Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[Cl:10][C:11]1[C:12](F)=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:23])([F:22])[F:21])[C:17]([C:24]([O:26]CC)=[O:25])=[CH:16][C:15]=2[CH:29]=1>>[Cl:10][C:11]1[C:12]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:9])[CH:4]=2)=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:22])([F:21])[F:23])[C:17]([C:24]([OH:26])=[O:25])=[CH:16][C:15]=2[CH:29]=1
Reactant: Oc1ccc(Cl)c(F)c1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc(Cl)c(F)c3)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 4-chloro-3-fluorophenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 206.8-207.4° C. 1H NMR (acetone-d6/300 MHz) 7.92 (s, 1H), 7.74 (s, 1H), 7.59 (m, 1H), 7.16 (m, 1H), 6.99 (m, 1H), 6.83 (s, 1H), 5.86 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz)-79.4 (d, 3F, J=6.5 Hz), −113.8 (m, 1F). Anal. Calc'd for C17H8Cl2F4O4: C, 48.25; H, 1.91; Cl, 16.76. Found: C, 48.20; H, 1.97; Cl, 16.92.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[CH2:9][N:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=O)=[O:12])[C:4]=2[CH:3]=1.CN1CCOCC1.[NH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[CH2:9][N:10]([C:11]([NH:13][CH2:14][C:15]([NH:31][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)=[O:17])=[O:12])[C:4]=2[CH:3]=1
Reactant: Nc1ccncc1
Reactant: O=C(O)CNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(CNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21)Nc1ccncc1
Yield: 15.3 %

Procedure:
By the method described in Example 5, the title compound of Example 4 (0.5 g, 1.5 mmol) in 20 mL of CH2Cl2 was converted to its mixed anhydride with NMM (0.16 mL, 1.5 mmol) and IBCF (0.2 mL, 1.5 mmol). This intermediate was condensed with 4-aminopyridine (0.21 g, 2.25 mmol) to produce the title compound (94 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][OH:10].[Br:11][CH2:12][C:13](Br)=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Br:11][CH2:12][C:13]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][OH:10])=[O:14]
Reactant: O=C(Br)CBr
Reactant: Nc1ccc(Cl)cc1CO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CBr)Nc1ccc(Cl)cc1CO
Reaction time: 0.08 h
Yield: 96 %

Procedure:
To a solution of (2-amino-5-chlorophenyl)methanol (4.30 g, 27.3 mmol) in dichloromethane (220 ml) was added 2-bromoacetyl bromide (6.06 g, 2.61 ml, 30.0 mmol) at 0-5° C. Stirring for 5 minutes was followed by dropwise addition of aqueous 2 M sodium carbonate solution (130 ml) during approximately 10 minutes. The cooling bath was removed, and stirring was continued for 2 h. The solvent was removed in vacuo. The aqueous residue was extracted with three 100-ml portions of ethyl acetate. The combined organic layers were washed with one 50-ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (7.30 g, 96%) as light grey solid, which was used in the next step without purification. MS m/e: 276 ([M+H]+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:26]([O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][C:35](Br)=[CH:34][CH:33]=1)([CH3:29])([CH3:28])[CH3:27].C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[C:26]([O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][C:35]([N:22]2[CH2:23][CH2:24][CH:19]([C:16]3[CH:15]=[CH:14][C:13]([C:12](=[O:25])[NH:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=4)=[CH:18][CH:17]=3)[CH2:20][CH2:21]2)=[CH:34][CH:33]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCNCC3)cc2)c1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CC(C)(C)OC(=O)c1ccc(N2CCC(c3ccc(C(=O)Nc4cccc(C(C)(C)C)c4)cc3)CC2)cc1

