Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]2=[N:6][N:7]([C:9]3[CH:10]=[C:11]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=3[OH:21])[CH2:12][CH2:13][C:14]([O:16]C)=[O:15])[N:8]=[C:4]2[CH:3]=1.[OH-].[Na+].[I-].[K+].[C:32]1([SH:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C=O>[C:32]1([S:38][C:2]2[CH:27]=[CH:26][C:5]3=[N:6][N:7]([C:9]4[CH:10]=[C:11]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=4[OH:21])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])[N:8]=[C:4]3[CH:3]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Sc1ccccc1
Reactant: COC(=O)CCc1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(CCC(=O)O)cc(-n2nc3ccc(Sc4ccccc4)cc3n2)c1O
Temperature: 77.5 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a 1 liter, 4 necked, round-bottomed flask equipped with mechanical stirring and a nitrogen atmosphere is charged 100.0 g (0.258 mol) of methyl 3-(5-chloro-2H-benzotriazol-2-yl)-5-tert-butyl-4-hydroxyhydrocinnamate, 350 mL of N,N-dimethylformamide, and 61.9 g (0.773 mol) of 50% aqueous sodium hydroxide solution. The mixture is heated at 75-80° C. for 3 hours at which point the ester hydrolysis is complete. A catalytic amount of potassium iodide (5.0 g) is added. Thiophenol (32.2 g, 0.258 mol) is then added over a 20 minute period while the temperature remains at 75-80° C. An additional portion of N,N-dimethylformamide (200 mL) is added during the addition of thiophenol to facilitate stirring. A 25 mL fraction of water/methanol is removed and the solution is refluxed for 48 hours. The reaction mixture is cooled, then partitioned between 1.0 L of 1N hydrochloric acid and 1.0 L of ethyl acetate. The phases are separated and the organic phase is dried over anhydrous magnesium sulfate, and the solvent is then removed under reduced pressure until the total volume is 500 mL. To this is added 200 mL of heptane and the solution is allowed to sit overnight. The resultant crystals are collected by vacuum filtration, washed with 9:1 heptane:ethyl acetate, and dried to afford 83.5 g (72% yield) of the title compound; mp 154-156° C.
Reaction SMILES: [C:1]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][C:7]1=O)([O:3][CH2:4][CH3:5])=[O:2].F[B-](F)(F)F.C([O+](CC)CC)C.C(=O)([O-])[O-].[K+].[K+].Br.Br[CH2:33][CH2:34][NH2:35].C[O-].[Na+]>C(Cl)Cl.C(O)C>[NH:35]1[C:7]2=[C:6]([C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH2:11][CH2:10][CH2:9][N:8]2[CH2:33][CH2:34]1
Reactant: CCOC(=O)C1CCCNC1=O
Reactant: NCCBr
Agent: Br
Agent: CC[O+](CC)CC
Agent: C[O-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C1=C2NCCN2CCC1
Reaction time: 6 h

Procedure:
A solution of 3-carboethoxy-2-piperidone (25 g., 0.15 mole) in methylenechloride (150 ml.) is added dropwise with stirring at 0° C. to a solution of triethyloxonium fluoroborate (29 g.) in methylenechloride (150 ml.). After stirring for six hours, 33 g. of a 50% aqueous potassium carbonate solution is added and the organic layer is separated, dried over anhydrous K2CO3, filtered and concentrated under reduced pressure. Distillation of the concentrate gives 7.1 g. of the lactam ether, b.p. 90°/5 mm. which is dissolved in 100 ml. of ethanol containing 2-bromoethylamine hydrobromide (7.1 g., 0.035 mole). The solution is stirred for two days at room temperature. To this solution is added 2.1 g. of sodium methoxide. The solution is heated under reflux for one hour and then evaporated. The residue is treated with aqueous sodium hydroxide and extracted with chloroform. The chloroform solution is dried over Na2SO4, filtered and the filtrate evaporated. Distillation of the residue gives 3.5 g. of product b.p. 14°-5°/0.2 mm. which crystallizes on standing, m.p. 89°-02° C.
