Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])([CH2:31][OH:32])[CH2:18][O:19][C:20](=[O:30])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-:29])=[O:28])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:43](OC)([CH3:45])[CH3:44].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:37]([O:36][C:34]([N:33]1[C:17]([CH2:16][CH2:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:13]=2)([CH2:18][O:19][C:20](=[O:30])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-:29])=[O:28])[CH2:31][O:32][C:43]1([CH3:45])[CH3:44])=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)NC(CO)(CCc1ccc(OCc2ccccc2)cc1)COC(=O)c1ccccc1[N+](=O)[O-]
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C(CCc2ccc(OCc3ccccc3)cc2)(COC(=O)c2ccccc2[N+](=O)[O-])COC1(C)C
Temperature: 95 °C
Reaction time: 6 h

Procedure:
To a solution of 2-nitro-benzoic acid 4-(4-benzyloxy-phenyl)-2-tert-butoxycarbonylamino-2-hydroxymethyl-butyl ester (105 mg, 0.19 mmol) in toluene (2 ml) is added 2.2 dimethoxypropane (0.06 ml, 0.57 mmol, 3 eq) and a catalytic amount of p-toluene sulfonic acid. The reaction mixture is stirred at 95° C. for 6 hours, then concentrated to dryness under negative pressure. 4-[2-(4-Benzyloxy-phenyl)-ethyl]-2,2-dimethyl-4-(2-nitro-benzoyloxy-methyl)-oxazolidine-3-carboxylic acid tert-butyl ester is isolated as an oil (88 mg, 78%) after purification by flash chromatography (Ethyl acetate/Hexane (1/3)).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1.[Cl:17]N1C(=O)CCC1=O>O1CCOCC1.O>[NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][C:3]=1[Cl:17]
Reactant: CCOC(=O)c1ccc(N)c2c1OCCO2
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(Cl)c(N)c2c1OCCO2
Reaction time: 8 h
Yield: 98.8 %

Procedure:
37 g (0.165 mol) of ethyl 8-amino-2,3-dihydro-1,4-benzodioxine-5-carboxylate dissolved in 370 ml of dioxane are introduced into a 1 l round-bottomed flask, 23.2 g (0.174 mol) of N-chlorosuccinimide are added, at room temperature and with magnetic stirring, and the mixture is stirred overnight. It is diluted with water, extracted with ethyl acetate and, after the usual processing of the organic phase, 42 g of compound are obtained, which product is recrystallized from a mixture of diethyl ether and diisopropyl ether.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:74][C:75]([CH3:79])([CH3:78])[CH2:76][NH2:77]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:30][CH2:31][CH:32]([N:35]4[CH2:36][CH2:37][CH:38]([CH3:41])[CH2:39][CH2:40]4)[CH2:33][CH2:34]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:77][CH2:76][C:75]([CH3:79])([CH3:78])[CH3:74])=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42]
Reactant: CC(C)(C)CN
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NCC(C)(C)C)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and 2,2-dimethyl-1-propanamine (8.65 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (17.8 mg, 50%). LC-MS m/z 643 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:27][O:28][CH2:29]Cl>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:27][O:28][CH3:29])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: COCCl
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCOc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 70 °C
Yield: 54 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (30 mg, 0.11 mmol), potassium carbonate (31 mg, 0.23 mmol) and chloromethyl methyl ether (26 μL, 0.34 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 70° C. for 2 hour. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using 20–30% hexanes/ethyl acetate afforded 1 g mg (54%) of 3-(2-Pyridyl)-5-(3-cyano-5-(methoxymethoxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.86 (d, 1H), 8.24 (d, 1H), 8.22 (s, 1H), 8.15 (s, 1H), 7.91 (t, 1H), 7.56 (s, 1H), 7.49 (m, 1H), 5.31 (s, 2H), 3.52 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17](=O)[C:16]3[C:15]([C:19](OCC)=[O:20])=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10][CH:9]2[C:24]2N(C)C=CN=2)=[CH:4][CH:3]=1.O.[NH2:31][NH2:32]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3=[N:31][NH:32][C:19](=[O:20])[C:15]4[CH:14]=[CH:13][CH:12]=[C:11]([C:16]=43)[NH:10][CH:9]2[C:24]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][CH:8]=[CH:17]3)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(F)cc1)C(c1nccn1C)N2
Solvent: CO
Solvent: O
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccc3ncccc3c1)C2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25 %

