Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].O[CH:14]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:15][CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[O:12][CH:14]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:15][CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23]
Reactant: Oc1cc(C(F)(F)F)ccc1Cl
Reactant: CCCCC(O)CCN(C)C(=O)OC(C)(C)C
Product: CCCCC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(C(F)(F)F)ccc1Cl

Procedure:
The title compound was prepared according to the method of Example 1 step (c) but using 2-chloro-5-(trifluoromethyl)phenol and (3-hydroxyheptyl)methylcarbamic acid, 1,1-dimethylethyl ester.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH2:38][CH2:39][OH:40]>>[OH:40][CH2:39][CH2:38][NH:37][C:30](=[O:32])[C:29]1[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=1[S:27][CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: NCCO
Product: O=C(NCCO)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 55.4 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and 2-aminoethanol (31 mg, 0.50 mmol, 1.0M in DMF) were combined to give 30 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 542 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:17])=[CH:10][CH:11]=2)[N:6]=1)=O.O.[NH2:19][NH2:20]>CO>[OH:15][C:13]1[C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:17])=[CH:10][CH:11]=2)[N:6]=[C:5]([C:3]([NH:19][NH2:20])=[O:2])[CH:14]=1
Reactant: COC(=O)c1cc(O)c2ccc(OC)cc2n1
Reactant: NN
Solvent: CO
Solvent: O
Product: COc1ccc2c(O)cc(C(=O)NN)nc2c1
Yield: 80 %

Procedure:
To a solution of 4-hydroxy-7-methoxy-quinoline-2-carboxylic acid methyl ester (2.0 g, 8.58 mmol) in methanol (85 mL) was added hydrazine mono hydrate (1.7 g, 34.3 mmol) and the mixture was refluxed for 6 hours. The crude reaction mixture was concentrated in vacuo and the residue was taken up in methanol and poured onto an ice/water mixture (800 mL). A white precipitate formed, which was collected by filtration and washed with cold water. The filter cake was then dried on house vacuum by passing air through in sintered glass funnel, and then dried on vacuum oven at 45° C. overnight to afford 4-hydroxy-7-methoxy-quinoline-2-carboxylic acid hydrazide (1.6 g, 80% yield). 1H NMR (DMSO-d6, 300 MHz) δ 11.57 (s, 1H), 10.28 (s, 1H), 7.95 (d, 1H), 7.43 (d, 1H), 7.01-6.91 (m, 1H), 6.54 (s, 1H), 4.72 (br s, 2H), 3.82 (s, 3H). LCMS found 234.18 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12]([NH2:14])[CH3:13]>>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:14][CH2:12][CH3:13])[N:10]=1
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Reactant: CCN
Product: CCNc1nc(Cl)ccc1C(=O)O
Yield: 62 %

Procedure:
A solution of 18.0 g (84.4 mmol) of 2,6-dichloronicotinic acid in 180 ml of a solution of ethylamine (70% in water) was stirred at ambient temperature for 72 hours. The excess amine was then evaporated off under reduced pressure, and an aqueous solution of acetic acid at 10% was added until the product precipitates. The beige solid was spin-filter-dried, rinsed with cold water and dried in an oven. 10.5 g of the expected product are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:20][C:21]1[S:25][CH:24]=[C:23]([N:26]2[C:30]([C:31]([OH:33])=O)=[CH:29][C:28]([C:34]([F:37])([F:36])[F:35])=[N:27]2)[CH:22]=1)[CH2:9][CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:38][O:39][C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH2:42][NH2:43]>>[C:16]([O:15][C:13]([N:11]([CH3:12])[CH2:10][CH2:9][N:8]([CH2:20][C:21]1[S:25][CH:24]=[C:23]([N:26]2[C:30]([C:31](=[O:33])[NH:43][CH2:42][C:41]3[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=3[O:39][CH3:38])=[CH:29][C:28]([C:34]([F:35])([F:36])[F:37])=[N:27]2)[CH:22]=1)[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:14])([CH3:18])([CH3:19])[CH3:17]
Reactant: COc1ccccc1CN
Reactant: CN(CCN(Cc1cc(-n2nc(C(F)(F)F)cc2C(=O)O)cs1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Product: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1-c1csc(CN(CCN(C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1

