Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([CH3:14])[CH:6]=[C:5]2[Cl:15].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.N1C=CC=CC=1.[Na+].[I-]>CCO>[ClH:15].[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([CH3:14])[CH:6]=[C:5]2[N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C1CCNC1
Reactant: COc1cc2nc(C)cc(Cl)c2cc1Br
Agent: [I-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Product: COc1cc2nc(C)cc(N3CCCC3)c2cc1Br
Product: Cl
Temperature: 25 °C
Yield: 67.9 %

Procedure:
A suspension of 1 g (3.5 mmol) of 6-bromo-4-chloro-7-methoxy-2-methyl-quinoline in 20 ml of EtOH was treated sequentially at RT and under stirring with 0.49 g (7 mmol) of pyrrolidine, 0.137 g (1.4 mmol) of pyridine and a catalytic amount of NaI. The mixture was then heated to reflux for 20 h, cooled to RT and concentrated in vacuo. The residue was applied to a silica gel column with CH2Cl2/MeOH (7:1) as eluent. Combinations of the purified fractions and concentration in vacuo gave 0.85 g (68.2%) of the 6-bromo-7-methoxy-2-methyl-4-pyrrolidin-1-yl-quinoline hydrochloride as light brown solid. ISP mass spectrum, m/e: 323.3 (M+1 calculated for C15H17BrN2O: 323).
Reaction SMILES: C(O[C@@H:5]1[O:22][C@H:21]([CH2:23][O:24][CH3:25])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.[BrH:26]>ClCCl.C(O)(=O)C>[C:8]([O:7][C@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][CH3:25])[O:22][C@@H:5]1[Br:26])(=[O:10])[CH3:9]
Reactant: COC[C@H]1O[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC[C@H]1O[C@H](Br)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
A solution of 1,2,3,4-tetra-O-acetyl-6-O-methyl-β-D-mannopyranose (2.8 g) in dry dichloromethane (2 ml) at 0°-5° C. is treated with 30% hydrobromic acid in glacial acetic acid (25 ml) for 2 hours. The reaction mixture is worked-up in the normal manner to give 2,3,4-tri-O-acetyl-6-O-methyl-α-D-mannopyranosyl bromide (2.8 g), which is reacted with thiourea (0.76 g) in dry acetone (5 ml) at reflux temperature for 2 hours. The solution is evaporated in vacuo to a syrup, which is partitioned between ethyl ether (25 ml) and water (25 ml). The aqueous layer is extracted three times with ethyl ether. A solution of cinnamyl bromide (1.44 g) in acetone (30 ml) is added to the aqueous solution containing 2-S-(2,3,4-tri-O-acetyl-6-O-methyl-α-D-mannopyranosyl)-2-thiopseudourea hydrobromide. This is followed by the addition of potassium carbonate (1.26 g) and potassium metabisulfite (1.77 g) and the reaction mixture is stirred vigorously for 2 hours at room temperature. Acetone is evaporated in vacuo and the product is extracted with chloroform and washed twice with water. The solution is dried and evaporated to an oil, which is put on a column of silica gel and eluted with CHCl3 --EtOAc (98:2, v/v). The desired fractions are combined and evaporated in vacuo to give 19 as an oil (1.15 g, 33% overall yield): [α]D27 +147° (C 2.08, chloroform).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]([CH:18]([CH3:20])[CH3:19])[C:10](=[O:21])[NH:9]2)=[CH:4][CH:3]=1.[Cl:22][CH2:23][C:24](Cl)=[O:25].C(N(CC)CC)C>>[CH:18]([CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:24](=[O:25])[CH2:23][Cl:22])=[CH:7][CH:6]=2)[NH:9][C:10]1=[O:21])([CH3:19])[CH3:20]
Reactant: CC(C)C1C(=O)NC(c2ccc(N)cc2)c2ccccc21
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Product: CC(C)C1C(=O)NC(c2ccc(NC(=O)CCl)cc2)c2ccccc21

