Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:8][C:9](=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[N:1]1([CH2:17][C:14]2[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][OH:8])=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: COC(=O)Cc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: OCCc1ccc(CN2CCCCC2)cc1
Reaction time: 8 h

Procedure:
A solution of piperidine (204 mg) and (4-formylphenyl)acetic acid methyl ester (Example 16, step a, 356 mg) in dichloromethane (10 mL) was stirred for 1 hour, treated with sodium triacetoxyborohydride (636 mg) and stirred overnight. The resultant mixture was loaded onto a conditioned SCX cartridge (10 g, Varian) and washed with methanol (50 mL), then eluted with methanolic ammonia solution (50 mL). The elution fraction was evaporated and the residue was dissolved in ethanol (20 mL), treated with anhydrous calcium chloride (444 mg), followed by sodium borohydride (303 mg) and stirred overnight. The mixture was quenched with aqueous potassium carbonate solution (2M, 20 mL) and concentrated to remove most of the ethanol. The residue was extracted with ethyl acetate and the washed and dried (sodium sulfate) extract was evaporated. The residue was purified on silica, eluting with 5% triethylamine in diethyl ether to give the subtitle product, as a colourless oil (287 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: O=C(O)c1cc(I)ccc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(I)ccc1Br
Temperature: 60 °C
Reaction time: 60 h

Procedure:
To a solution of 2-bromo-5-iodobenzoic acid (2-1), 5.0 g, 15.3 mmol, 1.0 equiv) in methanol (45 mL) was added sulfuric acid (1.06 mL, 19.9 mmol, 1.3 equiv). The reaction mixture was stirred for 60 hours at 60° C., then heated to reflux and stirred 24 hours more. The reaction mixture was cooled, partitioned between EtOAc and saturated sodium bicarbonate solution. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated to afford the product (2-2) as a white solid. ESI+ MS [M]+ C8H6BrIO2: 340.7 found, 340.9 required.
Reaction SMILES: [Br:1]Br.[Cl:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)=[O:8]>C(Cl)Cl>[Br:1][CH:6]([C:7]([C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)=[O:8])[CH2:5][CH2:4][Cl:3]
Reactant: BrBr
Reactant: O=C(CCCCl)c1ccc(Cl)cc1
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)C(Br)CCCl
Temperature: 10 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
A solution of 358 g of bromine in 350 ml of methylene chloride is added dropwise to a solution of 483 g (2.23 mols) of 4-chlorophenyl 3-chloropropyl ketone in 1200 ml of methylene chloride at 20° C. Stirring is continued for one hour and the mixture is then evaporated down in vacuo. 300 ml of petroleum ether are added to the residue, and stirring is continued until crystallization is complete. The mixture is cooled to 10° C., and the precipitate is filtered off under suction. 582 g (88.3% of theory) of 4-chlorophenyl 1-bromo-3-chloropropyl ketone of melting point 73° C. are obtained.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12](S(C)=O)[N:11]=[C:10]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:20]3)[CH:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[CH:36][C:5]=2[N:4]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.CN(C)C(=O)C>O>[F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[N:11]=[C:10]([O:17][CH2:18][CH:19]3[CH2:24][CH2:23][N:22]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH2:20]3)[CH:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[CH:36][C:5]=2[N:4]=1
Reactant: CS(=O)c1nc(OCC2CCN(NC(=O)OC(C)(C)C)CC2)cc(-n2c(C(F)F)nc3ccccc32)n1
Reactant: C1COCCN1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)NN1CCC(COc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 4-[({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(methylsulfinyl)pyrimidin-4-yl}oxy)methyl]piperidine-1-carbamate (240 mg), morpholine (0.3 mL), and N,N-dimethylacetamide (2 mL) was stirred at room temperature for 1 hour. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30-50:50) to obtain tert-butyl 4-[({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)methyl]piperidine-1-carbamate (246 mg) as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][O:23][Si](C(C)(C)C)(C)C)([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][C:33]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.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>[Cl:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][C:33]=1[C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][OH:23])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2cnccc2Cl)OC1(C)C
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)cc4)CC3)n2CCS1
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: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5cnccc5Cl)cc4)CC3)n2CCS1
Temperature: 25 °C
Reaction time: 16 h
Yield: 31.6 %

