Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[Cl:13])[CH:2]1[O:4][CH2:3]1.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[NH:22][CH2:23][CH2:24][NH2:25]>>[Cl:13][C:7]1[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:6]=1[O:5][CH2:1][CH:2]([OH:4])[CH2:3][NH:25][CH2:24][CH2:23][NH:22][C:16]1[C:17]([CH3:21])=[CH:18][CH:19]=[CH:20][C:15]=1[CH3:14]
Reactant: Cc1cccc(C)c1NCCN
Reactant: Clc1ccc(Cl)c(OCC2CO2)c1
Product: Cc1cccc(C)c1NCCNCC(O)COc1cc(Cl)ccc1Cl

Procedure:
This compound is obtained, in a manner analogous to that described in Example 17, from 2,5-dichlorophenyl glycidyl ether and N-(2,6-dimethylphenyl)-ethylenediamine, the base obtained crystallizing. The desired product is obtained in a yield of 4.2 g. (55% of theory) in the form of colorless crystals which, after recrystallization from diethyl ether-ligroin, melt at 66°-68° C.
Reaction SMILES: C([NH:8][CH2:9][C:10]([NH:12][CH2:13][C:14]1[S:15][C:16]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:17][C:18]=1[NH:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)=[O:21])=[O:11])(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][CH2:9][C:10]([NH:12][CH2:13][C:14]1[S:15][C:16]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:17][C:18]=1[NH:19][C:20]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=1)=[O:21])=[O:11]
Reactant: Cc1ccc(NC(=O)Nc2cc(C(C)(C)C)sc2CNC(=O)CNC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)Nc2cc(C(C)(C)C)sc2CNC(=O)CN)cc1
Reaction time: 3 h
Yield: 48.3 %

Procedure:
To a solution of N-(2-(N-(N-carbo-tert-butoxyglycyl)aminomethyl)-5-tert-butyl-3-thienyl)-N′-(4-methylphenyl)urea (0.050 g, 0.105 mmol) in CH2Cl2 (3 mL) at room temp. was added trifluoroacetic acid (0.50 mL, 6.49 mmol, 62 equiv). The resulting mixture was stirred for 3 h, washed with a saturated NaHCO3 solution, dried (MgSO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (for CH2Cl2 to 20% MeOH/CH2Cl2) to give N-(2-(N-glycylaminomethyl)-5-tert-butyl-3-thienyl)-N′-(4-methylphenyl)urea (0.019 g, 48%): mp 93-6° C.; 1H NMR (CDCl3) δ1.14 (s, 9H), 2.08 (s, 3H), 3.89 (s, 2H), 4.34 (br s, 7H), 6.67 (s, 1H), 6.87 (d, J=8.1 Hz, 2H), 7.12 (d, J=8.5 Hz, 2H), 7.3 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([N:17]4[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]4)=[O:16])=[CH:11][CH:10]=3)[S:8][C:4]=2[CH:3]=1.C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:38](O)=[O:39].C([O-])(O)=O.[Na+]>O>[OH:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([N:17]4[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]4)=[O:16])=[CH:11][CH:10]=3)[S:8][C:4]=2[C:3]=1[CH:38]=[O:39]
Reactant: O=C(O)C(F)(F)F
Reactant: CC1CCN(C(=O)c2ccc(-c3nc4ccc(O)cc4s3)cc2)CC1
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC1CCN(C(=O)c2ccc(-c3nc4ccc(O)c(C=O)c4s3)cc2)CC1
Temperature: 120 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
A mixture of [4-(6-Hydroxy-benzothiazol-2-yl)-phenyl]-(4-methyl-piperidin-1-yl)-methanone (120 mg, 0.34 mmol), hexamethylenetetramine (190 mg, 1.36 mmol) and trifluoroacetic acid (2 mL) was stirred in a closed vessel under argon atmosphere at 120° C. for 1 h. The reaction was cooled to room temperature and 10 mL of water was added. The pH of the mixture was adjusted to 8 by dropwise addition of saturated NaHCO3 solution, and extracted with dichloromethane (3×15 mL). The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica (Kieselgel 60), eluting with chloroform-methanol 99:1. The title compound (34 mg, 0.089 mmol, 26%) was obtained as pale yellow crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].[C:9](O)(=[O:11])[CH3:10].C(C=O)=O.C(=O)([O-])O.[Na+]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7]/[N:8]=[CH:10]/[CH:9]=[O:11]
Reactant: NNc1ccccn1
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: O=CC=O
Agent: [Na+]
Solvent: O
Product: O=C/C=N/Nc1ccccn1
Reaction time: 18 h
Yield: 60.4 %