Procedure:
The titled compound 214 (140 mg, 38%) was obtained as a white crusty solid after following the method described to obtain compound 15a (scheme 2, example 1c, step 8) by using 212 (0.300 g, 0.547 mmol) and 2-methoxybenzylamine (75 mg, 0.547 mmol). LRMS(ESI): (calc.) 667.2 (found) 690.4 (MNa)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH3:24]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH3:24])=[CH:4][C:3]=1[Cl:9]
Reactant: CCCOCCCl
Reactant: Oc1ccc(Br)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOCCOc1ccc(Br)c(Cl)c1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
In DMF (98 ml) was dissolved 4-bromo-3-chlorophenol (9.8 g), and to the solution were added at room temperature potassium carbonate (9.8 g), sodium iodide (7.8 g) and 2-chloroethylpropylether (7.8 ml). The mixture was stirred at 90° C. for 16 hours, cooled to room temperature, poured into water, and the mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed, and the residue was purified with silica gel column chromatography (hexane/ethyl acetate=8/1) to give 1-bromo-2-chloro-4-(2-propoxyethoxy)benzene (8.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24]O)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][N:27]3[CH2:31][CH2:30][CH2:29][C:28]3=[O:32])([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:6][CH:7]=1
Reactant: O=C1CCCN1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCN2CCCC2=O)(c2ccccc2)OC1=O

Procedure:
(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-(2-oxopyrrolidin-1-yl)propyl)-6-phenyl-1,3-oxazinan-2-one was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one following an analogous procedure using pyrrolidin-2-one in Step 2.
Reaction SMILES: C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[F:13][C:14]1[C:15](=[O:29])[NH:16][C:17](=[O:28])[N:18]([CH:27]=1)[C@@H:19]1[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[CH2:20]1.C(O[CH:34]1[CH2:38][CH2:37][CH2:36][O:35]1)(=O)C.C(N(CC)CC)C>ClCCl>[F:13][C:14]1[C:15](=[O:29])[N:16]([CH:34]2[CH2:38][CH2:37][CH2:36][O:35]2)[C:17](=[O:28])[N:18]([CH:27]=1)[C@@H:19]1[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[CH2:20]1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Reactant: CC(=O)OC1CCCO1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1c(F)cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1C1CCCO1
Reaction time: 3 h
Yield: 81.7 %

Procedure:
A 16.5 g quantity of N,O-bis(trimethylsilyl) acetamide was added to a suspension of 5.00 g of 2'-deoxy-5-fluorouridine in 50 ml of dry dichloromethane at room temperature with stirring, and the mixture was stirred for four hours. Then a solution of 4.00 g of 2-acetoxytetrahydrofuran and 1.17 ml of stannic chloride in 10 ml of dry dichloromethane was added and the mixture was stirred for 1.5 hours. Then 8.0 ml of triethylamine was added to neutralize the mixture and the mixture was washed with water. The dichloromethane layer was concentrated and the residue was dissolved in 100 ml of methanol. A 3 ml quantity of acetic acid was added thereto and the mixture was left to stand at 40° C. for 3 hours. The solvent was distilled off and the residue was applied to a silica gel column to conduct gradient elution using chloroform and methanol (up to 4%)-chloroform mixtures, giving 5.25 g of 2'-deoxy-5-fluoro-3-(2-tetrahydrofuranyl)uridine as an oil in a yield of 81.7%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C@@:10]2([CH3:17])[CH2:15][CH2:14][CH2:13][NH:12][C:11]2=[O:16])=[CH:4][CH:3]=1.[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][C:24](B(O)O)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[CH3:9][O:8][C:6]1[C:5]([C@@:10]2([CH3:17])[CH2:15][CH2:14][CH2:13][NH:12][C:11]2=[O:16])=[CH:4][CH:3]=[C:2]([C:24]2[CH:23]=[C:22]3[C:27](=[CH:26][CH:25]=2)[N:19]([CH3:18])[CH:20]=[CH:21]3)[N:7]=1
Reactant: Cn1ccc2cc(B(O)O)ccc21
Reactant: COc1nc(Cl)ccc1[C@@]1(C)CCCNC1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1nc(-c2ccc3c(ccn3C)c2)ccc1[C@@]1(C)CCCNC1=O
Temperature: 105 °C
Reaction time: 18 h
Yield: 93.8 %

