Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=2)=[O:12])[CH:6]=1.N>C(O)(=O)C>[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([C:13]2[CH:18]=[C:17]([N+:1]([O-:4])=[O:2])[C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=2)=[O:12])[CH:6]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(=O)c2cccnc2)ccc1O
Agent: N
Solvent: CC(=O)O
Product: COc1cc(C(=O)c2cccnc2)cc([N+](=O)[O-])c1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
da) 0.38 ml of 65 percent nitric acid is added dropwise at room temperature to 1.15 g of 4-hydroxy-3-methoxyphenyl 3-pyridyl ketone dissolved in 15 ml of acetic acid. After stirring for 2 hours, the reaction mixture is poured into 120 ml of ice-water, whereupon the mixture is adjusted to pH 5 with conc. ammonia and the precipitate formed is filtered off. The thus-obtained residue is heated under reflux in 20 ml of acetonitrile, whereupon it is again filtered off. There is obtained 4-hydroxy-3-methoxy-5-nitrophenyl 3-pyridyl ketone as brown crystals of m.p. 193°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:9]([O:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1)[C:10]#[C:11][CH3:12]
Reactant: NCc1ccccc1
Reactant: CC#CCOc1cc(Cl)ncn1
Solvent: CCO
Product: CC#CCOc1cc(NCc2ccccc2)ncn1
Temperature: 25 °C
Yield: 113.9 %

Procedure:
In 8 ml of ethanol were added 1 g of 4-chloro-6-(2-butynyloxy)pyrimidine and 1.17 g of benzylamine, followed by heating under reflux for 6 hours. The reaction mixture was then left for cooling to room temperature and concentrated under reduced pressure. A saturated aqueous ammonium chloride solution was poured onto the residue, which was extracted three times with ethyl acetate. The organic layers were combined and washed with a saturated aqueous sodium chloride solution, and the combined organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 1.58 g of 6-(2-butynyloxy)-4-benzylaminopyrimidine (the present compound (133)).
Reaction SMILES: [CH2:1]([NH:8][C:9](=O)[CH:10]1[CH2:15][CH2:14][NH:13]CC1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:23]1COC[CH2:24]1>>[NH2:13][CH2:14][CH:15]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:24][CH2:23]1
Reactant: C1CCOC1
Reactant: O=C(NCc1ccccc1)C1CCNCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCC1CCN(Cc2ccccc2)CC1

Procedure:
To a solution of N-benzylisonipecotamide (7.34g, 34 mmol) in 60 mL of anhydrous THF, was added, LiAlH4 (1.9 g, 51 mmol) and the mixture was stirred at room temperature for 10 minutes followed by heating to reflux for 3 h. The reaction was quenched by addition of 100 mL sat'd. sodium potassium tartrate, and was extracted with EtOAc (3×50 mL). The combined extracts were washed with 20 mL water and 20 mL brine then dried over MgSO4, filtered and concentrated to give the desired product. 1H-NMR (400 MHz, CDCl3) δ7.13 (m, 5H), 3.42 (s, 2H), 2H), 2.91 (m, 2H), 2.59 (m, 2H), 1.97 (m, 2H), 1.62 (m, 2H), 2.21 (m, 5H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:13]=2)[CH:10]=1)=[O:4].C(O)(=O)C>Br>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]2[N:13]=[C:8]3[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][N:9]3[CH:11]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)cn2c1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)cn2c1
Yield: 38 %

Procedure:
2-(4-Fluoro-phenyl)-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (example 1; 590 mg, 2.18 mmol) was heated in 5 ml hydrobromic acid (48%) and 15 ml acetic acid at 120° C. for 10 hours. The solid was filtered, washed and dried. Yield: 38%. MS: M+H+=257.04.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29].[NH2:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:30][C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[CH:34]=[CH:33][CH:32]=3)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29]
Reactant: Nc1cccc2ccccc12
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1ccccc1)C(=O)N(c1c(Cl)cccc1Cl)C2
Product: O=C1N(c2c(Cl)cccc2Cl)Cc2cnc(Nc3cccc4ccccc34)nc2N1c1ccccc1
Temperature: 130 °C
Yield: 40.8 %