Procedure:
10.0 g. (0.0357 moles) of 1-(4'-aminophenyl)-1,4-dihydro-4-isopropyl-3(2H)-isoquinolinone are reacted, in 150 ml. of glacial acid, with 5.07 g. (0.045 moles) of chloroacetyl chloride in the presence of 4.55 g. (0.045 moles) of triethylamine. The reaction conditions are the same as given in Example 1. The crude product is recrystallized from butanol to yield 9.95 g. of the title compound; m.p.: 269°-270°C.
Reaction SMILES: [C:1]([NH2:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].Cl[O:12]C(C)(C)C.CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1.[CH:75]([C:77]1[CH:88]=[CH:87][C:80]([C:81]([O:83][CH2:84][CH2:85][CH3:86])=[O:82])=[CH:79][CH:78]=1)=[CH2:76]>C(O)CC.O>[C:4]([O:3][C:1]([NH:8][CH:75]([C:77]1[CH:88]=[CH:87][C:80]([C:81]([O:83][CH2:84][CH2:85][CH3:86])=[O:82])=[CH:79][CH:78]=1)[CH2:76][OH:12])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(N)=O
Reactant: CC(C)(C)OCl
Reactant: C=Cc1ccc(C(=O)OCCC)cc1
Agent: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCO
Product: CCCOC(=O)c1ccc(C(CO)NC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 56 %

Procedure:
t-Boc-NH2(MW 108.57, 9.8 g, 0.0837 mol, 2.95 eq) was dissolved in n-PrOH (110 mL) in a 1 L RB flask, The solution was treated with NaOH (MW 40, 3.6 g, 0.9 mol, 3.17 eq) in H2O (220 mL) and tert-Butyl hypochlorite (MW 108.57, 10 mL, 0.0868 mol, 3.06 eq). After stirring for 20 minutes, the solution was cooled to 0° C. A solution of (DHQ)2phal (MW 779, 0.43 g, 0.552 mmol, 0.019 eq) in n-PrOH (110 mL) was added. A solution of propyl 4-vinylbenzoate (MW 190.24, 5.41 g, 0.0284 mol, 1 eq) in n-PrOH (220 mL) was then added, followed by the addition of K2OsO4 (MW 368.43, 427 mg, 0.00116 mol, 0.04 eq). The reaction mixture was stirred at 0° C. and monitored by LC/MS and TLC. After stirring at 0° C. for 2 hours, the reaction was quenched with sat. Na2SO3 and n-PrOH was removed under vacuum. The residue was diluted with water and extracted with EtOAc (3×). The combined EtOAc fraction was washed with 5% HCl (1×) and brine (1×). After drying over Na2SO4 and filtration, the filtrate was concentrated under vacuum to dryness. The residue was purified on a silica gel column, eluted with EtOAc/Hexanes (10˜40%) to give 5.17 g (56% yield) of the pure 1-3. The 1H NMR (DMSO-d6) data is depicted in FIG. 3.
Reaction SMILES: [Cl-].[Li+].[Cu](C#N)C#N.[CH2:8]([Mg]Br)[CH3:9].[C:12]([O:16][CH3:17])(=[O:15])[C:13]#[CH:14].[I:18]I>O1CCCC1>[CH3:17][O:16][C:12](=[O:15])/[C:13](/[I:18])=[CH:14]\[CH2:8][CH3:9]
Reactant: CC[Mg]Br
Reactant: II
Reactant: C#CC(=O)OC
Agent: N#C[Cu]C#N
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC/C=C(/I)C(=O)OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
A mixture of lithium chloride (1.7 g, 40 mmol, predried at 130° C. under high vacuum for 2 h) and copper cyanide (1.78 g, 20 mmol) in dry tetrahydrofuran (20 mL) was stirred at 25° C. under argon for 10 min to obtain a clear solution. The reaction mixture was cooled to −70° C. and then slowly treated with a 1 M solution of ethylmagnesium bromide in tetrahydrofuran (20 mL, 20 mmol). After addition, the reaction mixture was allowed to warm to −30° C. where it was stirred for 5 min. The resulting reaction mixture was again cooled back to −70° C. and then slowly treated with methyl propiolate (1.52 g, 18 mmol). The reaction mixture was stirred for 4 h at −40° C. to −30° C. and then cooled to −70° C. to −60° C., at which time, the reaction mixture was treated slowly with a solution of iodine (6.86 g, 27 mmol) in dry tetrahydrofuran (20 mL). After addition of the iodine solution, the cooling bath was removed, and the reaction mixture was allowed to warm to 25° C. where it was stirred for 1 h. The reaction mixture was then poured into a solution consisting of a saturated aqueous ammonium chloride solution (90 mL) and ammonium hydroxide (10 mL), and the organic compound was extracted into diethyl ether (3×50 mL). The combined organic extracts were successively washed with a saturated aqueous sodium thiosulfate solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 19/1 hexanes/diethyl ether) afforded (E)-2-iodo-pentenoic acid methyl ester (2.9 g, 67%) as a colorless oil: EI-HRMS m/e calcd for C6H9IO2 (M+) 239.9647, found 239.9646.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH2:11]Cl)=[CH:4][CH:3]=1.[CH3:20][CH:21]([CH3:37])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=1)=[O:23].C(N(C(C)C)CC)(C)C.N>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH2:11][N:34]2[CH2:35][CH2:36][CH:31]([C:27]3[CH:26]=[C:25]([NH:24][C:22](=[O:23])[CH:21]([CH3:20])[CH3:37])[CH:30]=[CH:29][CH:28]=3)[CH2:32][CH2:33]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1
Temperature: 90 °C
Reaction time: 72 h
Yield: 25.7 %