Procedure:
A mixture of the 1-(pyridin-2-yl)hydrazine (2.00 g, 18.33 mmol), water (13 mL), and acetic acid (10.49 ml, 183.3 mmol) was added with stirring into a 40% aqueous solution of glyoxal (10.51 ml, 91.63 mmol) over 20 minutes. Stirring was continued for 18 hours and then the aqueous was extracted with EtOAc. The diluted aqueous layer was slowly basified with sodium hydrogen carbonate (15.40 g, 183.3 mmol). The resulting solids were collected by filtration and washed with water to afford 1.65 g (85%) of the desired product and dimer. LRMS (apci pos): 150 (M+H).
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]1.[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1/[CH:23]=[CH:24]/[C:25](O)=[O:26]>>[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1/[CH:23]=[CH:24]/[C:25]([NH:12][C:9]1[CH:10]=[CH:11][N:7]([CH2:6][CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:14])[CH3:13])[N:8]=1)=[O:26]
Reactant: O=C(O)/C=C/c1cccc(Cl)c1Cl
Reactant: CC(F)(F)CCCCn1ccc(N)n1
Product: CC(F)(F)CCCCn1ccc(NC(=O)/C=C/c2cccc(Cl)c2Cl)n1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-3-ylamine and (E)-3-(2,3-dichloro-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.17 min; [M+H]+=401.99.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([OH:20])=[C:14]([Cl:19])[CH:15]=3)[O:10][CH:9]=2)=[CH:4][CH:3]=1.C1N2CN3CN(C2)CN1C3.Cl.O.[C:33](O)(=[O:35])C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([CH:33]=[O:35])[C:13]([OH:20])=[C:14]([Cl:19])[CH:15]=3)[O:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=c1c(-c2ccc(Br)cc2)coc2cc(O)c(Cl)cc12
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Product: O=Cc1c(O)c(Cl)cc2c(=O)c(-c3ccc(Br)cc3)coc12
Temperature: 100 °C

Procedure:
3-(4-Bromo-phenyl)-6-chloro-7-hydroxy-chromen-4-one (0.35 g, 1 mmol) and hexamethylene tetramine (0.14 g, 1 mmol) were dissolved in glacial acetic acid (20 ml) and heated overnight at 100° C. Warm 6M HCl (10 ml) was added and the mixture heated for a further hour before being poured in to water. The precipitate formed was filtered, washed and dried to provide the pure desired product as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)[CH2:15][NH:16]S(C3C=CC(C)=CC=3)(=O)=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.Br>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=3)[CH2:15][NH2:16])=[CH:9][CH:8]=2)=[CH:37][CH:38]=1
Reactant: Cc1ccc(S(=O)(=O)NCC(Nc2ccc(Oc3ccc(Cl)cc3)cc2)c2cccc(C(F)(F)F)c2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: Oc1ccccc1
Product: NCC(Nc1ccc(Oc2ccc(Cl)cc2)cc1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 49.3 %

