Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][OH:4].Cl[CH2:6][C:7]1[CH:12]=[C:11]([C:13]([NH:15][C:16]2[S:17][C:18]([C:26]([CH:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])=[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[O:14])[CH:10]=[CH:9][N:8]=1.O>CN(C=O)C>[O:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[C:19]1[N:20]=[C:16]([NH:15][C:13]([C:11]2[CH:10]=[CH:9][N:8]=[C:7]([CH2:6][O:4][CH3:3])[CH:12]=2)=[O:14])[S:17][C:18]=1[C:26]([CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:27]
Reactant: O=C(Nc1nc(-c2ccco2)c(C(=O)C2CCOCC2)s1)c1ccnc(CCl)c1
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCc1cc(C(=O)Nc2nc(-c3ccco3)c(C(=O)C3CCOCC3)s2)ccn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Under ice-cooling, 60% sodium hydride (10.0 mg, 0.250 mmol) was dissolved in DMF (1.0 mL), methanol (110 μL, 2.72 mmol) was slowly added dropwise thereto, and the mixture was stirred at 0° C. for 10 min. Then, 2-(chloromethyl)-N-[4-(2-furyl)-5-(tetrahydropyran-4-carbonyl)thiazol-2-yl]pyridine-4-carboxamide (81.0 mg, 0.189 mmol) obtained in step 1 of Reference Example 6, which was dissolved in DMF (1.0 mL), was slowly added dropwise thereto, and the mixture was stirred at room temperature for 5 hr. To the mixture were added water and a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50), and recrystallized from ethanol-water to give compound (IJ) (45.0 mg, 56%) as white crystals.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][N:28]([C:31]([C:33]2[CH:38]=[CH:37][C:36](I)=[CH:35][CH:34]=2)=[O:32])[CH2:27][CH2:26]1>>[CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[N:11]1[C:36]1[CH:35]=[CH:34][C:33]([C:31]([N:28]2[CH2:27][CH2:26][N:25]([C:19]3[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=3[CH3:17])[CH2:30][CH2:29]2)=[O:32])=[CH:38][CH:37]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@H](COCc5ccccc5)CCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 88.6 %

Procedure:
Using (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (536 mg) described in Preparation Example 1 and [4-(2,4-dimethylphenyl)piperazin-1-yl](4-iodophenyl)methanone (933 mg) described in Preparation Example 108 and by the reaction and treatment in the same manner as in Example 1, (S)-[4-(3-benzyloxymethyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (1.05 g) was obtained. Using the obtained (S)-[4-(3-benzyloxymethyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (1.05 g) and by the reaction and treatment in the same manner as in Example 29, the title compound (590 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9](O)=[O:10])[CH2:5][CH2:4]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[F:1][C:2]([F:12])([F:13])[C@H:3]1[CH2:4][CH2:5][C@H:6]([CH2:9][OH:10])[CH2:7][CH2:8]1
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OC[C@H]1CC[C@H](C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
trans-4-(Trifluoromethyl)cyclohexanecarboxylic acid (1.5 g, 7.65 mmol) was dissolved in tetrahydrofuran (20 mL). The reaction solution was cooled to 0° C., and lithium aluminum hydride (435 mg, 11.5 mmol) was added thereto, and then, the resulting mixture was stirred at room temperature for 3 hours. The reaction solution was cooled to 0° C., and water (0.4 mL), a 5 N aqueous solution of sodium hydroxide (0.4 mL), and water (1.2 mL) were added thereto, followed by filtration. To the filtrate, ethyl acetate was added, and the organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained as a colorless oily substance (1.18 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]2[CH:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18]CC)=[O:17])=[CH:11][CH:10]=3)[N:8]=[C:2]12.C(O)C.[OH-].[Na+]>O>[S:1]1[CH:5]=[CH:4][N:3]2[CH:6]=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:13][CH:14]=3)[N:8]=[C:2]12
Reactant: CCOC(=O)Cc1ccc(-c2cn3ccsc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)Cc1ccc(-c2cn3ccsc3n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56.4 %

