Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])(=O)C.[K+].[C:6]([O:10][C:11](=[O:23])[NH:12][C@@H:13]([C:15]1[C:20]([F:21])=[CH:19][C:18](Br)=[CH:17][N:16]=1)[CH3:14])([CH3:9])([CH3:8])[CH3:7].CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+].Br[C:52]1[CH:57]=[C:56]([Cl:58])[CH:55]=[C:54]([F:59])[C:53]=1[C:60]1[N:61]=[N:62][N:63]([CH3:65])[N:64]=1>CS(C)=O.[Pd].O>[C:6]([O:10][C:11](=[O:23])[NH:12][C@@H:13]([C:15]1[C:20]([F:21])=[CH:19][C:18]([C:52]2[CH:57]=[C:56]([Cl:58])[CH:55]=[C:54]([F:59])[C:53]=2[C:60]2[N:61]=[N:62][N:63]([CH3:65])[N:64]=2)=[CH:17][N:16]=1)[CH3:14])([CH3:9])([CH3:8])[CH3:7]
Reactant: Cn1nnc(-c2c(F)cc(Cl)cc2Br)n1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ncc(Br)cc1F
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: C[C@@H](NC(=O)OC(C)(C)C)c1ncc(-c2cc(Cl)cc(F)c2-c2nnn(C)n2)cc1F
Temperature: 90 °C

Procedure:
A mixture of potassium acetate (2.92 g, 29.8 mmol), the above carbamate (3.17 g, 9.9 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (2.77 g, 10.9 mmol) was dissolved in 10 mL of DMSO in a sealed tube reaction vessel caped with a rubber septum. This heterogeneous mixture was then evacuated and purged with nitrogen three times prior to introduction of [1,1′-bis-(diphenylphosphino)ferrocene]dichloro-palladium(II), complex with DCM (1:1) (0.363 g, 0.500 mmol). The heterogeneous mixture was then evacuated and purged with nitrogen twice before the septum was replaced with a teflon screw-top cap. This sealed vessel was then heated to 90° C. for 16 hours. After cooling to ambient temperature, potassium carbonate (2.74 g, 19.9 mmol), water (9.9 mL), 5-(2-bromo-4-chloro-6-fluorophenyl)-2-methyl-2H-tetrazole (3.04 g, 10.4 mmol) and additional palladium catalyst (0.363 g, 0.500 mmol) were added and the reaction vessel was sealed again. After heating to 80° C. for 5 hours, the reaction was cooled and then quenched with water. The mixture was flushed through a plug of celite and chased with EtOAc. The aqueous layer was extracted once with EtOAc. The combined organic layers were washed with water and brine prior and dried over sodium sulfate. Filtration and solvent removal provided material which was subjected to silica gel chromatography eluting with 0-10% EtOAc in hexanes to yield tert-butyl((1R)-1-{5-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)phenyl]-3-fluoropyridin-2-yl}ethyl)carbamate. This material was dissolved in 15 mL of dry EtOAc. Anhydrous HCl gas was then bubbled through the solution for 3 minutes. The reaction was stirred vigorously for one hour. The reaction mixture was slowly neutralized with a saturated aqueous sodium bicarbonate solution. The mixture was partitioned between water and EtOAc. The organic layer was washed with water and brine and dried over sodium sulfate. Filtration and concentration provided the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:14]4[CH:24]=[CH:25][C:26]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:27][C:13]=4[N:12]=3)=[N:9][N:8]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:49]2[CH:50]=[C:51]([CH:55]=[O:56])[CH:52]=[N:53][CH:54]=2)O1>C([O-])([O-])=O.[Na+].[Na+].COCCOC.C(Cl)Cl.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:30][C:29]([F:31])([F:32])[O:28][C:26]1[CH:25]=[CH:24][C:14]2[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:21])([CH3:23])[CH3:22])[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([C:49]5[CH:50]=[C:51]([CH:55]=[O:56])[CH:52]=[N:53][CH:54]=5)[CH:3]=4)[N:8]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[N:9]=3)=[N:12][C:13]=2[CH:27]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2nc3cc(OC(F)(F)F)ccc3n2COCC[Si](C)(C)C)c2cc(Br)cnc21
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(-c2nc3cc(OC(F)(F)F)ccc3n2COCC[Si](C)(C)C)c2cc(-c3cncc(C=O)c3)cnc21
Temperature: 100 °C

