Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:4]=[C:5]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:24]=[C:23]([NH2:25])[CH:22]=[CH:21][CH:20]=2)[C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.N1C=CC=CC=1.[F:33][C:34]([F:45])([O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:35](Cl)=[O:36].C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:1][N:2]([CH3:26])[C:3]1[CH:4]=[C:5]([C:9](=[N:16][O:17][CH2:18][C:19]2[N:24]=[C:23]([NH:25][C:35](=[O:36])[C:34]([F:33])([F:45])[O:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:22]=[CH:21][CH:20]=2)[C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)C(F)(F)Oc1ccccc1
Reactant: CN(C)c1cccc(C(=NOCc2cccc(N)n2)c2nnnn2C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CN(C)c1cccc(C(=NOCc2cccc(NC(=O)C(F)(F)Oc3ccccc3)n2)c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 25 h
Yield: 88 %

Procedure:
To a stirred solution of 6-{[({[3-(dimethylamino)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}pyridin-2-amine (90 mg, 0.26 mmol) in dry 1,4-dioxane (10 mL) were added pyridine (31 μL, 0.38 mmol) and 2,2-difluoro-2-phenoxyacetyl chloride (105 mg, 0.51 mmol). The reaction mixture was stirred at room temperature for 25 h, then poured into aq. NaHCO3 (10 g/L, 30 mL). After extraction with ethyl acetate (50 mL), the organic layer was dried (MgSO4) and concentrated in vacuo. Purification on silica gel afforded N-(6-{[({[3-(dimethylamino)phenyl](1-methyl-1H-tetrazol-5-yl)methylene}amino)oxy]methyl}pyridin-2-yl)-2,2-difluoro-2-phenoxyacetamide as an oil [123 mg, yield 88%; HPLC/MS:m/z=523 (M+H); log P(HCOOH)=4.14].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:39]=[CH:38][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:15][C@@H:14]([S:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][C@H:12]2[CH2:36][OH:37])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>ClCCl>[CH3:47][S:48]([O:37][CH2:36][C@@H:12]1[CH2:13][C@H:14]([S:16][C:17]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15][N:11]1[C:9]([O:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:39][CH:38]=1)=[O:10])(=[O:50])=[O:49]
Reactant: COc1ccc(COC(=O)N2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)N2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)C[C@H]2COS(C)(=O)=O)cc1
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
A solution of (2S,4S)-1-p-methoxybenzyloxycarbonyl-4-tritylthiopyrrolidine-2-methanol (22.33 g: 41.37 mmole) is diluted with dichloromethane (300 ml) and the mixture is cooled to -30° C. To this mixture, triethylamine (6.92 ml: 1.2 eq.) and methanesulfonyl chloride (3.52 ml: 1.1 eq.) are added, and the mixture is stirred for 20 minutes. The reaction mixture is successively washed with dilute hydrochloric acid and water, dried over magnesium sulfate, and filtered. The filtrate is concentrated in vacuo to give crude (2S,4S)-1-p-methoxybenzyloxycarbonyl-4-tritylthiopyrrolidine-2-methanol methanesulfonate (27.81 g: 45.02 mmole). Yield: 100%.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([O:9][C:10](=[O:34])[C:11]([CH3:33])([CH3:32])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([OH:31])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:30])([CH3:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:8].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH2:27]([O:26][C:24](=[O:25])[C:23]([CH3:29])([CH3:30])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:17]([O:31][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:11]([CH3:33])([CH3:32])[C:10]([O:9][CH2:7][CH3:8])=[O:34])[CH3:28]
Reactant: C1=COCCC1
Reactant: CCOC(=O)C(C)(C)CCCCCC(O)CCCCCC(C)(C)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)CCCCCC(CCCCCC(C)(C)C(=O)OCC)OC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
Under nitrogen atmosphere, 3,4-dihydro-2H-pyran (10.2 g, 121 mmol) was added dropwise to a stirred solution of 8-hydroxy-2,2,14,14-tetramethypentadecanedioic acid diethyl ester (16.1 g, 40 mmol) and p-toluenesulfonic acid monohydrate (catalytic amounts) in methylene chloride (100 mL) under cooling with an ice bath. The reaction mixture was allowed to warm to room temperature and stirred overnight. After the reaction was completed (TLC), the solution was filtered through basic aluminum oxide (50 g), which was washed with methylene chloride (4×30 mL). The filtrate was concentrated in vacuo to give crude product (19.5 g), which was purified by chromatography (silica gel, 200 g, heptanes/ethyl acetate=20:1, 10:1) yielding 2,2,14,14-tetramethyl-8-(tetrahydropyran-2-yloxy)-pentadecanedioic acid diethyl ester as a colorless oil (12.1 g, 62%). 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 4.69-4.59 (m, 1H), 4.11 (q, J=7.3 Hz, 4H), 3.98-3.82 (m, 1H), 3.65-3.40 (m, 2H), 2.00-1.18 (m, 26H), 1.24 (t, J=7.1 Hz, 6H), 1.15 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 177.74, 97.36, 76.48, 62.61, 60.02, 42.05, 40.70, 40.63, 34.90, 33.38, 31.16, 30.32, 30.26, 25.48, 25.10, 24.86, 19.96, 14.23.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][C:25]1[O:24][CH2:23][CH:22]([N:31]3[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]3)[CH2:21][C:20]2=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:15][O:16][C:17]1[CH:18]=[C:19]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][C:25]1[O:24][CH2:23][CH:22]([N:31]3[CH2:32][CH2:33][CH:34]([NH:37][C:12]([C:9]4[CH:10]=[CH:11][C:5]5[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)=[O:14])[CH2:35][CH2:36]3)[CH2:21][C:20]2=1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: COc1ccc2ncc3c(c2c1)CC(N1CCC(N)CC1)CO3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2ncc3c(c2c1)CC(N1CCC(NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1)CO3
Temperature: 25 °C
Reaction time: 15 h