Procedure:
4-{4-[4-(3-tert-Butyl-phenylcarbamoyl)-phenyl]-piperidin-1-yl}-benzoic acid tert-butyl ester was synthesized from N-(3-tert-butyl-phenyl)-4-piperidin-4-yl-benzamide and 4-bromo-benzoic acid tert-butyl ester in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C33H40N2O3 (m/e) 512, obsd 513 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:12]=2[N:13]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[CH2:28]Br>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[CH2:28][N:13]1[C:12]2[CH:14]=[C:15]([CH3:19])[CH:16]=[C:17]([CH3:18])[C:11]=2[N:10]=[C:9]1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Fc1cccc(F)c1CBr
Reactant: Cc1cc(C)c2[nH]c(-c3c(F)cccc3F)nc2c1
Product: Cc1cc(C)c2nc(-c3c(F)cccc3F)n(Cc3c(F)cccc3F)c2c1
Yield: 91.2 %

Procedure:
To 2-(2,6-difluorophenyl)-4,6-dimethylbenzimidazole (Example 94) (0.50 g, 1.94 mmol) was added 2,6-difluoro-α-bromotoluene (0.52 g, 2.51 mmol, 130 M %). Flash chromatography of the crude product eluting with 2% methanol/CH2Cl2, and recrystallization from hexane gave white crystals of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4,6-dimethylbenzimidazole (0.68 g, 1.77 mmol, 91% yield). 1H NMR (200 MHz, CD2Cl2): δ 7.51 (cm, 1H, H4), 7.23 (m, 1H, H4″), 7.11 (m, 1H, H5), 7.05 (cm, 2H, H3′,5′), 6.93 (m, 1H, H7), 6.80 (cm, 2H, H3″, 5″), 5.29 (s, 2H, CH2PhF2), 2.58 (s, 3H, CH3), 2.44 (s, 3H, CH3).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24].O.[CH2:26](I)[CH3:27]>CN(C)C=O>[CH2:26]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])[CH3:27]
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc([N+](=O)[O-])ccc1O
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc([N+](=O)[O-])cc1CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
To a mixture of sodium hydride (content, 60%; 36 mg) and anhydrous dimethylformamide (5 ml), a solution of the compound (224 mg) obtained in Example 318 in anhydrous dimethylformamide (3 ml) and ethyl iodide (0.072 ml) were successively added dropwise at 0° C. in a nitrogen atmosphere and stirred at room temperature for 24 h. Water was added to the reaction mixture, which was distilled under reduced pressure; thereafter, ethyl acetate and water were added to the resulting residue. The organic layer was washed with a saturated aqueous sodium chloride solution, dried with anhydrous sodium sulfate and distilled under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, n-hexane ethyl acetate=1:1) to give 213 mg of the titled compound (yield, 87%).
Reaction SMILES: [C:1]([O:10][CH2:11][CH2:12][CH:13]1[O:18][CH2:17][CH2:16][CH2:15][O:14]1)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23](S(C)(=O)=O)[N:22]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:19][O:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([O:10][CH2:11][CH2:12][CH:13]2[O:14][CH2:15][CH2:16][CH2:17][O:18]2)=[O:9])[N:22]=1
Reactant: O=C(OCCC1OCCCO1)c1ccccc1O
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Oc2ccccc2C(=O)OCCC2OCCCO2)n1
Reaction time: 1 h

Procedure:
0.84 Gram of 2-(1,3-dioxan-2-yl)ethyl salicylate and 0.73 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine was dissolved in 10 ml of N,N-dimethylformamide, and 0.51 g of anhydrous potassium carbonate was added thereto. The resulting solution was stirred at 100° to 110° C. for 1 hour. The reaction solution was allowed to cool, poured into diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer separated from the aqueous layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (mfd. by Merck & Co., Inc., solvent: chloroform) to obtain 0.50 g of 2-(1,3-dioxan-2-yl)ethyl 2-(4,6-dimethoxypyrimidin-2-yl)oxybenzoate [present compound (V-1)].
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([O:10]C)=O)=[CH:4][S:5][C:6]=1[CH3:7].Cl.[CH3:13][NH:14][O:15][CH3:16].C([Mg]Br)(C)C>C1COCC1.CC1CCCO1>[CH3:16][O:15][N:14]([CH3:13])[C:8]([C:3]1[C:2]([CH3:1])=[C:6]([CH3:7])[S:5][CH:4]=1)=[O:10]
Reactant: CNOC
Reactant: COC(=O)c1csc(C)c1C
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CC1CCCO1
Product: CON(C)C(=O)c1csc(C)c1C
Temperature: 0 °C
Yield: 80.9 %