Procedure:
To a large microwave vial was added (R)-3-(6-chloro-2-methoxypyridin-3-yl)-3-methylpiperidin-2-one (1.20 g, 4.7 mmol), 1-methyl-1H-indol-5-ylboronic acid (0.82 g, 4.7 mmol), dioxane (10 mL), 2 M Na2CO3 (5.9 mL, 11.8 mmol), and PdCl2(dppf) CH2Cl2 (193 mg, 0.236 mmol). Nitrogen gas was bubbled through the reaction mixture for 5 minutes prior to sealing the vessel. The reaction was stirred for 18 h at 105° C. The mixture was cooled to r.t., diluted with ethyl acetate, and filtered over Celite®. The filtrate was concentrated to a brown paste. Purification by column chromatography (80 g RediSep Gold column) with a 0-10% EtOH/DCM gradient provided (R)-3-(2-methoxy-6-(1-methyl-1H-indol-5-yl)pyridin-3-yl)-3-methylpiperidin-2-one (1.54 g, 94%) as a light orange solid. 1H NMR (600 MHz, CDCl3) δ: 1.62-1.69 (m, 1H), 1.72 (s, 3H), 1.77-1.86 (m, 1H), 1.93-2.03 (m, 1H), 2.39 (td, 1H), 3.36-3.44 (m, 1H), 3.52 (td, 1H), 3.82 (s, 3H), 4.11 (s, 3H), 6.16 (br s., 1H), 6.56 (d, 1H), 7.07 (d, 1H), 7.36 (d, 1H), 7.38 (d, 1H), 7.62 (d, 1H), 7.93 (dd, 1H), 8.29 (s, 1H); MS (ES+)(M+H) 350.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12][C:13]#[N:14].[OH-:15].[Na+].OO>CO.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:10])([F:11])[F:9])[C:3]=1[CH2:12][C:13]([NH2:14])=[O:15]
Reactant: N#CCc1c(F)cccc1C(F)(F)F
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: O
Product: NC(=O)Cc1c(F)cccc1C(F)(F)F
Temperature: 40 °C