Procedure:
A solution of the compound (508 mg, 1.0 mmol) obtained in Example 16-4), 4-chloropyridine-3-boronic acid pinacol ester (366 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was partially purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient). This partially purified product was dissolved in a solution of 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) in methanol (4 mL), and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (135 mg, 32%) as a colorless solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([OH:14])=O.[NH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2[CH:22]=[CH:23][CH:24]=[CH:25][C:16]1=2>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([N:15]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2[CH:22]=[CH:23][CH:24]=[CH:25][C:16]1=2)=[O:14]
Reactant: c1ccc2c(c1)CCCCN2
Reactant: O=C(O)CSc1nc2ccccc2s1
Product: O=C(CSc1nc2ccccc2s1)N1CCCCc2ccccc21
Yield: 23 %

Procedure:
The title compound was synthesized according to General Procedure B using 2-(benzo[d]thiazol-2-ylthio)acetic acid and 2,3,4,5-tetrahydro-1H-benzo[b]azepine (6) to yield 45 as a white solid (23%): MS m/z: 355 (M+H)+. Anal. Calcd. For, C19H18N2OS2: C, 64.38; H, 5.12; N, 7.90; S, 18.09. Found: C, 64.53; H, 5.06; N, 7.83; S, 17.93.
Reaction SMILES: [Cl-].C([Al+]CC)C.[Br:7][C:8]1[N:9]=[C:10]2[CH:16]=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1.[C:17]([CH2:19][CH2:20][CH2:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=[O:24])#[N:18].C([O-])(O)=O.[Na+]>ClCCl.C(OCC)(=O)C>[Br:7][C:8]1[N:9]=[C:10]2[C:16]([C:23](=[O:24])[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][CH2:19][C:17]#[N:18])=[CH:15][NH:14][C:11]2=[N:12][CH:13]=1
Reactant: CC(C)(CCCC#N)C(=O)Cl
Reactant: Brc1cnc2[nH]ccc2n1
Agent: CC[Al+]CC
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(CCCC#N)C(=O)c1c[nH]c2ncc(Br)nc12
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
Diethylaluminum chloride (1.0 M in CH2Cl2, 3.6 mL, 3.6 mmol) was added to a 0-5° C. mixture of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (0.237 g, 1.20 mmol) and 5 mL of dichloromethane in a sealed tube, and the mixture was stirred at 0-5° C. for 30 min. Crude 5-cyano-2,2-dimethyl-pentanoyl chloride from the previous step (“2.98 mmol”) dissolved in 3 mL of dichloromethane was added, and the mixture was stirred at 60° C. for 16 h. A sat. aq. NaHCO3 solution (50 mL) was carefully added, followed by 50 mL of ethyl acetate. The mixture was filtered through Celite, and the layers separate. The aqueous layer was extracted with 50 mL of ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated to a residue. Column chromatography (0→80% EtOAc/hexanes) afforded 0.079 g (20%) of 6-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-5,5-dimethyl-6-oxo-hexanenitrile as a yellow liquid.
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:23]([O:25]C)=[O:24])[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])(=[O:3])[CH3:2]>C(O)(=O)C.Cl>[C:1]([NH:4][C@H:5]([C:23]([OH:25])=[O:24])[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)[C@H](CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)NC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)N[C@@H](CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(=O)O
Reaction time: 1 h

