Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.CCN(C(C)C)C(C)C.[CH3:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[C:30]=1[S:37](Cl)(=[O:39])=[O:38]>O1CCOCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([NH:18][S:37]([C:30]3[C:31]([CH3:36])=[CH:32][C:33]([CH3:35])=[CH:34][C:29]=3[CH3:28])(=[O:39])=[O:38])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: Nc1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c(S(=O)(=O)Nc2ccc3nc(-c4c(Cl)cccc4Cl)[nH]c3c2)c(C)c1
Reaction time: 8 h

Procedure:
To a vial containing a solution of 2-(2,6-dichloro-phenyl)-3H-benzoimidazol-5-ylamine, prepared as described in Example 1-6, in dioxane (0.2 M, 0.10 mL) was added DIPEA (0.5 M in toluene, 0.050 mL), followed by 2,4,6-trimethyl-benzenesulfonyl chloride (0.2 M in toluene, 0.12 mL). After overnight at ambient temperature, solid phase extraction (SPE) by strong cation exchange (SCX) was followed by silica gel column chromatography to give N-[2-(2,6-Dichloro-phenyl)-3H-benzoimidazol-5-yl]-2,4,6-trimethyl-benzenesulfonamide: MS (m/z) 460.06 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([NH:18]C=O)/[CH:6]=[CH:7]/[CH:8]([P:10]([O:15]CC)([O:12]CC)=[O:11])[CH3:9])C.Cl>>[NH2:18][CH:5](/[CH:6]=[CH:7]/[CH:8]([CH3:9])[P:10]([OH:15])([OH:12])=[O:11])[C:4]([OH:21])=[O:3]
Reactant: CCOC(=O)C(/C=C/C(C)P(=O)(OCC)OCC)NC=O
Agent: Cl
Product: CC(/C=C/C(N)C(=O)O)P(=O)(O)O

Procedure:
E-2-formylamino-5-diethylphosphono-5-methyl-3-pentenoic acid ethyl ester is hydrolysed with 4.35 N hydrochloric acid in the manner described in Example 11. E-2-amino-5-methyl-5-phosphono-3-pentenoic acid is isolated in the form of an amorphous white solid mass. 1H-NMR (D2O) 1.05 (dd, 3H, CH3); 2.45 (m, 1H, C(5)-H); 4.33 (d, 2H, C(2)-H); 5.5 and 5.9 (2m, 2H, C(3)-H and C(4)-H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].O.[OH-].[Li+].O.CO>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C(C)Oc2ccccc2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(Oc1ccccc1)c1ccc(C(=O)O)c(Cl)c1
Temperature: 20 °C
Reaction time: 5 h
Yield: 66.9 %

Procedure:
A mixture of methyl 2-chloro-4-(1-phenoxyethyl)benzoate (750 mg, 2.7 mmol), lithium hydroxide monohydrate (571 mg, 13.6 mmol), water (5 mL) and methanol (5 mL) in tetrahydrofuran (15 mL) was stirred at 20° C. for 5 hours. The reaction mixture was concentrated. The residue was acidified to pH=2 with concentrated hydrochloride solution. The mixture was extracted with ethyl acetate (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give 2-chloro-4-(1-phenoxyethyl)benzoic acid as a white solid (500 mg, 71%). LRMS (M+H+) m/z: 276.06. found 276.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][CH3:30])=[O:28])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([NH:29][CH3:30])=[O:28])=[CH:24][CH:25]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CNC(=O)Cc1ccc(N)cc1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: CNC(=O)Cc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 150 °C
Yield: 46 %

