Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:18][C:19]3[N:28]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])[C:27](=[O:37])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[C:38]#[C:39][CH2:40][CH2:41][CH2:42][C:43](O)=[O:44])[N:20]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:3]=12.CCN=C=NCCCN(C)C.Cl.[NH:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1>CN(C)C1C=CN=CC=1.CN(C=O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:18][C:19]3[N:28]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])[C:27](=[O:37])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[C:38]#[C:39][CH2:40][CH2:41][CH2:42][C:43]([N:58]4[CH2:63][CH2:62][O:61][CH2:60][CH2:59]4)=[O:44])[N:20]=3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[C:3]=12
Reactant: C1COCCN1
Reactant: Nc1ncnc2c1c(-c1ccc(O)cc1)nn2Cc1nc2cccc(C#CCCCC(=O)O)c2c(=O)n1Cc1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc(O)cc1)nn2Cc1nc2cccc(C#CCCCC(=O)N3CCOCC3)c2c(=O)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 4 (16.0 mg, 26 μmol), 4-dimethylaminopyridine (0.6 mg, 5.2 μmol), and EDC hydrochloride (5.3 mg, 28 μmol) in DMF (0.5 mL) was added morpholine (2.3 μL, 26 μmol). The reaction mixture was stirred at RT overnight and then diluted with water (5.0 mL). The resulting solid was collected by filtration and purified by flash column chromatography, eluting with 0-7% methanol in DCM to afford the title compound, Example 5, (7.0 mg, 57%) as a yellow solid: m/z 689/691 (M+H)+ (ES+); Rt 3.54 min; 1H NMR (500 MHz, DMSO-d6) δ: 1.71 (2H, quin), 2.43-2.49 (2H, m), 2.52-2.55 (2H, m), 3.20-3.26 (2H, m), 3.28-3.33 (4H, m), 3.44 (2H, t), 5.28 (2H, s), 5.72 (2H, s), 6.17 (1H, d), 6.78 (1H, t), 6.87 (2H, d), 7.02 (1H, t), 7.10 (1H, d), 7.32 (2H, d), 7.60 (1H, d), 7.67 (1H, d), 7.79 (1H, t), 8.16 (1H, s), 9.75 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=O)[NH:9][CH:8]=[N:7][C:6]=2[N:12]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:10]1[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[N:12][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2nc(F)ccc12
Product: Fc1ccc2c(Cl)ncnc2n1

Procedure:
A suspension of 7-fluoropyrido[2,3-d]pyrimid-4 (3H)-one (0.20 g, 1.21 mmol) in POCl3 (10 mL) is heated under reflux for 2 h. The volatiles are then removed under reduced pressure, and the residue is partitioned between aqueous NaHCO3 and EtOAc. The organic extract is worked up to give crude 4-chloro-7-fluoropyrido[2,3-d]pyrimidine, which is used directly in the next reaction. A solution of this product (0.20 g, 1.09 mmol) and 3-bromoaniline (0.23 mL, 2.18 mmol) in propan-2-ol (1.0 mL) and THF (10 mL) containing a trace of conc. HCl is stirred at 20° C. for 1 h, and then concentrated to dryness. The residue is dissolved in EtOAc, washed with aqueous NaHCO3, and worked up to give an oil, which is chromatographed on silica gel. Elution with EtOAc/petroleum ether (1:5) gives 3-bromoaniline, while EtoAc/petroleum ether (1:1) elutes 4-(3-bromoanilino)-7-fluoropyrido[2,3-d]pyrimidine (0.18 g, 47%), mp (MeOH) 211-213° C. 1H NMR (DMSO) δ 10.18 (1H, brs), 9.17 (1H, t, J=8.6 Hz), 8.80 (1H, s), 8.17 (1H, t, J=1.8 Hz), 7.85 (1H, dt, Jd =7.6 Hz, Jt =1.8 Hz), 7.53 (1H, dd, J=8.6, 2.7 Hz), 7.41-7.34 (2H, m).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].[N+:7]([C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13]Br)([O-:9])=[O:8].P([O-])([O-])([O-])=O>CN(C=O)C.O>[N+:7]([C:10]1[CH:11]=[C:12]([CH2:13][O:3][CH2:2][CH2:1][OH:4])[CH:15]=[CH:16][CH:17]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: OCCO
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(COCCO)c1
Reaction time: 0.5 h
Yield: 358 %

