Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([OH:24])=O)=O)(C)(C)C.[NH2:25][C:26]1[C:27]([N:35]2[CH2:40][C@H:39]([CH3:41])[C@:38]([OH:43])([CH3:42])[C@H:37]([NH:44]C(=O)OC(C)(C)C)[CH2:36]2)=[C:28]2[CH2:34][CH2:33][O:32][C:29]2=[N:30][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([NH:25][C:26]1[C:27]([N:35]2[CH2:40][C@H:39]([CH3:41])[C@:38]([OH:43])([CH3:42])[C@H:37]([NH2:44])[CH2:36]2)=[C:28]2[CH2:34][CH2:33][O:32][C:29]2=[N:30][CH:31]=1)=[O:24]
Reactant: C[C@H]1CN(c2c(N)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@]1(C)O
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2c(NC(=O)c3nc(-c4c(F)cccc4F)sc3N)cnc3c2CCO3)C[C@@H](N)[C@]1(C)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.3 %

Procedure:
To a mixture of 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylic acid (55 mg, 0.15 mmol), tert-butyl [(3R,4R,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-hydroxy-4,5-dimethylpiperidin-3-yl]carbamate (44 mg, 0.12 mmol) and HATU (134 mg, 0.353 mmol), DMF (2.0 mL) was added, followed by DIPEA (86 mg, 0.67 mmol). The reaction mixture was stirred at room temperature for 3 h, and then concentrated under reduced pressure. DCM (2.0 mL) was added to the resulting residue followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min. and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min.) to afford the title compound as a white solid (20 mg, 34%). LCMS calc. for C24H27F2N6O3s (M+H)+: m/z=517.2. found 517.0. 1H NMR (500 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.61 (s, 1H), 7.59-7.45 (m, 3H), 7.21 (t, J=8.6 Hz, 2H), 4.52-4.42 (m, 2H), 4.06 (s, 1H), 3.37 (t, J=8.5 Hz, 2H), 2.99-2.92 (m, 1H), 2.90-2.79 (m, 2H), 2.77-2.64 (m, 2H), 1.93-1.82 (m, 1H), 1.46 (br, 2H), 0.92 (s, 3H), 0.71 (d, J=6.9 Hz, 3H) ppm.
Reaction SMILES: [CH2:1]=[C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[O:3]1.[CH2:11]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:12].[C-]#N.[K+]>C(#N)C>[CH2:11]([NH+:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:12].[OH:3][C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[CH:1]=1
Reactant: C=C1OC(=O)C2CCC1C2
Reactant: CCN(CC)CC
Agent: [C-]#N
Agent: [K+]
Solvent: CC#N
Product: CC[NH+](CC)CC
Product: O=C1C=C(O)C2CCC1C2

Procedure:
1.38 g (0.01 mol) of 4-methylene-3-oxabicyclo[3.2.1]octan-2-one are stirred for 12 hours at a temperature of 20° C. in the presence of 1.11 g (0.01 mol) of triethylamine and 65 mg (1 mmol) of potassium cyanide in 20 ml of acetonitrile, the 4-hydroxybicyclo[3.2.1]oct-3-en-2-one triethylammonium salt formed partially crystallising out. While controlling the temperature, 2.64 g (0.01 mol) of freshly prepared 4-methanesulfonyl-2-nitrobenzoyl chloride are introduced into the resulting suspension at a temperature of 20° C. After stirring for 30 minutes at a temperature of 20° C., extraction is carried out with ethyl acetate against 5% sodium hydrogen carbonate solution, followed by washing once with dilute hydrochloric acid and once with water and evaporating to dryness. The residue (3.2 g) is filtered through a small amount of silica gel (eluant: ethyl acetate/hexane 1:1), yielding 4-methanesulfonyl-2-nitrobenzoic acid 4-oxobicyclo[3.2.1]oct-2-en-2-yl ester in form of a viscous oil: yield: 2.48 g 67.9%); 1H-NMR (CDCl3): 8.84 ppm, s, 1H, 8.34 ppm, d, 1H, 8.03 ppm, d, 1H, 5.90 ppm, s, 1H, 3.17 ppm, s, 3H, 3.0–3.15 ppm, 2H, 1.6–2.3 ppm, 6H.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[K])(C)(C)C.[C:15]1([CH3:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CN(C)C=O.[C:27]1(/[CH:33]=[CH:34]/[C:35]2[N:40]=[N:39][C:38]3OC4C=CC=CC=4[O:44][C:37]=3[CH:36]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1.O>[CH2:1]([O:8][C:38]1[N:39]=[N:40][C:35](/[CH:34]=[CH:33]/[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:36][C:37]=1[O:44][CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1
Reactant: OCc1ccccc1
Reactant: C(=C/c1cc2c(nn1)Oc1ccccc1O2)\c1ccccc1
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: CN(C)C=O
Product: C(=C/c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1)\c1ccccc1
Reaction time: 0.33 h