Procedure:
A mixture of 100 mg (0.22 mmol) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-1-phenyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 320 mg (2.2 mmol) of 1-aminonaphthalene was heated at 130° C. for 4 hours. The mixture was left to cool and was then partitioned between 10 ml of ethyl acetate and 2M hydrochloric acid. The insoluble 1-aminonaphthalene hydrochloride was removed by filtration. The ethyl acetate phase was separated, washed with 10 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography on silica gel using ethyl acetate/hexane (1:1) for the elution. Product-containing fractions were evaporated to give 46 mg (40%) of 3-(2,6-dichlorophenyl)-3,4-dihydro-7-(1-naphthylamino)-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one as a pale pink solid of melting point 213-214° C.
Reaction SMILES: [BH4-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:9](=[O:10])[C:8]2=[CH:22][C:23]=1[O:24][CH3:25].O1CCOCC1.CO>O>[OH:13][CH:12]1[C:7]2[C:8](=[CH:22][C:23]([O:24][CH3:25])=[C:5]([O:4][CH3:3])[CH:6]=2)[C:9](=[O:10])[N:11]1[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc2c(cc1OC)C(=O)N(CCc1ccccc1)C2=O
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)C(O)N(CCc1ccccc1)C2=O
Yield: 96.9 %

Procedure:
Potassium borohydride (4.87 g) dissolved in distilled water (58.7 cc) is added to 4,5-dimethoxy-N-phenethyl phthalimide (28 g) suspended in a mixture (180 cc) consisting of equal volumes of dioxan and methanol. The reaction mixture is heated under reflux for 2 hours and then concentrated to a volume of 60 cc and distilled water (450 cc) is added. After cooling, the resulting precipitate is filtered off, washed three times with distilled water (total 1000 cc) and dried under reduced pressure (20 mm Hg) at 25° C. 3-Hydroxy-2-phenethyl-5,6-dimethoxy-2,3-dihydro-1H-isoindol-1-one (27.3 g), melting at 130° C., is thus obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:21]([OH:23])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24]OS(OC)(=O)=O.Cl>[OH-].[Na+]>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:21]([OH:23])=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:24])=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Reaction time: 8 h
Yield: 17.6 %

Procedure:
N-Benzyloxycarbonyl-L-tyrosine (31.5 g, 0.1 mol) was dissolved in aqueous sodium hydroxide (10 g in 100 ml H2O) and dimethylsulphate (10.5 ml, 0.11 mol) added dropwise to the stirred solution. The reaction was stirred overnight, additional dimethylsulphate (2 ml) added in one portion and the reaction stirred for a further 48 hours. 2M Hydrochloric acid was added until a white precipitate formed. This was filtered off, taken up in ethyl acetate, washed with brine and dried over anhydrous sodium sulphate, filtered and evaporated. The residue was crystallised from ethyl acetate to give N-benzyloxycarbonyl-O-methyl-L-tyrosine (5.8 g, 18%) as a white crystalline solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[N:24]1[CH:29]=[C:28](B(O)O)[CH:27]=[N:26][CH:25]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:28]5[CH:29]=[N:24][CH:25]=[N:26][CH:27]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: OB(O)c1cncnc1
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncnc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and pyrimidine-5-boronic acid (Frontier Scientific, Logan, USA, 16 mg, 0.129 mmol) to give the title compound as a white solid. (HPLC: tR 2.24 min (Method A); M+H=372 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 9.20 (s, 1H), 9.02 (s, 1H), 8.93 (s, 2H), 8.20-8.12 (m, 2H), 8.06-7.99 (m, 1H), 7.62-7.56 (m, 1H), 3.90 (s, 3H), 3.58 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [C:1]([N:5]=[C:6]=[S:7])([CH3:4])([CH3:3])[CH3:2].[CH:8]([NH2:11])([CH3:10])[CH3:9].C(N(C(C)C)CC)(C)C>C(Cl)Cl.CCOC(C)=O>[C:1]([NH:5][C:6]([NH:11][CH:8]([CH3:10])[CH3:9])=[S:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CC(C)(C)N=C=S
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=S)NC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
To a solution of tert-butylisothiocyanate (5.0 mL, 39 mmol) in CH2Cl2 (200 mL) were added isopropylamine (4.0 mL, 47 mmol) and diisopropylethylamine (DIEA) (6.8 mL, 39 mmol), and the mixture was stirred at rt for 2 h. The reaction mixture was diluted with EtOAc, washed with 10% citric acid (2×), saturated NaHCO3 (2×), H2O (2×), and brine (1×). The organic layer was dried (MgSO4) and evaporated to yield the title compound (3.3 g, 52%) as a white solid which was used without further purification.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[C:14](=[O:15])[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[C:12]([NH2:26])[O:11]1.[CH2:27](Br)[CH:28]=[CH2:29]>O.C(Cl)Cl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH:10]1[C:14](=[O:15])[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)=[C:12]([NH:26][CH2:29][CH:28]=[CH2:27])[O:11]1
Reactant: C=CCBr
Reactant: NC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2F)O1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C=CCNC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2F)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.9 %

