Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH:6]1([N:9]2[C:17]3[C:12](=[C:13]([O:23][CH3:24])[CH:14]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=3)[CH:11]=[CH:10]2)[CH2:8][CH2:7]1.CN([CH:28]=[O:29])C>CCOC(C)=O.[OH-].[Na+]>[CH:6]1([N:9]2[C:17]3[C:12](=[C:13]([O:23][CH3:24])[CH:14]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=3)[C:11]([CH:28]=[O:29])=[CH:10]2)[CH2:7][CH2:8]1
Reactant: CCOC(=O)c1cc(OC)c2ccn(C3CC3)c2c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(OC)c2c(C=O)cn(C3CC3)c2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.28 ml of POCl3 was added dropwise to a solution of 3.24 g of ethyl 1-cyclopropyl-4-methoxy-1H-indole-6-carboxylate in 30 ml of DMF and the mixture was stirred at 0° C. for 2 hrs. The mixture was diluted with EtOAc and 25 ml of 1N NaOH was added. Then the mixture was made basic using saturated NaHCO3aq. The mixture was extracted with EtOAc and the extract was washed with water and saturated brine, dried over Na2SO4, then concentrated. The residue was purified on SiO2 column chromatography (EtOAc-n-Hexane system) to give 2.4 g of ethyl 1-cyclopropyl-3-formyl-4-methoxy-1H-indole-6-carboxylate.
Reaction SMILES: Cl.C(O)C.[Br:5][C:6]1[C:7]([Cl:17])=[C:8]([N+:14]([O-])=O)[CH:9]=[C:10]([F:13])[C:11]=1[F:12]>O.[Fe]>[Br:5][C:6]1[C:7]([Cl:17])=[C:8]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[NH2:14]
Reactant: O=[N+]([O-])c1cc(F)c(F)c(Br)c1Cl
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cc(F)c(F)c(Br)c1Cl
Yield: 65.9 %

Procedure:
To a suspension of iron powder (38.6 g) in water (40 ml), with stirring vigorously at 50° to 60° C., was slowly added concentrated hydrochloric acid (5 ml). After mixed with ethanol (100 ml), 3-bromo-2-chloro-4,5-difluoronitrobenzene (58.8 g) was added portionwise to the suspension at 60° to 75° C. during 30 minutes. After stirring for 70 minutes, the hot reaction mixture was filtered and the insoluble materials were washed with hot ethanol (30 ml) and with benzene (100 ml) successively. The filtrate and washings were combined and mixed with ice water. The resulting organic layer was washed with water, dried over anhydrous sodium sulfate and then concentrated. The resulting residue was purified by silica gel chromatography eluting with dichloromethane-n-hexane (1:1) to give the title compound (34.5 g) as light brown prisms, mp 83°-86° C.
Reaction SMILES: Cl.[F:2][C:3]([F:24])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[C:29]([N:33]=[C:34]=[O:35])([CH3:32])([CH3:31])[CH3:30]>C(Cl)Cl>[F:24][C:3]([F:2])([F:23])[C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:34]([NH:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1
Reactant: Fc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Reactant: CC(C)(C)N=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)NC(=O)N1CC(OC(c2ccc(F)cc2)c2ccccc2C(F)(F)F)C1
Yield: 87.4 %

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-fluorobenzhydryloxy]azetidine hydrochloride (162) (200 mg, 0.55 mmol) in anhydrous DCM (5 mL) was added MP-carbonate (3.01 mmol/g; 550 mg, 1.65 mmol) and tert-butyl isocyanate (65 μL, 0.55 mmol). The resultant mixture was shaken at ambient temperature for 16 h, after which time it was poured onto a DCM-wetted SCX-2 (1 g) cartridge. The sample was eluted with DCM (16 mL), then evaporated to afford the desired product as a colourless glass (204 mg, 87%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](Br)[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].[F:11][C:12]([F:24])([F:23])[O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[F:1][C:2]1[CH:8]=[C:7]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][C:12]([F:11])([F:23])[F:24])[CH:15]=2)[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4]
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: Nc1c(F)cc(Br)cc1F
Product: Nc1c(F)cc(-c2cccc(OC(F)(F)F)c2)cc1F
Yield: 58.5 %

