Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH2:3])=[S:2].[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16](=O)[CH2:17]Br)=[CH:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1.C(OCC)(=O)C>C1COCC1>[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:16]3[N:3]=[CH:1][S:2][CH:17]=3)=[CH:10][C:11](=[O:15])[O:12]2)=[CH:7][CH:6]=1
Reactant: O=C(CBr)c1cc(=O)oc2cc(Br)ccc12
Reactant: NC=S
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1cc(-c2cscn2)c2ccc(Br)cc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Freshly prepared thioformamide (Helv. Chim. Acta, 31, 2065, 1948) (160 mg) was added to a solution of (α-bromoketone from Step 2 (200 mg) in THF (5 mL) and the reaction mixture was stirred at r.t. for 2 h. Ethyl acetate was then added and the organic phase was washed with saturated aqueous NH4Cl, H2O and brine, dried (MgSO4) and evaporated. Flash chromatography of the residue (silica gel; hexane/EtOAc (65:35) afforded the title compound as a white solid.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[C:38]([O:39]C)=[CH:37][CH:36]=[CH:35][C:7]=1[O:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]([CH3:34])([CH3:33])[CH2:15][CH2:16][C:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([NH2:20])=[O:19])[CH2:10]1>ClCCl>[NH3:11].[F:5][C:6]1[C:38]([OH:39])=[CH:37][CH:36]=[CH:35][C:7]=1[O:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]([CH3:34])([CH3:33])[CH2:15][CH2:16][C:17]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:18]([NH2:20])=[O:19])[CH2:10]1
Reactant: COc1cccc(O[C@@H]2CCN(C(C)(C)CCC(C(N)=O)(c3ccccc3)c3ccccc3)C2)c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(CCC(C(N)=O)(c1ccccc1)c1ccccc1)N1CC[C@@H](Oc2cccc(O)c2F)C1
Product: N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Boron tribromide (1M in dichloromethane, 1.1 mL, 1.224 mmol) was added to an ice-cooled solution of the product of example 75 (140 mg, 0.286 mmol) in dichloromethane (4 mL) and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with 0.88 ammonia solution and stirred at room temperature for 16 hours. The reaction mixture was adjusted to pH 8 by dropwise addition of 2N hydrochloric acid (aq) and extracted with dichloromethane (2×10 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography on silica gel, eluting with dichloromethane:methanol:0.88 ammonia, 95:5:0.5, afforded the title compound as a pale yellow foam in 15% yield, 20 mg.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].Cl[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([I:17])[CH:15]=2)[N:10]=[CH:9][C:8]=1[C:18]#[N:19].[H-].[K+]>C1COCC1>[CH2:1]([O:5][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([I:17])[CH:15]=2)[N:10]=[CH:9][C:8]=1[C:18]#[N:19])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCOc1c(C#N)cnc2ccc(I)cc12

Procedure:
Similar procedure as described in example 28a was used, starting from butanol, 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c) and potassium hydride in a solvent system of THF to give 4-butoxy-6-iodo-quinoline-3-carbonitrile. LC-MS m/e 352 (MH+).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:16])=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.[CH3:17][S:18]([C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:24]([OH:26])=O)(=[O:20])=[O:19]>>[F:1][C:2]1[C:3]([CH3:16])=[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:15])[C:24](=[O:26])[C:23]2[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=[C:21]([S:18]([CH3:17])(=[O:19])=[O:20])[CH:22]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1cccc(F)c1C
Product: Cc1c(F)cccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(3-fluoro-2-methyl-phenyl)-pyridin-3-yl]-methyl-amine and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 23 hours at room temperature. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). The Product was purified by preparative HPLC (Gemini NX column) with a gradient of MeOH:water (containing 0.05% formic acid) (80:20 to 98:2). Colorless solid (42%). MS (ESI): m/z=467.104 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:10]([CH3:14])C(O)=O)[CH:5]=[C:6]([I:9])[C:7]=1[OH:8].[I:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br.[C:24](=[O:27])([O-])[O-:25].[Cs+].[Cs+].Cl>CN(C=O)C>[I:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][O:25][C:24](=[O:27])[CH2:14][CH2:10][C:4]1[CH:5]=[C:6]([I:9])[C:7]([O:8][CH2:10][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=2)=[C:2]([I:1])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: BrCc1cccc(I)c1
Reactant: CC(C(=O)O)c1cc(I)c(O)c(I)c1
Agent: Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(CCc1cc(I)c(OCc2cccc(I)c2)c(I)c1)OCc1cccc(I)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 183.5 %

