10])=[C:4]([I:11])[C:3]=1[CH3:12].C([O:16][C:17](=[O:19])[CH3:18])(=O)C.S(=O)(=O)(O)O.[Mn]([O-])(=O)(=O)=O.[K+]>C(O)(=O)C>[I:1][C:2]1[C:3]([CH2:12][O:19][C:17](=[O:16])[CH3:18])=[C:4]([I:11])[C:5]([CH2:10][O:19][C:17](=[O:16])[CH3:18])=[C:6]([I:9])[C:7]=1[CH2:8][O:16][C:17](=[O:19])[CH3:18]
Reactant: Cc1c(I)c(C)c(I)c(C)c1I
Reactant: CC(=O)OC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)O
Product: CC(=O)OCc1c(I)c(COC(C)=O)c(I)c(COC(C)=O)c1I
Reaction time: 16 h

Procedure:
Triiodomesitylene (19.5 g, 39 mmol) was added to glacial acetic acid (200 ml) containing acetic anhydride (400 ml) and concentrated sulfuric acid (40 ml). Solid potassium permanganate (24.6 g, 156 mmol) was then added in small portions over a period of 3 h. After stirring for 16 h, the solvent was evaporated and water (200 ml) is was added. The aqueous suspension was extracted with dichloromethane (250 ml) and the organic phase was washed with water (3×50 ml), dried (MgSO4) and evaporated. The solid residue was suspended in acetone and the white crystalline product was collected by filtration. Yield: 9.3 g (35%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]3[CH2:17][NH:16][C:15](=[O:18])[CH2:14]3)=[CH:10][CH:11]=2)[N:6]([CH2:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:5]=1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CN1C(=O)N(C)CCC1>O1CCCC1>[CH2:28]([N:16]1[CH2:17][CH:13]([C:9]2[CH:8]=[C:7]3[C:12]([C:4]([CH3:3])=[CH:5][N:6]3[CH2:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:11][CH:10]=2)[CH2:14][C:15]1=[O:18])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1cn(CCCc2ccccc2)c2cc(C3CNC(=O)C3)ccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: Cc1cn(CCCc2ccccc2)c2cc(C3CC(=O)N(Cc4ccccc4)C3)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
A solution of sodium hydride (0.013 g) in tetrahydrofuran at 0° C., under argon, was treated with a solution of 4-[3-methyl-1-(3-phenyl-propyl)-1H-indole-6-yl]-pyrrolidine-2-one (0.184 g, Example 20) and benzyl bromide (0.094 g) in dry tetrahydrofuran. The mixture was allowed to warm to room temperature then treated with N,N′-dimethylpropyleneurea (0.05 g). After stirring at room temperature overnight the solution was partitioned between ethyl acetate (15 ml)and 1N hydrochloric acid (15 ml). The organic phase was dried over magnesium sulphate then evaporated. The residue was subjected to preparative layer chromatography on silica using a mixture of ethyl acetate and hexane (3:7, v/v) as eluent to yield the title compound (0.18 g) as an oil. [Elemental analysis:—C, 79.16; H, 6.98; N, 6.14%. Calculated for C29H30N2O.H2O:—C, 79.04; H, 7.33; N, 6.36%].
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[O:11]C(=O)OC(C)(C)C.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[C:27]3[CH:33]=[CH:32][NH:31][C:28]3=[N:29][CH:30]=2)[CH:20]=1.[OH-].[K+].O>CO>[F:1][C:2]1[C:7]([CH:8]([OH:9])[C:33]2[C:27]3[C:28](=[N:29][CH:30]=[C:25]([C:21]4[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=4)[CH:26]=3)[NH:31][CH:32]=2)=[C:6]([F:10])[CH:5]=[CH:4][C:3]=1[OH:11]
Reactant: c1cncc(-c2cnc3[nH]ccc3c2)c1
Reactant: CC(C)(C)OC(=O)Oc1ccc(F)c(C=O)c1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Oc1ccc(F)c(C(O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To carbonic acid tert-butyl ester 2,4-difluoro-3-formyl-phenyl ester (39, 0.405 g, 15.7 mmol) in methanol (36 mL), under an atmosphere of nitrogen, was added 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (89, 288.0 mg, 14.8 mmol, prepared as described in Example 17) and potassium hydroxide (145.0 mg, 25.9 mmol). The reaction was stirred at room temperature overnight. Then, the reaction was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The mixture was purified by silica gel column chromatography eluting with 4% methanol in methylene chloride to provide two separate compounds, a colorless oil (P-0009, 0.23 g, 44.1%, MS (ESI) [M+H+]+=354.1), and a colorless oil (P-0042, 0.050 g, 9.2%, MS (ESI) [M+H+]+=367.1).
Reaction SMILES: [Br:1]Br.[S:3]1[CH:7]=[CH:6][N:5]=[C:4]1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:7]1[S:3][C:4]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:5][CH:6]=1
Reactant: BrBr
Reactant: CCOC(=O)C1CCN(c2nccs2)CC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(c2ncc(Br)s2)CC1
Yield: 97.4 %