Procedure:
A mixture of 4,4-bis(4-fluoro-phenyl)-1-chloro-butane (39.0 mg, 0.126 mmol), 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (28.3 mg, 0.126 mmol), diisopropylethylamine (0.50 mL) and catalytic amount of tetrabutylammonium iodide in dioxane (2.0 mL) was stirred at 90° C. for 72 hrs. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (15.9 mg, 25.2% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.41 (s, 1H), 7.3–7.15 (m, 4H), 7.10 (m, 3H), 6.89 (apparent t, 5H), 3.81 (t, 1H, J=7.8 Hz), 3.30 (s, 1H), 2.91 (d, 1H, J=12.5 Hz), 2.80 (m, 1H), 2.40 (m, 2H), 2.31 (t, 1H, J=8.0 Hz), 1.93 (apparent q, 3H, J=8.0 Hz), 1.72 (m, 3H), 1.40 (m, 2H), 1.20 (m, 2H), 1.15 (d, 6H, J=8.1 Hz); ESMS m/e: 491.4 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[NH:6][CH:7]=[CH:8][N:9]=1)[CH3:4].Cl[CH2:11][C:12]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)[C:19]2[C:14](=[CH:15][C:16]([O:39][CH3:40])=[C:17]([O:37][CH3:38])[CH:18]=2)[N:13]=1.O>CN(C)C=O>[CH2:3]([C:5]1[N:6]([CH2:11][C:12]2[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:20]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=3)[C:19]3[C:14](=[CH:15][C:16]([O:39][CH3:40])=[C:17]([O:37][CH3:38])[CH:18]=3)[N:13]=2)[CH:7]=[CH:8][N:9]=1)[CH3:4]
Reactant: CCOC(=O)c1c(CCl)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: CCc1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Cn2ccnc2CC)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.5 %

Procedure:
Oily sodium hydride (60%, 0.323 g) was added to a solution of 2-ethylimidazole (0.776 g) in N,N-dimethylformamide (30 ml), and the mixture was stirred at room temperature for 15 minutes. Then ethyl 2-chloromethyl-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate(3.0 g) was added. The mixture was stirred at 80° C. for 1 hour and poured into water, and the resulting crystals were collected by filtration and recrystallized from ethanol to give ethyl 2-(2-ethylimidazol-1-ylmethyl)-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylate (2.5 g, 74%). Colorless prisms. mp. 163°-164° C.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.[C:15]1(=O)[CH2:18][CH2:17][CH2:16]1>ClCCl>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:15]2([C:5]#[N:6])[CH2:18][CH2:17][CH2:16]2)=[CH:9][CH:10]=1
Reactant: O=C1CCC1
Reactant: Cc1ccc(N)cc1
Reactant: C[Si](C)(C)C#N
Solvent: ClCCl
Product: Cc1ccc(NC2(C#N)CCC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 98 %