Procedure:
To a cooled (−30° C. to −20° C.) slurry of methyl 4,5-dimethylthiophene-3-carboxylate (5.44 g, 32.0 mmol) and N,O-dimethylhydroxylamine hydrochloride (4.80 g, 49.2 mmol) in THF (45 mL) at was added slowly (over 15 min) a solution of isopropylmagnesium bromide (3.85 mL, 11.16 mmol, 2.9 M) in 2-methyl-tetrahydrofuran. After complete addition of the base, the reaction mixture was warmed to 0° C. and partitioned between 1 N HCl (55 mL) and MTBE (50 mL). The aqueous phase was extracted with MTBE (2×) and the combined organic layer was washed with water (until the pH of the aqueous was ˜5). The organic layer was dried over Na2SO4 and concentrated to give a light yellow oil. The crude product was purified on Biotage system (gradient elution 7% EtOAc:93% Hexanes to 60% EtOAc:40% Hexanes) to give the titled compound as a yellow oil (5.17 g, 25.9 mmol, 81% yield). LC/MS m/z 200 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]([C:9]2[CH:14]=[C:13]([Cl:15])[N:12]=[C:11](Cl)[N:10]=2)[CH2:5][CH2:6][CH2:7][OH:8])[CH2:3][CH2:2]1.[OH-:17].[Na+]>O1CCOCC1.O>[Cl:15][C:13]1[CH:14]=[C:9]([N:4]([CH:1]2[CH2:3][CH2:2]2)[CH2:5][CH2:6][CH2:7][OH:8])[NH:10][C:11](=[O:17])[N:12]=1
Reactant: OCCCN(c1cc(Cl)nc(Cl)n1)C1CC1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=c1nc(Cl)cc(N(CCCO)C2CC2)[nH]1
Temperature: 100 °C
Reaction time: 4 h
Yield: 45.2 %

Procedure:
To a solution of 3-(cyclopropyl(2,6-dichloropyrimidin-4-yl)amino)propan-1-ol (5.0 g, 19.07 mmol) in 1,4-dioxane (50 mL) was added a solution of NaOH (7.63 g, 191 mmol) in water (50 mL) at r.t, stirred for 4 h at 100° C. The organic solvent was removed under reduce vacuum and the PH was adjusted to 8 with aq. HCl (12 N). Purification via reverse C-18 column afforded the title compound (2.1 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O.[NH2:15][C:16]1[S:17][C:18]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[C:19]([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:15][C:16]2[S:17][C:18]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[O:7])[CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: Nc1nc(-c2ccco2)c(N2CCOCC2)s1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccnc(Cl)c1
Yield: 66 %

Procedure:
2-Chloroisonicotinic acid (5.00 g, 31.7 mmol) was added to thionyl chloride (40 mL), followed by stirring under heating and reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in dichloromethane (1 mL). The resulting solution was added to a pyridine (16 ml) solution of 2-amino-4-(2-furyl)-5-morpholinothiazole (880 mg, 5.00 mmol) obtained in Step 1 of Example 29, and then N,N-dimethylaminopyridine (48.8 mmol, 0.400 mmol) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:3 to ethyl acetate) to afford the entitled Compound 39 (1.05.g, 66%)
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[C:14](OC)(=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[SH:17].C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:1]1([C:6]2[N:11]=[C:10]([C:12]3[S:17][C:16]4[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=4[C:14](=[O:22])[N:13]=3)[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: N#Cc1cccc(-n2cccn2)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2cccc(-n3cccn3)n2)sc2ccccc12
Yield: 66.9 %

