Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[Mg]Br.[CH2:13]([C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:34]2[CH:39]=[CH:38][C:37]([CH2:40][CH:41]([CH3:43])[CH3:42])=[CH:36][CH:35]=2)[CH2:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[CH:14]([CH3:16])[CH3:15].Cl>O1CCCC1.CCOCC.C(OCC)(=O)C>[CH2:40]([C:37]1[CH:38]=[CH:39][C:34]([CH:23]([C:20]2[CH:19]=[CH:18][C:17]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:22][CH:21]=2)[CH2:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)=[O:30])=[CH:27][CH:26]=2)=[CH:35][CH:36]=1)[CH:41]([CH3:43])[CH3:42]
Reactant: CC(C)Cc1ccc(C(Cc2ccc(C(=O)Cl)cc2)c2ccc(CC(C)C)cc2)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)Cc1ccc(C(Cc2ccc(C(=O)c3c[nH]c4ccccc34)cc2)c2ccc(CC(C)C)cc2)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 16.9 %

Procedure:
To a solution of indole (366 mg) in tetrahydrofuran (5 ml) was added 3M solution of methyl magnesium bromide in ether (1.5 ml) at 20° C., and the mixture was stirred at 20° C. for 1 hour. A solution of 4-[2,2-bis(4-isobutylphenyl)ethyl]benzoyl chloride (450 mg) in tetrahydrofuran (5 ml) was added to the mixture at 20° C. After stirred at 20° C. for 30 minutes, the mixture was poured into a mixture of 1N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water, aqueous sodium bicarbonate and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel (10 g) eluting with a mixture of hexane and ethyl acetate (20:1) to give 3-[4-[2,2-bis(4-isobutylphenyl)ethyl]benzoyl]indole (90 mg) as colorless crystals.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:13]([O-])([O-])=O.[K+].[K+].COS(OC)(=O)=O>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2[nH]ccc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
The solution of 1H-indole-5-carboxylic acid (1.0 g, 6.2 mmol, Aldrich) and K2CO3 (0.939 g, 6.8 mmol) in DMF (10 mL) was heated to 65° C., and Me2SO4 (0.78 g, 6.2 mmol) was added dropwise between 65-70° C. over 15 min. The reaction was stirred for 1 h at 80° C. then the mixture was poured into ice/water. The resulting precipitate was collected by filtration and dried in vacuo to give methyl 1H-indole-5-carboxylate (0.91 g, 5.2 mmol, 85.8%). MS (ESI, pos. ion) m/z: 176 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[C:22]([NH:31][CH2:32][C:33]3[O:34][CH:35]=[CH:36][CH:37]=3)=[N:23][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[N:25][CH:26]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:38]([OH:40])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:41]1(O)C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>ClCCCl.O>[NH2:41][C:38]([C@@H:10]1[CH2:11][C@H:12]([N:14]([C:19]([C:21]2[C:22]([NH:31][CH2:32][C:33]3[O:34][CH:35]=[CH:36][CH:37]=3)=[N:23][C:24]([C:27]([CH3:30])([CH3:28])[CH3:29])=[N:25][CH:26]=2)=[O:20])[CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)=[O:40]
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@H]1C[C@@H](C(N)=O)CN(C(=O)OC(C)(C)C)C1
Yield: 91.8 %

Procedure:
A solution of (3R*,5S*)-1-(tert-butoxycarbonyl)-5-[({2-tert-butyl-4-[(2-furylmethyl)amino]pyrimidin-5-yl}carbonyl)(isobutyl)amino]piperidine-3-carboxylic acid (1.03 g), 1H-1,2,3-benzotriazol-1-ol ammoniate (420 mg), WSC.HCl (530 mg) and triethylamine (520 μl) in 1,2-dichloroethane (16 ml) was stirred at room temperature for 24 hr. The mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography. The fraction eluted with ethyl acetate-hexane (1:9-1:0) was concentrated under reduced pressure to give the object compound (944 mg).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)=[N:13][C:14]([NH2:15])=[C:9]3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:22]([O-])([OH:24])=[O:23].C(O)(=O)C>S(=O)(=O)(O)O>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=4)=[N:13][C:14]([NH2:15])=[C:9]3[C:8]([N+:22]([O-:24])=[O:23])=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nc(-c2ccncc2)nc2c1cnn2C1CCCC1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Nc1nc(-c2ccncc2)nc2c1c([N+](=O)[O-])nn2C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-cyclopentyl-6-(4-pyridyl)pyrazolo[3,4-d]pyrimidin-4-amine (4.6 g, 0.016 mol) in sulfuric acid (60 ml) in an ice-bath was added dropwise 70% nitric acid (36.8 ml). The reaction mixture was warmed to room temperature, stirred for 30 minutes then heated on a steam bath for 3/4 hour. The reaction mixture was added to ice-water/50% sodium hydroxide and the pH was adjusted to 4-5 with acetic acid. The product was collected by filtration and washed with water. The solid residue was purified by preparative thin layer chromatography on silica eluting with ethyl acetate (100%) to afford, after recrystallization from ethyl acetate, 0.81 g (16%) of 1-cyclopentyl-3-nitro-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-amine, m.p. 239°-241° C. when dried for 16 hours at 110° C. in high vacuum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-])=O)[C:7](=[O:14])[N:6]([CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)[CH2:5]2>[Pd].CO>[NH2:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][N:6]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:17][CH2:16]3)[C:7]2=[O:14])=[CH:3][C:2]=1[F:1]
Reactant: CC(C)(C)OC(=O)N1CCC(N2Cc3cc(F)c([N+](=O)[O-])cc3C2=O)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2Cc3cc(F)c(N)cc3C2=O)CC1