Reaction SMILES: II.[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]OS(C1C=CC(C)=CC=1)(=O)=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:27]1[CH2:31]O[CH2:29][CH2:28]1>>[CH2:11]([O:10][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:29][CH2:28][CH2:27][CH2:31][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH2:3]
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCOCc2ccccc2)cc1
Agent: II
Product: C=CCCCCCCCCCCCCCCOCc1ccccc1
Temperature: -78 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Into a clean flame dried and Ar flushed 500 mL RBF was added 14.2 mL (65 mmol) of commercially available 24. To this mixture was added 100 mL of anhydrous THF, 1.9 g (78 mmol) of Mg turnings and a pellet of I2 to accelerate the reaction. The reaction mixture was refluxed for 2 h and then cooled to room temperature and further to −78° C. To this was added 7.0 g (20.0 mmol) of 21 in 20 mL of anhydrous THF followed by addition of 6.5 mL (0.65 mmol) of lithium cuprate. The resulting mixture was allowed to warm to room temperature while stirring overnight followed by quenching with saturated aq. NH4Cl and extracted with EtOAc (3×). The combined EtOAc layers were then successively washed with water, saturated aq. NaHCO3 and brine, dried over MgSO4 and the solvents evaporated under reduced pressure. The residue was then purified by combiflash using hexane/EtOAc as eluent to furnish 6.3 g of the compound 27 as colorless oil in 95% yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[NH:10][CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:4].C(Cl)(Cl)Cl.[Br-:27]>N1C=CC=CC=1>[Br:27][C:8]1[S:7][C:6]([NH:10][CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:9]=1
Reactant: CCOC(=O)C(=CNc1sccc1C(=O)OC)C(=O)OCC
Reactant: [Br-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)C(=CNc1sc(Br)cc1C(=O)OC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3.3 parts of diethyl (3-methoxycarbonylthienyl)aminomethylenemalonate in a mixture of 20 parts by volume of chloroform and 4 parts by volume of pyridine, 0.6 part by volume of bromide is added dropwise. The solution is further stirred at room temperature for 15 minutes, after which the reaction mixture is washed with dilute hydrochloric acid, an aqueous sodium hydrogen carbonate solution and water, followed by drying over Na2SO4. The solvent is distilled off to give diethyl (5-bromo-3-methoxycarbonylthienyl)aminomethylenemalonate. Recrystallization from ethanol gives light-yellowish needles melting at 129°-130°C.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br-].[Li+].C1([Mg]I)C=CC=CC=1.[CH3:19][C@:20]12[CH2:36][CH2:35][C@H:34]3[C@@H:25]([CH:26]=[CH:27][C:28]4[C@@H:33]3[CH2:32][CH2:31][C:30](=[O:37])[CH:29]=4)[C@@H:24]1[CH2:23][CH2:22][C:21]2=[O:38].C[Si](C)(C)Cl>C1COCC1.[Cu]I.[Cu].C(O)(=O)C.CN1C(=O)N(C)CCC1>[C:3]1([C@@H:26]2[CH2:27][C:28]3[C@H:33]([CH2:32][CH2:31][C:30](=[O:37])[CH:29]=3)[C@@H:34]3[C@@H:25]2[C@H:24]2[C@@:20]([CH2:36][CH2:35]3)([CH3:19])[C:21](=[O:38])[CH2:22][CH2:23]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Reactant: Brc1ccccc1
Agent: [Cu]
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Solvent: CN1CCCN(C)C1=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@]12CC[C@H]3[C@@H]([C@H](c4ccccc4)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
5.76 g of magnesium chips (237 mmol) is suspended in 60 ml of anhydrous THF, and a total of 36.1 g of bromobenzene (230 mmol), dissolved in 100 ml of anhydrous THF, is added slowly and then quickly to start the reaction, and it is heated for 1 hour to 80° C. The mixture of 24 g of copper(I) iodide (120 mmol) and 43 g of lithium bromide (480 mmol) in 115 ml of anhydrous THL is heated to about 50° C., then 40 ml of DMPU is added, and it is stirred for 30 minutes. The solution of phenylmagnesium iodide is cooled to −60° C., and it is slowly mixed with the solution of the copper salt. Then, it is kept at −30° C. for 15 minutes, cooled again to −65° C. and mixed with a solution of 12.4 g of estra-4,6-diene-3,17-dione (46 mmol) in 115 ml of anhydrous THF. After the last addition, the mixture is allowed to heat to −5° C. within 45 minutes, it is cooled again to −40° C., and 15 ml of trimethylchlorosilane (115 mmol) is added. During the next 45 minutes, the internal temperature increases to −18° C., it is mixed with 15 ml of glacial acetic acid, the cooling bath is removed, and it is stirred for another hour. Then, it is diluted with ethyl acetate, washed with semisaturated ammonium chloride solution, saturated bicarbonate solution and common salt solution, the organic phase is dried with sodium sulfate, and the solvent is concentrated by evaporation. The residue is chromatographed on silica gel with hexane, methylene chloride and ethyl acetate. The yield of 7α-phenyl-estr-4-ene-3,17-dione is 8.6 g (54% of theory).