Procedure:
5-bromo-3-[5-trifluoromethoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine Compound 16e (0.12 g, 0.18 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-3-carbaldehyde Compound 15b (0.063 g, 0.27 mmol) and 2M Na2CO3 (5 drops) were mixed in DME (10 mL) in a reaction tube. The resulting yellowish clear solution was degassed with nitrogen for 15 minutes, then tetrakis(triphenylphosphine)palladium(0) (0.021 g, 0.018 mmol) was added and the reaction tube was sealed and heated at 100° C. overnight. The sealed tube was cooled and opened and the contents was diluted with DCM and H2O, then filtered through Celite. The solvent was evaporated to dryness to provide 5-[3-[5-trifluoromethoxy-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-pyridine-3-carbaldehyde Compound 17a (0.241 g) as a brown semi-solid which was used directly in the next step without further purification. LCMS single peak, 4.614 min, MS (ESI) m/z 685.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[O:12][CH:13]([CH2:17][CH3:18])[C:14]([OH:16])=[O:15].[Si:19]([O:26][C@H:27]1[CH2:36][C@H:35](O)[C@H:34]2[C:29]([CH:30]=[CH:31][C@H:32]([CH3:55])[C@@H:33]2[CH2:38][CH2:39][C@H:40]2[O:45][C:44](=[O:46])[CH2:43][C@H:42]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])[CH2:41]2)=[CH:28]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>>[Si:19]([O:26][C@H:27]1[CH2:36][C@H:35]([O:15][C:14](=[O:16])[CH:13]([O:12][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:10]=[CH:11][C:2]=2[CH3:1])[CH2:17][CH3:18])[C@H:34]2[C:29]([CH:30]=[CH:31][C@H:32]([CH3:55])[C@@H:33]2[CH2:38][CH2:39][C@H:40]2[O:45][C:44](=[O:46])[CH2:43][C@H:42]([O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:49])[CH3:50])[CH2:41]2)=[CH:28]1)([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:21])[CH3:20]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCC(Oc1c(C)ccc2ccccc12)C(=O)O
Product: CCC(Oc1c(C)ccc2ccccc12)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 830 mg of (2RS)-2-(2-methyl-1-naphthyloxy)butyric acid and 1.0 gof (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-napthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], to give 1.52 g of the title compound as a colorless foam.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[C:7]([C:11]([OH:13])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:23].N#N>CO.C1(C)C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:14][C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[NH:8][C:7]=2[C:11]([O:13][CH3:23])=[O:12])=[CH:16][CH:17]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1[nH]c2cc(F)ccc2c1Sc1ccc(Cl)cc1
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1[nH]c2cc(F)ccc2c1Sc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of impure 1g product (0.19 g, 0.59 mmol) in a mixture of methanol and toluene (6 mL, 1:2) was added TMSCHN2 (2.0 M solution in diethyl ether) (0.6 mL, 1.2 mmol) dropwise under N2. The reaction was allowed to warm to rt and stirred for 2 h. The reaction mixture was concentrated and purified by flash column chromatography eluting with a linear gradient ranging from 0 to 50% EtOAc-hexanes to provide 0.15 g (75%) of product 34 as an off white solid. 1H NMR (300 MHz, CDCl3) δ 3.93 (s, 3H), 6.88-6.95 (m, 1H), 7.06-7.16 (m, 5H), 7.45-750 (m, 1H), 9.22 (s, 1H). LC-MS (CI): m/z 336.0 [(M+H)+ C16H11ClFNO2S requires 335.02].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[C:12]([O:16][C:17]([NH:19][CH2:20][CH:21]1[N:26]([C:27](=O)[CH2:28]Cl)[C:25]2[CH:31]=[CH:32][CH:33]=[CH:34][C:24]=2[S:23][CH2:22]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>O>[C:12]([O:16][C:17]([N:19]1[CH2:28][CH2:27][N:26]2[CH:21]([CH2:22][S:23][C:24]3[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=32)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCC1CSc2ccccc2N1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN2c3ccccc3SCC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