Procedure:
Under ice-cooling, to a solution (5 mL) of benzyl alcohol (350 μL) in toluene was added t-butoxy potassium (375 mg), and the mixture was stirred for 20 min. To the mixture was added a toluene-dimethylformamide (1:1) suspension (10 ml) of 3-[(E)-2-phenylvinyl][1,4]benzodioxino[2,3-c]pyridazine (386 mg) at 0° C., and the mixture was stirred at 120° C. for 19 hr. Water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3,4-bis(benzyloxy)-6-[(E)-2-phenylvinyl]pyridazine (473 mg).
Reaction SMILES: C1COCC1.ClC1C=C2C(C=CN2)=CC=1F.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][CH2:23][NH:24]2)=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28].B.N1C=CC=CC=1>>[Cl:17][C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[CH:23][NH:24]2)=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1cc2c(cc1Cl)NCC2
Agent: B
Agent: Fc1cc2cc[nH]c2cc1Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc2cc[nH]c2cc1Cl

Procedure:
This material was produced from 6-chloro-5-nitro-oxindole (1 eq) and BH3 /THF (6 mol eq.) utilizing a method analogous to that described for 6-chloro-5-fluoro-indole (Preparation 29) in 99% yield (contaminated with some 6-chloro-5-nitro-indoline) and used directly in the subsequent borane/pyridine reduction.
Reaction SMILES: [CH2:1]([C:9]1[N:13]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27]>>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH:27][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([C:12]2[O:11][N:10]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:13]=2)=[CH:15][CH:16]=1
Reactant: COc1ccccc1CN
Reactant: CCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Product: CCCCCCCCc1noc(-c2ccc(CNCc3ccccc3OC)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-octyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 2-methoxybenzylamine gave the title compound as an oil. M+(LC/MS(ESI)): 408.4. HPLC (Condition A), Rt: 4.12 min (HPLC purity: 91.9%).
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][N:13](N)[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C:32]([CH3:35])([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.C[N:40]1CCOCC1.[CH2:46]([O:48][C:49]([NH:51][C@H:52]([C:56]([OH:58])=O)[CH:53]([CH3:55])[CH3:54])=[O:50])[CH3:47].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C>CN(C=O)C>[S:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH:12]([NH2:40])[N:13]([C:56](=[O:58])[C@H:52]([CH:53]([CH3:55])[CH3:54])[NH:51][C:49]([O:48][CH2:46][CH3:47])=[O:50])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C:32]([CH3:35])([CH3:34])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CN1CCOCC1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1)C(C)(C)C
Reactant: CCOC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: CCOC(=O)N[C@H](C(=O)N(C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C(N)c1ccc(-c2cncs2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere, 344 mg of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-tert-leucyl)amino-6-phenyl-2-azahexane (Example 2d) and 191 μl (1.74 mmol) of NMM in 5.6 ml of DMF are added to 132 mg (0.7 mmol) of N-ethoxycarbonyl-(L)-valine (EP 0 604 368, Example 9a) and 173 mg (0.58 mmol) of TPTU in 2.9 ml of DMF, and the mixture is stirred at room temperature overnight and worked up analogously to Example 3, yielding the title compound: TLC: Rf=0.45 (methylene chloride/THF 4:1); HPLC20-100: tRet=14.7; FAB MS (M+H)+=711.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][C@H:21]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[CH:36][C:5]=2[N:4]=1.[ClH:38].C(OC(C)C)(C)C>O1CCOCC1>[ClH:38].[ClH:38].