Procedure:
Ethylene glycol (7.18 g) in anhydrous DMF (50 ml) was treated at 0° under nitrogen with sodium hydride (60% dispersion in mineral oil, 1.85 g) and the mixture stirred for 30 min. 3-Nitrobenzyl bromide (5.00 g) was added and the mixture was warmed to 200 over 1 h and stirred for a further 15 h. Phosphate buffer (pH 6.5, 100 ml) and water (100 ml) were added and the product was extracted with EtOAc (2×150 ml). The combined organic layer was washed with water (2×200 ml) and dried (Na2SO4). Solvent evaporation in vacuo gave a residue that was purified by Biotage. Elution with EtOAc-PE (1:1 then 2:1) followed by solvent evaporation in vacuo gave the title compound (16.34 g) HPLC RT=1.554 min. TSP+ve 215 (MNH4)+.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.N1C=CC=CC=1.[OH:29][CH2:30][C:31]1[N:32]([CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43])[C:33]2[C:38]([CH:39]=1)=[CH:37][CH:36]=[CH:35][CH:34]=2>ClCCl>[CH:30]([C:31]1[N:32]([CH2:40][CH2:41][C:42]([O:44][CH3:45])=[O:43])[C:33]2[C:38]([CH:39]=1)=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:29]
Reactant: COC(=O)CCn1c(CO)cc2ccccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CCn1c(C=O)cc2ccccc21
Reaction time: 0.08 h

Procedure:
Compound 1 was synthesized as follows. Dess-Martin periodinane (5.195 g, 12.25 mmol, 1.09 equiv) was suspended in a mixture of dichloromethane (20 mL) and pyridine (2.70 mL, 33.5 mmol, 3.0 equiv). After 5 min, the resulting white suspension was transferred to a solution of methyl 3-(2-(hydroxymethyl)-1H-indol-1-yl)propanoate (2.611 g, 11.19 mmol) in dichloromethane (10 mL), resulting in a red-brown suspension. After 1 h, the reaction was quenched with sodium thiosulfate (10% aqueous solution, 5 mL) and sodium bicarbonate (saturated aqueous solution, 5 mL). The aqueous layer was extracted with dichloromethane (3×20 mL), then dried over sodium sulfate, filtered, and concentrated to a brown oil. Purification by silica gel chromatography (5-50% ethyl acetate in hexanes) yielded the product as a colorless oil (2.165 g, 9.363 mmol, 84%). 1H NMR (400 MHz, CDCl3) δ 9.87 (s, 1H), 7.73 (dt, J=8.1, 1.0 Hz, 1H), 7.51 (dd, J=8.6, 0.9 Hz, 1H), 7.45-7.40 (m, 1H), 7.29 (d, J=0.9 Hz, 1H), 7.18 (ddd, J=8.0, 6.9, 1.0 Hz, 1H), 4.84 (t, J=7.2 Hz, 2H), 3.62 (s, 3H), 2.83 (t, J=7.2 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 182.52, 171.75, 140.12, 135.10, 127.20, 126.39, 123.46, 121.18, 118.55, 110.62, 51.83, 40.56, 34.97. HRMS (ESI) calcd for C13H13NO3Na [M+Na]+: 254.0793. found: 254.0786.
Reaction SMILES: C([O:3][P:4]([CH2:9][N:10]1[C:19]2[C:14](=[CH:15][C:16]([N+:26]([O-:28])=[O:27])=[C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[CH:18]=2)[NH:13][C:12](=[O:29])[C:11]1=[O:30])(=[O:8])[O:5]CC)C.C[Si](C)(C)Br.O>C(#N)C>[N+:26]([C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][C:17]=1[N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[N:10]([CH2:9][P:4]([OH:5])(=[O:3])[OH:8])[C:11](=[O:30])[C:12](=[O:29])[NH:13]2)([O-:28])=[O:27]
Reactant: CCOP(=O)(Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(N3CCOCC3)cc21)OCC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: O
Product: O=c1[nH]c2cc([N+](=O)[O-])c(N3CCOCC3)cc2n(CP(=O)(O)O)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
259 mg of (6-nitro-7-morpholino-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl)methanephosphonic acid diethyl ester is mixed in 10 ml of absolute acetonitrile with 628 mg of trimethylbromosilane and stirred for 1 hour at room temperature. A little water is added, and it is evaporated to dryness. The residue is chromatographed on silanized silica gel with methanol as eluant. 60 mg of (6-nitro-7-morpholino-1,2,3,4-tetrahydro-2,3-dioxoquinoxalin-1-yl)methanephosphonic acid is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:20][CH:19]=2)(=[O:23])=[O:22])=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1ccc(C2CCCN2)cc1
Product: COc1ccc(S(=O)(=O)N2CCCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, white solid, m.p. 134° C. and MS: m/e=335 (M+) was prepared in accordance with the general method of example I e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-methoxy-benzenesulfonyl chloride.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[S:12]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13]1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(COC)OC.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.O>[CH3:11][O:10][C:5]1[CH:4]=[CH:3][C:2]([C:14]2[CH:15]=[CH:16][S:12][CH:13]=2)=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: COc1ccc(Br)cc1C=O
Reactant: OB(O)c1ccsc1
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: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(-c2ccsc2)cc1C=O
Temperature: 80 °C
Reaction time: 5 h
Yield: 81.6 %