Procedure:
A solution of N-(2-(4-(4-chlorophenoxy)phenylamino)-2-(3-(trifluoromethyl)phenyl)ethyl)-4-methylbenzenesulfonamide (358 mg, 0.638 mmol) and phenol (180 mg, 1.92 mmol) in 30 wt % HBr in acetic acid (3.5 mL) is heated at 80° C. for 2 h. After cooling down to room temperature, most of the solvent is removed under vacuo. The residue is then quenched with cold saturated NaHCO3 aqueous solution (40 mL) and extracted with EtOAc (3×20 mL). The combined organic layer is concentrated and purified by reverse phase HPLC to provide N1-(4-(4-chlorophenoxy)phenyl)-1-(3-(trifluoromethyl)phenyl)ethane-1,2-diamine (128 mg, 49% yield) as a light yellow oil-like product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][NH:16][CH2:17][CH2:18][OH:19].Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:16]([CH3:15])[CH2:17][CH2:18][OH:19])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CNCCO
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: Cl
Solvent: O
Product: CN(CCO)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
A solution containing 500 g of 4-chloro-3-nitrobenzenesulfonyl chloride in 1,000 ml of acetonhitrile was dropwise added to a solution containing 161 g of N-methylethanolamine in 1,500 ml of water as the mixture was cooled with ice-cold water. After the conclusion of dropwise addition, the stirring was continued for 1 hour at 20° C., and then the reaction mixture was made weakly acidic with dilute hydrochloric acid, extracted with ethyl acetate, washed 4 to 5 times with dilute hydrochloric acid, and concentrated. Thus, the intended oily matter was obtained. Yield: 459 g. Yield rate: 86%.
Reaction SMILES: ClC1C=CC(C2(C[Br:17])CCC(CCC)O2)=CC=1.[OH:18][CH2:19][CH:20]([CH2:32][CH2:33][CH3:34])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[Cl:31])=[CH2:23].BrBr.N1C=CC=CC=1>ClCCl>[Cl:31][C:25]1[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:24]=1[C:22]1([CH2:23][Br:17])[CH2:21][CH:20]([CH2:32][CH2:33][CH3:34])[CH2:19][O:18]1
Reactant: C=C(CC(CO)CCC)c1ccc(Cl)cc1Cl
Reactant: CCCC1CCC(CBr)(c2ccc(Cl)cc2)O1
Agent: BrBr
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCC1COC(CBr)(c2ccc(Cl)cc2Cl)C1
Yield: 98 %

Procedure:
By the cyclisation procedure described for the preparation of 2-(4-chlorophenyl)-2-bromomethyl-5-prop-1-yltetrahydrofuran (see Example 1), 4-(hydroxymethyl)-2-(2,4-dichlorophenyl)hept-1-ene (1.5 g), bromine (0.88 g), and pyridine (0.43 g) in dry dichloromethane (30 ml) gave 2-(2,4-dichlorophenyl)-2-bromomethyl-4-prop-1-yltetrahydrofuran (1.9 g, 98%) as a pale yellow oil.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[C:11]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[O:19][CH2:20][CH2:21][N:10]2[CH2:9][C:8]1=[O:29])(=O)C.[OH-].[Na+].O>CO>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]2[N:7]([CH2:6][CH2:5][OH:4])[C:8](=[O:29])[CH2:9][N:10]3[CH2:21][CH2:20][O:19][C:11]3([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:12]=2[CH:17]=1
Reactant: CC(=O)OCCN1C(=O)CN2CCOC2(c2ccccc2F)c2cc(Cl)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1CN2CCOC2(c2ccccc2F)c2cc(Cl)ccc2N1CCO
Reaction time: 3 h

Procedure:
A solution of 0.5g (0.0012 M) of 7-(2-acetoxyethyl)-10-chloro-11b-(2-fluorophenyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one in 5 ml of methanol was treated with 2 ml of 3N sodium hydroxide. After 3 hours, 50 ml of water was added and the solution was extracted with 40 ml of dichloromethane, which was then dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from a mixture of methanol and water to give 10-chloro-11b-(2-fluorophenyl)-7-(2-hydroxyethyl)-2,3,5,11b-tetrahydrooxazolo(3,2-d)[ 1,4]benzodiazepin-6(7H)-one as white prisms, m.p. and m.m.p. 141°-146°.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[NH:4][N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[Br:15]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:3](=[O:14])[NH:4][N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:7]=1[Br:15]
Reactant: Nc1cc(-c2ccccc2)n[nH]c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Nc1c(Br)c(-c2ccccc2)n[nH]c1=O
Reaction time: 18 h