Procedure:
A mixture of 5.7 g of ethyl 4-(imidazo[2,1-b]thiazol-6-yl)phenyl-acetate, 25 ml of ethanol, 0.96 g of sodium hydroxide and 5 ml of water is stirred at room temperature for 10 minutes. The ethanol is distilled off under reduced pressure, and the residue is dissolved in water. The solution is adjusted to pH 6 by addition of dilute hydrochloric acid. The crystalline precipitate is filtered off and washed with water to give 2.9 g of 4-(imidazo[2,1-b]thiazol-6-yl)phenylacetic acid as colorless crystals melting at 248°-249°C with decomposition.
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][C:7]23[CH2:14][CH2:13][CH2:12][N:11]2[C:10](=[O:15])[N:9]([C:16]2[CH:21]=[C:20]([Cl:22])[C:19]([O:23]C)=[C:18]([Cl:25])[CH:17]=2)[C:8]3=[O:26])=[CH:4][CH:3]=1>Br>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]23[CH2:14][CH2:13][CH2:12][N:11]2[C:10](=[O:15])[N:9]([C:16]2[CH:21]=[C:20]([Cl:22])[C:19]([OH:23])=[C:18]([Cl:25])[CH:17]=2)[C:8]3=[O:26])=[CH:27][CH:28]=1
Reactant: COc1c(Cl)cc(N2C(=O)N3CCCC3(Cc3ccc(Br)cc3)C2=O)cc1Cl
Agent: Br
Product: O=C1N(c2cc(Cl)c(O)c(Cl)c2)C(=O)C2(Cc3ccc(Br)cc3)CCCN12
Yield: 83.7 %

Procedure:
The compound from Example 134 (0.8 g) was taken in aqueous HBr (10 mL) and the solution was refluxed overnight. The aqueous solution was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography on silica gel (1:1 EtOAc/Hexanes) to yield the titled compound (0.65 g). MS (m/z) 469 (MH+).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[CH:7].[Li]CCCC.[CH3:15][Si:16](Cl)([CH3:18])[CH3:17]>C1COCC1>[CH3:15][Si:16]([CH3:18])([CH3:17])[C:7]#[C:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:9])=[O:8]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCCCCC(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#CCCCCC(=O)O
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 91.9 %

Procedure:
A solution of hept-6-ynoic acid (1.90 g, 14.8 mmol) in anhydrous THF (90 mL) at −78° C. was treated with n-BuLi (2.3 M in hexanes, 14.5 mL, 33.3 mmol). After stirring for 2 min, TMSCl (5.8 mL, 46.0 mmol) was added. The reaction mixture was allowed to warm slowly to 25° C. and was stirred for 1 h. The reaction was quenched with the addition of aqueous 2 N HCl and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated. Column chromatography (SiO2, 4×6 cm, 20% EtOAc-hexanes) afforded 7-(trimethylsilyl)hept-6-ynoic acid (2.7 g, 13.6 mmol, 92%) as a white solid: 1NMR (CDCl3, 500 MHz) δ 2.40 (t, 2H, J=7.4 Hz), 2.24 (t, 2H, J=7.3 Hz), 1.78-1.72 (m, 2H), 1.62-1.56 (m, 2H), 0.15 (s, 9H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:29][O:30][C:31]1[C:32](=[O:55])[C:33]([CH3:54])=[C:34]([CH2:40][C:41]2[CH:42]=[CH:43][C:44]([O:50][C:51](=[O:53])[CH3:52])=[C:45]([CH:49]=2)[C:46](O)=[O:47])[C:35](=[O:39])[C:36]=1[O:37][CH3:38]>C(Cl)Cl>[CH3:1][N:2]([C:46](=[O:47])[C:45]1[CH:49]=[C:41]([CH2:40][C:34]2[C:35](=[O:39])[C:36]([O:37][CH3:38])=[C:31]([O:30][CH3:29])[C:32](=[O:55])[C:33]=2[CH3:54])[CH:42]=[CH:43][C:44]=1[O:50][C:51](=[O:53])[CH3:52])[C:3]1[CH:4]=[CH:5][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:7][CH:8]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: CNc1ccc(C(F)(F)F)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)N(C)c3ccc(C(F)(F)F)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.5 %

Procedure:
N-Methyl-4-trifluoromethylaniline (0.200 g, 1.143 mmol), triethylamine (0.116 g, 1.143 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.193 g, 1.143 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.285 g, 0.762 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.140 g, 0.263 mmol, 35%).
Reaction SMILES: [S:1]1[C:8]2[CH:7]=[C:6]([C:9]([OH:11])=O)[NH:5][C:4]=2[CH:3]=[CH:2]1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[N:12]1([C:9]([C:6]2[NH:5][C:4]3[CH:3]=[CH:2][S:1][C:8]=3[CH:7]=2)=[O:11])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: O=C(O)c1cc2sccc2[nH]1
Product: O=C(c1cc2sccc2[nH]1)N1CCNCC1
Yield: 35 %