Procedure:
The mixture of tert-butyl 4-(5-fluoro-6-nitro-1-oxoisoindolin-2-yl)piperidine-1-carboxylate (Step 3, 240 mg, 0.72 mmol), Pd (10% wt on active carbon, 24 mg) and MeOH (20 mL) was evacuated to remove air, and then the reaction was stirred under a hydrogen balloon until the starting material is consumed. Pd/C was filtered off and the solution was concentrated in vacuo to afford tert-Butyl 4-(6-amino-5-fluoro-1-oxoisoindolin-2-yl)piperidine-1-carboxylate; ESMS m/z 350.2 (M+H+).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1.CCN(CC)CC.[CH3:35][N:36]([CH3:41])[S:37](Cl)(=[O:39])=[O:38].O>C(Cl)Cl>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:37]([N:36]([CH3:41])[CH3:35])(=[O:39])=[O:38])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CN(C)S(=O)(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1
Temperature: 0 °C

Procedure:
trans-4-[2-(4-Furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate A) (150 mg, 0.34 mmol) was dissolved in CH2Cl2 (1.5 ml) and the solution was cooled to 0° C. Et3N (139 mg, 1.37 mmol) and dimethylsulfamoylchloride (98 mg, 0.68 mmol) were added and the reaction mixture was stirred over night at room temperature. H2O was added and the product was extracted with CH2Cl2. The organic layer was dried (Na2SO4) and the solvent was evaporated. Purification by flash chromatography over silica gel (CH2Cl2/MeOH/25% NH3 aq 140:10:1) yielded the title compound as a white solid (89 mg, 60%), MS (ISP) m/z=436.3 [(M+H)+].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH2:23]([CH2:25][NH2:26])[OH:24]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:26][CH2:25][CH2:23][OH:24])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: NCCO
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: OCCNCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
According to the method in example 6, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and ethanolamine were converted to yield 2-{4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butylamino}-ethanol as white solid, MS: 421 (MH+, 1Br).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].[F:18][C:19]1[CH:24]=[C:23](F)[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]([C:23]1[CH:22]=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[C:19]([F:18])[CH:24]=1)([CH2:11][CH:12]([CH3:13])[CH3:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)C(=O)OCC
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(C)C)(C(=O)OCC)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-isobutylmalonic acid diethyl ester (75.0 g, 0.35 mol) in DMF (200 mL) was added sodium hydride (60% in mineral oil, 13.0 g, 0.57 mol) over 20 min. at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h, then warmed to 25° C. The reaction mixture was cooled down to 0° C. again and a solution of 2,4-difluoronitro-benzene (50.0 g, 0.31 mol) in DMF (150 mL) was added dropwise at 0° C. The reaction mixture was stirred at 25° C. for 16 h. After cooling, the reaction mixture was poured into ice water (200 mL) and extracted with EtOAc (3×100 mL). The combined organic phases washed with water (3×100 mL), brine (100 mL), and dried (MgSO4). Evaporation of the solvent under reduced pressure gave a brown oil. The crude product (92.0 g, 82%) was used for the next step without purification. 1H NMR (300 MHz, CDCl3/TMS): δ 8.03 (t, J=8.4 Hz, 1H), 7.70 (dd, J=12.9, 1.7 Hz, 1H), 7.47 (d, J=8.5 Hz, 1H), 4.25-4.18 (m, 4H), 2.28 (d, J=6.3 Hz, 2H), 1.54-1.45 (m, 1H), 1.25 (t, J=7.0 Hz, 6H), 0.82 (d, J=7.0 Hz, 6H); 13C NMR (75 MHz, CDCl3/TMS): δ 169.2, 154.5 (d, 1JCF=263.1 Hz), 146.9 (d, unresolved), 125.3, 124.1 (d, 3JCF=3.6 Hz), 118.6 (d, 2JCF=23.3 Hz), 62.0, 60.3, 44.1, 24.7, 23.6, 13.9.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([F:28])=[C:12]([N:16]2[CH2:21][CH:20]=[C:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>[C].[Pd].CCO>[Si:1]([O:8][CH2:9][C:10]1[C:11]([F:28])=[C:12]([N:16]2[CH2:17][CH2:18][CH:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N2CC=C(c3cccnc3)CC2)c1F
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCc1cccc(N2CCC(c3cccnc3)CC2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
1′-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]-1′,2′,3′,6′-tetrahydro-3,4′-bipyridine (257 mg) was mixed with EtOH (5 ml), and 10% palladium carbon (55 mg) was added thereto under argon atmosphere, followed by stirring at room temperature overnight under hydrogen atmosphere. The reaction mixture was filtered using Celite as a filtration adjuvant, and the filtrate was concentrated under reduced pressure to obtain 3-{1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]piperidin-4-yl}pyridine (239 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:8])[CH:3]1[C:14]([OH:16])=[O:15]>C(Cl)(Cl)Cl>[CH3:17][C:2]1([CH3:1])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[O:8])[CH:3]1[C:14]([OH:16])=[O:15]
Reactant: CCCCOC(=O)C=CC1C(C(=O)O)C1(C)C
Solvent: ClC(Cl)Cl
Product: CC1(C)C(C=CC(=O)OCC2CC2)C1C(=O)O