Procedure:
The title compound (0.812 g) was prepared from 2,6-difluoro-4-bromo aniline (1 g, 4.8 mmol) and 3-(trifluoromethoxy)phenylboronic acid (1.28 g, 6.24 mmol) as a colourless liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]([CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][NH:17]1)[CH3:15]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:17]3[CH2:18][CH2:19][C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:16]3[CH2:14][CH3:15])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CCC1NCCc2ccccc21
Product: CCC1c2ccccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([CH:27]([CH:29]([CH3:31])[CH3:30])[NH2:28])=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)[O:10]C1(C)C)=O)(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>C(Cl)Cl>[OH:38][C:36]([C:35]([F:40])([F:39])[F:34])=[O:37].[NH2:8][C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[N:23][C:24]([CH:27]([CH:29]([CH3:31])[CH3:30])[NH2:28])=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)[OH:10]
Reactant: CC(C)C(N)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]3CF)cc2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(N)c1ccc(-c2ccc([C@@H](O)[C@H](N)CF)cc2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (4R,5R)-4-Fluoromethyl-5-{4-[6-(isopropyl amino-methyl)-pyridin-3-yl]-phenyl}-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (100 mg, 0.218 mmol) in CH2Cl2 (0.17 mL) is added trifluoroacetic acid (0.4 mL) at 0° C. Reaction mixture is allowed to stir at room temperature for 2 hours. The volatiles are removed under reduced pressure and crude material is purified by column chromatography over basic alumina using 50% methanol in CH2Cl2 as eluent to afford title compound (70 mg, impure). LC-MS (m/z): [M+H]=318.2.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:19]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1)([O-:21])=[O:20]>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:9]2[NH:27][C:26]([C:25]3[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:29][CH:28]=3)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1cccc(OC)c1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Product: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1cccc(OC)c1
Yield: 31.6 %

Procedure:
Ethyl 2-hydroxyimino-3-(3-methoxyphenyl)-3-oxopropionate (84.5 g) and 4-nitrobenzylamine (61.4 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(3-methoxyphenyl)-2-(4-nitrophenyl)imidazole-4-carboxylate (39.0 g), melting point 194-196° C.
Reaction SMILES: [H-].[Na+].[N:3]1[NH:4][N:5]=[N:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([C:36]([F:39])([F:38])[F:37])=[O:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1.Cl>CN(C)C=O.O>[F:39][C:36]([F:37])([F:38])[S:34]([C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][C:7]4[N:6]=[N:5][NH:4][N:3]=4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1)=[O:35]
Reactant: Oc1ccc(CCCCc2nn[nH]n2)cc1
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(c1ccc(/C=C/c2nc(COc3ccc(CCCCc4nn[nH]n4)cc3)co2)cc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 16.9 %

Procedure:
47.5 mg (1.88 mmol) 95% sodium hydride were given at 0° C. to a solution of 200 mg (0.916 mmol) 4-(4-2H-tetrazol-5-yl-butyl)-phenol in 5.0 ml N,N-dimethylformamide and stirred for 15 min. 308 mg (0.916 mmol) 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole were added and stirring continued at 25° C. for 2 h. The reaction mixture was neutralized with HCl, poured into water and the resulting precipitate washed with little methanol and diethyl ether. The obtained material (180 mg) was purified by chromatography on silica gel (dichloromethane/methanol 100:4) to give 80 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[CH3:11]C(C)=O.C(=O)([O-])[O-].[K+].[K+].IC>O>[CH3:11][O:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([Cl:1])=[C:3]([CH3:10])[CH:4]=1
Reactant: CC(C)=O
Reactant: Cc1cc(O)cc(C)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1cc(C)c(Cl)c(C)c1
Yield: 77 %