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (31 mg, 0.14 mmol, 1.0 eq) is added at room temperature to a stirred solution of 1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthrene-3-yl)-piperidin-4-ylamine (50 mg, 0.14 mmol, 1.0 eq) in N,N-dimethylformamide (3 mL), followed by 1-hydroxybenzotriazole (21 mg, 0.15 mmol, 1.1 eq), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (31 mg, 0.16 mmol, 1.15 eq) and N,N-diisopropylethylamine (53 μL, 0.31 mmol, 2.25 eq). After 15 hours stirring at room temperature, solvent is evaporated and the residue is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid [1-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthrene-3-yl)-piperidin-4-yl]-amide as an off-white lyophilizated powder (24 mg, 33% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Cl)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[I-:24].[Na+]>CC(CC)=O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][I:24])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CCCCCCCCl)cc1
Agent: [Na+]
Solvent: CCC(C)=O
Product: O=C(c1ccc(Cl)cc1)c1ccc(CCCCCCCI)cc1
Yield: 90.1 %

Procedure:
1.32 g of 4-chloro-4'-(7-chloroheptyl)benzophenone and 0.85 g of sodium iodide were heated under reflux in 20 ml of ethyl methyl ketone. After 24 hours the reaction mixture was evaporated. The residue was suspended in 50 ml of water, whereupon the suspension was extracted three times with 50 ml of ethyl acetate each time, the combined organic phases were washed with 50 ml of a saturated sodium chloride solution, dried over magnesium sulphate and evaporated. There were obtained 1.5 g (90%) of crude 4-chloro-4'-(7-iodoheptyl)benzophenone as a yellowish oil which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23][CH3:24])[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:26](I)[CH3:27].CCN(C(C)C)C(C)C>CO>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23][CH3:24])[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][N:18]2[CH2:26][CH3:27])=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCCN3)c2n1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCCN3CC)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A portion of the solution (3 ml) containing 2-(butyloxy)-8-(methyloxy)-9-[2-(2-piperidinyl)ethyl]-9H-purin-6-amine (approx 140 mg, 0.402 mmol) was treated with ethyl iodide (0.032 ml, 0.402 mmol) and DIPEA (0.140 ml, 0.804 mmol). The reaction was stirred at ambient temperature in a capped vial overnight. Methanol was added to give solution and this was purified by MDAP (Method A). Product fractions were evaporated under N2 in a Radleys blow down unit. The title compound was obtained as a white solid (103 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[F:15][C:16]([F:26])([F:25])[O:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>>[F:15][C:16]([F:25])([F:26])[O:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH:21][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Product: Cc1cc(Nc2cccc(OC(F)(F)F)c2)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (50 mg, 0.243 mmol) and 3-(trifluoromethoxy)aniline (65 μl, 0.243 mmol) similar to Example 11 and isolated as a pale white solid (78 mg, 93%). 1H NMR (DMSO-d6): 9.95 (s, 1H), 8.74 (s, 1H), 8.31 (d, J=9.3 Hz, 2H), 7.95 (t, J=7.7 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.53-7.43 (m, 2H), 6.98 (d, J=8.4 Hz, 1H), 6.71 (s, 1H), 2.44 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:23]2[C:22](=[O:24])[C:9]3[O:10][C:11](=[O:21])[C:12]4[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([O:19][CH3:20])[C:13]=4[C:8]=3[C:7](=[O:25])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([O:1][C:2]1[C:23]2[C:22](=[O:24])[C:9]3[O:10][C:11](=[O:21])[C:12]4[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([O:19][CH3:20])[C:13]=4[C:8]=3[C:7](=[O:25])[C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C)cc2c(=O)oc3c(c12)C(=O)c1cccc(O)c1C3=O
Solvent: c1ccncc1
Product: COc1cc(C)cc2c(=O)oc3c(c12)C(=O)c1cccc(OC(C)=O)c1C3=O
Reaction time: 8 h