Procedure:
6-(Pyrazol-1-yl)-2-pyridinecarbonitrile (0.68 g, 4.0 mmol) and methyl thiosalicylate (1.00 g, 5.9 mmol) were dissolved in toluene (5 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The mixture was refluxed for 8 hrs. After cooling, the precipitates were collected by filtration and recrystallized from hexane-tetrahydrofuran to give the titled compound (0.82 g, 67%) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:12]=1[C:13](Cl)=[O:14].C(N(CC)CC)C>O1CCOCC1>[Cl:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:12]=1[C:13]([NH:9][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=1[F:8])=[O:14]
Reactant: Nc1ccnc(Cl)c1F
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccnc(Cl)c1F)c1c(Cl)cccc1Cl
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A mixture of 2-chloro-3-fluoropyridin-4-ylamine (660 mg, 4.5 mmol), 2,6-dichlorobenzoyl chloride (1.43 mL, 2.10 g, 10.0 mmol) and triethylamine (1.53 mL, 1.11 g, 11.0 mmol) in dioxane (12 mL) was heated under reflux for 18 hours then cooled to ambient temperature. The resultant mixture was partitioned between EtOAc (50 mL) and water (50 mL). The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was triturated with diethyl ether, filtered, dried and further purified by silica gel flash chromatography (0-25% EtOAc in pentane) to afford the title compound as a pink solid (1.17 g, 81% yield). 1H NMR (300 MHz, CDCl3): δ 8.50 (t, J=5.3 Hz, 1H), 8.22 (d, J=5.5 Hz, 1H), 7.83 (br s, 1H), 7.40-7.39 (m, 3H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.O=[C:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[N:1]1([CH:16]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: c1ccc2c(c1)CCCN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
A solution of 1,2,3,4-tetrahydroquinoline (1.0 mL, 7.94 mmol) in 30 mL 1,2-dichloroethane was treated with tert-butyl 3-oxopyrrolidine-1-carboxylate (2.94 g, 15.87 mmol) followed by sodium triacetoxyborohydride (8.4 g, 39.68 mmol) then acetic acid (2.25 mL). The suspension was stirred at room temperature for 1 day. After this time, the mixture was cooled to 0° C., quenched with 20 mL 1N NaOH and stirred for 20 minutes. The suspension was extracted with 2×100 mL CH2Cl2. The organic layer was rinsed with brine, dried over MgSO4, filtered and concentrated to give a yellow residue which was subjected to flash chromatography on silica gel using 15% EtOAc/Hexanes to give a viscous oil (1.89 g, 78.8%). 1H-NMR (CDCl3) δ 7.07 (pseudo t, J=7.2 Hz, 1H), 6.97 (d, J=7.2 Hz, 1H), 6.69 (d, J=8.1 Hz, 1H), 6.62 (pseudo t, J=7.5 Hz, 1H), 4.44-4.40 (m, 1H), 3.63-3.20 (m, 6H), 2.75 (t, J=6.3 Hz, 2H), 2.13-2.08 (m, 2H), 1.94-1.90 (m, 2H), 1.48 (s, 9H). MS (ESI): 303.2 (M+1).
Reaction SMILES: [CH2:1]([CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C:7]2=[N:16][CH:17]=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19](=[O:20])[N:6]2[CH2:5]1)[CH:2]=[CH2:3].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[C:7]2=[N:16][CH:17]=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19](=[O:20])[N:6]2[CH:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCC1Cn2c(ncc(C(=O)OCC)c2=O)-c2cc(OC)ccc21
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: C=CCc1cn2c(=O)c(C(=O)OCC)cnc2c2cc(OC)ccc12