A 13.47 g (97.43 mmol) portion of potassium carbonate was added to DMF solution (360 ml) containing 11.59 g (32.48 mmol) of 3-(t-butoxycarbonyl)aminomethyl-4-chloroacetyl-3,4-dihydro-2H-1,4-benzthiazine and stirred at room temperature overnight and then at 60° C. for 3 hours. This was returned to room temperature, mixed with cool water and extracted with ethyl acetate. The extract was dried (Na2SO4) and then concentrated under a reduced pressure. The thus dried residue under a reduced pressure was dissolved in 180 ml of tetrahydrofuran and cooled to 0° C. This was mixed with 4.48 ml (48.72 mmol) of borane-dimethyl sulfide complex and stirred at 0° C. for 2 hours and then at room temperature for 2 hours. Cool water was added dropwise to the reaction solution which was subsequently stirred for 30 minutes and then extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and dried (Na2SO4), and then the solvent was removed by evaporation under a reduced pressure. The thus obtained residue was purified by a silica gel column chromatography (650 cc; elution by ethyl acetate-hexane=1:4) and further recrystallized from ethyl acetate-hexane to obtain 5.04 g of the title compound (51% in yield).
Reaction SMILES: Cl[C:2]1[C:11](OCCCC(O)=O)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:19])[NH:7]2.C(N(CC)CC)C.ClC(OCC(C)C)=O.C(NC1CCCCC1)CCC>CN(C=O)C>[NH:7]1[C:8]2[C:3](=[CH:2][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][C:6]1=[O:19]
Reactant: O=C(O)CCCOc1ccc2[nH]c(=O)ccc2c1Cl
Agent: CC(C)COC(=O)Cl
Agent: CCCCNC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=c1ccc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.0 Grams of 5-chloro-6-(3-carboxypropoxy)carbostyril and 2.97 ml of triethylamine are added to 100 ml of DMF, followed by dropwise addition thereto of 2.33 ml of isobutyl chloroformate under external ice cooling and agitation while maintaining the internal temperature at 0° to 10° C. After this dropwise addition, the mixture is agitated at room temperature for 1 hour, added dropwise with 2.8 g of N-n-butylcyclohexylamine and further agitated at room temperature for 3 hours. After the reaction, the solvent is distilled off and the residue is dissolved in 600 ml of chloroform, washed with diluted hydrochloric acid, aqueous K2CO3 solution and water in that order and then dried with anhydrous Na2SO4. After removing the inorganic matter by filtration, the mother liquor is concentrated and the residue is recrystallized from ethanol, resultantly obtaining 2.5 g of 5-chloro-6-[3-N-cyclohexyl-N-butylaminocarbonyl)propoxy]carbostyril in the form of colorless needle-like crystals. m.p., 178.5°-179.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][C:5]#[N:6].[CH2:8]([O:10][C:11](OCC)(OCC)[O:12][CH2:13][CH3:14])[CH3:9].C(OC(=O)C)(=O)C>>[CH3:1][O:2][C:3](=[O:7])[C:4]([C:5]#[N:6])=[C:11]([O:12][CH2:13][CH3:14])[O:10][CH2:8][CH3:9]
Reactant: COC(=O)CC#N
Reactant: CCOC(OCC)(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC(OCC)=C(C#N)C(=O)OC
Temperature: 130 °C