Procedure:
4H-Thieno[3,2-b]pyrrole-5-carboxylic acid (50 mg, 0.30 mmol) was coupled with piperazine according to Procedure D to provide the title compound (25 mg, 35%) as an off-white solid. TLC (silica, 10% MeOH/CH2Cl2): Rf=0.15. MS (electrospray): exact mass calculated for C11H13N3OS, 235.08; m/z found, 236.1 [M+H]+. 1H NMR (CD3OD, 400 MHz): 7.33 (d, J=5.3 Hz, 1H), 6.98 (dd, J=5.2, 0.7 Hz, 1H), 6.89 (d, J=0.6 Hz, 1H), 4.08 (t, J=5.3 Hz, 4H), 3.50-3.20 (m, 4H).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[C:33]([N+:34]([O-:36])=[O:35])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[C:33]([N+:34]([O-:36])=[O:35])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c([N+](=O)[O-])cccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c([N+](=O)[O-])cccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-4-nitrobenzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=1.[CH3:14][O:15][C:16](=[O:26])[C:17]([CH3:25])([CH3:24])[C:18](=O)[CH:19](Br)[CH2:20][CH3:21]>C(O)C>[CH3:14][O:15][C:16](=[O:26])[C:17]([CH3:25])([C:18]1[N:9]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:1])([F:12])[F:13])=[CH:4][CH:5]=2)[S:8][C:19]=1[CH2:20][CH3:21])[CH3:24]
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Reactant: CCC(Br)C(=O)C(C)(C)C(=O)OC
Solvent: CCO
Product: CCc1sc(-c2ccc(C(F)(F)F)cc2)nc1C(C)(C)C(=O)OC

Procedure:
A mixture of 4-Trifluoromethyl-thiobenzamide (12.3 g, 60 mmol) and the crude product from step A (16.6 g, 66 mmol) in ethanol (600 mL) is heated to reflux for 3 days. Solvent is evaporated and the residue is purified by chromatography on silica gel yielding the title compounds (14.5 g).
Reaction SMILES: C([C:5]1N=C(N2CCC(F)(F)C2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])N=2)[N:10]=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:42][C:38]3([CH2:41][O:40][CH2:39]3)[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Cl.ClCC1N(C)C(C)=NN=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:37][C:38]3([CH2:39][O:40][CH2:41]3)[CH2:42]2)[C:30]2[C:31](=[N:33][N:34]([CH2:8][C:9]3[N:10]([CH3:5])[C:14]([CH3:15])=[N:12][N:11]=3)[N:35]=2)[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn[nH]c2n1
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: Cc1nnc(CCl)n1C
Agent: Cl
Product: Cc1nnc(Cn2nc3nc(C(C)(C)C)nc(N4CC5(COC5)C4)c3n2)n1C

