Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=4[Cl:30])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>CS(C)=O.C(OCC)C>[Cl:30][C:24]1[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:23]=1[C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[O:14][C@@H:13]([CH2:12][NH:32][CH3:31])[CH2:22][CH2:21]2
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3cccc(-c4cc(Cl)ccc4Cl)c3O2)cc1
Solvent: CS(C)=O
Solvent: CCOCC
Product: CNC[C@H]1CCc2cccc(-c3cc(Cl)ccc3Cl)c2O1
Temperature: 60 °C

Procedure:
To a suspension of [(2R)-8-(2,5-dichlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.15 g, 0.324 mmol) in dimethylsulfoxide (0.5 mL) was added a solution of methylamine (2.0 M in tetrahydrofuran, 1.62 mL, 3.24 mmol) and the mixture heated to 60° C. in a sealed vial for 24 hours. The cooled reaction mixture was then diluted with diethyl ether (10 mL), washed with 1.0 M aqueous sodium hydroxide solution (5 mL) and water (5×5 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford a yellow oil. Purification by flash chromatography using a solvent gradient of 0.5 to 5% ammonia saturated methanol solution in dichloromethane gave {[(2R)-8-(2,5-dichlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}methylamine as a colorless syrup. The product was dissolved in diethyl ether (1 mL) and a solution of hydrogen chloride (1.0 M in diethyl ether, 0.25 mL, 0.25 mmol) was added followed by 2-propanol (3 drops). The resulting white precipitate was filtered and the solid product triturated with diethyl ether (3×3 mL) to afford 56 mg (48%) of {[(2R)-8-(2,5-dichlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl}methylamine hydrochloride as a white solid. MS (ESI) m/z 322.0 ([M+H]+).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:17])([CH2:12][C:13]([F:16])([F:15])[F:14])[N:5]([CH3:18])[C:4]=2[CH:3]=1.[CH3:19][C:20]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][N:22](C(OC(C)(C)C)=O)[N:21]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH3:18][N:5]1[C:4]2[CH:3]=[C:2]([C:24]3[CH:23]=[N:22][NH:21][C:20]=3[CH3:19])[S:10][C:9]=2[C:8](=[O:11])[NH:7][C:6]1([CH3:17])[CH2:12][C:13]([F:16])([F:15])[F:14]
Reactant: CN1c2cc(Br)sc2C(=O)NC1(C)CC(F)(F)F
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC(C)(CC(F)(F)F)N2C
Temperature: 100 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
A flask was charged with 6-bromo-1,2-dimethyl-2-(2,2,2-trifluoroethyl)-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (420 mg, 1.22 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.13 g, 3.7 mmol), sodium carbonate (366 mg, 6.1 mmol), 1,2-dimethoxyethane (6 mL) and water (3 mL). The flask was purged with argon. Then, 1,1′-bis(diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (98 mg, 0.12 mmol) was added to the mixture. The flask was purged with argon again. After stirring at 100° C. for 2 h, 8 M aqueous NaOH (1 mL) was added. After stirring at 100° C. for 1 h, the organic materials were extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and filtered. After removal of the solvent at reduced pressure, the residue was purified by column chromatography (Purif, silica gel, 80:20 hexane/EtOAc to EtOAc), then crystallized from MeOH/EtOAc/heptane) to give the title compound (212 mg, 50%) as a pale yellow solid:
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[N:10](C(=O)C(F)(F)F)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O[Li].O>O1CCOCC1>[C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:10][CH2:9]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN1C(=O)C(F)(F)F
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 327 (16.0 mmol) in 1,4-dioxane (120 mL) was added LiOH.H2O (32.0 mmol, 2 equiv). The suspension was allowed to stir at room temperature for 16 h at which point TLC indicated complete consumption of starting material (KMnO4 stain for S.M.). The reaction was diluted with THF (120 mL), filtered through a glass frit and concentrated. The resulting syrup was diluted with THF/CHCl3 (1:1, 200 mL) and washed with saturated NaHCO3 (100 mL), brine (100 mL), dried (MgSO4), and purified via column chromatography (0–10% MeOH in CH2Cl2 with 0–1% NH4OH) to give [5-(S)-(tert-Butoxycarbonylamino-methyl)-pyrrolidin-3-(S)-yl]-carbamic acid tert-butyl ester (328) as a colorless foam. 1H NMR (400 MHz, CD3OD) δ=1.45 ppm (s, 9H), 1.47 (s, 9H), 1.69 (br s, 1H), 2.32–2.39 (m, 1H), 2.82 (dd, 1H, J=6, 13 Hz), 2.89 (dd, 1H, J=4, 13 Hz), 3.00 (dd, 1H, J=7, 11 Hz), 3.81 (dd, 1H, J=7, 11 Hz), 3.92–3.98 (m, 1H); 13C NMR (100 MHz, DMSO-d6) δ=26.0, 29.0, 29.1, 58.9, 67.8, 78.5, 79.1, 154.3, 155.7 pm.
Reaction SMILES: Br.[F:2][C:3]([F:19])([CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([F:13])([F:12])[O:5][CH2:6][C:7]1([CH3:11])[CH2:10][O:9][CH2:8]1.[OH-:20].[Na+]>O>[F:19][C:3]([F:2])([CH2:14][C:15]([F:17])([F:18])[F:16])[C:4]([F:12])([F:13])[O:5][CH2:6][C:7]1([CH2:11][O:20][C:4]([F:12])([F:13])[C:3]([F:2])([F:19])[CH2:14][C:15]([F:16])([F:17])[F:18])[CH2:10][O:9][CH2:8]1
Reactant: CC1(COC(F)(F)C(F)(F)CC(F)(F)F)COC1
Reactant: [OH-]
Agent: Br
Agent: [Na+]
Solvent: O
Product: FC(F)(F)CC(F)(F)C(F)(F)OCC1(COC(F)(F)C(F)(F)CC(F)(F)F)COC1
Temperature: 5 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
A 2-L, 3-neck, jacketed flask fitted with a mechanical stirrer, thermocouple probe, and an addition funnel was charged with 48% hydrobromic acid (208.0 g, 1.23 mole). The flask was cooled to 5° C. by circulating coolant through the jacket, and 3-heptafluorobutoxymethyl-3-methyloxetane was added at a rate to maintain the temperature below 12° C. The addition was complete after 11/4 hours. GC analysis indicated 98% conversion of the starting material to product. Additional 48% HBr (14.9 g, 0.088 mole) was added, and the mixture was stirred overnight at room temperature. The mixture was poured into 200-ml water, and the pH of the aqueous layer was adjusted to a pH of about 5 with 1N NaOH. The layers were separated, and the organic layer was washed with water (250 ml), dried (MgSO4), and filtered to give 300.4 g (93.5%) of 3-bromo-2-heptafluorobutoxymethyl-2-methyl-1-propanol (2), a clear oil: 1H NMR (CDCl3) 1.00 (s), 3.43 and 3.52 (AB, J=10.4 Hz), 3.53 and 3.59 (AB, J=11.1 Hz), 3.58 (s), and 3.95 (t, J=13.4 Hz); Anal. Calcd for C9H12BrF7O2 : C, 29.60; H, 3.32; Br, 21.88; Found: C, 29.15; H, 3.27; Br, 21.09.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[C:4]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH:3]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[CH2:14]([S:11]([C:4]1[CH:3]=[C:2]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:9]=[C:8]([CH3:10])[C:5]=1[C:6]#[N:7])(=[O:13])=[O:12])[CH3:15]
Reactant: CCS(=O)(=O)c1cc(Cl)cc(C)c1C#N
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCS(=O)(=O)c1cc(N2CCOCC2)cc(C)c1C#N
Temperature: 150 °C
Yield: 96 %