Procedure:
In pyridine (10 ml) was dissolved 8-hydroxy-1-methoxy-3-methyl-7,12-dihydro-5H-benzo[d]naphtho[2,3-b]pyran-5,7,12-trione (150 mg) as obtained in Example 15, followed by addition of acetic anhydride (5 ml). The mixture was allowed to stand overnight. The solvent was then distilled off under reduced pressure and the residue was extracted with chloroform. The solvent layer was washed with dilute HCl and water, and dried over sodium sulfate. The solvent was distilled off and the residue was crystallized from diethyl ether to give crystals (45 mg) of 8-acetoxy-1-methoxy-3-methyl-7,12-dihydro-5H-benzo[d]naphtho[2,3-b]pyran-5,7,12-trione.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.F[C:22]1[C:27]([CH:28]2[CH2:32][CH2:31][C:30]([CH3:34])([OH:33])[CH2:29]2)=[CH:26][CH:25]=[CH:24][N:23]=1.CN1C(=O)CCC1>C(OCC)(=O)C>[CH3:34][C:30]1([OH:33])[CH2:31][CH2:32][CH:28]([C:27]2[C:22]([O:20][C:17]3[CH:18]=[CH:19][C:14]([NH:13][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=4)=[CH:15][CH:16]=3)=[N:23][CH:24]=[CH:25][CH:26]=2)[CH2:29]1
Reactant: Oc1ccc(Nc2ccccn2)cc1
Reactant: CC1(O)CCC(c2cccnc2F)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC1(O)CCC(c2cccnc2Oc2ccc(Nc3ccccn3)cc2)C1
Temperature: 200 °C
Reaction time: 0.25 h

Procedure:
To a 20 mL microwave vial was added cesium carbonate (834 mg, 2.56 mmol), 4-(pyridin-2-ylamino)phenol (191 mg, 1.024 mmol), and 3-(2-fluoropyridin-3-yl)-1-methylcyclopentanol (200 mg, 1.024 mmol) followed by NMP (2049 μL). The slurry was heated to 200° C. for 3 h in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden). The reaction mixture was diluted with ethyl acetate (35 mL) and washed with 5N NaOH (5×30 mL) before drying over magnesium sulfate, filtering, and concentrating to a dark orange oil under reduced pressure. The oil was dissolved in 2 mL DMSO and transferred to a preparative HPLC vial through a 0.45 μm syringe filter. The crude compound was purified in three aliquots over 25 minutes per sample (5% 0.1% TFA in ACN:0.1% TFA in water to 80% over 15 minutes with a ten minute hold at 80%) on a Shimadzu Prominence Prep HPLC. The major peaks were collected and diluted with DCM (40 mL) before washed with saturated aqueous sodium bicarbonate (3×40 mL), drying over magnesium sulfate, filtering, and concentrating under reduced pressure, yielding the product as a yellow oil. MS (ESI, pos. ion) m/z: 362.3 (M+1). IC50 (uM) 0.035.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]3[CH:24]=[CH:25][S:26][C:20]=3[CH:19]=2)=[CH:8]1)(C)(C)C.Cl.[Cl:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1.N1C=CC=C(CCCO)C=1>>[ClH:28].[N:34]1[CH:35]=[CH:36][CH:37]=[C:32]([CH2:31][CH2:30][CH2:29][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][C:21]4[CH:24]=[CH:25][S:26][C:20]=4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH:33]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3sccc3cn2)oc2ccc(O)cc12
Reactant: ClCCCc1cccnc1
Agent: Cl
Agent: OCCCc1cccnc1
Product: ON=c1cc(-c2cc3sccc3cn2)oc2ccc(OCCCc3cccnc3)cc12