Procedure:
One gram of sodium hydroxide in 4.0 ml of water was added to a mixture of 4.0 g of 2-(2-fluorophenyl)-3-oxo-4-(3-trifluoromethylphenyl)-5-amino-2,3-dihydrofuran in 80 ml of methylene chloride at room temperature followed by the addition of 1.44 g of allyl bromide and 0.27 g of benzyltriethylammonium chloride. The resulting two-phase mixture was stirred at room temperature for about 18 hours after which time it was washed three times with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography over silica gel eluting with chloroform to yield 2.5 g of the title compound.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]([C:13]1[N:14]=[C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]2[C:21]=1I)[CH3:12])C1C=CC=CC=1.CSC.[C:27](O)([C:29](F)(F)F)=O>>[N:10]1[CH:29]=[CH:27][CH:21]=[CH:13][C:11]=1[C:21]1[N:16]2[CH:17]=[CH:18][CH:19]=[N:20][C:15]2=[N:14][C:13]=1[CH:11]([NH2:10])[CH3:12]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(NC(=O)OCc1ccccc1)c1nc2ncccn2c1I
Solvent: CSC
Product: CC(N)c1nc2ncccn2c1-c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of [1-(3-iodo-imidazo[1,2-a]pyrimidin-2-yl)-ethyl]-carbamic acid benzyl ester (900 mg, 2.4 mmol) and dimethylsulfide (0.9 mL) in TFA (4.5 mL) was stirred at rt overnight. The mixture was concentrated in vacuo, dissolved in EtOAc washed with satd. sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo to provide 1-(3-pyridin-2-yl-imidazo[1,2-a]pyrimidin-2-yl)-ethylamine: LC-MS (ESI) m/z 240.0 [M+H]+.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[N+]([O-])(O)=O.[OH:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1>>[N+:6]([CH:20]1[C:15](=[O:14])[CH:16]=[CH:17][N:18]=[CH:19]1)([O-:9])=[O:7]
Reactant: Oc1ccncc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1C=CN=CC1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a cold solution of 35 ml. of fuming sulfuric acid and 45 ml. of fuming nitric acid was added 35 grams of the 4-hydroxypyridine nitrate. After allowing the mixture to warm to room temperature over night it was heated on a steam bath for 21/4 hours. It was cooled and poured onto 500 grams of ice. The resulting precipitate was collected on a filter, washed with a minimum of water and recrystallized from water to give 3-nitro-4-pyridone, m.p. 282-284° C.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:10][OH:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:13]([NH2:21])(=[S:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1C=CC=CC=1>[N:10](=[C:4]([C:3]1[N:21]=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:20][CH:2]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[OH:11]
Reactant: NC(=S)c1ccccc1
Reactant: CCOC(=O)C(=NO)C(=O)CCl
Solvent: c1ccccc1
Product: CCOC(=O)C(=NO)c1csc(-c2ccccc2)n1
Reaction time: 4 h
Yield: 107.9 %

Procedure:
A solution of ethyl γ-chloro-α-oximinoacetoacetate (2.10 g, 10.8 mmol) and thiobenzamide (1.49 g, 10.8 mmol) in dry benzene (15 mL) was heated to reflux. After 4 hours, the reaction mixture was poured onto NaHCO3 (sat., aq., 50 mL); The resulting mixture was extracted with ethyl acetate (2×50 mL); and the combined extracts dried over MgSO4 and evaporated under reduced pressure. Flash chromatography (ethyl acetate:hexane 1:4, Rf 0.30) then afforded impure ethyl α-oximino-2-phenylthiazole-4-acetate (3.22 g). The crude oxime was then dissolved in methanol (15 mL) and formic acid (50% aq., 15 mL) was added. The mixture was cooled to 0° C. and zinc dust (2.00 g, 30.6 mmol) was added portionwise over 30 minutes. The reaction mixture was allowed to warm to room temperature, and stirred for 6 hours. The solution was then filtered, basified to pH 9 with solid NaHCO3, and extracted with ethyl acetate (3×80 mL). The combined extracts were then dried and evaporated to afford D/L-2-phenylthiazol-4-ylglycine ethyl ester (1.43 g, 5.45 mmol, 50% from the chloro-oxime). The ester (194 mg, 0.74 mmol) was then dissolved in tetrahydrofuran (5 mL). Triethylamine (120 μL, 87 mg, 0.86 mmol) was added, followed by di-t-butyl dicarbonate (180 mg, 0.82 mmol). After stirring at room temperature for 4 days, water (20 mL) was added and the solution extracted with dichloromethane (2×20 mL). The combined extracts were evaporated and purified by flash column chromatography (ethyl acetate:hexane 1:4, Rf 0.45) to afford N-t-butyloxycarbonyl-D/L-2-phenylthiazol-4-ylglycine ethyl ester (158 mg, 0.44 mmol, 59%) as a clear oil. The oil was dissolved in tetrahydrofuran (2 ml) and LiOH.H2O (80 mg as a solution in 2 mL water) was added. After stirring at room temperature for 2 hours, water (10 mL) was added, and the solution extracted with ethyl acetate (5 mL). The aqueous layer was then acidified to pH 4 with 2N HCl, and extracted with ethyl acetate (2×20 mL); The latter extracts were combined and evaporated to afford N-BOC-D/L-2-phenylthiazol-4-ylglycine (116 mg, 0.35 mmol, 75%) as a white powder.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH2:9])[CH:5]=2)[CH2:3][CH2:2]1.[Cl:10][C:11]1[N:18]=[C:17](Cl)[C:16]([F:20])=[CH:15][C:12]=1[C:13]#[N:14].C(N(CC)CC)C>CC#N>[Cl:10][C:11]1[N:18]=[C:17]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)[C:16]([F:20])=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1cc(F)c(Nc2cc(C3CC3)[nH]n2)nc1Cl
Temperature: 82 °C
Yield: 72 %