Procedure:
A mixture of 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.100 g, 0.33 mmol) and 2-(4-aminophenyl)-N-methylacetamide (0.164 g, 1.0 mmol) was heated for 3 h at 150° C., then toluene added and the mixture continued heating for an additional 3 h. After this time, the mixture was purified by silica gel chromatography eluting with methylene chloride and methanol. The resulting solid was further purified by reverse phase preparative HPLC and then converted to the HCl salt to afford the title compound (0.065 g, 50%) as a white solid. MW=391.89. 1H NMR (DMSO-d6, 500 MHz) δ 14.07 (br s, 1H), 9.82 (s, 1H), 8.04-8.03 (m, 1H), 7.90-7.89 (m, 1H), 7.71-7.58 (m, 3H), 7.38-7.34 (m, 4H), 7.01 (s, 1H), 3.44 (s, 2H), 3.18-3.14 (m, 2H), 2.93 (t, J=7.3 Hz, 2H), 2.59 (d, J=4.6 Hz, 3H), 2.27-2.21 (m, 2H); ESI MS m/z 392 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:10]=1[O:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=[O:14])C1C=CC=CC=1>C(OC(=O)C)C.[Pd]>[Cl:22][C:20]1[CH:19]=[CH:18][C:10]([O:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=[O:14])=[C:9]([OH:8])[CH:21]=1
Reactant: CC(C)(Oc1ccc(Cl)cc1OCc1ccccc1)C(=O)O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(Oc1ccc(Cl)cc1O)C(=O)O
Reaction time: 3 h