Procedure:
6-(3-Pyridin-3-yl-propoxy)-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one oxime, hydrochloride was prepared in 10% overall yield using the method described in example 127, starting from 6-hydroxy-2-thieno[3,2-c]pyridin-6-yl-chromen-4-one O-tert-butyl oxime (example 127A) and 3-(3-Chloro-propyl)-pyridine hydrochloride, prepared from 3-pyridine propanol (U.S. Pat. No. 6,362,336).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]([CH2:24][N:25]([CH3:27])[CH3:26])[CH2:12][C:13]3[C:22]([CH:23]=2)=[N:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=3)[CH:7]=[CH:8][CH:9]=1.C[Si](C)(C)[Cl:30].O>CC(C)=O>[ClH:30].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[C:23]3[C:22](=[N:21][C:20]4[C:15]([CH:14]=3)=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:13][CH2:12][C:11]=2[CH2:24][N:25]([CH3:26])[CH3:27])[CH:7]=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)Cl
Reactant: COc1cccc(C2=Cc3nc4ccccc4cc3CC2CN(C)C)c1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: COc1cccc(C2=C(CN(C)C)CCc3nc4ccccc4cc32)c1
Yield: 22.9 %

Procedure:
18 g of the product from Step 1 were dissolved in 200 ml methanol under dry nitrogen. The reaction mixture was treated with 7.7 g 2-aminobenzaldehyde as the hydrochloride and was subsequently heated to 80° C. After adding 400 ml 1 N hydrochloric acid, the reaction solution was stirred for eight days at 80° C. After cooling to room temperature, the reaction mixture was diluted with 200 ml ethyl acetate and was made alkaline with concentrated sodium hydroxide solution while being cooled in ice. The aqueous phase was extracted three times with 100 ml portions of ethyl acetate each time, and the combined organic phases were dried over magnesium sulfate and evaporated to dryness under vacuum. The residue was eluted and purified by column chromatography on silica gel using ethyl acetate/methanol in a ratio of 4/1. The first product fraction contained 5.4 g [3-(3-methoxy-phenyl)-1,2-dihydro-acridin-2-yl-methyl]-dimethylamine base in the form of beige crystals. In order to prepare the hydrochloride, the solid was dissolved with heating in 200 ml acetone and was treated with trimethylchlorosilane and water in equimolar amounts. 5.2 g (28.3% theoretical) [3-(3-methoxy-phenyl)-1,2-dihydro-acridin-2-yl-methyl]-dimethyl-amine hydrochloride were obtained (light yellow crystals, m.p.: 201° C. to 204° C.). 4.4 g [1-(3-methoxy-phenyl)-3,4-dihydro-acridin-2-yl-methyl]-dimethylamine base in the form of a beige, amorphous solid was obtained as the second fraction. To release the hydrochloride, the solid was dissolved with heating in 200 ml acetone and was treated with trimethylchlorosilane and water in equimolar amounts. 4.2 g (22.90% theoretical) [1-(3-methoxy-phenyl)-3,4-di-hydro-acridin-2-yl-methyl]-dimethylamine hydrochloride were obtained in the form of light yellow crystals, m.p.: 195° C. to 198° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[C:27]=1[CH3:36].CCOC(C)=O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[C:27]=3[CH3:36])[C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2[nH]1
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Cn2c(C)nc3c(Br)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
A suspension of 4-bromo-2-methyl-6-(4-morpholinyl)-1H-benzimidazole, prepared as described in Example 62 (500 mg, 1.688 mmol) and potassium carbonate (700 mg, 5.06 mmol) in N,N-Dimethylformamide (DMF) (6 mL) was stirred at rt for 15 min. 1-(bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (641 mg, 2.53 mmol) was added in and the resulting reaction mixture was stirred for 3 h at 80° C. It was then cooled to room temperature and poured into ice/water. The precipitate was collected by filtration, washed with water, then few mLs of hexanes and air dried. The crude material was purified on a silica gel column (ISCO, 0-80% EtOAc in hexanes) to the desired product (565 mg, 1.182 mmol, 70.0% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.59 (d, J=7.83 Hz, 1H), 7.16 (d, J=2.02 Hz, 1H), 7.10-7.15 (m, 1H), 6.46-6.52 (m, 2H), 5.25 (s, 2H), 3.75-3.89 (m, 4H), 3.05-3.14 (m, 4H), 2.55 (s, 3H), 2.51 (s, 3H). MS(ES+) m/e 468.9 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([O:24][CH2:25][CH2:26]Cl)[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:28][C:29]1[CH:30]=[C:31]([NH:38][C:39](=[O:44])[CH2:40][N:41]([CH3:43])[CH3:42])[CH:32]=[CH:33][C:34]=1[NH:35][CH2:36][CH3:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.[N-:50]=[N+:51]=[N-:52].[Na+].[I-].[Na+]>CCOC(C)=O>[N:50]([CH2:26][CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:16]2[S:15][C:14](=[C:11]3[S:10][C:9](=[N:28][C:29]4[CH:30]=[C:31]([NH:38][C:39](=[O:44])[CH2:40][N:41]([CH3:43])[CH3:42])[CH:32]=[CH:33][C:34]=4[NH:35][CH2:36][CH3:37])[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:12]3=[O:13])[N:18]([CH3:19])[C:17]=2[CH:20]=1)=[N+:51]=[N-:52]
Reactant: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccc(OCCCl)cc3N2C)C(=O)N1Cc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNc1ccc(NC(=O)CN(C)C)cc1N=C1SC(=C2Sc3ccc(OCCN=[N+]=[N-])cc3N2C)C(=O)N1Cc1ccccc1
Temperature: 70 °C