Procedure:
4-Amino-6-phenyl-3(2H)-pyridazinone (prepared by the method of Example 1a), or according to McKillop et al., Heterocycles, 1989, 29(6), 1077) (4.69 g, 25 mmol) and N-bromosuccinimide (4.50 g, 25.3 mmol), suspended in dry acetonitrile (135 ml), was heated at reflux under a nitrogen atmosphere for 6 hours, then allowed to stand at room temperature for 18 hours. The solid was collected by filtration, washed with ethyl acetate (40 ml) and diethyl ether (40 ml), and dried in vacuo at 60° C., to afford the title compound, 6.25 g (94%), as a colourless solid. 1H NMR (400 MHz, DMSO-d6) δ12.93 (1H, s), 7.43 (5H, m), 6.69 (2H, br s); m/e (ES+) 266/268 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[C:14](OC(=O)C)(=[O:16])[CH3:15]>[OH-].[Na+]>[C:14]([O:13][C:12]1[CH:11]=[CH:10][C:4]([CH:5]=[CH:6][C:7]([OH:9])=[O:8])=[CH:3][C:2]=1[Cl:1])(=[O:16])[CH3:15]
Reactant: O=C(O)C=Cc1ccc(O)c(Cl)c1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Oc1ccc(C=CC(=O)O)cc1Cl
Temperature: 0 °C

Procedure:
104 g (0.525 mol) of 3-chloro-4-hydroxy-cinnamic acid are dissolved in 530 ml of 2 N sodium hydroxide solution, 800 g of ice are added and 107 g (1.05 mols) of acetic anhydride are introduced dropwise over the course of 15 minutes at 0°-5° C., whilst stirring. The crystals which have precipitated are then filtered off, suction-dried and recrystallised from alcohol-water. 4-Acetoxy-3-chloro-cinnamic acid of melting point 210°-213° C. is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[N:13]=[CH:14][N:15](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)Cl.CO>Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[N:13]=[CH:14][NH:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(/C=C/c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=[N+]([O-])c1ccc(/C=C/c2c[nH]cn2)cc1

Procedure:
Prepared by refluxing the 4-[2-(4-nitro-phenyl)-(E)-ethenyl]-1-triphenylmethyl-1-H-imidazole (melting point: 280-285° C.) obtained in Example 9.9 (a) in 1N hydrochloric acid (4 hours) and column chromatography on silica gel with CH2Cl2 /MeOH (10:1) as eluant.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=2[F:28])[CH2:9]/[C:10](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[C:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([OH:31])=[O:30]>>[F:28][C:22]1[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:21]=1[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([C:35]2[CH:36]=[CH:37][C:32]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=2)=[CH:3][CH:4]=1)[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]1[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(C(C/C(=N\O)c2ccc(=O)n(C)c2)c2ccc(Br)cc2)c(F)c1
Product: Cc1ccc(C(C/C(=N\O)c2ccc(=O)n(C)c2)c2ccc(-c3ccc(C(=O)O)cc3)cc2)c(F)c1

Procedure:
The title compound was prepared in analogy to example 166, from (E)-5-(3-(4-bromophenyl)-3-(2-fluoro-4-methylphenyl)-1-(hydroxyimino)propyl)-1-methylpyridin-2(1H)-one and 4-carboxyphenylboronic acid (CAS RN 14047-29-1). The compound was purified by silica gel chromatography using a MPLC system eluting with a gradient of dichloromethane:methanol (100:0 to 90:10). Yellow solid. MS (ESI+): m/z=485.2 ([M+H]+).
Reaction SMILES: Br[C:2]1[C:7]2=[CH:8][C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:10]3[C:20]([C:19]4=[C:21]5[C:11]3=[CH:12][CH:13]=[CH:14][C:15]5=[CH:16][CH:17]=[CH:18]4)=[C:6]2[C:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.C([Li])CCC.[B:39]([O:46]CC)([O:43]CC)OCC.Cl>C1COCC1.CCCCCC>[C:22]1([C:9]2[CH:8]=[C:7]3[C:2]([B:39]([OH:43])[OH:46])=[CH:3][CH:4]=[C:5]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:6]3=[C:20]3[C:10]=2[C:11]2[C:21]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]3=4)[CH:14]=[CH:13][CH:12]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOB(OCC)OCC
Reactant: Brc1ccc(-c2ccccc2)c2c3c(c(-c4ccccc4)cc12)-c1cccc2cccc-3c12
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc(-c2ccccc2)c2c3c(c(-c4ccccc4)cc12)-c1cccc2cccc-3c12
Temperature: -80 °C
Reaction time: 12 h
Yield: 54.3 %