Procedure:
A mixture of the product from step (ii) (1.4 g) and 10% Pd/C (0.14 g) in ethylacetate (30 ml) was hydrogenated at 2 Bar for 3 h then filtered through celite. The filtrate was evaporated under reduced pressure, yield 0.6 g.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:9]2=[O:14].[F:23][C:24]([F:35])([F:34])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]=[C:32]=[O:33])[CH:26]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[O:22]=[C:16]1[CH:15]([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[CH:13][C:5]=3[CH2:4][N:3]([CH3:2])[C:32]([NH:31][C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([C:24]([F:34])([F:35])[F:23])[CH:26]=3)=[O:33])[C:9]2=[O:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: CNCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O)C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
To a suspension of 3-(4-methylaminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.60 g, 1.86 mmol) and α,α,α-trifluoro-m-tolyl-isocyanate (0.29 mL, 2.23 mmol) in dry CH2Cl2 (80 ml), was added diisopropylethylamine (0.45 mL g, 2.60 mmol). The mixture was stirred at room temperature overnight. The mixture was quenched with MeOH and filtered. The resulting solid was rinsed with CH2Cl2 (5 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-3-(3-trifluoromethyl-phenyl)-urea (0.58 g, 66%): mp 198-200° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=1.91 (98%); 1H NMR (DMSO-d6): δ 2.00-2.05 (m, 1H), 2.28-2.39 (m, 1H), 2.56-2.63 (m, 1H), 2.85-2.93 (m, 1H), 3.01 (s, 3H), 4.32-4.53 (dd, J=8, 20 Hz, 2H), 4.67 (s, 2H), 5.11-5.18 (dd, J=5.9, 15.8 Hz, 1H), 7.30 (d, J=7.5 Hz, 1H), 7.44-7.57 (m, 3H), 7.65 (d, J=7.5 Hz, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.94 (s, 1H), 8.81 (s, 1H), 11.02 (s, 1H). 13C NMR (DMSO-d6) δ: 22.56, 31.17, 34.76, 46.25, 48.36, 51.60, 115.71, 118.50, 121.78, 123.15, 126.42, 128.49, 128.83, 129.44, 129.81, 131.94, 133.59, 140.14, 141.33, 155.41, 168.00, 171.01, 172.82. Anal Calcd for C23H21F3N4O4: C, 58.23; H, 4.46; N, 11.81, F, 12.01. Found: C, 58.06; H, 4.30; N, 12.09, F, 11.59.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[N:17]3)[CH:13]=[CH:12][N:11]=2)[CH2:5][CH2:4]1.[C:25](Cl)(=[O:27])[CH3:26]>C(Cl)Cl.O>[N:16]1([C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C@H:6]3[CH2:5][CH2:4][C@H:3]([CH2:2][NH:1][C:25](=[O:27])[CH3:26])[CH2:8][CH2:7]3)[N:15]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[N:17]1
Reactant: CC(=O)Cl
Reactant: NC[C@H]1CC[C@H](Nc2nccc(-n3nnc4ccccc43)n2)CC1
Solvent: O
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CC[C@H](Nc2nccc(-n3nnc4ccccc43)n2)CC1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
TEA (52 μL, 0.37 mmol) was added, under nitrogen atmosphere, to a solution of trans-(4-aminomethyl-cyclohexyl)-(4-benzotriazol-1-yl-pyrimidin-2-yl)-amine (60 mg, 0.185 mmol) in DCM (3 mL). The mixture was cooled to −78° C. and acetyl chloride (13.2 μL, 0.185 mmol) was added. The reaction mixture was stirred at RT overnight; it was then poured in water and extracted 3 times with a mixture of isopropanol and chloroform. The combined organic extracts were dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude residue was purified via preparative TLC to give 10 mg of trans-N-[4-(4-benzotriazol-1-yl-pyrimidin-2-ylamino)-cyclohexylmethyl]-acetamide. 1H NMR (400 MHz, CDCl3) δ ppm 8.55 (1 H, d, J=8.19 Hz), 8.41 (1 H, d, J=5.14 Hz), 8.12 (1 H, d, J=8.19 Hz), 7.57-7.67 (1 H, m), 7.42-7.51 (2 H, m), 7.16-7.24 (0.3 H, m), 5.55-5.64 (0.7 H, m), 5.18-5.43 (1 H, m), 3.80-3.93 (1 H, m), 3.11-3.25 (2 H, m), 2.27 (1 H, s), 2.19-2.35 (2 H, m), 2.00 (2 H, s), 1.85-1.95 (2 H, m), 1.50-1.63 (1 H, m), 1.11-1.37 (4 H, m).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2].S(Cl)(Cl)=O.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[S:29][C:30]3[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:31]=3[N:32]=2)=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[S:29][C:30]4[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:31]=4[N:32]=3)=[CH:26][CH:27]=2)=[O:11])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: COc1ccc2nc(-c3ccc(N)cc3)sc2c1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2nc(-c3ccc(NC(=O)c4ccc(OC(C)=O)c([N+](=O)[O-])c4)cc3)sc2c1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
A mixture of 4-acetoxy-3-nitrobenzoic acid (0.44 g, 1.95 mmol) and thionyl chloride (5 ml) was heated under reflux for 1.5 h. The reaction mixture was cooled to room temperature and excess reagent was removed under reduced pressure to give the crude acid chloride. The amide was prepared as described in the Amide Coupling section above using the acid chloride and 2-(4-aminophenyl)-6-methoxybenzothiazole (0.50 g, 1.95 mmol) in dry THF (25 ml) containing diisopropylethylamine (0.302 g, 2.34 mmol) to give the title compound (0.728 g, 86%) as a tan-coloured solid after work-up.
Reaction SMILES: C([Li])(C)(C)C.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:21][C:22]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].O>C1COCC1>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:24]([C:23]2[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:22]=2[F:21])=[O:25])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1cccc(F)c1F
Reactant: Brc1ccc(OCc2ccccc2)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1ccc(OCc2ccccc2)cc1)c1cccc(F)c1F
Temperature: -15 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
A solution of t-butyllithium (3.0 mL, 1.2 M in pentane) was added to a cooled (−78° C.) solution of benzyloxy-4-bromobenzene (500 mg, 1.9 mmol) in THF (20 mL). The temperature was raised to −15° C. over a period of 1 h and stirred at −15° C. for an additional 2 h. A slurry of MnCl2.2LiCl2 (1.9 mmol) in THF (13 mL) was added and the mixture was stirred for 30 min allowing the temperature to reach 0° C. 2,3-Difluorobenzoyl chloride was added and the reaction was stirred at r.t. for 1 h. Water (20 mL) was added, stirred for 10 min. The aqueous phase was extracted with dichloromethane (2×20 mL) and the organic phases were combined and washed with brine (20 mL), dried (Na2SO4), filtered and concentrated. Purified by flash chromatography (eluent: 100% heptane →10% ethyl acetate in heptane) to give the title compound 3 (320 mg, 52% yield). 1H-NMR (400 MHz, CDCl3): δ 7.88 (d, J=7.5 Hz, 2H), 7.48-7.15 (m, 8H), 7.08 (d, J=7.5 Hz, 2H), 5.18 (s, 2H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]1([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1)=[O:16]>CN(C=O)C>[CH:7]1([C:10]([O:12][CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)=[O:16])=[O:11])[CH2:9][CH2:8]1
Reactant: O=C(O)C1CC1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(COC(=O)C1CC1)c1ccc(Br)cc1
Reaction time: 0.25 h
Yield: 98.8 %

