Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)=[C:7]([CH3:20])[C:6]=1[CH3:21].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:18])=[CH:13][CH:12]=2)=[C:7]([CH3:20])[C:6]=1[CH3:21]
Reactant: Cc1c(OCCO)ccc(-c2ccc(C(=O)O)cc2)c1C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(OCCO)ccc(-c2ccc(C(=O)OCc3ccccc3)cc2)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-bromo-2,3-dimethylphenoxy)ethanol (0.531 g), 4-carboxyphenylboronic acid (0.360 g), tetrakis-(triphenylphosphine)palladium(0) (0.125 g), cesium fluoride (1.645 g), water (2 mL), ethanol (2 mL) and 1,4-dioxane (8 mL) was stirred at 80° C. for 3 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to afford 4′-(2-hydroxyethoxy)-2′,3′-dimethylbiphenyl-4-carboxylic acid (0.62 g) as a crude product. A mixture of the crude 4′-(2-hydroxyethoxy)-2′,3′-dimethylbiphenyl-4-carboxylic acid, benzyl bromide (0.445 g), and potassium carbonate (0.450 g) in N,N-dimethylformamide (20 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to afford the title compound (0.033 g).
Reaction SMILES: Cl[C:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][CH2:5][CH:6]([CH3:15])[CH2:7][CH:8]=[CH:9][C:10]([CH3:14])=[CH:11][CH2:12]Br.BrCC=C(C)C=CCC(C)CCC=C(C)C.C1C=CC=CC=1.[CH2:40]([NH:42][CH2:43][CH3:44])[CH3:41]>C(Cl)Cl>[CH2:40]([N:42]([CH2:12][CH:11]=[C:10]([CH3:14])[CH:9]=[CH:8][CH2:7][CH:6]([CH3:15])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:17])[CH3:16])[CH2:43][CH3:44])[CH3:41]
Reactant: CC(C=CCC(C)CCCC(C)(C)Cl)=CCBr
Reactant: CCNCC
Agent: CC(C)=CCCC(C)CC=CC(C)=CCBr
Solvent: c1ccccc1
Solvent: ClCCl
Product: CCN(CC)CC=C(C)C=CCC(C)CCC=C(C)C

Procedure:
Five grams of 1 bromo-3,7,11-trimethyldodeca-2,4,10-triene in 25 ml. of benzene is mixed with 4 g. of diethylamine and the mixture stirred for about three hours. Methylene chloride (50 ml.) is added and the mixture washed with dilute sodium hydroxide and then water and evaporated to yield N,N-diethyl 3,7,11-trimethyldodeca-2,4,10-trienylamine.
Reaction SMILES: [CH:1](=[C:8]1[CH:13]2[C:14]([CH3:16])([CH3:15])[C:10]([CH2:17][S:18]([O-:21])(=[O:20])=[O:19])([CH2:11][CH2:12]2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].Cl>O>[CH:1](=[C:8]1[CH:13]2[C:14]([CH3:16])([CH3:15])[C:10]([CH2:17][S:18]([OH:21])(=[O:20])=[O:19])([CH2:11][CH2:12]2)[C:9]1=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)C2CCC1(CS(=O)(=O)[O-])C(=O)C2=Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2=Cc1ccccc1
Yield: 81.7 %

Procedure:
20 g of the sodium salt of Example 8 are dissolved with heating in 200 ml of water. 100 ml of concentrated hydrochloric acid are then added with stirring. The precipitate obtained is filtered and dried in a dessicator in the presence of potash and phosphoric anhydride. Thus, 15.3 g of a white powder, melting at 124° C., are obtained. This product contains a mole of crystallization water.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]3[N:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]5[NH:23][C:24]([NH:32][C:19]=5[CH:18]=4)=[C:25]4[CH:31]=[CH:30][C:28](=[O:29])[CH:27]=[CH:26]4)[NH:16][C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.[Si]([N:40]1[C:44](=[O:45])[C:43]([Br:46])=[C:42]([Br:47])[C:41]1=[O:48])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]3[N:14]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]5[NH:23][C:24]([NH:32][C:19]=5[CH:18]=4)=[C:25]4[CH:31]=[CH:30][C:28](=[O:29])[CH:27]=[CH:26]4)[NH:16][C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.[CH2:15]([N:40]1[C:41](=[O:48])[C:42]([Br:47])=[C:43]([Br:46])[C:44]1=[O:45])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C(Br)=C(Br)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN1CCN(c2ccc3nc(-c4ccc5c(c4)NC(=C4C=CC(=O)C=C4)N5)[nH]c3c2)CC1
Agent: [F-]
Product: O=C1C(Br)=C(Br)C(=O)N1Cc1ccccc1