Procedure:
Using the procedure of Example 9, the product of Step C and (3-propyn-2-yl-2,5-dioxo-imidazolidinyl)-methanol were reacted to obtain (3-propyn-2-yl-2,5-dioxo-imidazolidinyl)-methyl (1R, cis, ΔZ) 2,2-dimethyl-2-(3-n-butoxy-3-oxo-1-propenyl)-cyclopropane-carboxylate with a specific rotation of [α]D20 =+17°±1° (c=1% in chloroform).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][C:11]1([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:20][CH2:19][C:14]2(OCC[O:15]2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+]>CC(C)=O.Cl>[CH2:1]([O:8][C:9](=[O:28])[NH:10][C:11]1([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:20][CH2:19][C:14](=[O:15])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1(c2ccc(F)cc2)CCC2(CC1)OCCO2)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C1CCC(NC(=O)OCc2ccccc2)(c2ccc(F)cc2)CC1

Procedure:
2.75 g of [8-(4-Fluoro-phenyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-carbamic acid benzyl ester (76) were dissolved in 30 mL of acetone and 15 mL of 5N HCl. When conversion was complete, the mixture was carefully poured into sat. sodium bicarbonate solution. The aqueous layer was extracted twice with dichloromethane,
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[B:18]1[O:22]C(C)(C)[C:20](C)(C)[O:19]1)[O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=1)=O.[BH4-].[Na+].Cl.C([O-])(O)=O.[Na+]>CCO.O>[OH:22][B:18]1[C:17]2[CH:3]=[CH:4][C:5]([O:6][C:7]3[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][N:8]=3)=[CH:15][C:16]=2[CH2:20][O:19]1
Reactant: CC1(C)OB(c2ccc(Oc3ccc(C#N)cn3)cc2C=O)OC1(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CCO
Solvent: O
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92.4 %

Procedure:
To a suspension of 6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile (1.67 g, 4.8 mmol, 1.0 eq.) in EtOH (30 mL) at 0° C. was added NaBH4 (180.4 mg, 4.76 mmol, 1.0 eq.) in small portions. The mixture was stirred at 0° C. for 20 minutes and allowed to warm to room temperature in another 1 h. After cooling to 0° C., the clear solution was carefully treated with H2O (1 mL), followed by slow addition of HCl (10 mL, 3N). The resulting yellow suspension was allowed to ward to room temperature gradually and stirred for 2 h. The mixture was then treated with sat. NaHCO3 drop wise until PH reaching 7. The precipitate was collected by filtration, washed with H2O to give 6-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-nicotinonitrile as a white solid. LCMS (m/z) 253 (M+H); 1H NMR (DMSO-d6) δ: 9.19 (s, 1H), 8.60-8.66 (m, 1H), 8.31 (dd, J=8.7, 2.4 Hz, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.20-7.28 (m, 2H), 7.13 (dd, J=8.0, 2.0 Hz, 1H), 4.96 (s, 2H). Amount obtained, 1.1 g, 92.4% yield.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][CH:6]1[NH:12]S(C1C=CC(C)=CC=1)(=O)=O)(=O)[NH2:2].[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[I:11][C:9]1[CH:8]=[CH:7][C:6]2[N:5]([CH:4]=[C:1]([NH:2][C:23](=[O:25])[CH3:24])[N:12]=2)[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)NC2C=CC(I)=CN2CC(N)=O)cc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cn2cc(I)ccc2n1
Temperature: 25 °C