Procedure:
A solution of 5-cyclopropyl-1H-pyrazol-3-amine (1.9 g, 16.0 mmol) in CH3CN (20 ml) was added dropwise to a solution of 2,6-dichloro-5-fluoronicotinonitrile (3.0 g, 16.0 mmol) and triethylamine (2.1 g, 20.0 mmol) in CH3CN (80 ml) at 25° C. The resulting solution was then heated to 82° C. for 18 hrs, and then cooled to 25° C., at which point the product precipitated from solution. The resulting solid was filtered, and washed with CH3CN (100 ml) to give the title compound (3.2 g, 73%). MS: Calcd.: 277. Found: [M+H]+ 278.
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]1[CH2:8][CH:7]([CH:9]=[CH:10][C:11](=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[C:5]1=[O:27]>[OH-].[Na+].C(O)C>[OH:27][CH:5]1[CH:4]([CH3:3])[CH2:8][CH:7]([CH:9]=[CH:10][CH:11]([OH:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:6]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]
Reactant: CCCCCC(=O)C=CC1CC(C)C(=O)C1CCCCCCC(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCC(O)C=CC1CC(C)C(O)C1CCCCCCC(=O)O
Temperature: 10 °C
Reaction time: 24 h
Yield: 80.6 %

Procedure:
A solution of sodium borohydride (0.18 g., 0.0046 mole) in 0.2N aqueous sodium hydroxide (1.8 ml.) was added dropwise to a solution of 7-[3-methyl-2-oxo-5-(3-oxo-1-octenyl)cyclopentyl]heptanoic acid (0.5 g., 0.0014 mole) in ethanol (15 ml.) and N aqueous sodium hydroxide (1.4 ml., 0.0014 mole). The resulting solution was stirred for 1 day, and then the ethanol was removed in vacuo. A small quantity of water was added, and the solution was extracted twice with diethyl ether (to remove non-acidic material). The aqueous solution was covered with a layer of diethyl ether and acidified to pH 1 by the dropwise addition of concentrated hydrochloric acid, cooling the solution to about 10°C. The ether layer was separated and the aqueous layer extracted twice more with diethyl ether. The combined ether extracts were dried over magnesium sulphate and evaporated to give 7-[2-hydroxy-5-(3-hydroxy-1-octenyl)-3-methylcyclopentyl]heptanoic acid (0.4 g., 80%) which required no further purification. N.M.R. (approximately 10% solution in deuterochloroform), 0.84 δ (triplet J=5c/s, terminal CH3), 0.95 δ (doublet J=6c/s, ring methyl), 1.31 δ (multiplet, chain CH2), 2.24 δ (triplet J=6c/s, CH2CO), 3.68 and 3.98 δ (overlapping multiplets, HCOH), 5.39 δ (multiplet CH=CH), 5.77 δ (singlet OH and COOH). (Found: C, 71.1; H, 10.7. C21H38O4 requires C, 71.2; H, 10.8%).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([C:16]3[N:24]4[C:19]([CH:20]=[N:21][C:22](O)=[N:23]4)=[CH:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:28]=[CH:29][C:30]2[N:34]=[C:33]([CH2:35][OH:36])[NH:32][C:31]=2[CH:37]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[N:1]1([S:7]([C:10]2[CH:11]=[C:12]([C:16]3[N:24]4[C:19]([CH:20]=[N:21][C:22]([NH:26][C:27]5[CH:28]=[CH:29][C:30]6[N:34]=[C:33]([CH2:35][OH:36])[NH:32][C:31]=6[CH:37]=5)=[N:23]4)=[CH:18][CH:17]=3)[CH:13]=[CH:14][CH:15]=2)(=[O:8])=[O:9])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccc2nc(CO)[nH]c2c1
Reactant: O=S(=O)(c1cccc(-c2ccc3cnc(O)nn23)c1)N1CCOCC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: O=S(=O)(c1cccc(-c2ccc3cnc(Nc4ccc5nc(CO)[nH]c5c4)nn23)c1)N1CCOCC1