Procedure:
As depicted in Scheme I, bisbenzimidazolomaleimide (3) was synthesized in an economical fashion from readily available precursors in two steps by condensing deprotonated bisbenzimidazole (4) with N-TBDMS-2,3-dibromomaleimide (6a) followed by deprotection with TBAF to afford 3. Lactam 4 was obtained by condensing deprotonated bisbenzimidazole 5 with N-benzyl-2,3-dibromomaleimide 7, yielding 9, followed by a reduction and deprotection sequence, as shown in Scheme 1.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[C:11](=[O:17])[NH:10][CH2:9][CH2:8]2.Br[CH2:19][CH2:20][CH2:21][Cl:22]>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[C:11](=[O:17])[N:10]([CH2:19][CH2:20][CH2:21][Cl:22])[CH2:9][CH2:8]2
Reactant: ClCCCBr
Reactant: COc1cc2c(cc1OC)C(=O)NCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C(=O)N(CCCCl)CC2
Temperature: 80 °C

Procedure:
2.1 gm (44 millimols) of sodium hydride were added to a solution of 8.0 gm (41 millimols) of 6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one in 100 ml of dimethyl formamide, and the mixture was heated at 80° C. for 30 minutes. Then, 20 ml of 1-bromo-3-chloro-propane were added dropwise, and the mixture was heated at 100° C. for 3 hours. The solvent was then removed in vacuo, the solid residue was digested in water, and the aqueous mixture was extracted with chloroform several times. The combined organic extracts were dried over sodium sulfate and evaporated to dryness, and the evaporation residue was purified by chromatography on silica gel (chloroform/methanol = 150/l), yielding 3.2 gm of 1-(6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl)-3-chloro-propane as a viscous oil having an Rf -value of 0.8 (ethyl acetate).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]#[C:17][Si](C)(C)C)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.O1CCCC1.Cl>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][C:10]([C:16]#[CH:17])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(=O)c2cc(C#C[Si](C)(C)C)ccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1ccc2[nH]c(CCCC)nc(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a solution of 0.70 g of 2-butyl-6-[(trimethylsilyl)ethynyl]-4(1H)-quinazolinone in 20 ml of methanol and 20 ml of tetrahydrofuran is added 10.0 ml of 1.0N sodium hydroxide solution. The reaction is stirred at room temperature for 2 hours and then diluted with 5% hydrochloric acid solution until the pH is 2. The resulting tan precipitate is collected filtration and dried in vacuo to yield 0.50 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:10]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]2[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH:29]3[O:31][CH2:30]3)=[CH:24][CH:25]=2)[C:10]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: ClCC1CO1
Reactant: COc1ccc(C(c2ccc(O)cc2)c2cccc3c2CCCC3)cc1
Product: COc1ccc(C(c2ccc(OCC3CO3)cc2)c2cccc3c2CCCC3)cc1
Temperature: 110 °C

Procedure:
A mixture of (4-methoxyphenyl)-(4-hydroxyphenyl)-5,6,7,8-tetrahydronaphth-1-yl-methane (450 mg, 0.0013 mol) anhydrous K2CO3 (2.8 gm, 1.44 mmol), epichlorohydrin (20 ml) was refluxed at 100-120° C. for 12 hrs. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with water, dried over sodium sulphate and concentrated to give an oil. The oil was chromatographed over silica gel using 20% hexane:chloroform as the eluent to give the desired compound as an oil. Yield 410 mg (78.39%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1ccc(F)cc1
Reaction time: 24 h