Procedure:
A mixture of ethyl 7-allyl-6,7-dihydro-10-methoxy-4-oxo-4H-pyrimido[2,1-a]isoquinoline-3-carboxylate (1.5 g., 4.41 mmoles) and DDQ (1.1 g., 4.85 mmoles) in toluene (30 ml.) containing acetic acid (0.05 ml.) was refluxed for 18 hours. The mixture was filtered and the filtrate concentrated to dryness. Trituration of the residue with methanol gave a solid which was recrystallized from ethanol to give 201 mgs. of brown crystals, m.p. 182°-186°. The methanol mother liquor was concentrated to dryness and the residue chromatographed on silicic acid with toluene-acetone (20:1) to give additional product (230 mgs.), m.p. 177°-183° after recrystallization from ethanol. The material with m.p. 182°-186° was chromatographed in a similar manner and the product so obtained combined with the material with m.p. 177°-183° and the lot recrystallized from ethanol to give yellow needles of the title compound, m.p. 187°-188°.
Reaction SMILES: CN1CCN(C2C=CC(NC3C4N(N=CN=4)C(C4C=C(C(N)=O)SC=4)=CN=3)=CC=2)CC1.[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36](Br)=[N:35][CH:34]=1.[F:43][C:44]1[CH:45]=[C:46]([NH2:56])[CH:47]=[CH:48][C:49]=1[N:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.CCN(C(C)C)C(C)C>CC(O)C>[Br:32][C:33]1[N:38]2[N:39]=[CH:40][N:41]=[C:37]2[C:36]([NH:56][C:46]2[CH:47]=[CH:48][C:49]([N:50]3[CH2:51][CH2:52][O:53][CH2:54][CH2:55]3)=[C:44]([F:43])[CH:45]=2)=[N:35][CH:34]=1
Reactant: Brc1ncc(Br)n2ncnc12
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Agent: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1cc(Nc2ncc(Br)n3ncnc23)ccc1N1CCOCC1
Yield: 98.5 %

Procedure:
This compound may be prepared using methods as described for Compound 6, step 1 using 5,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (0.5 g, 1.799 mmol), 3-fluoro-4-morpholin-4-yl-phenylamine (0.53 g, 2.70 mmol), and DIPEA (0.470 mL, 2.70 mmol) in 2-propanol (6 mL). The reaction mixture is partitioned between 10% citric acid aqueous solution and DCM. The organic phase is separated and washed with water and brine, dried over MgSO4, filtered and concentrated under vacuum to afford the title compound (697 mg, 98%) which is used in the next step without further purification. LCMS: Rt 3.52 min (98.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1.CC1C=CC(S(O[CH2:38][CH2:39][O:40][CH:41]2[CH2:43][CH2:42]2)(=O)=O)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:38][CH2:39][O:40][CH:41]2[CH2:43][CH2:42]2)=[CH:24][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CC2)cc1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCOC4CC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D1) (30 mg, 0.08 mmol) in anhydrous DMF (1 mL) were added 2-cyclopropoxyethyl 4-methylbenzenesulfonate (intermediate BP) (20 mg, 0.08 mmol) and Cs2CO3 (52 mg, 0.16 mmol). The mixture was stirred at room temperature for 12 h. Then the reaction mixture was poured into water, extracted with EA, washed with brine, dried with anhydrous Na2SO4 and concentrated to an oil. The oil was purified by preparative HPLC to obtain compound BQ (11 mg) as a colorless oil. 1H NMR (CD3OD): δ 7.30 (m, 3H), 7.11 (d, J=8.8 Hz, 2H), 6.82 (d, J=8.8 Hz, 2H), 4.13 (m, 5H), 3.85 (m, 3H), 3.81 (m, 1H), 3.40 (m, 4H), 3.30 (m, 1H), 0.52 (m, 4H); MS ESI (m/z) 465 (M+H)+, calc. 464.
Reaction SMILES: [CH2:1]1[C@H:9]2[C@H:4]([CH2:5][C:6]3[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=3[CH2:8]2)[CH2:3][NH:2]1.Br[CH2:15][CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[C:19]1(=[O:28])[N:18]([CH2:17][CH2:16][CH2:15][N:2]2[CH2:3][C@H:4]3[C@H:9]([CH2:8][C:7]4[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=4[CH2:5]3)[CH2:1]2)[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]12
Reactant: c1ccc2c(c1)C[C@H]1CNC[C@H]1C2
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCCN1C[C@H]2Cc3ccccc3C[C@H]2C1
Temperature: 25 °C
Yield: 770.6 %