Procedure:
To a 50 mL flask was added the product of Example 145 (225 mg, 345 μmol), anhydrous DMF (8 mL), sodium azide (112 mg, 1.73 mmol), and sodium iodide (15 mg, 103 μmol). The reaction slurry was heated at 70° C. for 6 h under N2. The reaction mixture was diluted with EtOAc (70 mL), washed with H2O (2×30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound. MS(ESI): 658 (MH+).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][C:2]1=[O:12].[Br:13]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Br:13][C:10]1[CH:9]=[CH:8][C:7]2[NH:1][C:2](=[O:12])[CH2:3][CH2:4][CH2:5][C:6]=2[CH:11]=1
Reactant: O=C1CCCc2ccccc2N1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CCCc2cc(Br)ccc2N1

Procedure:
To a solution of the title compound from Example 2 Step B (17.0 g, 106 mmol) in N,N-dimethylformamide (500 mL) was added N-bromosuccinimide (25.2 g, 141 mmol) at room temperature, and then the mixture was refluxed for 16 hours. The reaction mixture was diluted with ethyl acetate (1 L), and the separated organic layer was washed with 0.1 M aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over Na2SO4, filtered and concentrated. Purification by flash chromatography on silica gel (petroleum ether:ethyl acetate=12:1 to 3:1) provided a crude product that was recrystallized from ethyl acetate and petroleum ether (v:v=1:10) to give the title compound: LCMS m/z=241 [M+2+H]+. 1H NMR (400 MHz, d6-DMSO): δ 9.56 (s, 1H), 7.46 (s, 1H), 7.37 (d, J=8.4 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 2.65 (m, 2H), 2.12-2.07 (m, 4H).
Reaction SMILES: O.[OH-].[Li+].[F:4][CH:5]([F:29])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=1)[C:14]([O:16]C)=[O:15])[CH3:9]>O.C1COCC1>[F:4][CH:5]([F:29])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=1)[C:14]([OH:16])=[O:15])[CH3:9]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(O[C@@H](C)COC(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](COC(F)F)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.6 %

Procedure:
Lithium hydroxide monohydrate (19 mg, 0.45 mmol) in water (2 mL) was added to methyl 3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-phenylmethoxy-benzoate (0.11 g, 0.3 mmol) in THF (4 mL) and the mixture stirred at RT for 20 hours. The THF was removed in vacuo and the aqueous layer adjusted to pH 3 with citric acid then extracted into ethyl acetate (2×30 mL). The organics were washed with water (30 mL), brine (30 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give the desired compound (0.1 g).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[CH2:15]([O:22][C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1nc(SCc2ccccc2)ns1
Reactant: OCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COc2nc(SCc3ccccc3)ns2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
Into 3 ml of N,N-dimethylformamide were dissolved 243 mg of 5-chloro-3-benzylthio-1,2,4-thiadiazole and 108 mg of benzyl alcohol, 48 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 1 hour under ice-cooling and for 17 hours at room temperature. The reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 146 mg of 5-benzyloxy-3-benzylthio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (31)).