Procedure:
20 g (98.5 mmol) of 2-fluoro-6-trifluoromethyl-phenyl-acetonitrile is dissolved in 150 ml of methanol. It is adjusted to pH 10 with sodium hydroxide solution and heated to 40° C. Then, 15 ml (132.3 mmol) of hydrogen peroxide (30%) is instilled, diluted with 25 ml of water, and the pH is kept between 9-10 by simultaneous addition of sodium hydroxide solution. A solid precipitates with foaming. After completion of the addition, it is stirred for 30 more minutes, allowed to cool off, suctioned off from the solid, washed with water and dried in a vacuum. The title compound is obtained in crystalline form.
Reaction SMILES: [CH2:1]1[C:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[NH:8][C:7]=3[CH:6]=[CH:5][C:4]=2[C:3](=[O:17])[CH2:2]1.Br[CH2:19][CH2:20][CH2:21][N:22]([CH2:35][CH2:36][CH3:37])[S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N+:32]([O-:34])=[O:33])(=[O:25])=[O:24].[H-].[Na+].CCCCCC.C(OCC)(=O)C>C(Cl)Cl>[N+:32]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[S:23]([N:22]([CH2:35][CH2:36][CH2:37][N:8]1[C:7]2[CH:6]=[CH:5][C:4]3[C:3](=[O:17])[CH2:2][CH2:1][C:16]=3[C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2)[CH2:21][CH2:20][CH3:19])(=[O:25])=[O:24])([O-:34])=[O:33]
Reactant: CCCN(CCCBr)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: O=C1CCc2c1ccc1[nH]c3ccccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCN(CCCn1c2ccccc2c2c3c(ccc21)C(=O)CC3)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
Compound 46 (0.538 g, 2.43 mmol) and bromide 50 (0.9 g, 2.46 mmol) were dissolved in CH2Cl2 (30 mL). Then NaH (0.15 g, 3.75 mmol, 1.5 eq.) was added. The reaction mixture was stirred for 20 min (TLC monitoring, eluent: hexane-ethyl acetate, 1:1). Then, the mixture was poured onto ice. The product was extracted with ethyl acetate, and the extract was evaporated in a rotary evaporator. The residue of CH2Cl2 was removed in high vacuum. Methanol was added to the hardened precipitate. The product was triturated; the precipitate was filtered off. Yield of 47: 0.638 g (52%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH:57]1[C:65]2[C:60](=[CH:61][C:62]([CH:66]([CH3:73])[CH2:67][C:68]([O:70][CH2:71][CH3:72])=[O:69])=[CH:63][CH:64]=2)[CH2:59][CH2:58]1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:57]2[C:65]3[C:60](=[CH:61][C:62]([CH:66]([CH3:73])[CH2:67][C:68]([O:70][CH2:71][CH3:72])=[O:69])=[CH:63][CH:64]=3)[CH2:59][CH2:58]2)=[O:23])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: CCOC(=O)CC(C)c1ccc2c(c1)CCN2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(C)c1ccc2c(c1)CCN2C(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(OC)c1
Reaction time: 1 h
Yield: 57.3 %

Procedure:
A solution of [3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetic acid (2.9 g) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (3.7 g) in dimethylformamide (about 40 ml) was treated with diisopropylethylamine (10 ml), followed after about 30 seconds by a solution of (R/S) ethyl 3-(2,3-dihydro-1H-indol-5-yl)butyrate [about 2.5 g, Reference Example 5(a)] in dimethylformamide (about 10 ml). The resulting clear, dark brown solution was kept at room temperature for about one hour then evaporated to low bulk. The residue was partitioned between water and ethyl acetate and the organic layer was washed with dilute hydrochloric acid, then with aqueous sodium bicarbonate solution, then with brine, then dried and then evaporated. The residual brown gum was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and petrol (3:2 to 3:1, v/v) to give the title compound (2.8 g) as a light yellow, amorphous foam. MS (ES+) 552 (M−Na+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.Cl[C:15](Cl)([O:17]C(=O)OC(Cl)(Cl)Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:3]2[N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[C:15](=[O:17])[NH:8][C:4]=2[N:5]=[CH:6][CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccnc(N)c1-n1cccc1
Solvent: Cc1ccccc1
Product: Cc1ccnc2[nH]c(=O)c3cccn3c12
Temperature: 25 °C