Procedure:
A mixture of ethyl 3-(4-fluorophenyl)-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (260 mg, 0.59 mmol) in 85% hydrazine monohydrate (1 mL) and methanol (5 mL) was stirred at room temperature for 4 h. The resulting mixture was filtered and washed by water (20 mL) and methanol (5 mL) to obtain the title compound as a white solid (61 mg, yield 25%). LC-MS (ESI) m/z: 409(M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 4.52-4.55 (d, J=9.6 Hz, 1H), 4.98-5.01 (d, J=9.6 Hz, 1H), 6.97-7.01 (m, 2H), 7.19-7.22 (m, 3H), 7.41-7.43 (d, J=7.6 Hz, 1H), 7.46-7.50 (m, 1H), 7.54 (s, 1H), 7.59-7.63 (t, J=7.6 Hz, 1H), 7.77-7.79 (m, 1H), 7.84 (s, 1H), 7.91-7.93 (m, 1H), 8.24-8.26 (d, J=7.6 Hz, 1H), 8.85-8.86 (m, 1H), 12.20 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:13]=O.[OH:15][C:16]1[C:17]([C:26]([NH:28][NH2:29])=[O:27])=[CH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2>>[OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:13]=[N:29][NH:28][C:26]([C:17]1[C:16]([OH:15])=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)=[O:27]
Reactant: NNC(=O)c1cc2ccccc2cc1O
Reactant: O=Cc1c(O)cc(O)c2ccccc12
Product: O=C(NN=Cc1c(O)cc(O)c2ccccc12)c1cc2ccccc2cc1O
Yield: 83 %

Procedure:
Following the general procedure of Example 1, condensation of 2, 4-dihydroxy-1-naphthaldehyde and 3-hydroxy-2-naphthoic hydrazide yielded a yellow crystal (83%) [recrystallized from DMSO/H2O (8:2, v/v)]: mp>280° C. (dec); 1H NMR d 12.42 (br s, 1 H), 11.65 (s, 1 H), 10.96 (br s, 1 H), 10.59 (s, 1 H), 8.99 (s, 1H), 8.07 (s, 1H), 7.77 (d, 1 H, J=8.4 Hz), 7.67 (d, 1 H, J=8.4 Hz), 7.48 (d, 1 H, J=8.1 Hz), 7.32 (d, 1H, J=8.4 Hz), 7.13 (t, 1H, J=7.5 Hz), 7.06 (t, 1 H, J=7.5 Hz), 6.91 (s, 1 H), 6.90 (m, 2 H); 13C NMR d 162.92, 160.47. 157.70, 154.20, 148.22, 135.97, 132.99, 130.33, 128.72, 128.33 (2 C), 126.84, 125.92, 123.91, 122.94, 122.55, 120.80, 120.32, 119.66, 110.70, 101.38, 100.49; HRMS Calcd for C22H16N2O4 :372.1110, found 372.1095; Anal. (C22H16N2O4 2DMSO H2O) C, H, N.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[CH3:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17](O)=O.CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[CH3:1][N:2]1[C:3]2=[N:4][CH:5]=[C:6]([C:10]([F:13])([F:11])[F:12])[CH:7]=[C:8]2[N:9]=[C:17]1[C:16]1[CH:20]=[CH:21][N:22]=[CH:23][C:15]=1[CH3:14]
Reactant: Cc1cnccc1C(=O)O
Reactant: CNc1ncc(C(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: Cc1cnccc1-c1nc2cc(C(F)(F)F)cnc2n1C
Temperature: 120 °C
Reaction time: 5 h
Yield: 22.9 %