Reaction SMILES: C([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:32]([NH:34][C@@H:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:36])=[O:33])[NH:16][C:17](=[O:31])[CH:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)(OCC1C=CC=CC=1)=O.CC(O)=O.[ClH:47]>[Pd].CO>[ClH:47].[C:25]1([CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:17]([NH:16][C@H:15]([C:32]([NH:34][C@@H:35]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH3:36])=[O:33])[CH2:14][CH2:13][CH2:12][NH2:11])=[O:31])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C[C@@H](NC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)C(c1ccccc1)c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H](NC(=O)[C@H](CCCN)NC(=O)C(c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
Prepared according to the method described in Example 1(e) above from (R)-N5 -(Cbz)-N2 -(diphenylacetyl)-(S)-N-(1-phenylethyl)ornithine amide (2.0 g; 3.5 mmol; from step (b) above), 10% Pd/C (w/w; 150 mg), HOAc (100 mL; instead of MeOH), overnight reaction time. The crude acetate salt was converted to the sub-title hydrochloride and was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].C(N(CC)CC)C.[N+:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])([O-:19])=[O:18].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[N+:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:8]=[C:7]([Cl:9])[CH:6]=1)=[O:24])([O-:19])=[O:18]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: Nc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Nc1cc(Cl)cc(Cl)c1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a mixture of 3,5-dichloroaniline (8.1 g) and triethylamine (7.0 ml) in chloroform (100 ml) was added dropwise a solution of 3-nitrobenzoyl chloride (9.3 g) in chloroform (50 ml). The mixture was stirred at room temperature for 1 hour, then poured into aqueous sodium bicarbonate. The resultant precipitate was collected and washed with chloroform and water to give 3-nitro-N-(3,5-dichlorophenyl)benzamide (12.50 g).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[Br:11]N1C(=O)CCC1=O>C(#N)C>[Br:11][C:8]1[CH:9]=[C:2]([F:1])[C:3]([OH:10])=[C:4]([CH:7]=1)[C:5]#[N:6]
Reactant: N#Cc1cccc(F)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: N#Cc1cc(Br)cc(F)c1O

Procedure:
3-Fluoro-2-hydroxybenzonitrile and N-bromosuccinimide were stirred at room temperature in acetonitrile to obtain 5-bromo-3-fluoro-2-hydroxybenzonitrile. EI: 215, 217.