Procedure:
The product from Example 9d (2.1 mmol, 800 mg) was diluted with acetic acid (2 mL) and concentrated hydrochloric acid (2 mL) and warmed to 7zero degrees C. for one hour. The reaction mixture was concentrated, and azeotroped with toluene (3×5 mL), affording the title compound as a solid (quant.). MS MH+ calcd. for C17H17NO6S 364, found 364. DSC 1 degree C./minute: 193.0-195.1. The product was characterized spectroscopically.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:36]([OH:38])=[O:37])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([O:27]CC4C=CC=CC=4)=[C:22]([CH3:35])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=2[NH:3]1.[H][H]>C(Cl)Cl.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:36]([OH:38])=[O:37])[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH3:35])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=2[NH:3]1
Reactant: [H][H]
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: ClCCl
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Temperature: 25 °C

Procedure:
3.72 g (6.51 mmol) of (R)-2-(4-benzyloxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 50 mL DCM were combined with 300 mg 10% Pd/C and shaken at RT and 3 bar hydrogen until the reaction came to a stop. The catalyst was suction filtered and the solvent was evaporated down i. vac. The residue was triturated with DIPE and suction filtered.
Reaction SMILES: C1C(=O)N(O[C:9]([C:11]2[CH:16]=[CH:15][C:14]([N:17]=[N+:18]=[N-:19])=[CH:13][CH:12]=2)=[O:10])C(=O)C1.[NH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27]>C1COCC1>[N:17]([C:14]1[CH:13]=[CH:12][C:11]([C:9]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])=[O:10])=[CH:16][CH:15]=1)=[N+:18]=[N-:19]
Reactant: NCCCCCCN
Reactant: [N-]=[N+]=Nc1ccc(C(=O)ON2C(=O)CCC2=O)cc1
Solvent: C1CCOC1
Product: [N-]=[N+]=Nc1ccc(C(=O)NCCCCCCN)cc1
Reaction time: 8 h