Procedure:
A mixture of 0.40 g of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 0.32 g of 3-methylisonicotinic acid, 0.44 g of WSC and 10 ml of pyridine was stirred for 5 hours at 120° C. The reaction mixture was cooled down to room temperature. Into the reaction mixture was poured water, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate, then, concentrated under reduced pressure. To the residue was added a mixture of 0.60 g of p-toluenesulfonic acid monohydrate and 10 ml of toluene, and the mixture was stirred for 1 hour at 120° C. Toluene was distilled off from this mixture. To the residue was added 10 ml of phenyl bromide, and the mixture was stirred for 4 hours at 150° C. The reaction mixture was cooled down to room temperature. Into the reaction mixture was poured water, and the mixture was extracted three times with ethyl acetate. The organic layer was dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.14 g of 3-methyl-2-(3-methylpyridin-4-yl-)-6-trifluoromethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as present active compound 216).
Reaction SMILES: [NH3:1].C([Li])CCC.[C:7]1([C:13]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([CH2:18][CH:19]2[CH2:24][CH:23]3[CH2:25][CH2:26][N:20]2[CH2:21][CH2:22]3)[C:14]([O:16]C)=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)=O>CCCCCC.O1CCCC1>[C:27]1([C:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)([CH2:18][CH:19]2[CH2:24][CH:23]3[CH2:25][CH2:26][N:20]2[CH2:21][CH2:22]3)[C:14]([NH2:1])=[O:16])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: N
Reactant: COC(=O)C(CC1CC2CCN1CC2)(c1ccccc1)c1ccccc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: NC(=O)C(CC1CC2CCN1CC2)(c1ccccc1)c1ccccc1