Procedure:
To a 1 L round-bottom flask 4-chloro-3,5-dimethylphenol 63 (20 g, 127.7 mmol) and acetone (500 mL, 0.2 M) was placed. To this solution were added potassium carbonate (35.3 g, 255.4 mmol) and iodomethane (63.44 g, 447 mmol). The reaction was stirred and heated to reflux for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by silica gel chromatography eluted with hexane to yield 4-chloro-3,5-dimethylphenyl methyl ether 64 (16.88 g, 77%). 1HNMR (300 MHz, CDCl3): δ 2.41 (s, 3H), 2.59 (s, 3H), 2.62 (s, 3H), 2.68 (s, 3H), 3.82 (s, 3H), 4.06 (s, 3H), 4.11 (s, 2H), 5.97 (d, 1H), 6.44 (s, 1H), 6.70 (s, 1H), 7.15 (d, 1H), 8.41 (brd, 1H), 10.31 (brd, 1H), APCI-MS m/z 468.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[CH2:12])[C:6]2=[O:11].[CH2:13]=[C:14]([O:17][Si](C)(C)C)[CH:15]=[CH2:16].B(F)(F)F.CCOCC>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5]1([CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]1)[C:6]2=[O:11]
Reactant: C=CC(=C)O[Si](C)(C)C
Reactant: C=C1Cc2c(F)cccc2C1=O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1CCC2(CC1)Cc1c(F)cccc1C2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
To a solution of 4-fluoro-2-methylene-2,3-dihydro-1H-inden-1-one (249b) (3.71 g, 22.9 mmol) and (buta-1,3-dien-2-yloxy)trimethylsilane (5.2 mL, 29.8 mmol) in DCM (200 mL) at 0° C., there was added BF3.Et2O (0.5 mL dropwise. The resulting solution was stirred at 0° C. for another 30 min, quenched with MeOH (0.3 mL), warmed to room temperature, acidified with 2N HCl aqueous solution (15 mL) and extracted with DCM (10 mL×4). The combined organic layers were dried over Na2SO4, filtered and evaporated, and the residue was purified by flash chromatography (0 to 50% EtOAc/Hexane) to give 4′-fluorospiro[cyclohexane-1,2′-indene]-1′,4(3′H)-dione (249c) (2.77 g, 49%). LC-MS tR=1.41 min in 3 min chromatography, MS (ESI) m/z 233 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH:15][CH2:16][CH2:17][C:18]#[N:19])=[N:12][O:13][N:14]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:26][C:27]1[CH:36]=[CH:35][C:30]([C:31](=[O:34])[CH2:32]Br)=[CH:29][CH:28]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:26][C:27]1[CH:36]=[CH:35][C:30]([C:31](=[O:34])[CH2:32][N:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=[C:2]2[C:10]2[C:11]([NH:15][CH2:16][CH2:17][C:18]#[N:19])=[N:12][O:13][N:14]=2)=[CH:29][CH:28]=1
Reactant: N#CCCNc1nonc1-c1nc2ccccc2[nH]1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#CCCNc1nonc1-c1nc2ccccc2n1CC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 4-(1H-benzimidazol-2-yl)-furazan-3-yl-N-(2-cyanoethyl)-amine (0.10 g, 0.39 mmol), potassium carbonate (0.08 g, 0.58 mmol) and 4-chlorophenacyl bromide (0.11 g, 0.47 mmol) in DMF (5 ml) is stirred at room temperature for 16 hours. The reaction mixture is diluted with ethyl acetate, washed with water and dried over sodium sulphate. Filtration of the sodium sulphate, concentration of the filtrate under reduced pressure and chromatography of the residue on silicagel using hexane-ethyl acetate as eluent gives the title compound as a yellowish solid, m.p. 191-192° C.
Reaction SMILES: [C:1](=[O:48])([O:17][C:18]1[C:19]([CH3:47])=[C:20]2[C:25](=[C:26]([CH3:29])[C:27]=1[CH3:28])[O:24][C:23]([CH3:46])([CH2:30][CH2:31][CH2:32][CH:33]([CH3:45])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:44])[CH2:38][CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])[CH2:22][CH2:21]2)[O:2][CH2:3][C:4]1([CH3:16])[O:15][CH:5]1[CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[O:49]1CCCC1.Cl(O)(=O)(=O)=O>O>[C:1](=[O:48])([O:17][C:18]1[C:19]([CH3:47])=[C:20]2[C:25](=[C:26]([CH3:29])[C:27]=1[CH3:28])[O:24][C:23]([CH3:46])([CH2:30][CH2:31][CH2:32][CH:33]([CH3:45])[CH2:34][CH2:35][CH2:36][CH:37]([CH3:44])[CH2:38][CH2:39][CH2:40][CH:41]([CH3:42])[CH3:43])[CH2:22][CH2:21]2)[O:2][CH2:3][C:4]([OH:49])([CH3:16])[CH:5]([OH:15])[CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C1CCOC1
Reactant: Cc1c(C)c2c(c(C)c1OC(=O)OCC1(C)OC1COCc1ccccc1)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Product: Cc1c(C)c2c(c(C)c1OC(=O)OCC(C)(O)C(O)COCc1ccccc1)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2