Procedure:
2.6 g (10 mmol) HSAB 1 are dissolved in 70 ml THF and dropwise added to solution of 11.62 g (100 mmol) of hexamethylene diamine in THF under stirring and cooled on ice. Subsequently, the ice bath is removed and the temperature is allowed to adjust to room temperature. The solvent is drawn off on the rotation evaporator and excess hexymethylene diamine is removed in a high vacuum as far as possible. The remaining raw product is digested for 20 min in 100 ml of water and subsequently dried overnight in an exsiccator. Product 2b is a slightly yellow to brown solid material.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1.C([Li])CCC.N([F:49])(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O>C1COCC1>[CH2:16]([CH:15]([NH:14][C:11]1[CH:10]=[C:9]([CH3:20])[N:8]=[C:7]([O:6][C:5]2[C:21]([CH3:23])=[CH:22][C:2]([F:49])=[CH:3][C:4]=2[CH3:24])[C:12]=1[CH3:13])[CH2:18][CH3:19])[CH3:17]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(F)cc2C)c1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of [2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added n-butyllithium at −78° C. After stirring at −78° C. for 10 min, (PhSO2)2NF was added and the resulting mixture was stirred at −78° C. for 30 min, the dry-ice bath was removed. After stirring for 5 min, the mixture was quenched with brine and extracted with ethyl acetate. The organic layer was separated, dried, and concentrated to dryness. The residue was purified through silica gel chromatography to give the title compound. 1H NMR(CDCl3) d 6.77(s,1H), 6.73(s,1H), 6.08(s,1H), 3.3(m,1H), 2.12(s,3H), 2.09(s,6H), 2.08(s,3H), 1.4–1.8(m,4H), 0.97(t,6H)ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH3:10])[C:3]=1[C:11]([F:14])([F:13])[F:12].[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[CH2:17].C(N(CC)CC)C>CC([O-])=O.CC([O-])=O.[Pd+2].CN(C)C=O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2](/[CH:17]=[CH:16]/[C:15]([O:19][CH2:20][CH3:21])=[O:18])=[C:3]([C:11]([F:14])([F:13])[F:12])[C:4]=1[CH3:10]
Reactant: COc1ccc(Br)c(C(F)(F)F)c1C
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1ccc(OC)c(C)c1C(F)(F)F
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed 1-bromo-4-methoxy-3-methyl-2-(trifluoromethyl)benzene (300 mg, 1.12 mmol, 1.00 equiv), ethyl prop-2-enoate (560 mg, 5.59 mmol, 5.02 equiv), P(Tol)3 (61 mg, 0.20 mmol, 0.18 equiv), Pd(OAc)2 (30 mg, 0.13 mmol, 0.12 equiv), triethylamine (566 mg, 5.59 mmol, 5.02 equiv), N,N-dimethylformamide (2.0 mL). The resulting solution was stirred overnight at 110° C. in an oil bath. The reaction progress was monitored by GCMS. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×15 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×20 mL of H2O. The mixture was dried over anhydrous sodium sulfate. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:6). This resulted in 0.16 g (50%) of ethyl (2E)-3-[4-methoxy-3-methyl-2-(trifluoromethyl)phenyl]prop-2-enoate as a yellow solid.
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)([O-:5])=[O:4].[CH3:11][O:12][C:13]([C:15]1[O:16][C:17]([CH2:20]Cl)=[CH:18][CH:19]=1)=[O:14].C([O-])([O-])=O.[K+].[K+].[Br-]>CC(C)=O>[CH3:11][O:12][C:13]([C:15]1[O:16][C:17]([CH2:20][N:8]2[CH:7]=[C:6]([N+:3]([O-:5])=[O:4])[CH:10]=[N:9]2)=[CH:18][CH:19]=1)=[O:14]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: COC(=O)c1ccc(CCl)o1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(Cn2cc([N+](=O)[O-])cn2)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-nitro-1H-pyrazole (6.22 g, 55.0 mmol) in acetone (130 mL) was treated with 5-chloromethyl-furan-2-carboxylic acid methyl ester (9.61 g, 55.0 mmol) followed by K2CO3 (38.04 g, 275.2 mmol) and TBA bromide (3.55 g, 11.0 mmol). The reaction mixture was stirred at rt for 2 h before being quenched with water (500 mL), extracted with EA (3×100 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound as a yellowish solid. TLC: rf (50:50 hept-EA)=0.35. LC-MS-conditions 02: tR=0.88 min. 1H NMR (400 MHz, CDCl3) δ 3.91 (s, 3H), 5.39 (s, 2H), 6.59 (d, J=3.3 Hz, 1H), 7.17 (d, J=3.3 Hz, 1H), 8.09 (s, 1H), 8.23 (s, 1H).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([F:12])[C:9]=1[CH:10]=[O:11].O>CO>[F:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([F:12])[C:9]=1[CH2:10][OH:11]
Reactant: O=Cc1c(F)cncc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1c(F)cncc1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
NaBH4 (0.0788 g, 2.08 mmol) was dissolved in 3.2 mL MeOH(H2-formation). At 0° C. a solution of 3,5-difluoropyridine-4-carbaldehyde (0.200 g, 1.40 mmol) in 0.8 mL MeOH was added dropwise (H2-formation). The reaction mixture was stirred 5 h at rt. Water was added dropwise and the mixture was extracted 3 times with EtOAc. The combined organic phases were washed with brine. The organic phase was dried with Na2SO4, filtrated and the filtrate evaporated. The desired product was obtained as a white solid (203 mg),
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:57][N:58]1[CH2:63][CH2:62][N:61]([NH2:64])[CH2:60][CH2:59]1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:64][N:61]5[CH2:62][CH2:63][N:58]([CH3:57])[CH2:59][CH2:60]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCN(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NN2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 4-methylpiperazin-1-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.59-1.64 (m, 4 H) 1.67-1.75 (m, 2 H) 1.89-1.97 (m, 2 H) 2.79 (d, J=4.6 Hz, 3 H) 3.11-3.30 (m, 6 H) 3.32 (s, 3 H) 3.44 (d, J=12.6 Hz, 2 H) 3.93 (s, 3 H) 4.09 (t, J=13.9 Hz, 2 H) 4.76-4.81 (m, 1 H) 7.46 (d, J=8.3 Hz, 1 H) 7.48 (s, 3 H) 8.24 (d, J=8.34 Hz, 1 H) 8.27 (s, 1 H) 9.79 (s, 1 H). Melting point: 168-174° C. [M+H] calc'd for C26H34F2N8O3, 545; found 545.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]([CH3:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:15].[C:30](Cl)(=[O:32])[CH3:31].C(OC(=O)C)(=O)C>O1CCCC1.C(N(CC)CC)C.CO>[C:30]([N:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]([CH3:29])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:14]([C:5]1[C:6]([C:10]([F:13])([F:11])[F:12])=[N:7][N:8]([CH3:9])[C:4]=1[F:3])=[O:15])(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: CC(CC(C)(C)C)c1ccccc1NC(=O)c1c(C(F)(F)F)nn(C)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N(C(=O)c1c(C(F)(F)F)nn(C)c1F)c1ccccc1C(C)CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.6 %