Procedure:
To a solution of 25 parts by volume liquid ammonia in 22 parts dry tetrahydrofuran is added dropwise over a 5 minute period 10 parts by volume of a 2.3 M solution of butyl lithium in hexane under reflux under a dry ice condenser. Then, a solution of 3.9 parts methyl 2,2-diphenyl-3-(1-azabicyclo[2.2.2]oct-2-yl)propionate in 18 parts dry tetrahydrofuran is added dropwise, with stirring. After stirring the resulting mixture under reflux for 3 hours the dry ice condenser is removed, and the mixture stirred at ambient temperature for a further two hours. The solvents are then removed in vacuo. The residual gum is suspended in water and extracted with a 1:1 ether-benzene solution. The ether-benzene extract is separated, washed with water, dried over anhydrous sodium sulfate and stripped in vacuo. The residue is triturated with 50 parts of n-pentane. The undissolved solid is filtered off, washed with n-pentane and air dried to give a white powder. This powder is recrystallized from a mixture of benzene and petroleum ether to afford, as white needles, 2,2-diphenyl-3-(1-azabicyclo[2.2.2]oct-2-yl)propionamide. This compound melts at about 192°-194° C. and is represented by the following structural formula. ##STR12##
Reaction SMILES: [F:1][C:2]1([F:20])[C:10]2[C:5](=[C:6]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]=[C:8](I)[C:9]=2[OH:11])[CH2:4][CH2:3]1.[H][H]>[Pd].C(OCC)(=O)C>[F:1][C:2]1([F:20])[C:10]2[C:5](=[C:6]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]=[CH:8][C:9]=2[OH:11])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CCOC(=O)CCc1cc(I)c(O)c2c1CCC2(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(O)c2c1CCC2(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
Into a 50-mL round-bottom flask was placed ethyl 3-(1,1-difluoro-7-hydroxy-6-iodo-2,3-dihydro-1H-inden-4-yl)propanoate (80 mg, 0.20 mmol, 1.00 equiv), ethyl acetate (3 mL), Palladium on carbon (80 mg) and hydrogen was introduced last. The resulting solution was stirred overnight at 25° C. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The resultant residue was purified by TLC with ethyl acetate/petroleum ether (1:3) to give 40 mg (73%) of ethyl 3-(1,1-difluoro-7-hydroxy-2,3-dihydro-1H-inden-4-yl)propanoate as a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C14H16F2O3, 269.1 (M−H). found 269.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]=1[NH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].O>CN(C=O)C>[CH3:34][O:33][C:31](=[O:32])[CH2:30][NH:22][C:10]1[CH:11]=[CH:12][C:13]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1OCc1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CNc1ccc(Oc2ccccc2)cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 2-benzyloxy-4-phenoxyphenylamine (400 mg, 1.37 mmol) and K2CO3 (284 mg, 2.05 mmol) in DMF (5 mL) is added methyl bromoacetate (231 mg, 1.51 mmol). The mixture is stirred at 60° C. for 90 min., then an additional methyl bromoacetate (50 mg) is added and the mixture is stirred at 60° C. for 1 h. The mixture is allowed to cool to ambient temperature, then poured into water and extracted into EtOAc. The organic phase is washed with water (3×), saturated NaCl (1×) and dried over Na2SO4. The solvent is removed under reduced pressure to afford (2-benzyloxy-4-phenoxyphenylamino)acetic acid methyl ester. This is used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([F:20])([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.Cl.[OH:24][NH2:25].C([O-])(=O)C.[Na+]>O>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([F:20])([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[N:25][OH:24])=[CH:14][CH:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C=O)cc2)C1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C=NO)cc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 3-fluoro-3-(4-formyl-phenyl)-azetidine-1-carboxylic acid tert-butyl ester (4.5 g, 16.11 mmol, 1 eq) in mixture of methanol (50 mL) and water (40 mL) was added hydroxyl amine hydrochloride (1.66 g, 24.17 mmol, 1.5 eq) followed by addition of sodium acetate (2.37 g, 29.0 mmol, 1.8 eq) at room temperature. Resulting reaction mixture was stirred at room temperature for 24 hours. After complete consumption of starting material, reaction mixture was concentrated in vacuo to afford to yellow colored residue, which was diluted by water (120 mL) and extracted with ethyl acetate (3×80 mL). Combined organic phase was washed with brine solution (70 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get yellow semi solid (2.3 g, Crude). Crude was purified by Combiflash using 40 g Redisep column. Desired compound was eluted in 19% ethyl acetate in hexane to afford title compound as yellow semi solid (1.0 g, 21.1%). 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 4.20-4.27 (m, 2H), 4.36-4.44 (m, 2H), 7.47 (d, J=8.28 Hz, 2H), 7.64 (d, J=8.2 Hz, 2H), 8.13 (s, 1H). LC-MS (m/z): 293.1 (M−H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[NH2:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]1>>[F:26][CH:25]([F:27])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([NH:28][C@@H:29]3[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc(N2CCOCC2)n1
Yield: 88 %

Procedure:
Reaction of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole with tert-butyl (3R)-3-amino-1-piperidinecarboxylate as in Example 28 gave tert-butyl (3R)-3-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]amino}-1-piperidinecarboxylate in 88% yield: 1H NMR (DMSO-d6) (rotamers) δ 8.11 and 8.00 (2d, J=8.1, 8.2 Hz, 1H), 7.89 and 7.71 (2t, JHF=53.1 Hz, 1H), 7.38 (t, J=8.2 Hz, 1H), 6.95 and 6.94 (2d, J=8.0, 7.8 Hz, 1H), 3.97 (s, 3H), 3.79-3.69 (m, 10H), 3.02-2.80 (m, 2H), 1.97-1.93 (m, 1H), 1.76 (m, 1H), 1.59-1.20 (m, 2H), 1.35 (s, 9H). Anal. Calcd. for C26H34F2N8O4: C, 55.7; H, 6.1; N, 20.0. Found: C, 55.9; H, 6.1; N, 20.1%.
Reaction SMILES: N1C=CC=CC=1C1C=CC=CN=1.CN(C=O)C.Cl[C:19]1[C:20]([C:28]([OH:30])=[O:29])=[N:21][C:22]([Cl:27])=[C:23]([Cl:26])[C:24]=1[Cl:25]>[Zn].O>[Cl:25][C:24]1[C:23]([Cl:26])=[C:22]([Cl:27])[N:21]=[C:20]([C:28]([OH:30])=[O:29])[CH:19]=1
Reactant: O=C(O)c1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: [Zn]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Cl)c(Cl)c(Cl)n1
Reaction time: 0.08 h
Yield: 133.1 %