Procedure:
Trimethylsilyl cyanide (0.93 ml, 7 mmol) was added dropwise to a mixture of p-toluidine (0.535 g, 5 mmol) and cyclobutanone (0.42 g, 6 mmol). The reaction mixture was stirred at room temperature for 6 h and then concentrated under vacuum to obtain a brown liquid which was subjected to chromatography (dichloromethane) to yield 1-(4-methylphenyl)aminocyclobutanenitrile, 7a (0.912 g, 4.9 mmol, 98%) as a yellowish solid.
Reaction SMILES: N(C(=C[C:10]1C=CC=[C:15]2[C:11]=1[CH:12]=CN2)C(OC)=O)=[N+]=[N-].Br.[C:20]([O:23]CC)(=[O:22])C.[CH:26]1[C:30]2=[C:31]3[C:35]([CH:36]=[CH:37][C:29]2=[N:28][C:27]=1[C:38]([O:40][CH3:41])=[O:39])=[N:34][CH:33]=[CH:32]3.C1C2=C3C(=CC=C2NC1)NC(C(OC)=O)=C3.C(Cl)CCl>CN(C=O)C>[C:11]([O:23][C:20]([N:34]1[C:35]2[C:31](=[C:30]3[C:29](=[CH:37][CH:36]=2)[NH:28][C:27]([C:38]([O:40][CH3:41])=[O:39])=[CH:26]3)[CH2:32][CH2:33]1)=[O:22])([CH3:10])([CH3:12])[CH3:15]
Reactant: COC(=O)C1=Cc2c3c(ccc2=N1)=NC=C3
Reactant: CCOC(C)=O
Reactant: COC(=O)C(=Cc1cccc2[nH]ccc12)N=[N+]=[N-]
Agent: Br
Agent: COC(=O)c1cc2c3c(ccc2[nH]1)NCC3
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c3c(ccc2[nH]1)N(C(=O)OC(C)(C)C)CC3
Yield: 47.6 %

Procedure:
210 mg (0.63 mMol) of 2 was treated with an HBr-ethyl acetate solution for 30 minutes. The solvent was evaporated and the resulting salt 3 was dried under high vacuum. The 0.63 mmol of 3 prepared above was reacted with 210 mg (0.69 mMol) of 4 in 10 mL of DMF in the presence of 133 mg (0.69 mMol) of EDC for 2 hours. The solvent was evaporated and the crude purified over silica. To give 160 mg of 5 (47.6% yield). M+1=518
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([NH2:11])[C:3]=1[NH2:12].[CH:13](O)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]2[N:12]=[CH:13][NH:11][C:4]=2[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Nc1cc([N+](=O)[O-])cc(Br)c1N
Reactant: O=CO
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cc(Br)c2nc[nH]c2c1
Yield: 96.2 %

Procedure:
To a 100 mL round bottomed flask was added 3-bromo-5-nitrobenzene-1,2-diamine (5 g, 21.55 mmol) and formic acid (3.25 mL, 86 mmol) in Toluene (10 mL). The solution was heated to reflux overnight. The product precipitated and was triturated with toluene, diluted with water and adjusted to ph 9 with 6N NaOH. The solid was filtered, washed with water and placed in a vacuum oven overnight to yield 4-bromo-6-nitro-1H-benzo[d]imidazole (5.02 g, 20.74 mmol, 96% yield) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.16 (s, 1H) 8.29 (d, J=2.02 Hz, 1H) 8.51 (d, J=2.02 Hz, 1H) 8.66 (s, 1H); LC/MS: MS (ES+) m/e 243 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8](=[O:11])[CH2:9]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[NH2:1][C:4]1[CH:13]=[CH:12][C:7]([C:8](=[O:11])[CH2:9][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:6][CH:5]=1.[N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8](=[O:11])[CH2:9][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: C1COCCN1
Product: Nc1ccc(C(=O)CN2CCOCC2)cc1
Product: O=C(CN1CCOCC1)c1ccc([N+](=O)[O-])cc1

Procedure:
The compound of the present invention (I) is prepared by reacting 4-nitrophenacyl bromide with morpholine to produce the intermediate 1-(4-nitrophenyl)-2-morpholinylethanone (II) which is reduced to produce 1-(4-aminophenyl)- 2-morpholinylethanone (I). ##STR2##
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([C:17]1[N:18]=[CH:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=1)([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2.[CH:41](I)([CH3:43])[CH3:42]>>[CH:41]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)([OH:16])[CH:13]([CH3:14])[CH3:15])[CH:6]=[CH:5]2)([CH3:43])[CH3:42]
Reactant: CC(C)C(O)(c1ccc2cc(O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CC(C)I
Product: CC(C)Oc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1