Procedure:
At room temperature, 56.0 mg (2.3 mmol) of sodium hydride are added to a solution of 300.0 mg (0.78 mmol) of 5-fluoro-1-methyl-3-(trifluoromethyl)-N-[2-(1,3,3-trimethylbutyl)phenyl]-1H-pyrazole-4-carboxamide in 10.0 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature for 15 min, and 366.6 mg (4.7 mmol) of acetyl chloride and 2.2 g (21.2 mmol) of acetic anhydride are added. After 16 h of heating under reflux, the reaction mixture is added to 100 ml of methanol and 3 ml of triethylamine, and the mixture is filtered and concentrated under reduced pressure. Recrystallization from cyclohexane gives 182 mg (54.7% of theory) of N-acetyl-5-fluoro-1-methyl-3-(trifluoromethyl)-N-[2-(1,3,3-trimethylbutyl)phenyl]-1H-pyrazole-4-carboxamide of log P (pH 2.3)=4.63.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].Cl.C(O[C:11](=[NH:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])C>C(O)C>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:11](=[NH:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CN(C)CCN
Reactant: CCOC(=N)CC(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC(=N)NCCN(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N,N-dimethyl-1,2-diaminoethane (8.8 g, 0.1 mmol) in absolute ethanol (40 ml) is added ethyl 3-ethoxy-3-iminopropionate hydrochloride (20.0 g, 0.1 mmol). After stirring at ambient temperature for 16 hours, evaporated solvent and dissolved residue in water, made basic with sodium carbonate and extracted product into methylene chloride. This solution is evaporated to dryness to give 17 g of crude viscous title A product.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1.I[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.Br.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[CH:31][C:32]3[N:33]([CH:35]=[C:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:37]=3)[CH:34]=2)O1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:29]1[CH:30]=[CH:31][C:32]2[N:33]([CH:35]=[C:36]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:37]=2)[CH:34]=1
Reactant: CCOC(=O)c1cn2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Reactant: Ic1ccccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Br
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cn2cc(-c3ccccn3)ccc2n1
Temperature: 110 °C
Yield: 55.5 %

Procedure:
A mixture of 3.18 g of caesium carbonate, 25 mL of dioxane, 9.3 mL of water, 500 mg of 2-iodopyridine, 89 mg of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium and 848 mg of ethyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridine-2-carboxylate hydrobromide (1:1) is heated for 2 hours at 110° C., and then partially concentrated, diluted with dichloromethane and filtered. The organic phase is washed with water and dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The residue is chromatographed on a silica cartridge, eluting with a mixture of dichloromethane and cyclohexane (80/20). The fractions containing the expected product are combined and concentrated to dryness under reduced pressure to give 317 mg of ethyl 6-(pyrid-2-yl)imidazo[1,2-a]pyridine-2-carboxylate in the form of a brown oil.