Procedure:
To a slurry of sodium carbonate (9.00 g, 84.91 mmol) in DMF (100 ml) was added dropwise cyclopropane carboxylic acid (4.5 ml, 56.50 mmol). The mixture was stirred for 15 min and then treated with 2,4′-dibromoacetophenone (15.71 g, 56.52 mmol). After 3 h, the mixture was partitioned between Et2O and water. The aqueous phase was extracted with Et2O (4×125 ml). The combined organic phases were dried over MgSO4 and concentrated in vacuo to yield 2-(4-bromophenyl)-2-oxoethyl cyclopropane carboxylate as a yellow solid (15.81 g, 98%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[K+].Cl>CN(C=O)C.O.CO>[CH2:19]([O:1][C:2]1[CH:10]=[C:9]([O:11][CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=2)[C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)c1cc(Br)c(O)cc1O
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56 %

Procedure:
2,4-dihydroxy-5-bromobenzoic acid (5.16 g, 22.15 mmol) was dissolved in DMF (40 ml) and potassium carbonate (12.2 g) and benzyl bromide (8 ml) were sequentially added. The mixture was stirred at room temperature for 18 hours under nitrogen. An aqueous solution of potassium hydroxide (2 g) in water (25 ml) was then added, followed by methanol (50 ml) and the mixture heated to reflux with vigorous stirring for 24 hours. The mixture was then allowed to cool, was poured into 1N HCl (250 ml) and was then extracted with ether and then DCM. The combined organic layers were dried over magnesium sulphate and the solvent evaporated in vacuo. The resulting solid material was washed with P.E. and then Et2O (3×50 ml) to yield pure product (5.2 g, 56%). 1H NMR (MeOH-d4) 8.06 (1H, s), 7.51-7.30 (10H, m), 6.85 (1H, s), 5.22 (2H, s), 5.20 (2H, s). MS: [M+H]+ 413.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])/[CH:14]=[CH:15]/[CH3:16].C1(N(C)C2CCCCC2)CCCCC1.O>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C(OCC)(=O)C>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2](/[C:15](/[CH3:16])=[CH:14]\[C:13]([O:18][CH2:19][CH3:20])=[O:17])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: C/C=C/C(=O)OCC
Reactant: Cc1ccc2cccc(Br)c2n1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)/C=C(/C)c1cccc2ccc(C)nc12
Temperature: 25 °C
Yield: 35.2 %

Procedure:
A solution of 8-bromo-2-methylquinoline (2.00 g, 9.01 mmol), (E)-ethyl but-2-enoate (3.36 mL, 27.0 mmol), N-cyclohexyl-N-methylcyclohexanamine (5.79 mL, 27.0 mmol), and Pd(PtBu3)2 (0.23 g, 0.45 mmol) in dioxane (10 mL) was stirred at reflux for 20 hours. After cooling to ambient temperature, water (20 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 40M column, 0-100% CH3CN/water gradient; 30 column volumes) to give (Z)-ethyl 3-(2-methylquinolin-8-yl)but-2-enoate (0.81 g, 35.2%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:11]3[CH2:20][CH2:19][CH2:18][CH:12]3[C:13](=S)[NH:14][C:15]=2[CH:16]=1)=[O:4].[NH3:21]>>[NH2:21][C:13]1[CH:12]2[CH2:18][CH2:19][CH2:20][CH:11]2[C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[CH:16][C:15]=2[N:14]=1
Reactant: N
Reactant: COC(=O)CCc1ccc2c(c1)NC(=S)C1CCCC21
Product: COC(=O)CCc1ccc2c(c1)N=C(N)C1CCCC21
Yield: 28 %