Procedure:
A mixture of cis-2,3,3a,4,9,9a-hexahydro-1H-benz[f]isoindole (32 mg, 0.018 mmol), N-(3-bromopropyl)phthalimide (49 mg, 0.18 mmol), potassium iodide (31 mg, 0.18 mmol), and potassium carbonate (51 mg, 0.37 mmol) in 3 mL of methylethyl ketone was heated at reflux for 8 hours. The mixture was cooled to room temperature, the solids were filtered, and the filtrate was concentrated in-vacuo. The residue was dry-loaded onto a 1×5 cm silica column, and eluted with ethyl acetate followed by 20% methanol/chloroform. Obtained 50 mg of white solids. Yield=78%. NMR (300 MHz, CDCl3) δ 7.84-7.79 (m, 2H), 7.71-7.66 (m, 2H), 7.14-7.06 (m, 4H), 3.74 (t, 2H, J=7 Hz), 2.95-2.90 (m, 2H), 2.74-2.68 (m, 2H), 2.55-2.35 (m, 6H), 1.91-1.80 (m, 4H).
Reaction SMILES: [CH2:1]([N:3]([CH2:35][CH3:36])[C:4]([NH:6][C:7]1[C:8]([C:18]2[NH:22][C:21]3[CH:23]=[C:24]([N:28]4[CH2:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[C:25]([F:27])=[CH:26][C:20]=3[N:19]=2)=[N:9][N:10](C2CCCCO2)[CH:11]=1)=[O:5])[CH3:2].Cl>O1CCOCC1.C(OC(C)C)(C)C>[CH2:35]([N:3]([CH2:1][CH3:2])[C:4]([NH:6][C:7]1[C:8]([C:18]2[NH:22][C:21]3[CH:23]=[C:24]([N:28]4[CH2:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[C:25]([F:27])=[CH:26][C:20]=3[N:19]=2)=[N:9][NH:10][CH:11]=1)=[O:5])[CH3:36]
Reactant: CCN(CC)C(=O)Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(N3CCCOCC3)cc2[nH]1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Product: CCN(CC)C(=O)Nc1c[nH]nc1-c1nc2cc(F)c(N3CCCOCC3)cc2[nH]1
Temperature: 22 °C
Yield: 72.8 %

Procedure:
A solution of 380 mg of 1,1-diethyl-3-[3-(5-fluoro-6-perhydro-1,4-oxazepin-4-yl-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]urea in solution in 5 mL of a 4N solution of hydrochloric acid in dioxane is stirred at 22° C. for 2 hours. The reaction medium is concentrated under vacuum in a rotary evaporator, and then again reacted at 22° C. for 16 hours with 5 mL of a 4N solution of hydrochloric acid in dioxane is stirred at 22° C. The reaction medium is concentrated under vacuum in a rotary evaporator. The product is diluted in ethyl acetate, and washed with 2 times 20 mL of a 2N aqueous solution of sodium hydroxide. The aqueous phases are extracted with 3 times 20 mL of ethyl acetate. The organic phases are dried over MgSO4, filtered and concentrated under vacuum in a rotary evaporator. The yellow foam obtained is made into a paste in isopropyl ether, triturated, filtered and dried under vacuum at 40° C. 230 mg of 1,1-diethyl-3-[3-(5-fluoro-6-perhydro-1,4-oxazepin-4-yl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]urea are obtained in the form of a pale yellow solid. 1H NMR (500 MHz, DMSO-d6, δ in ppm): 1.23 (t, J=7.0 Hz, 6H); 1.96 (m, 2H); 3.35 (m masked, 4H); 3.39 (q partially masked, J=7.0 Hz, 4H); 3.79 (m, 4H); from 6.98 to 7.39 (broad m, 2H); 7.98 (s, 1H); 9.87 (broad s, 1H).