Procedure:
Bromine (0.14 mL, 2.7 mmol) was weighed into a vial and then diluted with acetic acid (1 mL). This solution was added dropwise (over 10 minutes) to a solution of ethyl 1-(1,3-thiazol-2-yl)piperidine-4-carboxylate (650 mg, 2.7 mmol) in acetic acid (12.5 mL). The mixture was then diluted with ethyl acetate (100 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 840 mg (2.63 mmol, 97% yield) of ethyl 1-(5-bromo-1,3-thiazol-2-yl)piperidine-4-carboxylate as a green oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].[I:12]Cl>C(Cl)Cl>[I:12][C:7]1[CH:6]=[CH:5][C:4]([NH2:9])=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:8]=1
Reactant: Nc1ccccc1C(F)(F)F
Reactant: ClI
Solvent: ClCCl
Product: Nc1ccc(I)cc1C(F)(F)F
Reaction time: 12 h
Yield: 42.5 %

Procedure:
2-Trifluoromethylphenylamine (30 mg, 0.21 mmol) and ICl (1.1 eq, 0.24 mmol, 38.97 mg) were added into methylene chloride. The reaction mixture was stirred for 12 hr. The reaction mixture was purified according to step 2 of Example 8 to give a title compound (25.6 mg, 42.48%).
Reaction SMILES: [OH:1][N:2]1C(=O)C2=CC=CC=C2C1=O.Br[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[C:25]1([S:22]([CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][O:1][NH2:2])(=[O:24])=[O:23])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=S(=O)(Cc1ccccc1CBr)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Product: NOCc1ccccc1CS(=O)(=O)c1ccccc1

Procedure:
Prepared by the same procedure as described for preparation 15, starting from N-hydroxyphthalimide and 1-(bromomethyl)-2-[(phenylsulfonyl)methyl]benzene (Aldrich).
Reaction SMILES: [C:1]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][C:4]([C:7](=[O:13])[CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:30](=[O:31])[O:29]1>C(Cl)(Cl)Cl>[C:1]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][C:4]([C:7](=[O:13])[CH2:8][CH2:9][C:10]([O:12][CH:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:30](=[O:31])[O:29]2)=[O:11])=[CH:5][CH:6]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccccc2)cc1
Reactant: O=C1OC(Br)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CCC(=O)c1ccc(-c2ccccc2)cc1)OC1OC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 73 %

Procedure:
To a solution of 7.5 g of 4-(4-biphenylyl)-4-oxobutyric acid in 40 ml of chloroform and 3.4 g of triethylamine is added a solution of 6.2 g of 3-bromophthalide in 20 ml of chloroform. The solution thus obtained is stirred 24 hours at room temperature, the organic phase is washed with an aqueous solution of sodium bicarbonate, then with water and finally it is dried on anhydrous sodium sulfate and evaporated to dryness to give the phthalidyl 4-(4-biphenylyl)-4-oxobutyrate; yield 73%.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[F:38])#[N:31]>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:34]3[CH:35]=[CH:36][C:37]([F:38])=[C:32]([CH:33]=3)[C:30]#[N:31])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: N#Cc1cc(B(O)O)ccc1F
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(F)c(C#N)c2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 3-cyano-4-fluorophenylboronic acid. The title compound was obtained in 22% yield as orange oil. MS (m/e): 525.2 (MH+, 100%).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=O)[O:22]C4C=CC=CC=4)=[C:16]([CH3:30])[CH:15]=3)[CH:8]=2)=[O:5])[CH2:3][CH2:2]1.[CH:31]([NH:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([NH2:45])[CH:36]=1)([CH3:33])[CH3:32].CCN(C(C)C)C(C)C>C1COCC1>[CH:31]([NH:34][C:35]1[CH:36]=[C:37]([NH:45][C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][C:9]3[N:10]=[CH:11][N:12]=[C:7]([NH:6][C:4]([CH:1]4[CH2:2][CH2:3]4)=[O:5])[CH:8]=3)=[CH:15][C:16]=2[CH3:30])=[O:22])[CH:38]=[C:39]([C:41]([F:43])([F:44])[F:42])[CH:40]=1)([CH3:33])[CH3:32]
Reactant: Cc1cc(Oc2cc(NC(=O)C3CC3)ncn2)ccc1NC(=O)Oc1ccccc1
Reactant: CC(C)Nc1cc(N)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(Oc2cc(NC(=O)C3CC3)ncn2)ccc1NC(=O)Nc1cc(NC(C)C)cc(C(F)(F)F)c1
Yield: 54.2 %