Procedure:
In a similar manner to that described in Example 31-(i), the reaction of 1-(6-hydroxynaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (0.965 g) with isopropyl iodide (0.20 ml) was carried out to give the titled compound (0.548 g) as a colorless solid.
Reaction SMILES: N1CCCC[C@H]1CCN.[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[CH2:18][NH:19][C:20]([C:22]1[C:23](=[O:49])[C:24]([O:41]CC2C=CC=CC=2)=[C:25]2[C:38](=[O:39])[N:29]3[CH2:30][CH2:31][C@@H:32]4[CH2:37][CH2:36][CH2:35][CH2:34][N:33]4[C@@H:28]3[CH2:27][N:26]2[CH:40]=1)=[O:21]>>[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[CH2:18][NH:19][C:20]([C:22]1[C:23](=[O:49])[C:24]([OH:41])=[C:25]2[C:38](=[O:39])[N:29]3[CH2:30][CH2:31][C@@H:32]4[CH2:37][CH2:36][CH2:35][CH2:34][N:33]4[C@@H:28]3[CH2:27][N:26]2[CH:40]=1)=[O:21]
Reactant: O=C(NCc1ccc(F)cc1F)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N1CC[C@@H]3CCCCN3[C@@H]1C2
Agent: NCC[C@@H]1CCCCN1
Product: O=C(NCc1ccc(F)cc1F)c1cn2c(c(O)c1=O)C(=O)N1CC[C@@H]3CCCCN3[C@@H]1C2
Yield: 107.3 %

Procedure:
In a manner similar to that described in example Z-35, from {2-[(2S)-2-piperidinyl]ethyl}amine (28 mg, 0.218 mmol) and 16a (30 mg, 0.0638 mmol) was prepared (4aS,14aS)—N-[(2,4-difluorophenyl)methyl]8,10-dioxo-9-[(phenylmethyl)oxy]-2,3,4,4a,5,6,8,10,14,14a-decahydro-1H-pyrido[1,2-c]pyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-11-carboxamide (29 mg, 82%). This material was deprotected in a second step similar to that described in example Z-37 to give the title compound as a white solid (26 mg, quantitative), 1H NMR (CDCl3) δ 12.44 (br s, 1H), 10.48 (s, 1H), 8.26 (s, 1H), 7.35 (m, 1H), 6.80 (m, 2H), 4.68-4.67 (m, 2H), 4.38 (m, 1H), 4.20 (m, 1H), 3.93 (s, 1H), 3.63-3.39 (m, 2H), 2.91 (m, 2H), 2.29 (br s, 1H), 2.02 (m, 1H), 1.69-1.45 (m, 4H), 1.30-1.24 (m, 2H), 1.12 (br s, 1H); ES+ MS: 459 (M+1).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[N:17]([CH2:18][C:19](=[O:28])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=3)[C:16]3[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH2:34][CH2:35][O:36][Si](C(C)(C)C)(C)C)[C:15]=3[N:14]=2)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(O)(=O)C>[CH:1]([N:4]1[CH2:5][CH2:6][CH:7]([NH:10][C:11]([C:13]2[N:17]([CH2:18][C:19](=[O:28])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=3)[C:16]3[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH2:34][CH2:35][OH:36])[C:15]=3[N:14]=2)=[O:12])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(OCCO[Si](C)(C)C(C)(C)C)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)N1CCC(NC(=O)c2nc3c(OCCO)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
250 mg (0.40 mmol) 4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-1-[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide were dissolved in 15 mL THF. 435 μl of a 1 M TBAF-solution in THF and 26 μl acetic acid were added. The resulting mixture was stirred for 48 h at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was taken up in 50 mL CH2Cl2 and washed once with a saturated NaHCO3-solution and five times with water. The organic layer was dried over anhydrous MgSO4 and concentrated under vacuo. Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave pure 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-4-(2-hydroxy-ethoxy)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide as its formiate in form of a colorless amorphous material. The title compound was transformed into its acetate. Yield: 132 mg MS (ES+): m/e=515, chloro pattern.
Reaction SMILES: Cl[C:2](Cl)([O:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].[CH3:10][OH:11].N1C=CC=CC=1.N1CCCC1.[CH2:23]([O:25]CC)C>>[CH3:10][O:11][C:2]([O:25][CH3:23])([O:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Cl)(Cl)OC
Reactant: CO
Reactant: CCOCC
Solvent: C1CCNC1
Solvent: c1ccncc1
Product: COC(=O)C(OC)(OC)OC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 80 %