Reaction SMILES: CO[C:3]1[C:8](OC)=[CH:7][C:6]([CH:11]([O:18]C(=O)C(Cl)(Cl)Cl)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:5]([N+:25]([O-:27])=O)[CH:4]=1.CN(C)C1C=CC([N+]([O-])=O)=C([CH:39]([O:46]C(=O)C(Cl)(Cl)Cl)C2C=CC=CC=2)C=1[N+]([O-])=O>ClCCl>[CH3:39][O:46][C:15]1[CH:14]=[CH:13][C:12]([C:11](=[O:18])[C:6]2[CH:7]=[CH:8][CH:3]=[CH:4][C:5]=2[N:25]=[O:27])=[CH:17][CH:16]=1
Reactant: COc1cc(C(OC(=O)C(Cl)(Cl)Cl)c2ccccc2)c([N+](=O)[O-])cc1OC
Reactant: CN(C)c1ccc([N+](=O)[O-])c(C(OC(=O)C(Cl)(Cl)Cl)c2ccccc2)c1[N+](=O)[O-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccccc2N=O)cc1

Procedure:
Esters 39 and 40, 2% solution in dichloromethane (3.5 mL), and ester 43, 0.25% solution in dichloromethane (3.5 mL), were irradiated in the photoreactor at 350 nm for 200 minutes. The degree of photoconversion could be conveniently monitored by TLC. Each solution was concentrated to a half of its volume and applied onto a column of silicagel (4 g, Coarse silicagel). The column was eluted with CH2Cl2, appropriate fractions were combined and the solvent was removed in vacuo. The residue was dissolved in water/ethanol (1:1) (2 mL) and freeze-dried to give the photoproduct.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:17])[C:9](=[N:15][NH2:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1.[H-].[Na+].[Cl-].[NH4+]>CN(C)C=O.O>[O:17]=[C:8]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:2]=2)[N:16]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH:30]=[CH:29][CH:28]=[N:27]3)=[CH:24][CH:25]=2)[N:15]=[C:9]1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: BrCc1ccc(-n2cccn2)cc1
Reactant: CCOC(=O)C(=NN)C(=O)c1ccccc1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nn(Cc2ccc(-n3cccn3)cc2)c2ccccc2c1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 3-(2-fluorophenyl)-2-hydrazono-3-oxopropanoate (1.16 g, 4.87 mmol) and 1-[4-(bromomethyl)phenyl]-1H-pyrazole (1.50 g, 6.33 mmol, 1.3 equiv) were dissolved in degassed N,N-dimethylformamide (15 mL), cooled to 0° C. and treated with sodium hydride (0.312 g, 7.79 mmol, 1.6 equiv). After stirring for 1 hour at 0° C., the mixture was treated with ammonium chloride (3 mL, saturated aqueous) and water (40 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 20:80; hexanes:ethyl acetate) to provide the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:23]Br.[OH-].[Na+]>C(O)(=O)C.O.C(O)C>[Br:23][C:9]1[CH:10]=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[S:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: BrBr
Reactant: COC(=O)Cc1ccc(-c2ccc(Cl)cc2)s1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1cc(Br)c(-c2ccc(Cl)cc2)s1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methyl 5-p-chlorophenylthien-2-ylacetate (5.32 g.) was stirred with a mixture of glacial acetic acid (100 ml.) and sodium acetate (4.8 g.). A solution of bromine (1 ml.) in glacial acetic acid (15 ml.) was added. The mixture was stirred for two hours and then poured into ice/waer (1 l.). After 4 days at ambient temperature the mixture was extracted with ether (4 × 200 ml.), the combined ethereal extracts were successively washed with water (3 × 200 ml.), 10% w/v aqueous sodium bicarbonate (2 × 200 ml.), and water (200 ml.), dried over anhydrous sodium sulphate, and evaporated to give a pale yellow oil. Part of this oil (1.75 g.) was refluxed with ethanol (15 ml.), water (40 ml.) and 11N-sodium hydroxide (15 ml.) for 3 hours. The mixture was added to ice/water (100 ml.) and extracted with ether (3 × 20 ml.). The aqueous layer was acidified with 2N-acetic acid and extracted with ether (3 × 20 ml.). The combined ethereal extracts were washed with water (2 × 20 ml.), dried over anhydrous sodium sulphate and evaporated in a relatively high vacuum (0.5 mm.). The residual solid was dissolved in the minimum volume of ether, and after the addition of 4 volumes of petroleum ether (b.p. 60°-80°C.), gave crystals of α-(4-bromo-5 -p-chlorophenylthien-2-yl)acetic acid, m.p. 136°-137°C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].I[CH2:18][CH2:19][CH3:20]>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH2:16][CH2:15][N:14]([CH2:18][CH2:19][CH3:20])[CH2:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CCCI