Procedure:
Dissolve phenyl N-[4-[6-(cyclopropanecarbonylamino)pyrimidin-4-yl]oxy-2-methyl-phenyl]carbamate (343 mg, 1.57 mmol), N1-isopropyl-5-(trifluoromethyl)benzene-1,3-diamine (700 mg, 1.73 mmol) and DIEA (608 mg, 4.72 mmol) in THF (4 mL), heat the reaction at 80° C. for 3 hrs. After the reaction is complete, remove the volatiles under reduced pressure. Purification by chromatography (silica gel, EtOAc:PE=1:1) affords the title compound (450 mg, 83%). MS: (M+1): 529.3.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:7]=[N:6][C:5]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C(O)=O>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:8]2[C:4]([CH:3]=[O:2])=[C:5]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:6]=[CH:7]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(Cn2cnc(-c3ccccc3)c2C(OC)OC)cc1
Solvent: O=CO
Solvent: O
Product: COc1ccc(Cn2cnc(-c3ccccc3)c2C=O)cc1
Yield: 99.6 %

Procedure:
5-(Dimethoxymethyl)-1-(4-methoxybenzyl)-4-phenyl-1H-imidazole (Intermediate 29) (1.5 g) was dissolved in formic acid (10 mL) and water (10 mL) and stirred for 16 hours at ambient temperature. The solvents were evaporated in vacuo, the residue was azeotroped with toluene (2×10 mL) and the residual oil dried in vacuo over P2O5 to give the title compound as a colourless oil (1.29 g, 100%);
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([CH3:24])[CH:16]=[C:17]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:12]=2[O:11][CH2:10][C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:30](C)=O.[Na+]>C(Cl)Cl>[CH2:1]([N:8]1[C:13]2[CH:14]=[C:15]([CH3:24])[CH:16]=[C:17]([N:18]3[CH2:19][CH2:20][N:21]([CH3:30])[CH2:22][CH2:23]3)[C:12]=2[O:11][CH2:10][C:9]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(N2CCNCC2)c2c(c1)N(Cc1ccccc1)C(=O)CO2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(N2CCN(C)CC2)c2c(c1)N(Cc1ccccc1)C(=O)CO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-Benzyl-6-methyl-8-piperazin-1-yl-4H-benzo[1,4]oxazin-3-one (140 mg, 0.42 mmol) in CH2Cl2 (5 ml) from Example 1 was added formaldehyde (37 wt % solution in water, 50 μl, 0.67 mmol) and NaBH(OAc)3. The solution was stirred with a magnetic stirrer at room temperature for 2 hours, and then partitioned between CH2Cl2 (20 ml) and saturated NaHCO3 solution (20 ml). The aqueous layer was extracted with CH2Cl2 (2×20 ml). After drying over MgSO4, the organic fraction was concentrated in vacuo to give 4-Benzyl-6-methyl-8-(4-methyl-piperazin-1-yl)-4H-benzo[1,4]oxazin-3-one as yellow solid. (140 mg, 95%) MS: (M+H)+352.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[N+:10]([C:13]1[CH:20]=[CH:19]C(CO)=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[C:1]([O:7][CH2:8][C:9]1[CH:19]=[CH:20][C:13]([N+:10]([O-:12])=[O:11])=[CH:14][CH:15]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: CCOC(=O)CC(C)=O
Product: CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 76.6 %