Procedure:
An amount of 3 g (6.21 mmol) of 9-bromo-7,12-diphenylbenzofluoranthene synthesized in the same manner as in Exemplary Synthesis 1 was dissolved in dehydrated THF and cooled to −80° C. Then, 4.3 ml (6.8 mmol) of a solution of n butyllithium in n-hexane was added dropwise. Forty minutes later, 1.81 g (12.4 mmol) of triethyl borate was added. After two-hour reaction, a diluted hydrochloric acid solution was passed and allowed to stand for 12 hours. Then, the separated organic layer was recrystallized to obtain 1.51 g (3.37 mmol) of 7,12-diphenylbenzofluoranthene-9-boronic acid. The yield was 54.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][F:22])[C:17](O)=[O:18])[C:10](=[O:23])[CH:9]=2)[CH:7]=1.[NH2:26][C:27]1[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][CH:28]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][F:22])[C:17]([NH:26][C:27]3[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])=[CH:29][CH:28]=3)=[O:18])[C:10](=[O:23])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CCF)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: COc1cn(C(CCF)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
100 mg (274 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-fluorobutanoic acid (racemate), 53.0 mg (274 μmol) of tert-butyl 4-aminobenzoate, 39.0 mg (274 μmol) of Oxima and 43.0 μl (274 μmol) of DIC in 5 ml of dimethylformamide were reacted according to General Method 5B. Filtration gave the title compound. Yield: 117 mg (78% of theory)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[O:11]=[CH:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:16]([O:17][CH3:18])[C:14]=1[OH:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:18][O:17][C:16]1[C:14]([O:15][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[C:13]([CH:21]=[CH:20][CH:19]=1)[CH:12]=[O:11]
Reactant: COc1cccc(C=O)c1O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(C=O)c1Oc1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 71 %

Procedure:
A mixture of 14.10 g (0.10 mole) of 4-fluoronitrobenzene, 16.40 g (0.10 mole) of o-vanillin, 30 g of powdered potassium carbonate, and 40 mL of DMF is heated with stirring to the boiling point. After 10 minutes the mixture is cooled to 100° C. and 300 mL of ice water is added. Petroleum ether (200 mL) is added and the entire mixture filtered and the cake is washed with 200 mL of water and then 200 mL of petroleum ether. The damp cake slurried in 100 mL of methanol and filtered; wt 19.50 g (71% yield); mp 130°-131° C.; mass spectrum (DEI), 273 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[N+:11]([C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1)([O-:13])=[O:12]>>[N+:11]([C:14]1[CH:19]=[C:18]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[NH:9][CH:8]=[CH:7]3)[CH:17]=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: Brc1cccc2cc[nH]c12
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Product: O=[N+]([O-])c1cccc(-c2cccc3cc[nH]c23)c1

Procedure:
Prepared by Procedure I and Scheme T using 7-bromo-1H-indole and 3-nitrophenylboronic acid: ESMS m/e: 238.9 (M+H)+.
Reaction SMILES: FC(F)(F)C1C=C([C:12]([OH:14])=[O:13])C=C2C=1NN=C2.Br[C:18]1[CH:26]=[C:25]2[C:21]([C:22]([C:27]([F:30])([F:29])[F:28])=[N:23][NH:24]2)=[CH:20][CH:19]=1>>[F:28][C:27]([F:30])([F:29])[C:22]1[C:21]2[C:25](=[CH:26][C:18]([C:12]([OH:14])=[O:13])=[CH:19][CH:20]=2)[NH:24][N:23]=1
Reactant: O=C(O)c1cc(C(F)(F)F)c2[nH]ncc2c1
Reactant: FC(F)(F)c1n[nH]c2cc(Br)ccc12
Product: O=C(O)c1ccc2c(C(F)(F)F)n[nH]c2c1

Procedure:
The title compound was prepared by a method analogous to that described in Steps 3-4 of Intermediate 21, using 6-bromo-3-(trifluoromethyl)-1H-indazole. −ESI (M−H) 229.1.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Br:23][C:24]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27].Cl.[CH3:35][NH:36][O:37][CH3:38].Cl>CN(C)C1C=CN=CC=1.ClCCl>[Br:23][C:24]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:25]=1[C:26]([N:36]([CH3:35])[O:37][CH3:38])=[O:27]
Reactant: CNOC
Reactant: Cc1ccc(C(=O)O)c(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(C)cc1Br
Temperature: 25 °C
Reaction time: 13 h
Yield: 100 %