Procedure:
A mixture of 4-fluorobenzoic acid (4.9 g, 35.3 mmol), benzyl bromide (3.8 mL, 31.7 mmol), and cesium carbonate (17.2 g, 53 mmol) in DMF (50 mL) at room temperature was stirred for 24 hours, diluted with water, and extracted with diethyl ether. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (DCI) m/e 248 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][CH:10]([OH:13])[CH2:11]Cl)[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].Cl.[CH2:15]([NH2:19])[CH2:16][C:17]#[CH:18].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:15]([NH:19][CH2:11][CH:10]([OH:13])[CH2:9][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2])[CH2:16][C:17]#[CH:18]
Reactant: C#CCCN
Reactant: O=[N+]([O-])c1nccn1CC(O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CCCNCC(O)Cn1ccnc1[N+](=O)[O-]
Yield: 70.5 %

Procedure:
A mixture of 5 (2.67 g, 13.1 mmol), but-3-ynylamine HCl salt (2.76 g, 26.2 mmol) and potassium carbonate (3.62 g) in 40 ml of methanol was refluxed for 5 h. After the workup, the residue was purified by column chromatography (THF-EtOH=9:0.5) to give 2.2 g of yellow solid (6, 70% yield). 1H NMR (DMSO-d6, δppm): 2.26 (dt, 2H, ≡C—CH2—, J=7.2 Hz, 2.7 Hz), 2.50 (d, 2H, J=5.7 Hz), 2.63 (t, 2H, J=7.2 Hz), 2.78 (t, 1H, CH≡C—, J=2.7 Hz), 3.82 (m, 1H, HO—CH—), 4.25 (dd, 1H, imidazole-CHa—, J=13.8 Hz, 8.4 Hz), 4.54 (dd, 1H, imidazole-CHb—, J=13.8 Hz, 3.6 Hz), 5.13 (d, 1H, OH, J=5.1 Hz), 7.13 (s, 1H, —CH═), 7.55 (s, 1H, —CH═). 13C NMR (DMSO-d6, δppm): 18.80, 47.79, 52.04, 52.89, 68.09, 71.60, 82.87, 126.98, 128.19, 144.83.
Reaction SMILES: Br[C:2]1[NH:22][C:5]2=[N:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[CH:13]=3)[N:9]=[C:4]2[CH:3]=1.[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:31]=2)[CH:26]=[N:25]1>>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([O:18][CH3:19])[CH:15]=1)[CH2:11][CH2:10][C:8]1[N:9]=[C:4]2[CH:3]=[C:2]([C:30]3[CH:31]=[C:32]4[C:27]([CH:26]=[N:25][N:24]4[CH3:23])=[CH:28][CH:29]=3)[NH:22][C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(CCc2cnc3[nH]c(Br)cc3n2)cc(OC)c1
Reactant: Cn1ncc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Product: COc1cc(CCc2cnc3[nH]c(-c4ccc5cnn(C)c5c4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 53, Step 2 starting from 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazine and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (from Combi-Blocks). LCMS calculated for C24H24N5O2 (M+H)+: m/z=414.2. Found 414.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[S:11][C:12]([CH2:17][OH:18])=[C:13]([O:15][CH3:16])[CH:14]=2)[CH:5]=[CH:4][C:3]=1[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.O>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[S:11][C:12]([CH:17]=[O:18])=[C:13]([O:15][CH3:16])[CH:14]=2)[CH:5]=[CH:4][C:3]=1[CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)CCc1ccc(OCc2cc(OC)c(CO)s2)cc1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(OCc2cc(OC)c(C=O)s2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.8 %