Procedure:
A mixture of ethyl acetoacetate (140 g, 1.08 mole) and p-nitrobenzyl alcohol (153 g, 1.00 mole; was washed with diethyl ether prior to use) in toluene (1 L) was slowly distilled, 900 ml of the solvent being collected over a period of 15 hours. After cooling, any insoluble material was removed by filtration over Celite, washed with toluene and evaporated in vacuo to obtain 280 g of a crude oil. This oil was crystallized at 5° C. from diethyl ether (280 ml) to yield 181.55 g (0.766 mole, 76.6% yield) of the title compound as off-white crystals: mp 40°-42° C.; ir (film) νmax : 1740 (ester), 1715 (C=O), 1515 and 1345 (NO2) cm-1 ; 1Hmr (CDCl3) δ: 1.98 (s, impurity), 2.32 (3H, s, CH3), 3.62 (2H, s, --COCH2CO2R), 5.08 (s, impurity), 5.28 (2H, s, --CO2CH2Ar), 7.53 (2H, "d", J=9 Hz, ArH's), and 8.23 ppm (2H, "d", J=9 Hz, ArH's); Rf 0.45 (diethyl ether). An analytical sample was obtained by recrystallization from toluene-hexanes: mp 47°-49° C.
Reaction SMILES: [CH3:1][C:2]([O:4][CH:5]1[CH:9]([O:10][C:11]([CH3:13])=[O:12])[CH:8]2[CH:14]([O:19][C:20]([CH3:22])=[O:21])[CH:15]=[CH:16][C:17](=[O:18])[N:7]2[CH2:6]1)=[O:3].[H][H]>C(O)C>[CH3:22][C:20]([O:19][C@H:14]1[C@@H:8]2[C@H:9]([O:10][C:11]([CH3:13])=[O:12])[C@H:5]([O:4][C:2]([CH3:1])=[O:3])[CH2:6][N:7]2[CH:17]([OH:18])[CH2:16][CH2:15]1)=[O:21]
Reactant: CC(=O)OC1C=CC(=O)N2CC(OC(C)=O)C(OC(C)=O)C12
Reactant: [H][H]
Solvent: CCO
Product: CC(=O)O[C@H]1[C@H]2[C@H](OC(C)=O)CCC(O)N2C[C@H]1OC(C)=O
Reaction time: 8 h

Procedure:
14. (1S,2R,8R,8aR)-1,2,8-triacetoxy-1,2,3,5,8,8a-hexahydro-5-oxyindolizine, 13, 22 g (0.070 mole), was hydrogenated at atmospheric pressure of hydrogen in 400 mL ethanol containing 3 g 10% Pd on carbon. The reaction was allowed to proceed overnight. The catalyst was filtered, and the filtrate was evaporated to dryness. The crystalline residue was taken up in ether and hexane and filtered to afford (1S,2R,8R,8aR)-1,2,8-triacetoxy-octahydro-5-oxyindolizine, 14, 21.4 g (0.068 mole; 97%) as a white crystalline solid of m.p. 146°-147° C. (lit. 143-145 ; A. C. Richardson et. al., Carb. Res., 136: 225(1985)).
Reaction SMILES: [C:1]([C:4]1[C:16]([O:17]C)=[CH:15][C:14]2[N:13]([CH2:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[C:12]3[CH:11]=[CH:10][C:9]4[C:25](=[O:28])[CH2:26][CH2:27][C:8]=4[C:7]=3[C:6]=2[CH:5]=1)(=[O:3])[CH3:2].Cl.N1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[C:1]([C:4]1[C:16]([OH:17])=[CH:15][C:14]2[N:13]([CH2:19][CH2:20][CH2:21][N:22]([CH3:23])[CH3:24])[C:12]3[CH:11]=[CH:10][C:9]4[C:25](=[O:28])[CH2:26][CH2:27][C:8]=4[C:7]=3[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1C(C)=O)c1c3c(ccc1n2CCCN(C)C)C(=O)CC3
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: CC(=O)c1cc2c3c4c(ccc3n(CCCN(C)C)c2cc1O)C(=O)CC4
Temperature: 25 °C