Procedure:
1-Hydroxybenzotriazole (3.78 g), 4-dimethylaminopyridine (3.42 g), and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.40 g) were added to a solution (100 mL) of 2-bromo-4-methylbenzoic acid (5.00 g) and N,O-dimethylhydroxylamine hydrochloride (2.73 g) in dichloromethane, followed by stirring at room temperature for 13 hours. 1N Hydrochloric acid was added to the reaction mixture, followed by extraction with dichloromethane and evaporation of the solvent. After purification, 2-bromo-4,N-dimethyl-N-methoxybenzamide (6.0 g) was yielded. The 2-bromo-4,N-dimethyl-N-methoxybenzamide (6.0 g) was dissolved in an anhydrous tetrahydrofuran solution (50 mL) under a stream of argon. Diisobutylaluminum hydride (24.7 mL, 0.93M hexane solution) was added dropwise to the solution at −78° C., and the mixture was stirred at the same temperature for 2 hours. Methanol (5 mL) was added dropwise to the reaction mixture, and an aqueous saturated ammonium chloride solution (5 mL) was added thereto, the mixture was stirred at room temperature for 1 hour. Sodium sulfate anhydrate was added to the reaction mixture, followed by further stirring for 1 hour. The precipitated matter was removed through filtration by use of Celite, and the filtrate was purified, to thereby yield 2-bromo-4-methylbenzaldehyde (4.0 g). The procedure of Referential Example 9 was repeated, except that 2-bromo-4-methylbenzaldehyde (4.0 g) was used, to thereby yield the title compound (3.7 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:4][CH:3]1[NH:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>CCOC(C)=O.[Pd]>[NH2:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[N:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH:3]([NH:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])[CH2:4]1
Reactant: CCOP(=O)(NC1CN(c2ccncc2[N+](=O)[O-])CCC1C)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOP(=O)(NC1CN(c2ccncc2N)CCC1C)OCC
Reaction time: 18 h
Yield: 86 %

Procedure:
To a solution of diethyl 4-methyl-1-(3-nitropyridin-4-yl)piperidin-3-ylphosphoramidate (1.0 equiv.) in degassed EtOAc (0.1M) was added Pd/C (10% by weight) and the reaction was stirred under a hydrogen atmosphere for 18 h. Filtered and concentrated the filtrate to yield diethyl 1-(3-aminopyridin-4-yl)-4-methylpiperidin-3-ylphosphoramidate in 86% yield. LCMS (m/z): 343.0 (MH+), Rt=1.85 min.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[CH:10]1[C:22]2[NH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH2:13][CH2:12][NH:11]1.Cl[C:24]1[N:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:26][N:25]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH:2]1[CH:10]1[C:22]2[NH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH2:13][CH2:12][N:11]1[C:24]1[N:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:26][N:25]=1
Reactant: Clc1ncc(-c2ccccn2)cn1
Reactant: c1ccc2c(c1)CC(C1NCCc3c1[nH]c1ccccc31)O2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: c1ccc(-c2cnc(N3CCc4c([nH]c5ccccc45)C3C3Cc4ccccc4O3)nc2)nc1

Procedure:
1-(2,3-dihydrobenzofuranyl)-2,3,4,9-tetrahydro-1H-β-carboline (prepared according to the process as disclosed in WO97/43287, Intermediate 10, page 25) (1.35 g, 4.66 mmol), 2-chloro-5-(2-pyridinyl)-pyrimidine (893 mg, 4.66 mmol) and N,N-diisopropylethylamine (1.4 mL) were stirred in DMF (10 mL, anhydrous) at 120° C. for 16 h. The resulting mixture was quenched with 10% NaCl and extracted with ethyl acetate. The extracted organic layer was washed with 10% NaCl, brine and then dried with MgSO4. The reaction mixture solvent was evaporated and the residue purified by column chromatography (silica gel, ethyl acetate:hexanes=4:6) to yield the product as a white solid.