Procedure:
A 100 mL round bottom flask equipped with a magnetic stir bar was charged with NiCl2.6H2O (105 mg, 0.442 mmol), 2,2′-bipyridine (150 mg, 0.960 mmol), DMF (15 mL) and water (2 mL). The resulting mixture was allowed to stir for 5 min, and then zinc dust (2.006 g, 30.7 mmol) was added. The reaction mixture was allowed to stir at ambient temperature for 15 min until a very dark blue/black solution was present. Solid 3,4,5,6-tetrachloropicolinic acid (2.017 g, 7.7 mmol) was added through the top of the reactor. The reaction mixture was allowed to stir at 27° C. for 5.25 h, and the crude reaction mixture was filtered through a course frit filter and washed with DMF (5 mL). The resulting filtrate was diluted with an equal volume of 10% HCl (aq) which resulted in the precipitation of a light yellow solid that was collected by filtration. The solid was collected by vacuum filtration to give the title compound (2.32 g, 81.5%) that was 61.5% pure as analyzed by calibrated HPLC.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:12][C:11]([NH2:26])=[CH:10][CH:9]=2)=[O:5])[CH3:2].C[Si]([N:31]=[C:32]=[O:33])(C)C>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:12][C:11]([NH:26][C:32]([NH2:31])=[O:33])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccc(N)cc2c1CCCNC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1[nH]c2ccc(NC(N)=O)cc2c1CCCNC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
5-Amino-3-[3-(t-butoxycarbonylamino)-propyl]-1H-indole-2-carboxylic acid ethyl ester (40 mg, 0.11 mmol, 1.0 equiv) was dissolved in 10 mL of methylene chloride and 1 mL of triethylamine. Trimethylsilyl isocyanate was added and the solution was stirred overnight. In the morning the reaction was washed with 10 mL of water and the organic layer was concentrated. The crude residue was purified by flash chromatography on silica (10 g of SiO2) using 0% ethyl acetate in methylene chloride to 100% ethyl acetate graded over 25 min at a flow rate of 15 mL/min-then 100% ethylacetate for another 15 min. The fractions with pure product (TLC) were combined and concentrated to provide 5-ureido-3-[3-(t-butoxycarbonylamino)-propyl]-1H-indole-2-carboxylic acid ethyl ester as a white solid (41 mg). This material was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](O)=[O:24].[CH3:37][N:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[CH2:47][NH2:48]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH:48][CH2:47][C:39]1[N:38]([CH3:37])[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=1)=[O:24]
Reactant: Cn1c(CN)nc2ccccc21
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCc2nc3ccccc3n2C)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with C-(1-methyl-1H-benzoimidazol-2-yl)-methylamine.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([C:4]2[C:5]3[O:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[C:9]=3[CH:1]=[CH:2][CH:3]=2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: OB(O)c1cccc2c1oc1ccccc12
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: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2cccc3c2oc2ccccc23)cc1
Temperature: 0 °C
Yield: 62.6 %

Procedure:
To a mixture of dibenzofuran-4-boronic acid (30 g, 0.14 mol), 4-bromonitrobenzene (25.7 g, 0.127 mol), sodium carbonate (150 g) in toluene/water (500 mL/500 mL) was added tetrakis(triphenylphosphine)palladium(0) (8.2 g, 0.7 mol %) and the resulting reaction mixture was refluxed for 20 h under N2 atmosphere. The toluene layer was separated and concentrated to 200 mL. The concentrated solution was cooled to 0° C. and filtered off. The collected solid was dried and dissolved in chloroform and the obtained solution was filtered through celite bed to remove insoluble materials. The filtrate was concentrated under vacuum to give the title compound (23 g, 58%).