Procedure:
To a solution of ethyl 3-[2-fluoro-4-[[5-(hydroxymethyl)-4-methoxy-2-thienyl]methoxy]phenyl]propanoate (1.6 g, 4.3 mmol) in anhydrous dichloromethane (10 mL), cooled to 0° C., is added Dess-Martin periodinane (2.76 g, 6.5 mmol). The reaction mixture is warmed to room temperature and stirred for 2 hours. The reaction mixture is diluted with water (15 mL), extracted with ethyl acetate, washed with water (15 mL), brine (15 mL), dried over sodium sulfate, filtered, and evaporated to dryness. The crude material is purified by silica gel chromatography eluting with hexane:ethyl acetate (8.8:1.2) to give the title compound (0.8 g, 50%). ESI/MS m/z 367.1 (M+H)+.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].[CH2:25](O)[CH2:26][CH2:27][OH:28].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:24][CH2:25][CH2:26][CH2:27][OH:28])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: OCCCO
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)OCCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of z,z,z,z,z,z-docosa-4,7,10,13,16,19-hexaenoic acid (6.4 g, 19.5 mmol) in methylene chloride (225 ml) was added dropwise to a solution of 1,3-propane diol (7.5 g, 99 mmol), 1,3-dicyclohexylcarbodiimide (4.65 g, 20 mmol) and 4-(N,N-dimethylamino)pyridine (2.1 g, 17 mmol) in methylene chloride (225 ml) at −10° C. The reaction mixture was stirred overnight, warming up to room temperature. The reaction was filtered, concentrated and purified by flash chromatography (ethyl acetate/hexane) to yield 1-(z,z,z,z,z,z-docosa-4,7,10,13,16,19-hexaenoyloxy)-3-hydroxypropane as a pale yellow oil.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][C:10]([CH3:18])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=2)[CH2:4][C@H:3]1[O:19][CH3:20].[CH2:21]([C:23]1[NH:27][C:26]([C:28](O)=[O:29])=[N:25][C:24]=1[C:31]([F:34])([F:33])[F:32])[CH3:22].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[CH2:21]([C:23]1[NH:27][C:26]([C:28]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[S:9][C:10]([CH3:18])=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=3)[CH2:4][C@H:3]2[O:19][CH3:20])=[O:29])=[N:25][C:24]=1[C:31]([F:33])([F:34])[F:32])[CH3:22]
Reactant: CCOC(=O)c1nc(N2CC[C@H](N)[C@H](OC)C2)sc1C
Reactant: CCc1[nH]c(C(=O)O)nc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(C(F)(F)F)c(CC)[nH]3)[C@H](OC)C2)sc1C

Procedure:
The same operation as in Example (1g) was performed using ethyl cis(±)-2-(4-amino-3-methoxypiperidin-1-yl)-5-methyl-1,3-thiazole-4-carboxylate obtained in Example (40e) (44.9 mg, 0.15 mmol), 5-ethyl-4-(trifluoromethyl)-1H-imidazole-2-carboxylic acid obtained by the method described in Example (39e) (29 mg, 0.14 mmol), WSC hydrochloride (80 mg, 0.42 mmol) and HOBT (20 mg, 0.15 mmol), to obtain 29.2 mg of the title compound as a colorless oily substance (43%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([N:24]2[CH2:28][CH:27]([CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:26][C:25]2=[O:37])[CH:20]=[CH:21][C:22]=1[OH:23]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:23][C:22]1[CH:21]=[CH:20][C:19]([N:24]2[CH2:28][CH:27]([CH2:29][O:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:26][C:25]2=[O:37])=[CH:18][C:17]=1[F:16]
Reactant: O=C1CC(COc2ccccc2)CN1c1ccc(O)c(F)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(N4CC(COc5ccccc5)CC4=O)cc3F)c2cc1OC
Temperature: 180 °C

Procedure:
A mixture of 4-chloro-6,7-dimethoxyquinoline (0.185 g, 0.83 mmol), 1-(3-fluoro-4-hydroxyphenyl)-4-(phenoxymethyl)pyrrolidin-2-one (Step 4, 250 mg, 0.83 mmol) and DMAP (101 mg, 0.83 mmol) in 8 mL of toluene (in a microwave tube) was heated in a microwave (Personal Chemistry, Emrys Optimizer) at 180° C. for 1.5 h. The mixture was cooled to RT and diluted with 50 mL of EtOAc. The solution was washed with 20 mL of satd. NaHCO3 followed by 20 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (50% to 100% EtOAc/hexane) to provide the product as white solid. MS (ESI pos. ion) m/z: 489.3 (M+H). Calc'd Exact Mass for C28H25FN2O5: 488.51.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[Br:10]N1C(=O)CCC1=O.O.O.O.O.O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.O>[Br:10][C:3]1[C:4]2[C:9](=[N:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Brc1c[nH]c2ncccc12
Temperature: 25 °C