Procedure:
A suspension of 3,5-diiodo-4-hydroxyphenylpropionic acid (209 mg, 0.5 mmol), 3-iodobenzyl bromide (371 mg, 1.25 mmol), and cesium carbonate (490 mg, 1.5 mmol) in 5 mL DMF was stirred for 15 hours at room temperature. After that time, 1 M HCl (15 mL) was added and an oil formed. The oil was extracted with ether and methanol was added. Crystals formed in the solution upon cooling, yielding the title compound as white crystals (390 mg, 92%). 1H NMR (400 MHz, CDCl3): δ 8.00 (s, 1H), 7.71-7.60 (m, 6H), 7.29-7.26 (m, 1H), 7.16 (appar. t, J=7.8 Hz, 1H), 7.11 (appar. t, J=7.8 Hz, 1H), 5.05 (s, 2H), 4.91 (s, 2H), 2.87 (t, J=7.6 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H). TLC (9:1 Hex:EtOAc), Rf 0.29.
Reaction SMILES: [Na].Cl.[NH2:3][C:4]([NH2:6])=[NH:5].C([O:9][C:10](=O)[CH:11]([C:20]#[N:21])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[Cl:19])C>C(O)C>[NH2:5][C:4]1[N:6]=[C:20]([NH2:21])[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])=[C:10]([OH:9])[N:3]=1
Reactant: CCOC(=O)C(C#N)c1cccc(Cl)c1Cl
Reactant: N=C(N)N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Nc1nc(N)c(-c2cccc(Cl)c2Cl)c(O)n1

Procedure:
Sodium (1.2 g, 0.052 mol) was added in portions to absolute ethanol (50 ml) with stirring. After the sodium had dissolved guanidine hydrochloride (3.69 g, 0.039 mol) was added followed by ethyl-2-cyano-2-(2,3-dichlorophenyl)acetate (5 g, 0.0195 mol). The mixture was refluxed for 8 hours, EtOH was removed under reduced pressure and the residue was partitioned between EtOAc and water. The EtOAc layer was extracted with 2N NaOH and the extract was neutralised with 2N HCl with cooling. The precipitated solid was filtered and dried to give the title compound. (0.22 g), mp. 275° C. (decomp). Microanalysis:
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]([CH2:9][C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=2)[CH:6]=[CH:7][N:8]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=1[O:26][CH3:27].C([O-])([O-])=O.[K+].[K+].Cl>O.CS(C)=O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:3][C:4]2[N:5]([CH2:9][C:10]3[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=3)[CH:6]=[CH:7][N:8]=2)=[CH:21][C:20]=1[O:26][CH3:27]
Reactant: ClCc1nccn1Cc1cc(Cl)cc(Cl)c1
Reactant: COc1cc(O)ccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(OCc2nccn2Cc2cc(Cl)cc(Cl)c2)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a mixture of 2-chloromethyl-1-(3,5-dichlorobenzyl)-1H-imidazole hydrochloride (see Example 1) (150 mg, 0.5 mmol), 4-chloro-3-methoxyphenol (158 mg, 1 mmol) and DMSO (1 mL) was added K2CO3 (415 mg, 3 mmol). The reaction was stirred at ambient temperature for 8 h before diluting with water (10 mL). A solution of 1N HCl was added until the mixture was only slightly basic (pH 8) before extracting with EtOAc (30 mL). The EtOAc phase was washed with water (10 mL), dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 1:2, hexanes/EtOAc) to afford the title compound (194 mg, 97%) as a white solid: ESI MS m/z 397 [C18H15Cl3N2O2+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:11])=[C:7]([CH3:10])[NH:8][CH:9]=1)=[O:4].[OH-].[Na+].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:11])=[C:7]([CH3:10])[N:8]([S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1c[nH]c(C)c1C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cn(S(=O)(=O)c2ccc(C)cc2)c(C)c1C
Temperature: 7.5 °C
Reaction time: 0.08 h
Yield: 85.3 %