Procedure:
8.6 g (0.013 mol) of 4-benzyloxy-2,3-epoxy-2-methylbutyl 2,5,7,8-tetramethyl-2-(4',8',12'-trimethyltridecyl)-6-chromanyl carbonate, 150 ml of tetrahydrofuran and 30 ml of water were mixed together. To the obtained mixture was slowly added dropwise a solution of 7 ml of 60% perchloric acid in 20 ml of water under ice-cooling and stirring. After the completion of the addition, the mixture was further stirred at the same temperature for 4 hours and then poured into water. After confirming that no peroxide remained therein with potassium iodide starch paper, the mixture was extracted with ether. The extract was washed with water and dried. After distilling off the solvent, the obtained oily residue was purified by column chromatography (silica gel, benzene:ethyl acetate=8:2). Thus 4.8 g of the title compound was obtained as a pale yellow, viscous liquid.
Reaction SMILES: [I-:1].[Na+].Br[C:4]1[CH:5]=[CH:6][C:7]([C:12]([F:15])([F:14])[F:13])=[C:8]([CH:11]=1)[C:9]#[N:10]>O1CCOCC1.[Cu]I>[I:1][C:4]1[CH:5]=[CH:6][C:7]([C:12]([F:15])([F:14])[F:13])=[C:8]([CH:11]=1)[C:9]#[N:10]
Reactant: N#Cc1cc(Br)ccc1C(F)(F)F
Reactant: [I-]
Agent: [Cu]I
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1cc(I)ccc1C(F)(F)F
Reaction time: 0.17 h