Procedure:
A 500 mL round bottom flask was charged with methyl 2,2-dichloro-2-methoxyacetate (50 g, 248.5 mmol, 1 equiv). This was cooled to 0° C. with an ice bath at which point anhydrous methanol (34.33 g, 745.7 mmol, 44 mL, 3 equiv) was added with stirring over the course of 5 minutes. The mixture was then immediately diluted with anhydrous diethyl ether (150 mL). While maintaining the reaction at 0° C. with an external ice bath, anhydrous pyridine (49.10 g, 621.4 mmol, 50.20 mL, 2.5 equiv) was added via a pressure equalizing addition funnel over 1 hour. The reaction mixture was then rapidly stirred for an additional 30 minutes at 0° C. The stirring was then stopped and the mixture allowed to stand at room temperature for 72 hours where upon long white needles were formed in solution. The resulting mixture was filtered through a medium porosity glass frit, and the recovered solids were washed with diethyl ether. The filtrate was then concentrated by rotary evaporation under reduced pressure to yield a pale yellow oil. This oil was subsequently cooled to 0° C. with an ice bath. The oil was then rapidly stirred, and pyrrolidine (25 mL) was added in a drop wise fashion, by means of a pressure equalizing addition funnel, over a period of 20 minutes. The solution rapidly turned yellowish-orange in color. Upon completion of addition of the pyrrolidine, the mixture was stirred for an additional 30 minutes at 0° C., and then subjected to a reduced pressure distillation collecting unreacted pyrrolidine and ethanol at 40 Torr and 28° C. followed by the desired material, methyl 2,2,2-trimethoxyacetate (44 g, 80% yield) at 2 Torr and 58° C., as a colorless liquid.
Reaction SMILES: [OH:1][C:2]1[C:6]2[CH:7]=[CH:8][C:9]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:10][C:5]=2[O:4][C:3]=1[C:15]#[N:16].N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:15]([C:3]1[O:4][C:5]2[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=2[C:2]=1[O:1][S:24]([CH3:23])(=[O:26])=[O:25])#[N:16]
Reactant: CS(=O)(=O)c1ccc2c(O)c(C#N)oc2c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Oc1c(C#N)oc2cc(S(C)(=O)=O)ccc12
Temperature: 25 °C

Procedure:
A suspension of 13 (3.9 g) in CH2Cl2 (200 mL) was treated with pyridine (10 mL), methanesulfonyl chloride (4 mL), and a catalytic amount of dimethylaminopyridine at 0° C., under an N2 atmosphere, for 2 h. The reaction was allowed to warm to ambient temperature overnight. The reaction was partitioned between 1:1 Et2O/hexanes and brine. The organic layer was dried (MgSO4), filtered, and evaporated. The residue was purified by chromatography (silica gel, 1:1 EtOAc/hexanes) giving 1.05 g of methanesulfonic acid 2-cyano-6-methanesulfonyl-benzofuran-3-yl ester 14.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][N:10](C)C)[C:5]([N+]([O-])=O)=[CH:4][N:3]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C([O-])=O.[NH4+]>[Pd].CO.C(Cl)Cl>[N:16]1([C:4]2[CH:5]=[C:6]3[CH:8]=[CH:9][NH:10][C:7]3=[CH:2][N:3]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: CN(C)C=Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: c1cc2cc(N3CCOCC3)ncc2[nH]1
Temperature: 65 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
A solution of 450 mg (2 mmol) of [2-(2-chloro-5-nitro-pyridin-4-yl)-vinyl]-dimethyl-amine in a 20 mL of mixed solvent of MeOH—CH2Cl2 (1:1) was treated with 3 mL of morpholine. The reaction mixture was stirred at 65° C. for 8 h. Volatiles were then removed. CH2Cl2 (100 mL) and H2O (30 mL) were added. The organic layer was separated and washed with H2O (30 mL), brine (30 mL), dried over Na2SO4, and concentrated. The red powder was treated with 4.0 g (63 mmol, 32 eq) of ammonium formate and 10% Pd—C (120 mg). The reaction mixture was stirred at 65° C. for 30 min. The reaction mixture was then filtered through a pad of celite and concentrated to obtain a yellow solid. Column chromatography (silica, 5% MeOH/CH2Cl2) provided 210 mg (52% for 2 steps) of 5-morpholin-4-yl-1H-pyrrolo[2,3-c]pyridine as a yellow solid. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.40. MS (electrospray): exact mass calculated for C11H13N3O, 203.11; m/z found, 204.2 [M+H]+.