Procedure:
To a stirred solution of 2,3-dimethyl-1H-pyrrole-4-carboxylic acid methyl ester (Heterocycles 1977, 7, 77) (7.95 g, 51.9 mmol) in THF (160 mL) was added dropwise 50% NaOH (80 mL). The reaction mixture was stirred for 5 minutes and then a solution of p-toluenesulfonyl chloride (11.87 g, 62.3 mmol) in THF (160 mL) was added dropwise to the stirred mixture at room temperature. The mixture was stirred at room temperature for 30 minutes then cooled to 5 to 10° C. and treated dropwise with water (200 mL). The THF was evaporated in vacuo and the aqueous residue was thoroughly extracted with CH2Cl2. The organic extract was washed, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed over silica gel using toluene as eluant to give the required compound (13.6 g, 85%) as a pale yellow solid, m.p. 108°-114° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([CH2:13][CH:14]([C:34]([OH:36])=O)[C:15]([C@H:20]2[CH2:25][CH2:24][C@@H:23]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:22][CH2:21]2)(O)C(O)=O)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:39]([O:42]C(=O)C)(=[O:41])C>>[Si:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C:14]2[C:34](=[O:36])[O:42][C:39](=[O:41])[C:15]=2[C@H:20]2[CH2:25][CH2:24][C@@H:23]([O:26][Si:27]([C:30]([CH3:32])([CH3:31])[CH3:33])([CH3:29])[CH3:28])[CH2:22][CH2:21]2)=[CH:37][CH:38]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(C(=O)O)C(O)(C(=O)O)[C@H]2CC[C@@H](O[Si](C)(C)C(C)(C)C)CC2)cc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC2=C([C@H]3CC[C@@H](O[Si](C)(C)C(C)(C)C)CC3)C(=O)OC2=O)cc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
3-(4-((tert-Butyldimethylsilyl)oxy)benzyl)-2-(cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)-2-hydroxysuccinic acid (90 mg, 0.16 mmol) was dissolved in acetic anhydride (2.0 ml), and the mixture was stirred at 120° C. for 18 hr. The mixture was allowed to cool, excess acetic anhydride was concentrated under reduced pressure, and the residue was chromatographed on silica gel column (hexane:ethyl acetate=94:6) to give the title compound as a yellow oil (60 mg, yield 70%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=2)[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16]1C=CC=CC=1.CO.C[Si](C=[N+]=[N-])(C)C>CCCCCC>[C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=2)[C:10]([O:12][CH3:16])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccccc1
Reactant: O=C(O)c1ccnc(-c2ccccc2)c1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)c1ccnc(-c2ccccc2)c1
Reaction time: 6 h

Procedure:
Preparation H1, Step 2: A solution of 2-phenylisonicotinic acid (459 mg, 2.30 mmol) in 9:1 benzene/methanol (20 mL) was cooled to 0° C., and treated with the dropwise addition of a 2.0 M hexane solution of (trimethylsilyl)diazomethane (1.15 mL, 2.30 mmol). The mixture was allowed to come to room temperature and stirred for 6 h. Analysis by TLC indicated incomplete reaction, so the mixture was treated with additional (trimethylsilyl)diazomethane solution (230 μL, 0.23 mmol), and the reaction was stirred for an additional 2 h. TLC of the mixture remained unchanged. The solvent was stripped, and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The layers were separated, the organic phase was washed 2× with saturated sodium bicarbonate, the combined aqueous phases were extracted with ethyl acetate, and the combined organic phases were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified over silica gel, eluting with 20% ethyl acetate/heptane, to yield 372 mg of methyl 2-phenylisonicotinate as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.83 (d, J=5.27 Hz, 1H), 8.29 (s, 1H), 8.04 (d, J=7.03 Hz, 2H), 7.77 (d, J=3.52 Hz, 1H), 7.51–7.42 (m, 3H), 3.98 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6]CCCC#N)=[CH:4][C:3]=1[CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.ClC1C=CC(O)=CC=1C=O.N1CCCCC1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([OH:6])=[CH:4][C:3]=1[CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: N#CCCCOc1ccc(Cl)c(CN2CCCCC2)c1
Agent: O=Cc1cc(O)ccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCNCC1
Product: Oc1ccc(Cl)c(CN2CCCCC2)c1