Procedure:
4-Chloro-2-(ethylsulfonyl)-6-methyl-benzonitrile (0.43 g, 1.77 mmol), morpholine (0.46 ml, 5.31 mmol) and potassium carbonate (0.32 g, 2.30 mmol) are taken up in N-methyl-2-pyrrolidone (3 ml) in a sealed tube and the resulting mixture is heated at 150° C. for 2 d. The mixture is then diluted with water (6 ml) and extracted with ethyl acetate (3×10 ml). The organic layer is washed with water (2×10 ml), brine (20 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 25% ethyl acetate/hexane) to yield 2-(ethylsulfonyl)-6-methyl-4-morpholin-4-yl-benzonitrile (0.50 g, 1.70 mmol, 96%).
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].Cl[CH2:6][CH2:7][C:8]([OH:10])=[O:9]>>[CH2:1]([NH:4][CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH:2]=[CH2:3]
Reactant: O=C(O)CCCl
Reactant: C=CCN
Product: C=CCNCCC(=O)O
Reaction time: 0.08 h

Procedure:
To a cooled solution of 125 mL aqueous allylamine (60%), 3-chloropropionic acid (20 g) was added portionwise while stirring over 5 minutes. The mixture was stirred at ambient temperature for 72 hours. The mixture was then evaporated to a viscous oily residue (40 g). The product consisted of a 1:1 mixture of 3-allylaminopropionic acid and allylamine hydrochloride. This product mixture was used without further purification for the preparation of the title compound in step 2.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[C:17]([O:18][CH:19]([CH3:21])[CH3:20])=[C:16]([C:22](OC)=[O:23])[CH:15]=[C:14]([CH:26]2[CH2:28][CH2:27]2)[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[F:36].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[Cl:11][C:12]1[C:17]([O:18][CH:19]([CH3:20])[CH3:21])=[C:16]([CH2:22][OH:23])[CH:15]=[C:14]([CH:26]2[CH2:28][CH2:27]2)[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[F:36]
Reactant: COC(=O)c1cc(C2CC2)c(-c2ccc(F)cc2F)c(Cl)c1OC(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1c(CO)cc(C2CC2)c(-c2ccc(F)cc2F)c1Cl
Reaction time: 0.33 h
Yield: 75.9 %

Procedure:
Diisobutylaluminum hydride (1.5 M toluene solution, 16.3 mL) was added at 0 C to a THF (30 mL) solution of methyl 2-chloro-6-cyclopropyl-2′,4′-difluoro-3-isopropoxybiphenyl-4-carboxylate (3.10 g), and then, the mixture was stirred at 0 C for 20 minutes in a nitrogen atmosphere. Sodium sulfate decahydrate was added to the reaction mixture, and the mixture was stirred for 1 hour. After filtration, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (2.18 g).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(O)(=O)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Cc2cccnc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: c1ccc(CC2CCCNC2)cc1
Reaction time: 6 h
Yield: 41.4 %

Procedure:
Combine 3-benzyl-pyridine (0.524 g, 3.10 mmol) and 10% palladium on carbon (0.165 g) in acetic acid (30 mL) and stir at 60° C. at a H2 pressure of 60 psi. After 6 h, purify the reaction mixture by ion exchange chromatography (SCX resin, methanol→2 M ammonia/methanol) and silica gel chromatography (10:1→3:1 methylene chloride:methanol) to provide 0.225 g (42%) of the title compound as a yellow oil: 1H NMR (DMSO-d6): 7.28 (t, 2H, J=7.3 Hz), 7.22-7.13 (m, 3H), 3.01 (s br, 1H), 2.87-2.76 (m, 2H), 2.50-2.34 (3H), 2.16 (dd, 1H, J=9.3, 11.7 Hz), 1.70-1.49 (m, 3H), 1.29 (tq, 1H, J=3.9, 12.7 Hz), 1.03 (dq, 1H, J=3.9, 12.7 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:13][NH:14][O:15][CH3:16].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl.CCN(CC)CC>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:14]([O:15][CH3:16])[CH3:13])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(C)c1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.9 %