Procedure:
Under nitrogen atmosphere, to a solution of 5-bromo-2-methoxybenzaldehyde (350 mg) in dimethoxyethane (3.5 ml) were added 3-thiopheneboronic acid (417 mg), tetrakis(triphenylphosphine)palladium (0) (282 mg), and 2M sodium carbonate (4.9 ml) at room temperature. After being heated at 80° C. with stirring for 5 hours, the reaction mixture was poured into mixed solvents of ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (6 g) using a mixed solvent of hexane and ethyl acetate (10:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give 2-methoxy-5-(3-thienyl)benzaldehyde (290 mg) as yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:18])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]#[N:17])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[OH-].[Na+].CCOCC>C1COCC1>[NH2:17][CH2:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)([OH:18])[CH2:13][CH2:12]1
Reactant: N#CCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
To a stirred solution of 3-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]propionitrile (3.51 g, 13.2 mmol, 1.0 equiv) in anhydrous THF (20 mL) under argon was added a solution of BH3 in THF (1.Q M, 46.4 mL, 3.5 equiv) at room temperature. The mixture was refluxed for 4.5 hours and then cooled to room temperature. Aqueous HCl (6 N, 30 mL) was added and stirring was continued for 2 hours at 55-60° C. The mixture was basified to pH 9 by addition of 6 N aqueous NaOH and extracted with CH2Cl2 (3×150 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was dissolved in CH2Cl2 (20 mL) and treated with HCl in ether (1.0 M, 27.7 mL, 2.1 equiv). The solvents were removed, ether (60 mL) was added, the mixture was filtered, and the filter cake was washed with ether (2×20 mL). Water (40 mL) was added to the resulting white solid, the pH was adjusted to 10 with 1 M NaOH, and the aqueous phase was extracted with CH2Cl2 (3×80 mL). The combined organic solutions were dried over MgSO4 and concentrated to give 3.10 g (87%) of white solid, which was characterized spectroscopically.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:13][C:14]1[C:19]2[C@H:20]3[C@H:25]([CH2:26][CH2:27][C:18]=2[CH:17]=[CH:16][CH:15]=1)[NH:24][CH2:23][CH2:22][CH2:21]3>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:24]3[C@@H:25]4[C@H:20]([C:19]5[C:14]([F:13])=[CH:15][CH:16]=[CH:17][C:18]=5[CH2:27][CH2:26]4)[CH2:21][CH2:22][CH2:23]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: Fc1cccc2c1[C@@H]1CCCN[C@H]1CC2
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@H]2c3c(F)cccc3CC[C@@H]21
Yield: 41 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and trans-10-fluoro-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 41% of theory; LC (method 1): tR=2.76 min; Mass spectrum (ESI+): m/z=350 [M+H]+.
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=CC=1.[CH3:32][C:33]1([CH3:39])[CH2:38][NH:37][CH2:36][CH2:35][NH:34]1>>[CH3:32][C:33]1([CH3:39])[N:34]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])[CH2:35][CH2:36][N:37]([C:27]([C@@H:11]2[CH2:10][C@H:9]([SH:8])[CH2:13][N:12]2[C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)=[O:15])=[O:29])[CH2:38]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: CC1(C)CNCCN1
Product: CC1(C)CN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 106 %