Procedure:
In a similar manner to that described in Example 17 4-(4-chloro-3-piperidinomethylphenoxy)butyronitrile was prepared by the reaction of 2-chloro-5-hydroxybenzaldehyde (1.379 g), piperidine (1.8 ml) and sodium borohydride (0.33 g) in absolute ethanol (10 ml) to produce N-(2-chloro-5-hydroxybenzyl)piperidine which was then reacted with 4-bromobutyronitrile to yield the above-mentioned product.
Reaction SMILES: [CH:1]([CH:3]([C:10]#[N:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:2].[C:12]1([N:18]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:19]2[CH:26]=[CH:25]C(C=O)=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.N1CC[CH2:35][CH2:34]1.CC(=O)OCC>CO>[C:27]1([N:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:19]2[CH:26]=[CH:25][C:2](/[CH:1]=[C:3](/[C:4]3[CH:9]=[CH:8][C:7]([CH:34]=[CH2:35])=[CH:6][CH:5]=3)\[C:10]#[N:11])=[CH:21][CH:20]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C=CC(C#N)c1ccccc1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: C1CCNC1
Solvent: CCOC(C)=O
Solvent: CO
Product: C=Cc1ccc(/C(C#N)=C/c2ccc(N(c3ccccc3)c3ccccc3)cc2)cc1
Yield: 24.4 %

Procedure:
Vinyl benzylcyanide (2.2 g, 0.0154 mol) was dissolved in methanol (10 mL) and 4-(diphenylamino)benzaldehyde (1 ME, 0.0154 mol, 4.2 g) was added, followed by the addition of pyrrolidine (1.5 ME, 0.0231 mol, 1.64 g, 1.9 mL). The resulting reaction mixture was heated at reflux overnight under argon. TLC analysis on the mixture (H:EA, 8.5:1.5) showed the formation of a yellow coloured product along with some unreacted vinyl benzylcyanide. The reaction mixture was purified by column chromatography (hexane:ethyl acetate, 8.5:1.5). After chromatography, the pure product, AG1-78, was obtained as a yellow colloured brightly fluorescent material solid (1.5 g, 23%), 1H NMR (400 MHz, CDCl3) δ 5.3 (d, 1H, ethylene —CH), δ5.8 (d, 1H, ethylene-CH), δ 6.7 (m, 1H), δ 7.1 (m, 8H), δ 7.3 (m, 4H), δ 7.45 (m, 3H), δ 7.6 (dd, 2H), δ 7.7 (dd, 2H), 13C NMR (CDCl3, ppm, δ): 149.94, 146.60, 141.18, 137.85, 135.97, 134.34, 130.66, 129.56, 126.75, 126.44, 125.78, 125.70, 124.37, 120.89, 118.66, 114.81, 107.38.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Br:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=[C:14]2[NH:28][C:29]1[N:33]([CH:34]2[CH2:39][CH2:38][CH:37]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:36][CH2:35]2)[C:32]2[CH:48]=[CH:49][C:50]([C:52](O)=[O:53])=[CH:51][C:31]=2[N:30]=1.[I-].Cl[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][N+:58]=1C.ON1C2C=CC=CC=2N=N1.C1(N)CCCC1>C(OCC)(=O)C>[CH:59]1([NH:58][C:52]([C:50]2[CH:49]=[CH:48][C:32]3[N:33]([CH:34]4[CH2:39][CH2:38][CH:37]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:36][CH2:35]4)[C:29]([NH:28][C:14]4[C:13]5[C:17](=[CH:18][CH:19]=[C:11]([Br:10])[CH:12]=5)[N:16]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:26])[CH3:27])[N:15]=4)=[N:30][C:31]=3[CH:51]=2)=[O:53])[CH2:57][CH2:62][CH2:61][CH2:60]1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(n2c(Nc3nn(COCC[Si](C)(C)C)c4ccc(Br)cc34)nc3cc(C(=O)O)ccc32)CC1
Reactant: C[n+]1ccccc1Cl
Agent: NC1CCCC1
Agent: On1nnc2ccccc21
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OC1CCC(n2c(Nc3nn(COCC[Si](C)(C)C)c4ccc(Br)cc34)nc3cc(C(=O)NC4CCCC4)ccc32)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
N,N-Diisopropylethylamine (19.6 uL, 0.000112 mol) was added to a solution of 2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-ylamino)-1-(4-(tert-butyldimethylsilyloxy)cyclohexyl)-1H-benzo[d]imidazole-5-carboxylic acid (26.8 mg, 0.0000375 mol), 2-chloro-1-methylpyridinium iodide (19.2 mg, 0.0000750 mol) and 1-hydroxybenzotriazole (10.1 mg, 0.0000750 mol) tetrahydrofuran (0.40 mL). The mixture was stirred at room temperature for 20 minutes. Cyclopentanamine (0.000112 mol) was then added and the mixture stirred for 2 hours. The mixture was diluted with ethyl acetate, washed with water, dried over magnesium sulfate and purified by flash chromatography.
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([S:10][CH2:11][C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[O:20]>>[CH3:17][N:18]([CH3:22])[C:19]([N:7]1[C:8]([S:10][CH2:11][C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6]1)=[O:20]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)c1n[nH]c(SCc2ccco2)n1
Product: CN(C)C(=O)n1nc(C(C)(C)C)nc1SCc1ccco1