Procedure:
Analogously to Example 4, 7-(methoxycarbonylethyl)-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione (150 mg, 0.52 mmol) in 7N methanolic ammonia solution (20 ml) is reacted to form 40 mg (28%) of product.
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:36]1[CH:40]=[N:39][CH:38]=[N:37]1.C(OCC)(=O)C>C(#N)C>[N:36]1([CH2:12][CH2:13][CH2:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=3)[CH2:19][CH2:20]2)[CH:40]=[N:39][CH:38]=[N:37]1
Reactant: c1nc[nH]n1
Reactant: Cc1ccc(S(=O)(=O)OCCCC2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCC(CCCn3cncn3)CC2)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
The 4-tosyloxypropyl-N-(4-nitrophenyl)piperidine (4.19 g, 10.0 mmol) obtained in Example 11(2) was dissolved in acetonitrile (40 ml), and potassium carbonate (2.76 g, 20 mmol) and 1,2,4-triazole (1.04 g, 15.0 mmol) were added thereto, followed by stirring at 80° C. for 18 hours. After the reaction mixture was allowed to cool to room temperature, ethyl acetate was added to the reaction mixture, and the organic layer was washed with water and saturated sodium chloride, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the residue obtained by evaporation under reduced pressure was purified using medium pressure silica gel flash column chromatography (methanol:chloroform=1:100 to 1:30), thereby obtaining 4-[3-(1,2,4-triazol-1-yl)-propyl]-N-(4-nitrophenyl)piperidine (2.47 g, 78%) as a yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([NH:9][CH:10]=[C:11]([C:17](OCC)=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[CH:7][CH:8]=1.C(OC=C(C(OCC)=O)C(OCC)=O)C.COC1C=CC=C(N)C=1>>[OH:2][C:3]1[CH:4]=[C:5]2[C:6]([CH:17]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=[N:9]2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(=CNc1cccc(OC)c1)C(=O)OCC
Agent: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: COc1cccc(N)c1
Product: CCOC(=O)c1cnc2cc(O)ccc2c1
Temperature: 125 °C
Yield: 99 %

Procedure:
Diethyl 2-(((3-methoxyphenyl)amino)methylene)malonate. Diethyl ethoxymethylenemalonate (5.00 g, 40.6 mmol) and m-anisidine (8.13 mL, 40.6 mmol) were mixed and heated at 125° C. for 3 h. After cooling to ambient temperature, residual solvent was removed under reduced pressure and dried under high vacuum to afford the title compound as a yellow oil (11.81 g, 99%). 1H NMR (400 MHz, CDCl3) δ 11.57 (d, J=13.7 Hz, 1H), 9.11 (d, J=13.7 Hz, 1H), 7.90-7.83 (m, 1H), 7.31 (ddd, J=15.5, 8.2, 2.2 Hz, 2H), 7.25 (d, J=2.3 Hz, 1H), 4.90 (q, J=7.0 Hz, 2H), 4.84 (q, J=7.3 Hz, 2H), 4.42 (s, 3H), 1.98 (t, J=7.0 Hz, 3H), 1.92 (t, J=7.0 Hz, 3H). [M+H]=294.3.
Reaction SMILES: [F:1][C:2]1([F:22])[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[C:18]3[C:13](=[C:14]([N+:19]([O-])=O)[CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH2:4][CH2:3]1.[NH4+].[Cl-]>CCO.[Fe]>[F:22][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([NH:8][C:9]2[C:18]3[C:13](=[C:14]([NH2:19])[CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1cccc2c(NC3CCC(F)(F)CC3)ncnc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1cccc2c(NC3CCC(F)(F)CC3)ncnc12
Yield: 86.1 %