Procedure:
A mixture of the product from Step B (300 mg, 0.70 mmol) and 1.0 mL of acetic anhydride was warmed at reflux for 2.5 h. The solution was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water, and the ethyl acetate layer was washed sequentially with saturated aqueous sodium bicarbonate solution and saturated aqueous brine, dried (magnesium sulfate) and concentrated under reduced pressure. The crude residue was purified by preparative thin-layer chromatography (silica gel, 7% methanol/dichloromethane) to afford the title compound as a pale yellow powder. LC/MS 301.9 (M+1).
Reaction SMILES: C([O:3][P:4]([CH:7]([N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH3:19])([CH3:18])[CH2:13]1)[P:8](=[O:11])([OH:10])[OH:9])(=[O:6])[OH:5])C>Cl>[CH3:18][C:14]1([CH3:19])[CH2:15][CH2:16][CH2:17][N:12]([CH:7]([P:8](=[O:9])([OH:11])[OH:10])[P:4](=[O:3])([OH:5])[OH:6])[CH2:13]1
Reactant: CCOP(=O)(O)C(N1CCCC(C)(C)C1)P(=O)(O)O
Agent: Cl
Product: CC1(C)CCCN(C(P(=O)(O)O)P(=O)(O)O)C1

Procedure:
A mixture comprising 8 g of 3,3-dimethylpiperidinomethylene bisphosphonic acid ethyl ester obtained in Example 57 and 80 ml of 12N hydrochloric acid, was treated in the same manner as in Example 2 to give 1.5 g of the above identified compound.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][N:19]([CH3:26])[C:20](=[O:25])[CH2:21][CH:22]([CH3:24])[CH3:23])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[CH3:27][N:28](C)C=O>>[CH3:26][N:19]([CH2:18][C:8]1[N:6]2[CH:7]=[C:2]([C:27]#[N:28])[CH:3]=[CH:4][C:5]2=[N:10][C:9]=1[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)[C:20](=[O:25])[CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: Cc1ccc(-c2nc3ccc(I)cn3c2CN(C)C(=O)CC(C)C)cc1
Reactant: CN(C)C=O
Product: Cc1ccc(-c2nc3ccc(C#N)cn3c2CN(C)C(=O)CC(C)C)cc1
Yield: 96 %

Procedure:
3.7 g (0.041 mole) of cuprous cyanide and 19 g (0.041 mole) of N-{[6-iodo-2-(4-methylphenyl)imidazo[1,2-a]pyrid-3-yl]methyl}-N,3-dimethylbutanamide, prepared according to the process described in European Patent Application No. 0,172,096, are introduced into 100 ml of dimethylformamide. The mixture is heated under reflux for 4 hours and the solvent then evaporated off under reduced pressure. The residue is taken up with water and dichloromethane and the mixture treated with ammonia solution. The organic phase is washed with water and dried, and the solvent evaporated off. The residue is purified by column chromatography and taken up with pentane. 14.4 g (96%) of white solid are obtained. M.p. 151°-153° C.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12]([CH3:14])=[C:11]([CH3:15])[N:10]=[C:9]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:8]=2[N:7]=[C:6]1[CH2:26][OH:27])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[Cl-].[NH4+]>ClCCl.CS(C)=O>[CH2:1]([N:5]1[C:13]2[C:12]([CH3:14])=[C:11]([CH3:15])[N:10]=[C:9]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:8]=2[N:7]=[C:6]1[CH:26]=[O:27])[CH:2]([CH3:3])[CH3:4]
Reactant: COc1ccc(CNc2nc(C)c(C)c3c2nc(CO)n3CC(C)C)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CNc2nc(C)c(C)c3c2nc(C=O)n3CC(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
Under a nitrogen atmosphere {1-isobutyl-4-[(4-methoxybenzyl)amino]-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-2-yl}methanol (2.00 g, 5.43 mmol, prepared as in Parts A-F of Example 9) was dissolved in dichloromethane (20 mL) and dimethylsulfoxide (10 mL). Triethylamine (2.27 mL, 16.3 mmol) was added and the solution was cooled to 0° C. Sulfur trioxide pyridine complex (2.60 g, 16.3 mmol) was then added in four portions and the solution was stirred at 0° C. for another 2 hours. The solution was then poured into saturated aqueous ammonium chloride (70 mL) and extracted with diethyl ether (3×80 mL). The organics were washed with water (2×30 mL) and brine (20 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 1.84 g of 1-isobutyl-4-[(4-methoxybenzyl)amino]-6,7-dimethyl-1H-imidazo[4,5-c]pyridine-2-carbaldehyde as a yellow residue.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:13][C:11]1[CH:10]=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([Cl:1])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ccc(C)cc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(CBr)cc1Cl