[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][C@H:21]3[CH2:25][CH2:24][NH:23][CH2:22]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[CH:36][C:5]=2[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(N3CCOCC3)cc(-n3c(C(F)F)nc4ccccc43)n2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Product: FC(F)c1nc2ccccc2n1-c1cc(N2CCOCC2)nc(N[C@H]2CCNC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of tert-butyl (3S)-3-({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-ylpyrimidin-2-yl}amino)pyrrolidine-1-carboxylate (300 mg) and 1,4-dioxane (3 mL) was added a 4 M solution (1.5 mL) of hydrogen chloride in 1,4-dioxane, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added diisopropyl ether (10 mL). The resulting powder was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to obtain 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-N-[(3S)-pyrrolidin-3-yl]pyrimidin-2-amine dihydrochloride (354 mg) as a pale yellow powder.
Reaction SMILES: CN(C)C=O.CS([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:19])=[C:16]([F:18])[F:17])(=O)=O.[S:20]1[C:24]([C:25](O)=[O:26])=[CH:23][C:22]2[CH:28]=[CH:29][CH:30]=[CH:31][C:21]1=2.C(=O)([O-])O.[Na+]>O>[S:20]1[C:24]([C:25]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:19])=[C:16]([F:17])[F:18])=[O:26])=[CH:23][C:22]2[CH:28]=[CH:29][CH:30]=[CH:31][C:21]1=2
Reactant: CC(CCCCOS(C)(=O)=O)=C(F)F
Reactant: O=C(O)c1cc2ccccc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(CCCCOC(=O)c1cc2ccccc2s1)=C(F)F
Temperature: 100 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
To 40 ml of N,N-dimethylformamide were dissolved 5.00 g (22 mmol) of 6,6-difluoro-5-methyl-5-hexenyl methanesulfonate and 4.30 g (24 mmol) of benzo[b]thiophene-2-carboxylicacid, followed by the addition of 6.00 g (71 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (diisopropyl ether:hexane=1:7) to obtain 5.50 g (yield: 81%) of 6,6-difluoro-5-methyl-5-hexenyl benzo[b]thiophene-2-carboxylate.
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.C(=O)([O-])O.[Na+].O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29]>O1CCCC1.C(OCC)(=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)(=[O:26])=[O:25])=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: c1ccc2c(c1)CCCN2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(S(=O)(=O)N2CCCc3ccccc32)ccc1Cl
Yield: 67.2 %

Procedure:
To a suspension of 1,2,3,4-tetrahydroquinoline(3.12 g) and sodium hydrogen carbonate (2.66 g) in tetrahydrofuran (60 mL) were added water (6 mL) and a solution of 4-chloro-3-nitro -benzenesulfonyl chloride (5.4 g) in tetrahydrofuran (30 mL) successively, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water, 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 1-[(4-chloro-3-nitrophenyl)sulfonyl]-1,2,3,4-tetrahydroquinoline (5.0 g). This material was dissolved in tetrahydrofuran (45 mL). To the solution were added methanol (45 mL), nickel(II) bromide (0.15 g) and sodium borohydride (1.61 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. Then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1) to give the title compound (4.33 g).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18]([NH2:20])[C:17]([NH2:21])=[C:16]([CH3:22])[N:15]=2)=[N:6]1.Cl[C:28]([O:30][CH3:31])=[O:29]>N1C=CC=CC=1.ClCCl>[CH:28]([OH:30])=[O:29].[NH2:20][C:18]1[C:17]([NH:21][C:28](=[O:29])[O:30][CH3:31])=[C:16]([CH3:22])[N:15]=[C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:23]=[CH:24][CH:25]=[CH:26][C:2]=3[F:1])[N:6]=2)[N:19]=1
Reactant: Cc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1N
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Nc1c(C)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Product: O=CO
Temperature: 0 °C
Reaction time: 8 h