Procedure:
Following a procedure similar to that described in Preparation 38, but using 0.35 g of (2S,4S)-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)-2-pyrrolidinecarboxylic acid, 0.15 g of N,N'-carbonyldiimidazole and 0.13 g of 2,2-dimethylpiperazine, 250 mg of the title compound were obtained as an amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([CH2:7][CH:8](C(OCC)=O)[C:9]([O:11]CC)=[O:10])=[CH:4][C:3]=1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26].[OH-].[K+]>C(O)C>[NH2:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[C:19](=[O:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26]
Reactant: CCOC(=O)C(Cc1cc(C(=O)c2ccccc2Cl)c(N)s1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Nc1sc(CCC(=O)O)cc1C(=O)c1ccccc1Cl
Temperature: 80 °C
Yield: 72.8 %

Procedure:
Diethyl 2-(5-amino-4-(2-chlorobenzoyl)thiophen-2-ylmethyl)malonate (20 g) and a 4M potassium hydroxide aqueous solution (30 ml) were added to ethanol (120 ml), and the mixture was refluxed under heating for 2 hours. The solvent was evaporated, and the residue was dissolved in water. 1.2M Hydrochloric acid was added to adjust the solution to pH 3. The mixture was extracted with ethyl acetate to give a product and the product was washed with brine, and dried over magnesium sulfate. The solvent was evaporated. Dimethylformamide (30 ml) and toluene (70 ml) were added to the residue, and the mixture was heated at 80° C. for 1 hour. The mixture was washed with water, dried over magnesium sulfate and concentrated to give 11.0 g of 3-(5-amino-4-(2-chlorobenzoyl)thiophen-2-yl)propionic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[C:12](Cl)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C(=O)([O-])O.[Na+].Cl>O.CCOCC>[C:12]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11])([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cc(C(=O)O)ccc1N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: Cc1cc(C(=O)O)ccc1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 45.3 %