Procedure:
7-Azaindole (2, 3.57 g, 30.2 mmol) was dissolved in tetrahydrofuran (240 mL) under an atmosphere of nitrogen. At −40° C., N-bromosuccinimide (5.38 g, 30.2 mmol) in tetrahydrofuran was added under an atmosphere of nitrogen. The reaction mixture was stirred for a few hours as it was gradually warmed to room temperature and the reaction was followed by TLC. The reaction was quenched with sodium thiosulfate pentahydrate (7.50 g, 30.2 mmol) in water (1M). Two layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried with anhydrous sodium sulfate, and evaporated to dryness. The crude material was purified by column chromatography (25-40% ethyl acetate in hexanes) to yield the desired product as a white solid, 3, (4.20 g, 21.3 mmol). MS(ESI) [M+H+]+=198.5.
Reaction SMILES: Br[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[F:12].[NH2:13][C:14]1[CH:19]=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][C:15]=1[N+:29]([O-:31])=[O:30]>>[F:12][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]=1[C:17]1[CH:18]=[CH:19][C:14]([NH2:13])=[C:15]([N+:29]([O-:31])=[O:30])[CH:16]=1
Reactant: CC1(C)OB(c2ccc(N)c([N+](=O)[O-])c2)OC1(C)C
Reactant: Fc1cccc(C(F)(F)F)c1Br
Product: Nc1ccc(-c2c(F)cccc2C(F)(F)F)cc1[N+](=O)[O-]
Yield: 89 %

Procedure:
Using the procedure for step A in Example 4, the title compound was prepared from 1-bromo-2-fluoro-6-trifluoromethylbenzene (0.850 mL, 6.09 mmol) and 4-amino-3-nitrophenylboronic acid pinacol ester (1.3 eq., 2.09 g, 7.92 mmol) in 89% yield (1.62 g). 1H-NMR (400 MHz, CDCl3) δ: 8.10 (s, 1H), 7.53-7.61 (m, 1H), 7.43-7.53 (m, 1H), 7.35 (t, J=8.5 Hz, 1H), 7.30 (d, J=7.3 Hz, 1H), 6.89 (d, J=8.3 Hz, 1H), 5.47 (br. s., 2H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:9]=[C:10]([CH3:11])[C:5]2=[C:4]([CH2:18]OS(C)(=O)=O)[CH:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][C:35]([CH3:38])([CH3:37])[NH:34][CH2:33][C:32]1([CH2:40][CH3:41])[CH3:39])=[O:30])([CH3:27])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C.[I-].[K+]>C1COCC1.O>[C:24]([O:28][C:29]([N:31]1[CH2:36][C:35]([CH3:38])([CH3:37])[N:34]([CH2:18][C:4]2[CH:3]=[C:2]([Br:1])[N:7]=[C:6]3[N:8]([CH:12]4[CH2:17][CH2:16][CH2:15][CH2:14][O:13]4)[N:9]=[C:10]([CH3:11])[C:5]=23)[CH2:33][C:32]1([CH2:40][CH3:41])[CH3:39])=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: Cc1nn(C2CCCCO2)c2nc(Br)cc(COS(C)(=O)=O)c12
Reactant: CCC1(C)CNC(C)(C)CN1C(=O)OC(C)(C)C
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCC1(C)CN(Cc2cc(Br)nc3c2c(C)nn3C2CCCCO2)C(C)(C)CN1C(=O)OC(C)(C)C
Temperature: 160 °C
Yield: 41.3 %

Procedure:
A mixture of 130 mg of methanesulfonic acid 6-bromo-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-ylmethyl ester, 99 mg of 2-ethyl-2,5,5-trimethyl-piperazine-1-carboxylic acid tert-butyl ester, 0.11 ml of DIPEA and 5 mg of potassium iodide in 2 ml of dry THF was heated to 160° C. for 50 min in a microwave reactor. For workup the mixture was taken up in water and ethyl acetate, the phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtrated and concentrated in vacuo and the resulting residue was purified by flash chromatography (silica, heptane/ethyl acetate). 75 mg (41%) of the title compound were obtained.
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.N([O-])=O.[Na+].[Cl-:14].[Na+].[OH-].[Na+]>Cl.O>[Cl:14][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: [Cl-]
Reactant: Cc1cc(C)nc(N)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)nc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 21.6 %