Procedure:
A reaction mixture consisting of methylcyanoacetate (5.0 ml, 57 mmol) and tetraethylorthocarbonate (17.99 ml, 86 mmol) in acetic anhydride (8.11 ml, 86 mmol) was heated at 130° C. for 5 hours, and then heated at 110° C. for 18 hours. The cooled reaction residue was extracted twice with 125 ml portions of hexane. A hexane-insoluble orange oil containing approximately 40% by weight of the desired compound (as established by NMR inspection) remained. This crude product was used in the next step without further purification. TLC Rf (silica gel plates, u.v. detection, ethyl acetate/hexane=15:85 in volume): 0.13.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH:19]([S:23](Cl)(=[O:25])=[O:24])([CH2:21][CH3:22])[CH3:20]>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:23]([CH:19]([CH2:21][CH3:22])[CH3:20])(=[O:25])=[O:24])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: CCC(C)S(=O)(=O)Cl
Product: CCC(C)S(=O)(=O)Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Yield: 22 %

Procedure:
According to the general procedure A, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with sec-butylsulfonyl chloride to obtain the desired product. Yield: 22%. 1H-NMR (500 MHz, MeOH[d4]): δ=7.60-7.40 (m, 3H), 7.18-7.00 (q, 1H), 6.55-6.45 (m, 1H), 3.55-3.50 (m, 1H), 2.20-2.00 (m, 1H), 1.80-1.60 (m, 1H), 1.43-1.40 (d, 3H), 1.06-1.04 (t, 3H); m/z=483 [M−1]−.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH:29](/[CH:41]=[CH:42]/[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[OH:49])[CH2:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)=[CH:23][CH:22]=1)#[N:20]>C(#N)C>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][O:49][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2/[CH:42]=[CH:41]/[CH:29]([CH2:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[CH:22][CH:23]=2)[CH2:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCc2ccc(C#N)cc2)cc1
Yield: 92 %

Procedure:
2.20 g (9.71 mmol) of 4-(tert-butyl)benzyl bromide and 2.02 g (14.59 mmol) of anhydrous potassium carbonate are added to a solution of 2 g (3.6 mmol) of methyl E4-[2-[2-(4-cyanophenyl)ethyl]-4-(2-hydroxyphenyl)but-3-enyl]benzoate in 8 ml of dry acetonitrile, and the mixture is heated under reflux for 12 hours. The mixture is then filtered and the filtrate is evaporated to dryness. The residue is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). 1.9 g (3.30 mmol, 97% purity, 92% yield) of an oil are isolated.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]([CH3:13])=[CH:5][C:4](=[O:14])[CH2:3]1.[OH:16]O.[OH-].[Na+].Cl>CO>[CH3:15][C:2]1([CH3:1])[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]2([CH3:13])[O:16][CH:5]2[C:4](=[O:14])[CH2:3]1
Reactant: CCOC(=O)C1C(C)=CC(=O)CC1(C)C
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)C1C(C)(C)CC(=O)C2OC21C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5 g of 3,3,5-trimethyl-4-ethoxycarbonyl-5-cyclohexen-1-one [which can be prepared according to the method described in Example 1] in 800 ml of methanol were cautiously mixed with a solution of 24 ml of a 30% solution of H2O2 and 6 ml of a 6N solution of NaOH. The reaction mixture, after having been stirred for 2 days at room temperature, was neutralized with a diluted HCl solution and the volatile portions were separated by evaporation. Distillation of the residue gave 3,3,5-trimethyl-4-ethoxycarbonyl-5,6-epoxy-cyclohexanone in a pure state.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15].CO>C(Cl)(Cl)(Cl)Cl>[C:14]([NH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: NCCNc1ccc([N+](=O)[O-])cn1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CO
Product: CC(=O)NCCNc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A suspension of 2-(2-aminoethylamino)-5-nitropyridine (5.0 g, 27.47 mmol) in carbon tetrachloride (60 ml) was treated with acetic anhydride (5.6 g, 54.9 mmol) and methanol (0.5 ml) and the resulting mixture was refluxed for 2 h then allowed to cool to room temperature. The mixture was filtered and the residue partitioned between 1M sodium hydroxide and CH2Cl2. The organic phase was dried (MgSO4) and concentrated to afford the title compound (5.03 g) as a buff solid m.p. 177-180°. MS(ES+) 225 (MH+).
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[NH:2]1.[H-].[Na+].Cl[CH2:15][C:16]#[N:17].O>CN(C=O)C>[O:11]=[C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[N:2]1[CH2:15][C:16]#[N:17]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCN1C(=O)c2ccccc2C1=O
Yield: 89.4 %