Procedure:
3-t-Butyl-5-(fur-2-yl-methylthio)-1H-1,2,4-triazole was reacted with dimethylcarbamoyl chloride by substantially the same procedure as described in Example 1 to yield 1-dimethylcarbamoyl-3-t-butyl-5-(fur-2-yl-methylthio)-1H-1,2,4-triazole, an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:12][CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7]C)=O.Br[C:27]1[C:32]([CH:33]=O)=[C:31]([CH3:35])[CH:30]=[CH:29][N:28]=1.C[Al](C)C.[CH3:40][NH:41][CH2:42][CH:43]1[CH2:46][CH2:45][CH2:44]1>>[CH:43]1([CH2:42][N:41]([CH3:40])[C:5]([C:4]2[CH:9]=[CH:10][C:11]3[C:2]([C:3]=2[O:12][CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:1][C:27]2[N:28]=[CH:29][CH:30]=[C:31]([CH3:35])[C:32]=2[CH:33]=3)=[O:7])[CH2:46][CH2:45][CH2:44]1
Reactant: Cc1ccnc(Br)c1C=O
Reactant: CNCC1CCC1
Reactant: COC(=O)c1cccc(N)c1OC(c1ccccc1)c1ccccc1
Agent: C[Al](C)C
Product: Cc1ccnc2nc3c(OC(c4ccccc4)c4ccccc4)c(C(=O)N(C)CC4CCC4)ccc3cc12

Procedure:
For example, methyl 3-amino-2-diphenylmethoxybenzoate A28.8 is reacted, as described above, with 2-bromo-4-methylpyridine-3-carboxaldehyde A28.9 (Arkivoc, 2000, 1, 52) to produce after cyclization, the tricyclic ester A28.10. The ester is then reacted with trimethylaluminum and N-methylcyclobutylmethylamine A28.11 to give 9-benzhydryloxy-4-methyl-benzo[b][1,8]naphthyridine-8-carboxylic acid cyclobutylmethyl-methyl-amide A28.12. Benzylic bromination then gives the bromomethyl analog A28.13. The latter compound is heated at 120° C. with excess of a trialkyl phosphite to produce after deprotection the phosphonate A28.14.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[CH2:10])[CH:6]=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C1(C=CC(O)=CC=1)O>CC(O)C>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:10][CH2:9][C:7]2[CH:6]=[CH:5][C:4]([N+:11]([O-:13])=[O:12])=[C:3]([O:2][CH3:1])[CH:8]=2)[CH2:17][CH2:16]1
Reactant: C=Cc1ccc([N+](=O)[O-])c(OC)c1
Reactant: CN1CCNCC1
Agent: Oc1ccc(O)cc1
Solvent: CC(C)O
Product: COc1cc(CCN2CCN(C)CC2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 69.4 %