Procedure:
2-Amino-4,6-dimethyl-pyridine (4 g, 32.7 mmol) was dissolved in conc. hydrochloric acid (50 mL) and cooled to 0° C. A solution of sodium nitrite (3.39 g, 49.1 mmol) in water (20 mL) was added dropwise, followed by a solution of sodium chloride (3.8 g, 65 mmol) in water (20 mL). The mixture was stirred for 30 min. then basified with 20% sodium hydroxide solution and extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate and concentrated in vacuo to give a residue which was purified by column chromatography on silica gel (60-120 mesh) using 5% ethyl acetate/petroleum ether as eluent to afford 2-chloro-4,6-dimethyl-pyridine (1 g, 22%) as a solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:24])[CH2:4][CH2:3]1.[O:25]=[C:26]1[CH2:31][O:30][C:29]2[CH:32]=[CH:33][C:34]([CH:36]=O)=[N:35][C:28]=2[NH:27]1.C([BH3-])#N.[Na+]>>[CH3:23][S:20]([C:17]1[CH:18]=[CH:19][C:14]2[O:13][CH2:12][C:11](=[O:24])[N:10]([CH2:9][CH2:8][N:5]3[CH2:6][CH2:7][CH:2]([NH:1][CH2:36][C:34]4[CH:33]=[CH:32][C:29]5[O:30][CH2:31][C:26](=[O:25])[NH:27][C:28]=5[N:35]=4)[CH2:3][CH2:4]3)[C:15]=2[CH:16]=1)(=[O:22])=[O:21]
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: CS(=O)(=O)c1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: CS(=O)(=O)c1ccc2c(c1)N(CCN1CCC(NCc3ccc4c(n3)NC(=O)CO4)CC1)C(=O)CO2
Yield: 8 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-6-(methylsulfonyl)-2H-1,4-benzoxazin-3(4H)-one (Intermediate 99), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) and sodium cyanoborohydride were reacted as described under Example 21 to give the product as an off-white solid in 8% yield.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([N:10]2[CH2:17][CH:16]3[CH:12]([CH2:13][N:14]([CH2:18][CH2:19][C:20]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21]4)[CH2:15]3)[CH2:11]2)=[O:9])=[C:6]([CH3:31])[N:5]=[CH:4][N:3]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33].C1(C(Cl)=O)CCCC1.C1(CC(Cl)=O)CCCC1.C(Cl)(=O)C(C)(C)C>>[CH3:31][C:6]1[C:7]([C:8]([N:10]2[CH2:17][CH:16]3[CH2:15][N:14]([CH2:18][CH2:19][C:20]4([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH2:24][CH2:23][N:22]([C:32](=[O:34])[CH3:33])[CH2:21]4)[CH2:13][CH:12]3[CH2:11]2)=[O:9])=[C:2]([CH3:1])[N:3]=[CH:4][N:5]=1
Reactant: Cc1ncnc(C)c1C(=O)N1CC2CN(CCC3(c4ccccc4)CCNC3)CC2C1
Reactant: CC(=O)OC(C)=O
Agent: CC(C)(C)C(=O)Cl
Agent: O=C(Cl)C1CCCC1
Agent: O=C(Cl)CC1CCCC1
Product: CC(=O)N1CCC(CCN2CC3CN(C(=O)c4c(C)ncnc4C)CC3C2)(c2ccccc2)C1

Procedure:
The following were prepared analogously from (4,6-dimethyl-pyrimidin-5-yl)-{5-[2-(3-phenyl-pyrrolidin-3-yl)-ethyl]-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl}-methanone using the acid chloride in parenthesis in place of acetic anhydride in the final step: III-1 (cyclopentanecarbonyl chloride), III-2 (cyclopentyl-acetyl chloride) and III-4 (pivaloyl chloride).