Procedure:
32 g (0.217 mol) of isoindole-1,3-dione in 160 mL of DMF were treated with 11.75 g (0.294 mol, 1.35 eq) of NaH (60% in oil) over 45 min at 0° C. 22.17 g (0.294 mol, 1.35 eq) of chloro-acetonitrile were added, and the reaction was stirred over night. The reaction mixture was poured into 1.5 L of water, and the precipitate was collected by filtration, washed with Et2O and dried under high vacuum to afford 36.1 g (89%) of (1,3-dioxo-1,3-dihydro-isoindol-2-yl)-acetonitrile as a white solid, MS: 187 (MH+).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)c1
Agent: Cl
Product: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(C)=O)CC4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f12) and commercially acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Al].[Br:14]Br>C(OCC)C>[Br:14][C:9]1[C:10]([CH3:12])=[CH:11][C:2]([CH3:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: BrBr
Reactant: COC(=O)c1ccc(C)cc1C
Agent: [Al]
Solvent: CCOCC
Product: COC(=O)c1cc(Br)c(C)cc1C
Temperature: 25 °C

Procedure:
To a mixture of the above methyl 2,4-dimethylbenzoate (19.75 g) and activated aluminum neutral oxide (120 g) was added dropwise bromine (9.25 ml) while stirring at room temperature. The mixture was stirred at room temperature for 8 hours, and diluted with diethyl ether (1000 ml). Insoluble materials were filtered off, and washed with diethyl ether (500 ml). The combined filtrate was washed successively with 10% aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution and brine. The filtrate was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from methanol (40 ml) to give methyl 5-bromo-2,4-dimethylbenzoate (6.34 g) as colorless crystals. APCI-Mass m/Z 243/245 (M+H).
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].C1CCN2C(=NCCC2)CC1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:31][C:32]1[CH:33]=[C:34](O)[CH:35]=[CH:36][C:37]=1[Cl:38]>C(#N)C>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([O:6][C:2]([CH3:3])([CH3:1])[C:4]#[CH:5])=[CH:36][C:37]=1[Cl:38]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: C#CC(C)(C)O
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Product: C#CC(C)(C)Oc1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
2-Methyl-but-3-yn-2-ol (1.68 g, 20 mmol) in acetonitrile (10 ml) was treated with DBU (20 mmol) and trifluoroacetic anhydride (20 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 20 mins and then transferred to the solution of 3,4-dichlorophenol in acetonitrile (15 ml) with DBU (22 mmol) and CuCl2.H2O (10 mg) at the same temperature over a period of about 10 mins. The reaction mixture was stirred for 2 h and then quenched with H2O. Ethyl acetate was added to extract the product twice. Organic layer was washed with brine, dried and concentrated to yield the title compound as a colorless liquid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[N+:23]([O-])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)(=O)C.[Fe]>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[NH2:23])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OCCCNc1c(N)cnc2ccccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of the product from step (i) (8.5 g), iron powder (14 g) in acetic acid was stirred at rt for 3 h the partitioned between EtOAc/water. The organics were separated, washed with saturated NaHCO3 solution, brine, dried and evaporated under reduced pressure, yield 4.85 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=3)[CH:20]=[CH:19]2)=[CH:5][CH:4]=1.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(CCl)cc1
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: COc1ccc(Cn2ccc3ccc(CC(=O)O)cc32)cc1

Procedure:
The titled compound (44 mg) as a light brown solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 4-methoxybenzyl chloride according to the method of the process (7) of Example 4.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][C@@H:12]([CH3:14])[NH:11][CH2:10][C@@H:9]2[CH3:15])[CH:5]=[N:4][CH:3]=1.[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][C@@H:12]([CH3:14])[NH:11][CH2:10][C@@H:9]2[CH3:15])[CH:5]=[N:4][CH:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@@H]1CN(c2cncc(Cl)n2)[C@@H](C)CN1
Reactant: OCc1ccccc1
Product: C[C@@H]1CN(c2cncc(OCc3ccccc3)n2)[C@@H](C)CN1
Temperature: 95 °C

Procedure:
The title compound was prepared according to the procedure of example 20, starting from 1-(6-chloro-2-pyrazinyl)-trans-2,5-dimethylpiperazine (1.23 g, 5.40 mmol; obtained in step 1 above), benzyl alcohol (8.36 g, 77.3 mmol), and K-t-BuO (1.99 g, 17.7 mmol). The reaction mixture was heated at 95° C. for 5.5 h. The yield of the title compound was 0.47 g (29%) which was obtained as an oil. Purity 99% (HPLC). MS m/z 298 (M)+. HRMS m/z calcd for C17H22N4O (M)+ 298.1794, found 298.1798.