Procedure:
A solution of 9-acetyl-8-methoxy-1,2-dihydro-6-(3-dimethylaminopropyl)-cyclopenta[c]carbazole-3-one (84) (22 g, 58.2 mmol, 1 eq) and pyridine hydrochloride (134.4 g, 1164 mmol, 20 eq) in NMP (150 mL) was refluxed for 10 h. The reaction mixture was cooled to room temperature and poured into the 10% aqueous K2CO3 solution (3 L). The precipitated dark green solid was filtered off, washed with water (5×100 mL) and dried. The crude product was purified by column chromatography (eluent 10%-20% MeOH in EtOAc) to give 7.81 (37%) of pure 9-acetyl-8-hydroxy-1,2-dihydro-6-(3-dimethylaminopropyl)-cyclopenta[c]carbazole-3-one as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[CH:18][C:17]([CH:21]=O)=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.[Cl-:23].[OH:24][CH2:25][CH2:26][N+:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH3:37])=[CH:29][CH:28]=1.N1CCCCC1>C(O)C>[Cl-:23].[OH:24][CH2:25][CH2:26][N+:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](/[CH:37]=[CH:21]/[C:17]2[CH:18]=[CH:19][C:20]3[N:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[C:9]4[C:14]([C:15]=3[CH:16]=2)=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:29][CH:28]=1
Reactant: Cc1cc[n+](CCO)c2ccccc12
Reactant: COCCOCCn1c2ccccc2c2cc(C=O)ccc21
Agent: [Cl-]
Solvent: C1CCNCC1
Solvent: CCO
Product: COCCOCCn1c2ccccc2c2cc(/C=C/c3cc[n+](CCO)c4ccccc34)ccc21
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution mixture of 3a (0.12 g, 0.55 mmol), 5 (0.2 g, 0.66 mmol) and piperidine (0.1 mL) in ethanol (35 mL) was heated to reflux overnight. After cooling down to room temperature, the organic solvent was removed. The residue was purified by recrystallization from methanol to afford SLOH (0.17 g) as red solid in 62% yield. 1H NMR (400 MHz, DMSO-d6) δ 9.20 (d, J=6.4 Hz, 1H), 9.15 (d, J=8.8 Hz, 1H), 8.87 (s, 1H), 8.56 (d, J=9.2 Hz, 1H), 8.52 (d, J=6.4 Hz, 1H), 8.40 (m, 2H), 8.24 (m, 2H), 8.13 (d, J=8.8 Hz, 1H), 8.05 (t, J=7.6 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 5.27 (t, J=5.6 Hz, 1H), 5.05 (t, J=4.8 Hz, 2H), 4.64 (t, J=4.8 Hz, 2H), 3.94 (m, 2H), 3.84 (t, J=5.2 Hz, 2H), 3.47 (m, 2H), 3.31 (m, 2H), 3.11 (s, 3H). 13C NMR (400 MHz, DMSO-d6) δ 153.3, 147.8, 145.0, 142.1, 140.9, 138.1, 134.7, 128.7, 127.1, 126.8, 126.7, 126.5, 122.8, 122.2, 121.7, 120.3, 119.8, 119.2, 116.3, 114.8, 110.4, 110.3, 71.2, 69.8, 68.8, 58.9, 58.5, 58.0, 42.9. HRMS (MALDI-TOF) m/z Calcd for C30H31N2O3 467.2342. Found 467.2340 [M+]. Calcd for C30H31ClN2O3: C, 71.53; H, 6.21; N, 5.57. Found: C, 71.04; H, 6.23; N, 5.36.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1)[CH3:2].C(N1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31])(OCC)=O.C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[CH2:1]([O:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@H:9]([N:10]2[C:25](=[O:26])[C:24]3[C:23](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:22]2=[O:31])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOc1ccc(C[C@@H](C(=O)O)N2C(=O)c3ccccc3C2=O)cc1
Reaction time: 24 h