Procedure:
A mixture of ethyl 2-chloro-4-methylbenzoate (2.34 g, 0.0118 mol), N-bromosuccinimide (2.05 g, 0.0115 mol), and benzoyl peroxide (0.5 g) in carbon tetrachloride (50 ml) was heated under reflux for 90 minutes. The resulting solution was filtered and the solvent was evaporated off under reduced pressure to yield ethyl 4-(bromomethyl)-2-chlorobenzoate as a yellow crystalline solid having the following structural characteristics:
Reaction SMILES: N[C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH:4]=[CH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[NH:8])=[O:7].CO[CH:21](OC)[N:22](C)C>CN(C)C=O.C(OCC)(=O)C>[C:9]1([SH:6]2(=[O:7])[CH:5]=[C:4]([C:3]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:2]=3)[N:22]=[CH:21][NH:8]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(OC)N(C)C
Reactant: N=S(=O)(C=Cc1ccccc1N)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[SH]1(c2ccccc2)C=C(c2ccccc2)N=CN1
Temperature: 80 °C
Yield: 79.7 %

Procedure:
To a solution of 2 g (7.75 mmole) of S-(2-aminostyryl)-S-phenyl sulfoximine in 20 ml of dimethylformamide was added 1 g (8.5 mmole) of dimethylformamide dimethyl acetal and the mixture was heated at 80° C. for 15 minutes. The mixture was then cooled and diluted with 100 ml of ethyl acetate. The organic phase was washed 3 times with 75 ml of water, dried over magnesium sulfate and evaporated to an oil which was crystallized from ether/petrol to obtain 1.67 g (80%) of 1,5-diphenyl-1H-1,2,4-thiadiazine-1-oxide melting at 110°-111° C.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:9][C:10]1[CH:15]=[CH:14][C:13](B2OC(C)(C)C(C)(C)O2)=[CH:12][C:11]=1[C@:25]1([CH2:36][F:37])[CH2:30][C@@H:29]([C:31]([F:34])([F:33])[F:32])[O:28][C:27]([NH2:35])=[N:26]1.Br[C:39]1[CH:40]=[CH:41][C:42]([C:45]#[C:46][Si:47]([CH3:50])([CH3:49])[CH3:48])=[N:43][CH:44]=1.CCCCCC>O1CCOCC1.O.O.C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:39]2[CH:44]=[N:43][C:42]([C:45]#[C:46][Si:47]([CH3:48])([CH3:50])[CH3:49])=[CH:41][CH:40]=2)=[CH:12][C:11]=1[C@:25]1([CH2:36][F:37])[CH2:30][C@@H:29]([C:31]([F:33])([F:32])[F:34])[O:28][C:27]([NH2:35])=[N:26]1
Reactant: C[Si](C)(C)C#Cc1ccc(Br)cn1
Reactant: CC1(C)OB(c2ccc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)c2)OC1(C)C
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCCCCC
Solvent: C1COCCO1
Product: C[Si](C)(C)C#Cc1ccc(-c2ccc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)c2)cn1
Reaction time: 0.25 h
Yield: 44.3 %

Procedure:
A mixture of potassium phosphate (0.676 g, 3.19 mmol), (4S,6S)-4-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (8b, 1.428 g, 3.40 mmol), 5-bromo-2-((trimethylsilyl)ethynyl)pyridine (0.270 g, 1.062 mmol) and 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (0.038 g, 0.053 mmol) in dioxane/water (5.0/1.2 mL) was heated in microwave reactor at 110° C. for 35 min. The reaction mixture was diluted with water and extracted with DCM three times. The combined organic layers were washed with brine, dried on sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography: 0-100% EtOAc/hexane in 15 min. The product was obtained as an off-white solid. Trituration with hexane afforded the pure product as a white solid (0.22 g, 44% yield). MS m/z=468 [M+H]+. Calculated for C22H22F5N3OSi: 467.5.