Procedure:
In a 1 L round-bottomed flask was added 2-amino-3-methylbenzoic acid (11.2 g, 74.1 mmol), N,O-dimethylhydroxylamine hydrochloride (14.45 g, 148 mmol) in CH2Cl2 (500 mL) to give a pale brown suspension. The reaction mixture was treated with Et3N (35 mL) to give a light brown/red solution. The solution was treated with HOBT (11.35 g, 74.1 mmol) and EDC (14.20 g, 74.1 mmol) and stirred at room temperature for 24 hours. The mixture was then washed with 10% LiCl aq acidified with 1N HCl. The organic layer was washed successively with 10% aqueous LiCl and aqueous NaHCO3. The organic layer was decolorized with charcoal, filtered and the filtrate dried over MgSO4. The mixture was filtered and concentrated to give 13.22 g (92% yield) of 2-amino-N-methoxy-N,3-dimethylbenzamide as an oil. MS(ES):m/z=195.1 [M+H+]; HPLC: RT=1.118 min. (H2O/MeOH with TFA, CHROMOLITH® ODS S5 4.6×50 mm, gradient=4 min, wavelength=220 nm); 1H NMR (500 MHz, chloroform-d) δ 7.22 (dd, J=7.8, 0.8 Hz, 1H), 7.12-7.06 (m, 1H), 6.63 (t, J=7.5 Hz, 1H), 4.63 (br. s., 2H), 3.61 (s, 3H), 3.34 (s, 3H), 2.17 (s, 3H). This was used without further purification in next reaction.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)=[O:7].[Br:18][C:19]1[C:20](Cl)=[N:21][C:22]([Cl:25])=[N:23][CH:24]=1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[Br:18][C:19]1[C:20]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)=[O:7])=[N:21][C:22]([Cl:25])=[N:23][CH:24]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: NCCCNC(=O)Nc1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(NCCCNc1nc(Cl)ncc1Br)Nc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 1.6 g (6.7 mmol) of 1-(3-amino-propyl)-3-(3-nitro-phenyl)-urea in 30 ml of acetonitrile is mixed with a solution of 1.6 g (7.0 mmol) of 5-bromo-2,4-dichloro-pyrimidine in 10 ml of acetonitrile. 2.0 ml of triethylamine is added, and it is stirred for 90 minutes at room temperature. It is diluted with ethyl acetate (150 ml) and washed with citric acid (10%), saturated NaHCO3 solution as well as saturated NaCl solution, dried (Na2SO4), filtered and concentrated by evaporation. The remaining residue is purified by chromatography (hexane/ethyl acetate 1:1). 1.7 g (4.0 mmol, corresponding to 60% of theory) of the product is obtained.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:14]=[C:13]2[CH2:15][CH2:16][CH2:17][C:12]2=[C:11]2[C:7]=1[C:8]([C:26](=[O:30])[C:27]([NH2:29])=[O:28])=[C:9]([CH3:25])[N:10]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Li+]>CO.O1CCCC1>[NH2:29][C:27](=[O:28])[C:26]([C:8]1[C:7]2[C:11](=[C:12]3[CH2:17][CH2:16][CH2:15][C:13]3=[CH:14][C:6]=2[O:5][CH2:4][C:3]([OH:31])=[O:2])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]=1[CH3:25])=[O:30]
Reactant: COC(=O)COc1cc2c(c3c1c(C(=O)C(N)=O)c(C)n3Cc1ccccc1)CCC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(C(=O)C(N)=O)c2c(OCC(=O)O)cc3c(c2n1Cc1ccccc1)CCC3
Yield: 69.5 %

Procedure:
A solution of 2-[[3-(2-amino-1,2-dioxoethyl)-2-methyl-1-benzyl-1,6,7,8-tetrahydrocyclopent[g]indol-4-yl]oxy]acetic acid methyl ester (95 mg, 0.23 mmol) in a 1:1 mixture of methanol/tetrahydrofuran (1 mL) was treated with excess 1M lithium hydroxide for 19 h at room temperature. The mixture was concentrated in vacuo, diluted with water, and acidified with 5N hydrochloric acid. The resulting precipitate was collected via vacuum filtration and recrystallized (absolute ethanol) to provide 65 mg (71%) of the title product as yellow crystals: mp 255-257° C. 1H NMR (DMSO6) δ 12.84 (bs, 1H, —OH), 7.69 (bs, 1H), 7.33 (m, 4H), 6.92 (d, J=7.0 Hz, 2H), 6.46 (s, 1H), 5.54 (s, 2H), 4.61 (s, 2H), 2.95 (t, J=7.0 Hz, 2H), 2.82 (t, J=7.3 Hz, 2H), 2.42 (s, 3H), 1.96 (quintet, J=7.0 Hz, 2H); MS ES+ m/e 407 (p+1).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH:15]([CH3:17])[CH3:16])=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[CH:10]=1)=[O:4].Cl.[N:19]1([C:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[S:27][N:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[S:27]1[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:25]([N:19]2[CH2:20][CH2:21][N:22]([CH2:2][C:3]([C:5]3[CH:6]=[CH:7][C:8]([CH:15]([CH3:17])[CH3:16])=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[CH:10]=3)=[O:4])[CH2:23][CH2:24]2)=[N:26]1
Reactant: CC(=O)Nc1cc(C(=O)CCl)ccc1C(C)C
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Product: CC(=O)Nc1cc(C(=O)CN2CCN(c3nsc4ccccc34)CC2)ccc1C(C)C
Yield: 55.8 %