Procedure:
To 5-ethenyl-2-nitrophenyl methyl ether (0.55 g, 3.1 mmol) in 10 mL of iPrOH was added, 1-methylpiperazine (0.614 g, 6.13 mmol), and catalytic hydroquinone (0.033 g, 0.31 mmol). The mixture was heated to 90° C. for 18 h. The solvent was rotovaped down and the crude product was purified by flash chromatography to give the title compound of step C (0.6 g, 2.15 mmol, 70%). 1H NMR (400 MHz, CDCl3) δ ppm 7.79 (d, J=8.24 Hz, 1H), 6.93 (s, 1H), 6.84 (dd, J=8.33, 1.19 Hz, 1H), 3.93 (s, 3H), 2.79-2.89 (m, 2H), 2.40-2.69 (m, 10H), 2.29 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:3]([C:8]2[CH:19]=[CH:18][C:11]3[C:12]([OH:17])=[N:13][S:14](=[O:16])(=[O:15])[C:10]=3[CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.CC1C=CC(C2C([C:33]([F:36])([F:35])[F:34])=CC=CN=2)=CC=1.ClC1C(C2C=CC(C)=CC=2)=NC=CC=1>>[F:34][C:33]([F:36])([F:35])[C:2]1[C:3]([C:8]2[CH:19]=[CH:18][C:11]3[C:12]([OH:17])=[N:13][S:14](=[O:16])(=[O:15])[C:10]=3[CH:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ncccc2C(F)(F)F)cc1
Reactant: O=S1(=O)N=C(O)c2ccc(-c3ncccc3Cl)cc21
Agent: Cc1ccc(-c2ncccc2Cl)cc1
Product: O=S1(=O)N=C(O)c2ccc(-c3ncccc3C(F)(F)F)cc21

Procedure:
The title compound was prepared using the procedures as described for the preparation of the product of Example 1B, substituting the product of Example 7A for the product of Example 1A. MS (DCI+) m/z 329 (M+H)+; 1H NMR (DMSO-d6) δ 7.77 (m, 1H), 7.94 (d, J 7.8, 1H), 8.05 (d, J 7.8, 1H), 8.17 (s, 1H), 8.40 (dd, J 1.3, 7.8, 1H), 8.97 (d, J 4.7, 1H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14].[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.C([O-])([O-])=O.[K+].[K+].O>C1(C)C=CC=CC=1.CCOC(C)=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>[CH3:14][O:13][CH2:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH3:24]
Reactant: Cc1ccccc1B(O)O
Reactant: COCc1cc(C(=O)OC)ccc1Br
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COCc1cc(C(=O)OC)ccc1-c1ccccc1C
Temperature: 25 °C

Procedure:
Methyl 4-bromo-3-(methoxymethyl)benzoate, (40 g; 154 mmol), o-tolylboronic acid (23 g; 170 mmol), K2CO3 (107 g; 772 mmol), tetrakis(triphenylphosphine)palladium (0) (1.8 g; 1.5 mmol) were taken up in toluene (200 mL) and water (200 mL) under N2 atmosphere. The reaction mixture was purged with vacuum, then degassed with N2 and then refluxed for 1 hour. The reaction mixture was cooled to RT, filtered over a pad of celite and washed with EtOAc (1 L). The filtrate was concentrated, affording a yellow oil which was taken in EtOAc (800 mL). The organic layer was washed with a saturated aqueous solution of NaHCO3 solution (250 mL), water (250 mL) and brine (250 mL), dried over MgSO4 and concentrated affording the title compound as a yellow oil used without further purification (42 g, quantitative). HPLC (Method A) Rt 5.34 min (Purity: 89.4%).