Procedure:
150 mg (0.343 mmol) of the compound from example 54A were initially charged in pyridine (3 ml) under argon and cooled to 0° C. Subsequently, a solution of 27 μl (0.34 mmol) of methyl chloroformate in dichloromethane (1 ml) was added dropwise, and the mixture was brought to RT and stirred overnight. Then the mixture was cooled again to 0° C., then 5 μl of methyl chloroformate (dissolved in 0.5 ml of dichloromethane) were added and the mixture was stirred at RT for a further 30 min. Subsequently, another 5 μl of methyl chloroformate (dissolved in 0.5 ml of dichloromethane) were added at 0° C. and the mixture was stirred at RT overnight. The reaction mixture was brought to RT and concentrated by rotary evaporation. The residue was separated by means of preparative HPLC (eluent: acetonitrile-water with 0.1% formic acid gradient) and the product fractions were concentrated. This gave 113 mg (71% of theory) of the title compound in solid form.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][O:9][CH2:10]Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:8][O:9][CH2:10][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCCl
Reactant: Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.7 %

Procedure:
Under an ice bath, about 200 g of phenol and about 256 g of chloromethyl methyl ether were mixed and stirred in about 2 L of methylene chloride (MC), and about 740 ml of diisopropylethylamine (DIPEA) was gradually dropped. Next, the ice bath was removed and a temperature was increased, and then a synthesis reaction (see Equation 1 below) was performed while stirring for about 12 hours at room temperature. Next, distilled water was added in a reaction mixed liquid to complete the synthesis reaction and to extract an organic phase. Next, the organic phase was washed using about 0.5 N of HCl aqueous solution, distilled water, about 1 N of NaOH aqueous solution, and distilled water in the stated order, and then dried using magnesium sulphate. Next, the organic phase was filtered and concentrated to obtain about 240 g (a yield: about 81.7%) of methoxymethoxybenzene, and a structure of the methoxymethoxybenzene was observed by 1H-NMR (see FIG. 1):
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)=[O:4].[CH3:18][C:19]1[NH:20][CH:21]=[CH:22][N:23]=1.O.[OH-].[Na+].[ClH:27]>C(OCC)C.CN(C)C=O>[ClH:27].[CH:6]1[C:7]2[CH2:8][C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15]=2[CH:16]=[CH:17][C:5]=1[C:3](=[O:4])[CH2:2][N:20]1[CH:21]=[CH:22][N:23]=[C:19]1[CH3:18]
Reactant: Cc1ncc[nH]1
Reactant: O=C(CBr)c1ccc2c(c1)Cc1ccccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: Cc1nccn1CC(=O)c1ccc2c(c1)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 12.0 g. of 2-(bromoacetyl)fluorene in 150 ml. of dimethylformamide was added to an ice-cooled solution of 24 g. of 2-methylimidazole in 150 ml. of dimethylformamide. The mixture was allowed to warm to room temperature and was stirred overnight. The reaction mixture was poured into water containing one equivalent of sodium hydroxide. The resulting precipitate was filtered and the filtrate was extracted with ethyl acetate. The ethyl acetate solution was washed first with water and then with a saturated sodium chloride solution, dried over sodium sulfate, filtered, and evaporated in vacuo. The residue was combined with the filtered precipitate and dissolved in hot acetone. Three equivalents of hydrochloric acid were added and upon the addition of diethyl ether, 6.65 g. of the desired title product formed which were recovered by filtration, m.p. 275°-276° C. with decomposition.
Reaction SMILES: [CH2:1]([C:4]1([CH2:13][CH2:14][CH3:15])[C:9](=[O:10])[NH:8][C:7](=[O:11])[NH:6][C:5]1=[O:12])[CH2:2][CH3:3].C(N(CC)CC)C.[CH2:23]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:24]1[O:26][CH2:25]1>CN(C)C=O.O>[CH2:28]([O:27][CH2:23][CH:24]([OH:26])[CH2:25][N:8]1[C:9](=[O:10])[C:4]([CH2:1][CH2:2][CH3:3])([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[NH:6][C:7]1=[O:11])[CH2:29][CH2:30][CH3:31]
Reactant: CCCC1(CCC)C(=O)NC(=O)NC1=O
Reactant: CCCCOCC1CO1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCOCC(O)CN1C(=O)NC(=O)C(CCC)(CCC)C1=O
Temperature: 60 °C
Yield: 47.6 %