Procedure:
Starting with N-[5-(2-chloro-acetyl)-2-isopropyl-phenyl]-acetamide (0.50 g, 1.971 mmol), and 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride (0.504 g, 1.971 mmol) and following the procedure as outlined in Example 517, N-{5-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-acetyl]-2-isopropyl-phenyl}-acetamide (0.480 g, 1.099 mmol) was obtained as its hydrochloride salt from treatment with dioxane/HCl(gas). Yield=56%. 100% purity at 254 nM. 1H NMR (400 MHz, DMSO-d6) δ 10.46 (bs, 1H), 9.63 (s, 1H), 8.12 (d, J=8.13 Hz, 1H), 8.09 (d, J=8.13 Hz, 1H), 7.90 (s, 1H), 7.79 (d, J=8.13 Hz, 1H), 7.61–7.52 (m, 2H), 7.45 (t, J=7.47 Hz, 1H), 5.13 (s, 2H), 4.12–4.01 (m, 2H), 3.67–3.49 (m, 8H), 3.40 (bs, H2O), 3.37–3.30 (m, 1H), 3.23 (heptet, J=6.81 Hz, 1H), 2.07 (s, 3H), 1.14 (d, J=6.81 Hz, 6H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC.C([O:14][C:15]([C:17]1[S:18][CH:19]=[C:20]2[C:26]=1[C:25]1[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=1[O:23][C:22]1[CH:31]=[CH:32][CH:33]=[CH:34][C:21]2=1)=O)C>O>[C:17]1([CH2:15][OH:14])[S:18][CH:19]=[C:20]2[C:26]=1[C:25]1[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=1[O:23][C:22]1[CH:31]=[CH:32][CH:33]=[CH:34][C:21]2=1
Reactant: CCOC(=O)c1scc2c1-c1ccccc1Oc1ccccc1-2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCc1scc2c1-c1ccccc1Oc1ccccc1-2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of LiAlH4 in dry ether (10 mmoles in 15 ml of dry ether) an ether solution of the ester 5 (2 mmoles in 15 ml of dry ether) was added drop by drop. The reaction mixture was stirred at room temperature for 4 hours. After the complete quantity of the ester had been reacted (the course of the reaction was followed by thin layer chromatography), the excess of LiAlH4 was decomposed by the addition of diethyl ether and water. The obtained white precipitate was filtered off and after drying on anhydrous Na2SO4 the filtrate was evaporated under reduced pressure. The crude product was purified by chromatography on a column to give a pure product in the form of yellowish crystals.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[ClH:11].Cl.[F:13][C:14]([F:30])([F:29])[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]([NH2:28])=[NH:27])=[NH:24])=[CH:18][CH:17]=1>C(O)C>[ClH:11].[CH2:2]([CH:1]1[N:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][C:14]([F:13])([F:29])[F:30])=[CH:17][CH:18]=2)[C:23]([NH2:24])=[N:25][C:26]([NH2:28])=[N:27]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCC=O
Reactant: N=C(N)NC(=N)Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Product: CCCCCCCCC1N=C(N)N=C(N)N1c1ccc(OC(F)(F)F)cc1