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-Butyl-7-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(chloromethyl)-4,5-dimethyl-4H-1,2,4-triazole hydrochloride and isolated as white solid. MS (m/e): 384.3 (MH+).
Reaction SMILES: [CH3:1][Li].[CH3:3][O:4][C:5]([C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][C:9]([C:17](Cl)=[O:18])([CH2:10]3)[CH2:8]1)[CH2:14]2)=[O:6].CO.[Cl-].[NH4+]>[Cu]I.CCOCC>[C:17]([C:9]12[CH2:15][CH:13]3[CH2:12][CH:11]([CH2:16][C:7]([C:5]([O:4][CH3:3])=[O:6])([CH2:14]3)[CH2:8]1)[CH2:10]2)(=[O:18])[CH3:1]
Reactant: [Li]C
Reactant: COC(=O)C12CC3CC(CC(C(=O)Cl)(C3)C1)C2
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C12CC3CC(CC(C(C)=O)(C3)C1)C2
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
Under nitrogen, a chilled (0° C.) diethyl ether suspension of copper (1) iodide (3.0 eq) was treated with methyl lithium (6.0 eq, 1.4 M in ethyl ether). The resulting solution was chilled to −78° C. and after ten minutes a chilled (−30° C.) diethyl ether solution of 3-methoxycarbonyladamantane-1-carboxylic acid chloride was added dropwise over a five minute period. The reaction was stirred for 45 minutes at −78° C. and then quenched with MeOH (11.0 eq) and allowed to warm to room temperature. After addition of Et2O and saturated aqueous ammonium chloride solution, the mixture was stirred for ten minutes and then the organic phase was washed with saturated NH4Cl, saturated NaHCO3, brine, dried (MgSO4), filtered and concentrated to a volatile oil, which was used without further purification.
Reaction SMILES: [CH:1]1[C:6]([S:7](Cl)(=[O:9])=[O:8])=[CH:5][CH:4]=[C:3]([I:11])[CH:2]=1.[NH3:12]>>[I:11][C:3]1[CH:4]=[CH:5][C:6]([S:7](=[O:9])(=[O:8])[NH2:12])=[CH:1][CH:2]=1
Reactant: N
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Product: NS(=O)(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Pipsylchloride (100 mg) was dissolved in 28% ammonia solution (4 ml) and the solution was stirred at room temperature for 1 hours. The resulting mixture was extracted with ethyl acetate (20 ml), washed with water and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was chromatographed on column eluting with ethyl acetate/hexane (1/2) to yield the compound 2-2 (89 mg, 100%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].O[C:12]1([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)=[N:13]1>C1COCC1.CCOCC>[CH3:37][O:36][C:33]1[CH:34]=[CH:35][C:30]([CH:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]([C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[NH:13]2)=[CH:31][CH:32]=1
Reactant: COc1ccc(C2(O)N=C(c3ccc4c(c3)OCO4)c3ccccc32)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C2NC(c3ccc4c(c3)OCO4)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 62 %

Procedure:
To a flask containing dry ether (2 ml) was added with stirring aluminum chloride (0.037 g, 0.28 mmol) at 0° C. under argon, followed by 1M lithium aluminum hydride in THF (0.28 ml, 0.28 mmol). The mixture was stirred at 0° C. for 5 minutes, then to it was rapidly added (1RS)-1-Hydroxy-1-(4-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)-1H-isoindole (0.050 g, 0.14 mmol), followed by dry THF (2 ml). After stirring for 10 minutes at 0° C. the reaction was quenched with water, 15% sodium hydroxide, and water. The mixture was extracted with ethyl acetate and the combined organic extract was successively washed with: water, brine and dried (MgSO4). After removing the solvent, flash chromatography of the residue (silica gel, 3:7 ethyl acetate:hexane) afforded the title compound as a yellow solid (0.030 g, 45%). MS (ESI) m/e 346 [M+H]+ ; mp: 123°-125° C.
Reaction SMILES: [H-].[Na+].Br[C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([C:18]#[N:19])=[CH:6][N:5]=1.[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=[O:27])[CH3:21].[I-].C[N+]1C=CN(C)C=1>CN(C=O)C.C(Cl)Cl.O>[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([C:18]#[N:19])=[CH:6][N:5]=1)=[O:27])[CH3:21]
Reactant: COc1cc2c(C#N)cnc(Br)c2cc1OC
Reactant: CCOc1cccc(C=O)c1
Agent: Cn1cc[n+](C)c1
Agent: [H-]
Agent: [I-]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cccc(C(=O)c2ncc(C#N)c3cc(OC)c(OC)cc23)c1
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Sodium hydride (0.21 g, 5.1 mmol) was added to a stirred mixture of 1-Bromo-6,7-dimethoxy-isoquinoline-4-carbonitrile (1.0 g, 3.4 mmol), 3-Ethoxy-benzaldehyde (0.72 mL, 5.1 mmol), 1,3-dimethylimidazolium iodide (0.32 g, 1.36 mmol) in DMF (40 mL). The reaction mixture became dark color. After 30 min, water was added to the above mixture, and extracted with chloroform. The extract was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo to afford a solid. Flash chromatography (Merck Silica gel 60, 70–230 mesh, methylenechloride) afforded 1-(3-Ethoxy-benzoyl)-6,7-dimethoxy-isoquinoline-4-carbonitrile (1.22 g, 98%) as a white solid. LC-MS m/e calcd for C21H18N2O4 (MH+) 363, found 363.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:30][O:31][CH2:32][CH3:33])[N:15]([CH2:16][CH:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[C:11]=2[C:10]2[CH:9]=[CH:8][C:7]([C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)=[CH:6][C:5]=2[N:4]=1>C(O)C>[ClH:1].[ClH:1].[ClH:1].[CH2:32]([O:31][CH2:30][C:14]1[N:15]([CH2:16][CH:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)[C:11]2[C:10]3[CH:9]=[CH:8][C:7]([C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)=[CH:6][C:5]=3[N:4]=[C:3]([NH2:2])[C:12]=2[N:13]=1)[CH3:33]
Reactant: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCO
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC1CCNCC1
Temperature: 25 °C