Procedure:
O-Ethyl-L-tyrosine (IV, EXAMPLE 3, 20.9 g, 100 mmol) and N-carbethoxyphthalimide (23.0 g, 105 mmol) are suspended in water (210 mL). Sodium carbonate (11.1 g, 105 mmol) is added and the mixture is stirred at 20-25° for 24 hr. Hydrochloric acid (1N, 200 mL) is added to the resulting mixture and stirred for 2 hr. The mixture is filtered, washed with water (100 mL) and dried to give the title compound, NMR (MeOH-d4) δ7.78-7.72, 7.14, 6.68, 5.11, 3.90, 3.47 and 1.28; CMR (MeOH-d4) δ172.2, 169.0, 159.2, 135.6, 132.8, 130.9, 130.3, 124.2, 115.5, 64.3, 54.8, 34.7 and 15.0.
Reaction SMILES: Cl.CO[CH2:4][C:5]1[S:9][CH:8]=[N:7][C:6]=1[CH3:10].Cl.[NH2:12][CH2:13][CH2:14][SH:15]>C(O)(=O)C>[NH2:12][CH2:13][CH2:14][S:15][CH2:4][C:5]1[S:9][CH:8]=[N:7][C:6]=1[CH3:10]
Reactant: COCc1scnc1C
Reactant: NCCS
Agent: Cl
Solvent: CC(=O)O
Product: Cc1ncsc1CSCCN

Procedure:
5-Methoxymethyl-4-methylthiazole hydrochloride (1.04 g.) and 0.66 g. of cysteamine hydrochoride in 5.5 ml. of acetic acid was refluxed for 24 hours. The mixture was concentrated and the residue was dissolved in water. The aqueous solution was neutralized with sodium hydroxide and extracted with chloroform. The extract was dried (MgSO4) and evaporated to dryness to give 5-(2-aminoethyl)thiomethyl-4-methylthiazole.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH2:11][CH2:12][O:13][C:14]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=4)=[CH:17][C:15]=3[CH:16]=2)=[O:9])[CH2:3][CH2:2]1.[O:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[O:28]1[CH2:33][CH2:32][CH:31]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]3[CH2:11][CH2:12][O:13][C:14]4[CH:20]=[CH:19][C:18]([C:21]5[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=5)=[CH:17][C:15]=4[CH:16]=3)=[O:9])[CH2:5][CH2:6]2)[CH2:30][CH2:29]1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCNCC2)CCO3)cc1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCN(C4CCOCC4)CC2)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To N-(4-piperidinyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (0.15 g) and tetrahydro-4H-pyran-4-one (0.06 g) dissolved in 1,2-dichloroethane (7 ml) was added under ice cooling sodium triacetoxyborohydride (0.13 g), and the resulting mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction mixture was neutralized with a 1 N aqueous solution of sodium hydroxide, was then concentrated and was extracted with ethyl acetate. The organic layer was washed with water and an aqueous saturated solution of sodium chloride, and was then dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain crude crystals. The crude crystals were recrystallized from ethyl acetate/hexane to obtain N-(1-(tetrahydropyran-4-yl)piperidin-4-yl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 56) (0.13 g) as colorless prisms.
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[Br:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.CO>O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[Br:10][C:11]1[CH:16]=[C:15]([N:1]2[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]2=[O:3])[CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: O
Product: Cc1cn(-c2cccc(Br)c2)c(=O)[nH]c1=O
Reaction time: 48 h

Procedure:
A 500 mL round bottom flask was charged with thymine (0.314 g, 2.49 mmol), 3-bromophenylboronic acid (1.00 g, 4.98 mmol), tetramethylethyldiamine (0.75 mL, 4.98 mmol), copper(II) acetate monohydrate (0.497 g, 2.49 mmol), methanol (200 mL), and H2O (50 mL). The blue reaction mixture was stirred for 48 h, concentrated and purified by CombiFlash (0 to 8% MeOH/CH2Cl2) to give desired product. LCMS-ESI+: calc'd for C11H9BrN2O2: 281.0 (M+H+); Found: 281.1 (M+H+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH:2]12.[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31](ON3C(=O)CCC3=O)=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[N:1]1([C:31]([O:30][CH2:29][CH:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:28]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:32])[CH2:5][CH2:4][CH:3]2[CH2:6][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH:2]12
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N1CC2CCNC2C1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC2CCN(C(=O)OCC3c4ccccc4-c4ccccc43)C2C1

Procedure:
A solution of tert-butyl hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (424 mg, 2 mmol), N-(9-fluorenylmethoxycarbonyloxy) succinimide (600 mg, 1.8 mmol) and DIPEA (310 mg, 2.4 mmol) in dioxane (20 mL) was stirred at room temperature overnight and then concentrated in vacuo. The residue was treated with EtOAc/H2O, separated, and the aqueous layer was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound. MS (m/z): 355 (M-boc+H)+.