Procedure:
100 ml of ethanol, 4.4 ml (25.6 mmol) of 1-nonanal, and 0.7 ml of concentrated hydrochloric acid were added to 5.0 g (16.8 mmol) of N1-(4-trifluoromethoxyphenyl)-biguanide hydrochloride, and the mixture was refluxed for 9 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from hydrous ethanol to obtain 0.7 g of colorless crystals having a melting point of 216 to 220° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[C:14]([CH3:23])=[C:15]([O:19]C(=O)C)[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.O.C(=O)([O-])[O-].[K+].[K+]>Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[C:14]=3[CH3:23])=[O:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)Oc1cccc(C(=O)c2c[nH]c3ncc(Br)cc23)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1c(O)cccc1C(=O)c1c[nH]c2ncc(Br)cc12

Procedure:
A solution of acetic acid 3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-methyl-phenyl ester (84, 25.0 mg, 0.067 mmol) in 6 N HCl (4.0 mL) was heated with a CEM Discover microwave instrument at 110° C. for 10 min. The reaction mixture was poured into water, neutralized with 1 M aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The desired compound was isolated by silica gel column chromatography eluting with 10% ethyl acetate in hexane to give a colorless oil (P-0055, 4.7 mg, 21%). MS (ESI) [M−H+]−=329.0, 331.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][NH2:11])=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:12](=S)=[S:13].OO.Cl>C(#N)C.O>[Cl:1][C:2]1[C:3]2[N:4]([C:12](=[S:13])[NH:11][N:10]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Cl)c(NN)n1
Reactant: S=C=S
Agent: Cl
Agent: OO
Solvent: O
Solvent: CC#N
Product: COc1ncc(Cl)c2n[nH]c(=S)n12
Yield: 142 %

Procedure:
5-Chloro-4-hydrazino-2-methoxypyrimidine (17.45 g, 0.10 mol) and 25 g (0.033 mol) of carbon disulfide were combined in 120 mL of acetonitrile and 30 mL of water at ambient temperature with stirring and 11.4 g (0.10 mol) of 30 percent hydrogen peroxide was added to the resulting mixture with stirring over a 2-hour period. The temperature rose from 20° C. to 48° C. Analysis of the mixture by high pressure liquid chromatography (HPLC) indicated that the reaction was complete. A 79.8 g (47.2 percent of the total) portion of the reaction mixture was diluted with 50 mL of water and the mixture was acidified with hydrochloric acid. The solids present were then recovered by vacuum filtration and dried to obtain 10.15 g of a mixture of the title compound and sulfur. The sulfur was then removed by extracting the solids with 45 g of carbon disulfide to obtain 8.08 g (80 percent of theory) of the title compound as a tan powder. This material was 92 percent pure by HPLC analysis; it decomposed on heating.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:22]1([NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28].CC(C)([O-])C.[Na+].N#N>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[CH-]1C(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=C1.[Fe+2]>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH:9]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:8][C:7]2[C:2]([NH:28][C:23]3[C:22]([NH2:29])=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=1
Reactant: Clc1ncccc1CC(c1cccnc1)c1cccnc1
Reactant: Nc1ccccc1N
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: Nc1ccccc1Nc1ncccc1CC(c1cccnc1)c1cccnc1

Procedure:
To a solution of 2-chloro-3-(2,2-dipyridin-3-ylethyl)pyridine in 160 mL toluene was added phenylenediamine (8.41 g), tris(dibenzylideneacetone)-dipalladium(0) (356 mg), 1,1-bis(diphenylphosphino)ferrocene (431 mg), and sodium tert-butoxide (2.24 g) under N2. The reaction was heated at 100 C under a stream of N2 for 14 h, then partitioned between saturated aqueous sodium bicarbonate and CH2Cl2. The aqueous solution was extracted with CH2Cl2 (3×), and the combined organic solutions were dried (Na2SO4) and concentrated. To the resulting black residue were added CH2Cl2 and hexane, and the precipitated solid was filtered off (washing with 1:1 CH2Cl2:hexane, followed by toluene). The filtrate was concentrated and purified by flash chromatography to give 4.1 g of N-[3-(2,2-dipyridin-3-ylethyl)pyridin-2-yl]benzene-1,2-diamine as a grey solid.