Procedure:
(6-{7-[3-(Morpholine-4-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino}-1H-benzoimidazol-2-yl)-methanol was prepared from 7-[3-(morpholine-4-sulfonyl)-phenyl]-pyrrolo[2,1-f][1,2,4]triazin-2-ol and (6-amino-1H-benzoimidazol-2-yl)-methanol; dihydrochloride in an analogous manner to Example 1052a. Product isolated as a yellow solid (31 mg, 21%). m.p.=232-237° C.; LCMS (m/e) 506 (M+H); 1H-NMR (d6-DMSO, 400 MHz) δ 12.05 (bs, 1H), 9.40 (s, 1H), 9.03 (s, 1H), 8.72 (d, 1H, J=7.8 Hz), 8.28 (s, 1H), 7.86-7.74 (m, 2H), 7.72 (d, 1H, J=7.8 Hz), 7.55 (d, 1H, J=8.7 Hz), 7.46 (d, 1H, J=8.7 Hz), 7.29 (d, 1H, J=4.8 Hz), 6.97 (d, 1H, J=4.8 Hz), 4.66 (s, 2H), 3.62-3.55 (m, 4H), 2.93-2.86 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40]N>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:40][C:35]3[C:36]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:37][CH:38]=[CH:39][C:34]=3[CH3:33])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1NN
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(Cl)cc3)CC2)c1
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccc(Cl)cc3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 528.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:7]2[C:12]([C:13](=[O:25])[C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][CH:17]=1)=[CH:11][CH:10]=[C:9]([Cl:26])[CH:8]=2)=[O:4].[NH2:33][C:34]([CH3:42])([CH3:41])[CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:7]2[C:12]([C:13](=[O:25])[C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:23])[NH:33][C:34]([CH3:42])([CH3:41])[CH2:35][C:36](=[O:37])[N:38]([CH3:40])[CH3:39])=[CH:18][CH:17]=1)=[CH:11][CH:10]=[C:9]([Cl:26])[CH:8]=2)=[O:4]
Reactant: CN(C)C(=O)CC(C)(C)N
Reactant: COC(=O)c1c(Cc2ccc(C(=O)O)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1c(Cc2ccc(C(=O)NC(C)(C)CC(=O)N(C)C)cc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
A mixture of 3-(4-carboxy-benzyl)-7-chloro-4-oxo-1-phenyl-1,4-dihydroquinoline-2-carboxylic acid methyl ester (75 mg, 0.17 mmol), 3-amino-3,N,N-trimethyl-butyramide (24 mg, 0.17 mmol), BOP (150 mg, 0.34 mmol) and DIPEA (1 mL) in THF (15 mL) was stirred at RT overnight. The reaction mixture was partitioned between water and EtOAc, the organic layer separated, washed with water, dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude residue was purified by preparative TLC (EtOAc/hexane, 75:25) to yield 7-chloro-3-[4-(2-dimethylcarbamoyl-1,1-dimethyl-ethylcarbamoyl)-benzyl]-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid methyl ester (71 mg) as a light brown foam. MS=574 [M+H]+; MP=84.1-95.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:26]([N:30]([CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][NH:35]1)[CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29].C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[CH2:26]([N:30]([CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][N:35]1[C:4]([C:3]1[CH:7]=[CH:8][C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])=[CH:10][C:2]=1[Cl:1])=[O:6])[CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCCCN(CC)CC1CCCCN1
Agent: ClCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(CC)CC1CCCCN1C(=O)c1ccc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, rac.-2-(N-butyl-N-ethylaminomethyl)piperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 4.23 minutes; C29H37Cl2N5O2 (558.55); mass spectrum: (M−H)−=558/560 (chlorine isotope).