Procedure:
4-Methyl-3-(1H-pyrrol-1-yl)pyridine-2-amine (1.0 g, 5.8 mmol) and triphosgene (2.6 g, 8.7 mmol) were dissolved in 100 mL of toluene. The mixture was refluxed for 3 hours, then cooled to room temperature. The red solid was collected after filtration and washed with CH3CN 0.5 g (43%). The material was used directly for the next step reaction without purification. 1H NMR (400 MHz, DMSO) δ 11.64 (s, 1H), 8.15 (dd, J=1.4, 2.9 Hz, 1H), 8.13 (d, J=4.9 Hz, 1H), 7.20-7.08 (m, 2H), 6.75 (dd, J=2.9, 3.9 Hz, 1H), 2.81 (s, 3H).
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:13][CH2:14][CH2:15][C:16](=[O:20])[CH2:17][CH2:18][CH3:19].[ClH:21].CCOCC>C(O)(C)C>[ClH:13].[ClH:21].[CH2:1]([N:7]1[CH2:8][CH2:9][N:10]([CH2:14][CH2:15][C:16](=[O:20])[CH2:17][CH2:18][CH3:19])[CH2:11][CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CCNCC1
Reactant: CCCC(=O)CCCl
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: CCCCCCN1CCN(CCC(=O)CCC)CC1
Temperature: 100 °C

Procedure:
A mixture of 15.3 g (0.09 mole) of n-hexyl piperazine and 12.3 g (0.091 mole) of 1-chloro-3-hexanone was heated to 100° C. for 5 minutes, cooled and dissolved in isopropanol. Isopropanolic HCl was added until acidic. Ether was added and the salt was filtered off. The product was crystallized from acetonitrile to yield 16.5 g of product with a melting point of 225°-230° C.
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=1)[C:21]([C:34](OCC)=[O:35])=[CH:20]2.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[C:6]([NH:5][C:34]([C:21]2[N:22]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[C:23]3[C:19]([CH:20]=2)=[CH:18][C:17]([F:16])=[CH:25][CH:24]=3)=[O:35])[CH:7]=1
Reactant: Nc1cnc2ccccc2c1
Reactant: CCOC(=O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Agent: C[Al](C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(Nc1cnc2ccccc2c1)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 44.9 %

Procedure:
1.19 mL (2.38 mmol) of a 2M solution of trimethylaluminium in toluene are added dropwise to a solution, stirred at 0° C. under an inert atmosphere, of 0.274 g (1.9 mmol) of 3-aminoquinoline in 40 mL of dry toluene. The mixture is then stirred at 50° C. After 15 minutes, a solution of 0.5 g (1.59 mmol) of ethyl 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylate (WO2006/024776) in 10 mL of toluene is added dropwise. 15 mL of 1N hydrochloric acid solution and 100 mL of ethyl acetate are added to the mixture. The organic phase is separated out and then washed successively with 20 mL of 1N hydrochloric acid solution, 20 mL of water and 20 mL of saturated sodium chloride solution, and then concentrated under reduced pressure. The product thus obtained is triturated in 10 mL of hot toluene. A precipitate is collected by filtration. After drying, 295 mg of the expected product are thus isolated.
Reaction SMILES: BrC1C=C(Cl)C=CC=1N1[C:13]2=[N:14][C:15]3[C:20](Cl)=[CH:19][CH:18]=[C:17]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:16]=3[N:12]2CC1.C([Li])CCC.CN(C)C=[O:35]>O1CCCC1>[CH2:23]([CH:22]([C:17]1[C:16]2[NH:12][C:13](=[O:35])[NH:14][C:15]=2[CH:20]=[CH:19][CH:18]=1)[CH2:25][CH3:26])[CH3:24]
Reactant: CN(C)C=O
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(Cl)cc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)c1cccc2[nH]c(=O)[nH]c12
Temperature: -78 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
A solution of 1-(2-bromo-4-chlorophenyl)-8-Chloro-5-(1-ethylpropyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole (140 mg, 0.309 mmol) in tetrahydrofuran was cooled to −78° C. under nitrogen atmosphere and n-butyllithium (1.6 M solution in n-hexane, 0.213 mL, 0.340 mmol) was added dropwise. After the mixture was stirred at −78° C. for 1 hr, N,N-dimethylformamide (0.120 mL, 1.545 mmol) was added. The mixture was allowed to warm to room temperature for 1 hr. The reaction was quenched by an addition of saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 5-40% ethyl acetate/n-hexane gradient mixture. The desired fractions for 5-chloro-2-[8-chloro-5-(1-ethylpropyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl]benzaldehyde were concentrated in vacuo, and the resulting solid was recrystallized from methanol to give the title compound of example 6 (41 mg, 0.102 mmol, 33%) as a colorless crystal. The desired fractions for 8-chloro-1-(4-chlorophenyl)-5-(1-ethylpropyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole were concentrated in vacuo, and the resulting solid was recrystallized from methanol to give the title compound of example 7 (17 mg, 0.04542 mmol, 15%) as a colorless crystal.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]([OH:20])=O)=[CH:16][N:17]=3)[CH:14]=2)=[CH:5][CH:4]=1.[NH2:23][C:24]1[CH:29]=[C:28]([C:30]([NH:32]O)=[NH:31])[CH:27]=[CH:26][N:25]=1>>[F:22][C:2]([F:21])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[N:13]([C:15]([C:18]4[O:20][N:32]=[C:30]([C:28]5[CH:27]=[CH:26][N:25]=[C:24]([NH2:23])[CH:29]=5)[N:31]=4)=[CH:16][N:17]=3)[CH:14]=2)=[CH:7][CH:8]=1
Reactant: O=C(O)c1cnc2ccc(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: N=C(NO)c1ccnc(N)c1
Product: Nc1cc(-c2noc(-c3cnc4ccc(-c5ccc(C(F)(F)F)cc5)cn34)n2)ccn1