Procedure:
Ethanolic hydrochloric acid (17.68 mL of 4.25 M) was added to a solution of tert-butyl 4-{[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidine-1-carboxylate (9.71 g, 18.8 mmol) in anhydrous ethanol, and the reaction was heated at reflux for two hours. A precipitate formed, and the reaction was allowed to cool to ambient temperature. The solid was isolated by filtration, washed with a small volume of cold ethanol, and dried under reduced pressure to provide 7.1 g of 2-ethoxymethyl-1-(piperidin-4-ylmethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine trihydrochloride as an off-white solid, mp>250° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][CH2:14][CH2:15][CH3:16])[N:9]2[CH:17]=[CH:18][CH:19]=[C:8]2[C:7]=1[OH:20])=[O:5])C.[NH2:21][CH2:22][C:23]([O-:25])=[O:24].[Na+]>>[CH2:13]([N:10]1[C:11](=[O:12])[C:6]([C:4]([NH:21][CH2:22][C:23]([OH:25])=[O:24])=[O:5])=[C:7]([OH:20])[C:8]2=[CH:19][CH:18]=[CH:17][N:9]12)[CH2:14][CH2:15][CH3:16]
Reactant: NCC(=O)[O-]
Reactant: CCCCn1c(=O)c(C(=O)OCC)c(O)c2cccn21
Agent: [Na+]
Product: CCCCn1c(=O)c(C(=O)NCC(=O)O)c(O)c2cccn21

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 1-butyl-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 308 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].[C:12](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH3:12])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(Cl)c(C=O)c(Cl)c1
Temperature: 80 °C
Yield: 86.8 %

Procedure:
To a solution of 2,6-dichloro-4-hydroxybenzaldehyde (225 mg, 1.18 mmol) in DMF (2.0 mL) was added potassium carbonate (0.81 g, 5.9 mmol) and methyl iodide (1.47 mL, 23.6 mmol). The resulting mixture was heated at 80° C. for 3 h. Reaction was diluted with water and ethyl acetate. The organic layer was separated and dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (20% ethyl acetate/hex) to give the desired product as a white solid (210 mg, 87%). LCMS for C8H7Cl2O2(M+H)+: m/z=205.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[S:3]([O:6][CH2:7][CH:8]=[CH2:9])(=[O:5])=[O:4].[CH2:12](O)[C:13]1C=CC=[CH:15][CH:14]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(Cl)(Cl)(Cl)Cl>[F:11][C:2]([F:10])([F:1])[S:3]([O:6][CH2:7][C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:9]=1)(=[O:4])=[O:5]
Reactant: C=CCOS(=O)(=O)C(F)(F)F
Reactant: OCc1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(OCc1ccccc1)C(F)(F)F

Procedure:
Benzyl trifluoromethanesulfonate was prepared in carbon tetrachloride solution and used as a dried solution in Examples 53 through 55, in the same way the 2-propen-1-yl trifluoromethanesulfonate was prepared and used in Examples 41 through 44, starting with benzyl alcohol and trifluoromethanesulfonic anhydride.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1.[C:18](=O)([O-])[O-].[K+].[K+].CI.Cl>CN(C)C=O.C(OCC)(=O)C>[CH3:18][N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7]1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2c1ncc[nH]1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: Cn1ccnc1N1CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
230 mg 1-(1H-imidazol-2-yl)-5-nitro-2,3-dihydro-1H-indole are dissolved in 6 ml dimethylformamide, combined with 200 mg potassium carbonate and 75 μl methyl iodide and stirred overnight at ambient temperature. The mixture is divided between ethyl acetate and 2 N hydrochloric acid and the aqueous phase is washed twice with dichloromethane. Then the pH of the aqueous phase is adjusted to 12 by the addition of 40% sodium hydroxide solution and it is extracted with dichloromethane. The organic phase is washed with saturated sodium chloride solution and dried on magnesium sulphate. The solvents are eliminated in vacuo and the residue is chromatographed on silica gel (dichloromethane/methanol 99:1 to 90:10).