Procedure:
A solution of 5,5 dipropyl-(1H,3H,5H)-pyrimidine-2,4,6-trione (30.8 g, 0.15 mole) in dimethylformamide (30 ml) containing triethylamine (2.02 g, 0.2 mole) was mixed with butyl glycidyl ether (13 g, 0.1 mole). The mixture was heated at 60° C. for 6 hours. The solution was then diluted with water (150 ml) and extracted with toluene (2×50 ml). The organic layer was separated, washed with water (2×100 ml) dried and extracted with 5% aqueous sodium carbonate (6×100 ml). The toluene phase was then extracted with 1M aqueous sodium hydroxide (2×100 ml), the aqueous layers separated, washed with toluene (100 ml) and the pH was adjusted to 3 with sulphuric acid. The precipitated oily product was extracted with toluene (100 ml), and the organic layer was separated, washed with water, dried and evaporated to yield the title compound (16.3 g; 51.6%); purity by HPLC 96.5%.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([Cl:12])=[C:10]([F:11])[C:5]2=[N:4][CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([C:35]#[N:36])[C:17]([C:20]2[CH:25]=[C:24](B3OCC(C)(C)CO3)[CH:23]=[CH:22][C:21]=2[F:34])=[CH:18][CH:19]=1>>[Cl:12][C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:24]3[CH:23]=[CH:22][C:21]([F:34])=[C:20]([C:17]4[C:16]([C:35]#[N:36])=[CH:15][C:14]([F:13])=[CH:19][CH:18]=4)[CH:25]=3)=[CH:3][N:4]=[C:5]2[C:10]=1[F:11]
Reactant: CC1(C)COB(c2ccc(F)c(-c3ccc(F)cc3C#N)c2)OC1
Reactant: Fc1c(Cl)ccn2c(Br)cnc12
Product: N#Cc1cc(F)ccc1-c1cc(-c2cnc3c(F)c(Cl)ccn23)ccc1F
Yield: 70.9 %

Procedure:
3-Bromo-7-chloro-8-fluoroimidazo[1,2-α]pyridine (45 mg, 0.18 mmol) was coupled with 4,2′-difluoro-5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)biphenyl-2-carbonitrile (49 mg, 0.19 mmol), as described in Example 1, to afford 5′-(7-chloro-8-fluoroimidazo[1,2-α]pyridin-3-yl)-4,2′-difluorobiphenyl-2-carbonitrile as a white amorphous solid (49 mg, 71%): δH (360 MHz, CDCl3) 6.86 (1H, dd, J 7 and 7), 7.35-7.44 (2H, m), 7.58-7.64 (4H, m), 7.71 (1H, s), 8.20 (1H, d, J 7); m/z (ES+) 384 (100%, [MH]+).
Reaction SMILES: [Br:1][C:2]1[C:6]([Br:7])=[C:5]([Br:8])[N:4]([CH2:9][C:10]([O:12]CC)=O)[N:3]=1.[NH3:15]>C(O)C>[Br:1][C:2]1[C:6]([Br:7])=[C:5]([Br:8])[N:4]([CH2:9][C:10]([NH2:15])=[O:12])[N:3]=1
Reactant: N
Reactant: CCOC(=O)Cn1nc(Br)c(Br)c1Br
Solvent: CCO
Product: NC(=O)Cn1nc(Br)c(Br)c1Br
Reaction time: 72 h