Procedure:
To a solution of N-(4,4-difluorocyclohexyl)-8-nitroquinazolin-4-amine (90 mg, 0.292 mmol) in EtOH (2 mL) were added iron powder (163 mg, 2.92 mmol) and NH4Cl (127 mg, 2.33 mmol) and the reaction mixture was heated at reflux for 2 h. Then the reaction mixture was filtered through celite. The celite bed was washed with 10% MeOH in CHCl3. The filtrate was washed with a saturated aq. NaHCO3 solution and water. The organic layer was separated, dried, filtered and concentrated to afford 70 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.38 (s, 1H), 7.64 (d, J=7.2 Hz, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.19-7.14 (t, J=7.8 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 5.71 (s, 2H), 4.38 (m, 1H), 2.09-1.97 (m, 6H), 1.73-1.69 (m, 2H); MS (m/z): 279.12 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24]([OH:26])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:31][N:32]1[CH:36]=[C:35]([C:37]2([NH2:40])[CH2:39][CH2:38]2)[N:34]=[CH:33]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:26])[NH:40][C:37]5([C:35]6[N:34]=[CH:33][N:32]([CH3:31])[CH:36]=6)[CH2:39][CH2:38]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: Cn1cnc(C2(N)CC2)c1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cn(C)cn5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.15 g, 0.37 mmol, 1 eq), 1-(1-methyl-1H-imidazol-4-yl)cyclopropanamine (0.061 g, 0.44 mmol, 1.2 eq), EDCI.HCl (0.078 g, 0.40 mmol, 1.1 eq), HOBT (0.049 g, 0.37 mmol, 1.0 eq) and TEA (0.15 ml, 1.1 mmol, 3 eq) were dissolved in dichloromethane and the above mixture was stirred at room temperature for 18 h. The mixture was then added with water. The organic layer was separated, washed with water, concentrated and the crude product purified by Prep. HPLC. Yield: 24.69 mg (10%). 1HNMR (400 MHz, DMSO-d6): δ1.04-1.07 (m, 2H), 1.17-120 (m, 2H), 2.29 (s, 3H), 2.82 (d, J=4.4 Hz, 3H), 3.54 (s, 3H), 6.7 (s, 1H), 7.37-7.43 (m, 5H), 7.58 (s, 1H), 7.74-7.77 (d, J=8.8 Hz, 1H), 7.81-7.82 (m, 2H), 7.97-8.01 (m, 2H), 8.46-8.47 (m, 1H), 9.06 (s, 1H) LCMS: (ES+) m/z=523.2 (M+H)+
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[C:4](=[O:6])[CH3:5].C(O)[C:10]([CH3:13])([CH3:12])[CH3:11]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:1][O:2][CH:3]([O:7][CH2:8][C:10]([CH3:13])([CH3:12])[CH3:11])[C:4](=[O:6])[CH3:5]
Reactant: COC(OC)C(C)=O
Reactant: CC(C)(C)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC(=O)C(OCC(C)(C)C)OCC(C)(C)C
Temperature: 80 °C
Yield: 67.2 %

Procedure:
Add p-toluenesulfonic acid hydrate (1.21 g, 10.58 mmol) to 1,1-dimethoxy-propan-2-one (25.00 g, 211.63 mmol) and neopentyl alcohol (46.64 g, 529.08 mmol) at room temperature. Heat in an open flask in an 80° C. oil bath for 8 hours. Allow to cool to room temperature and stir over the weekend. Purify (silica gel chromatography, eluting with 0:100 to 8:92 ethyl acetate:hexanes) to give the desired compound as a colorless oil (32.78 g 67.2%)