Procedure:
4-Amino-3-methylbenzoic acid (5.0 g) was suspended in water (80 ml) and, thereafter, an ether solution (20 ml) of carbobenzoxychloride (3.7 g) and sodium hydrogen carbonate (3.6 g) were alternately added to the suspension under cooling with ice. Following stirring for 2.5 h at room temperature, an ether solution (95 ml) of carbobenzoxychloride (3.7 g) and sodium hydrogen carbonate (7.2 g) were further added alternately under cooling with ice, and the mixture was stirred for 1.5 h at room temperature. After rendering the reaction solution acidic with 4N HCl, the separating insoluble matter was recovered by filtration. The recovered solids were vacuum-dried to yield the end product (2.8 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:14][Si:15]([CH2:18][CH2:19][O:20][CH2:21]Cl)([CH3:17])[CH3:16]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:9])([O:11][CH2:21][O:20][CH2:19][CH2:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[CH3:10])=[CH:6][N:7]=1
Reactant: CC(C)(O)c1ccc(Br)nc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(OCOCC[Si](C)(C)C)c1ccc(Br)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
To compound 31 (532 mg, 2.46 mmol) in anhydrous DMF (5 mL) at 0° C. is added sodium hydride (60% in mineral oil, 138 mg, 3.45 mmol). The mixture is stirred at rt for 1 h and then cooled to 0° C., to which is added SEMCl (0.564 uL, 3.2 mmol). The mixture is stirred at rt for 16 h, 50° C. for 1 h, cooled to rt and quenched with water, extracted with ethyl acetate. The organic phase is washed with brine, dried and rotavaped. The oily residue is purified by silica gel chromatography (10-15% ethyl acetate in heptane) to afford the title compound as clear oil (474 mg, 56%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:21][C:22]1[N:23]=[CH:24][C:25]2[C:30]3[CH:31]=[CH:32][NH:33][C:34](=[O:35])[C:29]=3[N:28]([CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[C:26]=2[N:27]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:36]1([N:28]2[C:26]3[N:27]=[C:22]([NH:21][C:2]4[N:7]=[N:6][C:5]([N:8]5[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]5)=[CH:4][CH:3]=4)[N:23]=[CH:24][C:25]=3[C:30]3[CH:31]=[CH:32][NH:33][C:34](=[O:35])[C:29]2=3)[CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: Nc1ncc2c3cc[nH]c(=O)c3n(C3CCCC3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)nn2)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4c5cc[nH]c(=O)c5n(C5CCCC5)c4n3)nn2)CC1
Temperature: 120 °C

Procedure:
A mixture of tert-butyl 4-(6-chloropyridazin-3-yl)piperazine-1-carboxylate (0.060 g, 0.20 mmol), compound 83 (0.054 g, 0.20 mmol), Xantphos (0.017 g, 0.030 mmol), Pd2(dba)3 (0.014 g, 0.015 mmol), and sodium tert-butoxide (0.029 g, 0.30 mmol) in dioxane was purged with nitrogen gas for 1 minute. The reaction was heated at 120° C. for 6 hours and then cooled to room temperature. The solvent was removed by filtration. The residue was washed with 2×1 ml dioxane. The product was then dissolved in 10 mL methanol/DCM (1:1) and concentrated. The crude material was re-dissolved in 4 mL methanol and purified on a C-18 reversephase column (150×30 mm, 4 micro) using Mass directed preperative HPLC and gradient elution of acetonitrile in water containing 0.1% TFA to give the title compound 162. LCMS-ESI (POS), M/Z, M+1: 532.3
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]([C:12]2[CH:17]=[C:16]([N:18]3[CH:22]=[CH:21][N:20]=[CH:19]3)[CH:15]=[CH:14][C:13]=2[N+:23]([O-])=O)[C:10]=1[CH3:11])=[O:5])[CH3:2]>C(O)C.[Pd]>[NH2:23][C:13]1[CH:14]=[CH:15][C:16]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[CH:17][C:12]=1[N:9]1[C:10]([CH3:11])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=[CH:8]1
Reactant: CCOC(=O)c1ncn(-c2cc(-n3ccnc3)ccc2[N+](=O)[O-])c1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ncn(-c2cc(-n3ccnc3)ccc2N)c1C
Yield: 97.1 %