Procedure:
In a microwave vial 2.24 g 5-bromo-2-(trifluoromethyl)benzonitrile are dissolved in 10 ml 1,4-dioxane. 90 mg copper-(I)-iodide and 2.7 g sodium iodide are added and the mixture is purged for 5 minutes with argon. 142 μl trans-N,N′-dimet6hylcyclohexane-1,2-diamine and 1.9 ml hexamethyldisilazane are added and the mixture is heated for 6 hours to 110° C. The mixture is diluted in 100 ml 4 M hydrochloric acid and stirred for 10 minutes. This aqueous phase is three times extracted with dichloromethane. The combined organic phases are washed with brine and dried with magnesium sulphate. The solvents are evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethylacetate 85:15).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1([CH3:16])[CH2:13][C:12](=[O:14])[O:11][C:10]1=[O:15].[Al]>ClC(Cl)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:12](=[O:14])[CH2:13][C:9]([CH3:16])([CH3:8])[C:10]([OH:15])=[O:11])=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: CC1(C)CC(=O)OC1=O
Agent: [Al]
Solvent: CC(Cl)Cl
Product: CC(C)(CC(=O)c1ccc(Br)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
To a chilled solution (ice/water bath) of bromobenzene (7.71 g, 49.1 mmol) and 3,3-dimethyldihydro-2,5-furandione (5.99 g, 46.7 mmol) in dichloroethane (150 mL) was added aluminum trichworide (13.28 g, 99.58 mmol). The ice bath was removed and the reaction mixture was stirred at rt overnight. The mixture was again chilled in an ice/water bath, and then quenched with 1 M aqueous hydrochloric acid. Water (70 mL) was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage apparatus, 17:83 ethyl acetate/hexane) to give 4-(4-bromophenyl)-2,2-dimethyl-4-oxobutanoic acid as a white solid (8.34 g, 63%). LC-MS: ret. time 2.79 min; m/z 284.8 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.36 (s, 6H), 3.27 (s, 2H), 7.60 (d, 2H), 7.81 (d, 2H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:6]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:3].Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][NH:26]2.CCN(C(C)C)C(C)C>C(O)CCC>[N:30]1[C:22]([NH:1][C@H:2]([C:4]2[N:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:7]=3[N:8]=2)[CH3:3])=[C:23]2[C:27]([NH:26][CH:25]=[N:24]2)=[N:28][CH:29]=1
Reactant: C[C@H](N)c1nc2ccc(C#N)cc2n1-c1ccccc1
Reactant: Clc1ncnc2[nH]cnc12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(C#N)cc2n1-c1ccccc1
Temperature: 120 °C
Reaction time: 6 h
Yield: 37.6 %

Procedure:
A mixture of 2-((S)-1-aminoethyl)-3-phenyl-3H-benzoimidazole-5-carbonitrile from Example 11 (370 mg, 1.4 mmol), 6-chloro-9H-purine (217 mg, 1.4 mmol) and DIPEA (0.36 mL, 2.1 mmol) in n-butanol (2.8 mL) was stirred in a sealed tube for 6 h at 120° C. After cooling to RT, the crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in EtOAc followed by gradient 0-10% 2M NH3/MeOH in DCM) affording 122 as a white solid (200 mg, 37%). LCMS: RT 3.29 min [M+H]+ 381.1. 1H NMR (DMSO, 400 MHz): δ 8.21-7.97 (3H, m), 7.84 (1H, d, J=8.35 Hz), 7.72-7.46 (7H, m), 5.49 (1H, br), 1.59 (3H, d, J=6.87 Hz)
Reaction SMILES: [CH3:1][C:2]1([CH3:41])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([F:40])=[C:16]([NH:18][C:19]([C:21]2[N:25]3[CH:26]=[CH:27][C:28]([C:30]4[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[C:32]([F:39])[CH:31]=4)=[CH:29][C:24]3=[N:23][CH:22]=2)=[O:20])[CH:17]=1)=[O:11].[NH2:42][C:43]([CH3:47])([CH3:46])[CH2:44][OH:45]>>[CH3:1][C:2]1([CH3:41])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]([F:40])=[C:16]([NH:18][C:19]([C:21]2[N:25]3[CH:26]=[CH:27][C:28]([C:30]4[CH:38]=[CH:37][C:33]([C:34](=[O:36])[NH:42][C:43]([CH3:47])([CH3:46])[CH2:44][OH:45])=[C:32]([F:39])[CH:31]=4)=[CH:29][C:24]3=[N:23][CH:22]=2)=[O:20])[CH:17]=1)=[O:11]
Reactant: CC1(C)CCCN1CCNC(=O)c1ccc(F)c(NC(=O)c2cnc3cc(-c4ccc(C(=O)O)c(F)c4)ccn23)c1
Reactant: CC(C)(N)CO
Product: CC(C)(CO)NC(=O)c1ccc(-c2ccn3c(C(=O)Nc4cc(C(=O)NCCN5CCCC5(C)C)ccc4F)cnc3c2)cc1F