Procedure:
The title compound was prepared from 6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.35) (153 mg, 0.5 mmol) and 2-amino-N-hydroxy-pyridine-4-carboxamidine (example B.6) (114 mg, 0.75 mmol) according to general procedure II. Obtained after purification by column chromatography on silica gel (dichloromethane/MeOH 16:1)) and crystallization (MeOH/dichloromethane/hexane) as an off-white solid (80 mg, 38%). MS (EI) 422.9 [(M)+]; mp 280° C.
Reaction SMILES: [CH2:1]([Cl:4])[CH:2]=[CH2:3].[CH3:5][N:6]([CH3:23])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Cl-]>>[Cl-:4].[CH2:1]([N+:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:5])[CH3:23])[CH:2]=[CH2:3]
Reactant: C=CCCl
Reactant: CCCCCCCCCCCCCCCCN(C)C
Agent: [Cl-]
Product: C=CC[N+](C)(C)CCCCCCCCCCCCCCCC

Procedure:
Allyl hexadecyl dimethyl ammonium chloride was prepared by reacting allyl chloride and dimethyl hexadecyl amine as set forth in Example 1. 17.8 grams of the chloride in 23.5% aqueous solution were treated with a stoichiometric excess of AgF in aqueous solution until analysis of the filtrate showed only a trace of chloride ion present. Excess silver ion was removed by the careful addition of NaCl, AgCl being removed by filtration.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[Cl:12][C:13]1[CH:18]=[C:17]([N+]([O-])=O)[CH:16]=[CH:15][N:14]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:16]=[CH:15][N:14]=1
Reactant: COc1cccc(O)c1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: COc1cccc(Oc2ccnc(Cl)c2)c1
Yield: 95.2 %

Procedure:
Using the method of Example 3, Step A, 3-methoxyphenol (2.35 g, 18.9 mmol), 60% sodium hydride in mineral oil (0.757 g, 18.9 mmol), and 2-chloro-4-nitropyridine (3.00 g, 18.9 mmol) were reacted to provide 2-chloro-4-(3-methoxyphenoxy)pyridine (4.24 g, 95.1% yield) as a thick oil. 1H NMR (CDCl3) 6 (8.23 (d, 1H), 7.34 (t, 1H), 6.80-6.85 (m, 3H), 6.63-6.69 (m, 2H), 3.82 (s, 3H).