Procedure:
A solution of 4-ethoxycarbonyl-5-methyl-1-(2-nitro-5-(1-imidazolyl)phenyl)-1H-imidazole (14 g, 41 mmol) in ethanol (1.0 l) was hydrogenated in a PARR hydrogenation apparatus at 30 psi and 25° C. using 1.0 g 5% Pd-C as a catalyst. The reaction mixture was filtered and concentrated in vacuo to give 12.4 g (98%) of 1-(2-amino-5-(1-imidazolyl)phenyl)-4-ethoxycarbonyl-5-methyl-1H-imidazole.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:7][C:6](=[N:9]O)[CH2:5][CH2:4]1>CO.[OH-].[Na+].O>[CH3:1][N:2]([CH3:17])[C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2ccccc2)CCC(=NO)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)C1(c2ccccc2)CCC(N)CC1

Procedure:
4-Dimethylamino-4-phenyl-cyclohexanone oxime (11 g) was dissolved in methanol (200 ml) and diluted with 5M NaOH (200 ml). Devarda alloy (30 g) was added in portions to this mixture. The reaction temperature here was between 50-60° C. 15 minutes after completion of the addition, the mixture was diluted with water (150 ml), methanol was removed in vacuo, and the aqueous solution was extracted with ether (5×50 ml). The combined extracts were dried over Na2SO4 and concentrated. N,N-Dimethyl-1-phenylcyclohexane-1,4-diamine was obtained as a yellow oil (10.0 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:12]=2[CH:13]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>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.CCO>[OH:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:12]=3[CH:13]=2)=[C:2]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: Oc1ccc(-c2cc3cc(O)ccc3o2)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Product: Oc1ccc(-c2cc3cc(O)ccc3o2)c(-c2ccccc2)c1
Yield: 47.9 %

Procedure:
Compound 102 (0.2 g, 0.69 mmol) in a solution consisting of Tol/EtOH/2M Na2CO3 aq (5/1/5) was treated with phenylboronic acid (0.12 g, 1.0 mmol) and cat Pd(PPh3)4 and heated to reflux until TLC analysis indicated complete reaction. The reaction was worked up by acidifying with 2 N HCl aq and extracting with EtOAc. The organic layer was washed with saturated NaHCO3 aq, brine, and dried over MgSO4. After filtering and concentrating, the crude material was chromatographed on silica gel (1:9 EtOAc/hexanes to 4:6 EtOAc/hexanes) and then triturated with hexanes to yield 0.10 g of the desired material: Mp=167-170° C.; 1H NMR (DMSO-d6) δ 9.98 (br s, 1 H), 9.07 (br s, 1 H), 7.68 (d, 1 H, J=8.5 Hz), 7.4-7.38 (m, 3 H), 7.26-7.22 (m, 2 H), 7.18 (d, 1H, J=8.7 Hz), 6.90 (dd, 1 H, J=8.5 Hz, 2.5 Hz), 6.72 (d, 1 H, J=2.5 Hz), 6.67 (d, 1 H, J=2.3 Hz), 6.62 (dd, 1 H, J=8.7 Hz, 2.4 Hz), 5.81 (s, 1 H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[Cl:22][C:23]1[CH:28]=[C:27](Cl)[N:26]=[CH:25][N:24]=1.O>CN(C=O)C>[Br:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)=[CH:10][CH:11]=2)[N:6]([C:27]2[CH:28]=[C:23]([Cl:22])[N:24]=[CH:25][N:26]=2)[CH:5]=1
Reactant: O=[N+]([O-])c1cccc(-c2ccc3c(Br)c[nH]c3c2)c1
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(-c2ccc3c(Br)cn(-c4cc(Cl)ncn4)c3c2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.3 %

Procedure:
Sodium hydride (60% in mineral oil, 114 mg, 2.84 mmol) was added to a mixture solution of 3-bromo-6-(3-nitrophenyl)-1H-indole (450 mg, 1.42 mmol) and 4,6-dichloropyrimidine (212 mg, 1.42 mmol) in anhydrous DMF (10 mL) at room temperature. After stirring at room temperature for 5 hours, followed by addition of ice, the mixture was added to icy water. After stirring at room temperature for 12 hours, the produced solid was filtered, washed with water, and then dried. The target compound (600 mg) was obtained as yellow solid.