Procedure:
A solution consisting of 9.7 gm. (0.025 mole) ethyl 3,4,5-tribromopyrazole-1-acetate in 250 ml. ethanol was saturated with gaseous ammonia and held at about 25° C. for 3 days. After removing most of the ethanol by evaporation under reduced pressure, the solids that formed were collected on a filter and recrystallized from a mixture of ethanol and water. There was thus obtained 5.8 gm. of 3,4,5-tribromopyrazole-1-acetamide having a melting point at 234° to 236° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH3:17][NH2:18]>C1COCC1.CN(C=O)C.CCO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:18][CH3:17])=[O:6]
Reactant: CN
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCO
Product: CNC(=O)c1ccnc(Cl)c1
Temperature: 0 °C

Procedure:
2-Chloro-isonicotinic acid (12-1, 5.15 g, 32.7 mmol) was stirred in 65 mL anhydrous THF under N2. The reaction (not homogeneous) was cooled to 0° C. and oxalyl chloride (2.85 mL, 32.7 mmol) was added, followed by addition of 1 drop anh DMF. Slight bubbling occurs. The reaction was allowed to warm to RT. After 4 h reaction is homogeneous and after a total of 5 h the reaction was quickly added by pipet to a solution of methylamine (7.11 g, 228 mmol) in EtOH (20 mL). The resulting solution was concentrated in vacuo and diluted with sat NaHCO3 (aq). The solution was extracted 3× with EtOAc and the organic extracts were dried over Na2SO4, filtered ands concentrated to provide the titled compound. 1H NMR (CDCl3) δ 8.50 (d, 1H, J=5.1 Hz), 7.66 (s, 1H), 7.53 (d, 1H, J=5.1 Hz), 6.36 (bs, 1H), 3.04 (d, 2H, J=5.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:18])[C:16]=3[N:17]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH2:22][CH3:23]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH:18][CH2:22][CH3:23])[C:16]=3[N:17]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncnc2ccc(-c3cccc(F)c3)nc12
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Product: CCNc1ncnc2ccc(-c3cccc(F)c3)nc12

Procedure:
Following the same reaction and purification procedure, the amine 1 (150 mg, 0.62 mmol) was treated with sodium hydride 60% dispersion in mineral oil (37 mg, 0.94 mmol) and iodoethane (0.05 mL, 0.62 mmol) to provide 6-(3-fluorophenyl)-N-ethylpyrido[3,2-d]pyrimidin-4-amine 29.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[C:5]2[NH:11][C:12](=[O:22])[N:13]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=3[F:21])[C:4]=2[C:3]=1[F:23].[CH3:24][N:25]([CH3:30])[S:26](Cl)(=[O:28])=[O:27]>CN(C1C=CN=CC=1)C>[CH3:24][N:25]([CH3:30])[S:26]([N:11]1[C:5]2[C:6]3[O:10][CH:9]=[N:8][C:7]=3[C:2]([F:1])=[C:3]([F:23])[C:4]=2[N:13]([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=2[F:21])[C:12]1=[O:22])(=[O:28])=[O:27]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: O=c1[nH]c2c3ocnc3c(F)c(F)c2n1-c1ccc(I)cc1F
Agent: CN(C)c1ccncc1
Product: CN(C)S(=O)(=O)n1c(=O)n(-c2ccc(I)cc2F)c2c(F)c(F)c3ncoc3c21
Yield: 60.3 %

Procedure:
Intermediate I-20a was prepared from 4,5-difluoro-6-(2-fluoro-4-iodo-phenyl)-6,8-dihydro-imidazo[4′,5′:3,4]benzo[1,2-d]oxazol-7-one (I-15a: 80 mg, 0.185 mmol), N,N-dimethylaminosulfonyl chloride (41 mg, 0.277 mmol), TEA (78 mg, 0.55 mmol) and DMAP (10 mg) using procedures analogous to those described above for Intermediate I-19a to afford 60 mg of the product (60% yield). H1NMR (CDCl3, 300 MHz): δ 8.16 (s, 1H), 7.72-7.69 (m, 1H), 7.68-7.65 (m, 1H), 7.29-7.22 (m, 1H), 3.2 (s, 6H).