Reactant: CS(=O)(=O)c1cccc(C2=CCNCC2)c1
Product: CCCN1CC=C(c2cccc(S(C)(=O)=O)c2)CC1

Procedure:
Beginning with 4-(3-methanesulfonyl-phenyl)-1,2,3,6-tetrahydro-pyridine and iodopropane: MS m/z (relative intensity, 70 eV) 279 (M+, 26), 250 (bp), 171 (6), 128 (12), 115 (8).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][N:10]3[C:11]=2[C:3]=1[C:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=13.C([BH3-])#N.[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:14]=[CH:13][C:12]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][N:10]3[C:11]=2[C:3]=1[CH:4]1[CH:9]3[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: Fc1ccc2c3c1c1c(n3CCNCC2)CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Fc1ccc2c3c1C1CCCCC1N3CCNCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.2 %

Procedure:
To a solution of 8-fluoro-2,3,4,5,9,10,11,12-octahydro-1H-[1,4]diazocino[7,8,1-jk]carbazole (0.30 g, 1.16 mmole) in acetic acid (50 mL) was added sodium cyanoborohydride (0.22 g, 3.32 mmole) and the reaction mixture was stirred at room temperature for 4 hours. The solvent was removed in vacuo and the residue was diluted with methylene chloride (200 mL) and washed with aqueous sodium hydroxide (1N, 150 mL), saturated sodium chloride (150 mL), dried (sodium sulfate) and concentrated. Purification by flash column chromatography (silica gel, 1.5% to 5% methanol in methylene chloride) provided 0.23 g of the title compound as a colorless oil. The oil was further treated with one equivalent of fumaric acid in ethanol to form a fumarate salt, mp 189-190° C. MS (ESI) m/z 261 ([M+H]+).
Reaction SMILES: Cl[CH:2]([CH:8]=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[SH:10][C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][N:12]=1.[OH-].[K+]>C(O)C>[CH2:6]([O:5][C:3]([C:2]1[S:10][C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:16]=2[NH:17][CH:8]=1)=[O:4])[CH3:7]
Reactant: CCOC(=O)C(Cl)C=O
Reactant: Nc1cccnc1S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1=CNc2cccnc2S1
Temperature: 50 °C

Procedure:
4.8 g of ethyl α-chloro-formylacetate, dissolved in 70 ml of ethanol, are added to a solution of 4 g (0.0317 mole) of 2-mercapto-3-aminopyridine and 1.78 g (0.0317 mole) of potassium hydroxide in 200 ml of ethanol at 25° C. under nitrogen. The mixture is warmed at 50° C. for 1 hour, the ethanol is then stripped off in vacuo and the residue is chromatographed on silica gel with methylene chloride/methanol (95:5) as the mobile phase. Yield: 3.3 g (47% of theory) Melting point: 194°-195° C.
Reaction SMILES: C([O:3][C:4](=[O:22])/[C:5](/[CH3:21])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=1)C.[Li+].[OH-].O.[OH-].[Li+]>CO.O>[CH:16]1([O:15][C:9]2[CH:8]=[C:7](/[CH:6]=[C:5](\[CH3:21])/[C:4]([OH:22])=[O:3])[CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CCOC(=O)/C(C)=C/c1ccc(OC)c(OC2CCCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(/C=C(\C)C(=O)O)cc1OC1CCCC1
Yield: 66.8 %

Procedure:
A suspension of (E)-3-(3-cyclopentoxy-4-methoxyphenyl)-2-methyl-acrylic acid ethyl ester (30 g 98.6 mmol) and LiOH.OH2O (lithium hydroxide hydrate) (5.0 g, 119.2 mmol, 1.2 equiv.) in methanol-water (4:1, 100 mL) was stirred at room temperature for 24 hours. Methanol was removed under reduced pressure and the resulting residue was dissolved in water (100 mL), washed with three 100 mL portions of ethyl acetate, neutralized with 1.0N HCl (hydrochloric acid) (100 mL), and extracted with two 150 mL portions of ethyl acetate. The extract was washed with brine, dried over anhydrous Na2SO4 (sodium sulfate), and concentrated under reduced pressure to afford the desired product as a light yellow powder (18.2 g, 66% yield). 1H NMR (300 MHz, CDCl3) δ (ppm): 12.4 (br. s, 1H, COOH), 7.56 (s, 1H, olefinic), 7.04 (m, 3H, aromatic), 4.81 (m, 1H), 3.78 (s, 3H, OCH3) , 2.06 (s, 3H, CH3), 1.91-1.57 (m, 8H, cyclopentyl).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[CH:15]=[C:16]([Cl:31])[C:17]([CH3:30])=[C:18]([C:27]([NH2:29])=[O:28])[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:31][C:16]1[C:17]([CH3:30])=[C:18]([C:27]([NH2:29])=[O:28])[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:15]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1C(N)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c(-c2cccc(F)c2)c1C(N)=O
Temperature: 90 °C
Yield: 41.2 %

Procedure:
A mixture of 6-bromo-9H-purine (110 mg, 0.56 mmol), 6-(1-aminoethyl)-4-chloro-3′-fluoro-3-methylbiphenyl-2-carboxamide (0.086 g, 0.28 mmol), and N,N-diisopropylethylamine (0.16 mL, 0.94 mmol) in isopropyl alcohol (2 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (49 mg, 41%). LCMS calculated for C21H19ClFN6O (M+H)+: m/z=425.1. found: 425.0.
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].[C:9]([CH2:11][C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])#[N:10].C(N(CC)CC)C>C(Cl)Cl>[OH:5]/[C:4](/[CH:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[C:11](/[C:9]#[N:10])\[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13]
Reactant: CC(C)OC(=O)CC#N
Reactant: CCC(CC)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)/C(O)=C(\C#N)C(=O)OC(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
22.2 g (0.16 mol) of 2-ethylbutyryl chloride were added to a solution of 21 g (0.16 mol) of isopropyl cyanoacetate in CH2Cl2, and the reaction mixture was cooled to 0° C. At this temperature, with ice-cooling, 33.5 g (0.33 mol) of triethylamine were added dropwise, and the mixture was then stirred at 25° C. for 2 h. Following subsequent acidic hydrolysis, the organic phase was washed, dried and concentrated. Purification by customary methods gave 24.4 g of the title compound (68% of theory) as a colorless oil (b.p. 70-75° C./1.5 mbar).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH:17]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=2)[CH2:18][NH:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21])=[C:11]([N+:35]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pt]>[NH2:35][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:14]([O:15][CH3:16])=[CH:13][C:12]=1[CH:17]([NH:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]#[N:34])=[CH:31][CH:32]=1)[CH2:18][NH:19][S:20]([CH2:23][CH2:24][CH3:25])(=[O:22])=[O:21]
Reactant: CCCS(=O)(=O)NCC(Nc1ccc(C#N)cc1)c1cc(OC)c(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: CCO
Product: CCCS(=O)(=O)NCC(Nc1ccc(C#N)cc1)c1cc(OC)c(OCc2ccccc2)cc1N
Reaction time: 3 h
Yield: 56.4 %

Procedure:
Propane-1-sulfonic acid [2-(4-benzyloxy-5-methoxy-2-nitro-phenyl)-2-(4-cyano-phenylamino)-ethyl]-amide (0.250 g) was dissolved in ethanol (10 ml) and added to Pt/C (5%). The reaction was placed under a hydrogen atmosphere and stirred vigorously for 3 hours. The catalyst was filtered off and the product chromatographed (hexanes:ethyl acetate 1:2) to yield 133 mg of Propane-1-sulfonic acid [2-(2-amino-4-benzyloxy-5-methoxy-phenyl)-2-(4-cyano-phenylamino)-ethyl]-amide. 1HNMR(CDCl3): 7.3-7.45 (m, 7H), 6.71 (s, 1H), 6.52 (d, 2H), 6.3 (s, 1H), 5.33 (2, 1H), 5.08 (s, 2H), 5.0 (t, 1H), 4.42 (q, 1H), 3.75 (s, 3H), 3.70 (bs, 2H), 3.45 (t, 2H), 2.97 (m, 2H), 1.80 (m, 2H), 1.03 (t, 3H).