Procedure:
The title compound was prepared analogously to Example 7.4 from 4-(3-(5-(2-(2,2-dimethylpyrrolidin-1-yl)ethylcarbamoyl)-2-fluorophenylcarbamoyl)imidazo[1,2-a]pyridin-7-yl)-2-fluorobenzoic acid (step 3) and 2-amino-2-methylpropan-1-ol;
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.Cl[CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36]>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([F:14])=[CH:8][C:7]=2[C:15]2[C:16]3[N:23]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:22]([CH3:24])=[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3cc(F)c(OC)cc3OCC3CC3)ncnc12
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(F)c(OC)cc3OCC3CC3)ncnc12

Procedure:
Starting from ethyl 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example D.a12) and commercially available (2-chloromethoxy-ethyl)-trimethyl-silane the title compound is obtained as yellow viscous oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][C:18]([O:27][CH:28]([CH3:30])[CH3:29])=[C:19]([N+:24]([O-:26])=[O:25])[CH:20]=3)[CH:15]2[OH:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:15](=[O:31])[C:16]3[C:21](=[CH:20][C:19]([N+:24]([O-:26])=[O:25])=[C:18]([O:27][CH:28]([CH3:29])[CH3:30])[CH:17]=3)[C:22]2=[O:23])[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)Oc1cc2c(cc1[N+](=O)[O-])C(=O)N(C1CCN(C(=O)OC(C)(C)C)CC1)C2O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Oc1cc2c(cc1[N+](=O)[O-])C(=O)N(C1CCN(C(=O)OC(C)(C)C)CC1)C2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the solution of 4-(1-hydroxy-6-isopropoxy-5-nitro-3-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester from the previous step (173.9 mg, 0.4 mmol) in DMF (4 mL) is added pyridinum dichromate (286.5 mg, 0.8 mmol) in one portion. After stirring at room temperature for 2 h, the reaction mixture is poured into 25 mL of water and the product is extracted with EtOAc. The organic extracts are dried over Na2SO4, filtered and concentrated in vacuo to give crude 4-(5-isopropoxy-6-nitro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester, which is directly used in the next step without further purification.
Reaction SMILES: Br[C:2]1[C:3]([NH2:10])=[N:4][C:5]([Cl:9])=[C:6]([Br:8])[N:7]=1.[Br-].C([O:14][C:15](=O)[CH2:16][CH2:17][Zn+])C>C1COCC1.O>[Br:8][C:6]1[N:7]=[C:2]2[CH2:17][CH2:16][C:15](=[O:14])[NH:10][C:3]2=[N:4][C:5]=1[Cl:9]
Reactant: CCOC(=O)CC[Zn+]
Reactant: Nc1nc(Cl)c(Br)nc1Br
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCc2nc(Br)c(Cl)nc2N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture comprising 3,5-dibromo-6-chloropyrazin-2-amine (step 1) (1.0 g, 3.48 mmol) and bistriphenylphosphinepalladium(II)chloride (0.122 g, 0.174 mmol) in THF (15 ml) under nitrogen was treated with (3-ethoxy-3-oxopropyl)zinc(II) bromide 0.5 M in THF (15.31 ml, 7.66 mmol) and the mixture was stirred at room temperature for 3 hours. A further portion of (3-ethoxy-3-oxopropyl)zinc(II) bromide 0.5 M in THF (7.5 mL, 3.8 mmol) was added and stirring continued for 1.5 hours. More (3-ethoxy-3-oxopropyl)zinc(II) bromide 0.5 M in THF (3.8 mL, 1.9 mmol) was added and the mixture was stirred at RT for 65 hours. The mixture was diluted with water (10 ml) and concentrated in vacuo. The residue was diluted with EtOAc (100 ml) the emulsion was filtered through Celite® (filter material). The phases were separated and the aqueous portion was extracted with EtOAc (50 ml). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was triturated with EtOAc (˜10 ml) to afford the title compound as yellow solid.