Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl/[CH:2]=[CH:3]/[C:4]([C:6]1([CH3:12])[CH2:9][CH:8]([CH2:10][CH3:11])[CH2:7]1)=[O:5].[I-:13].[Na+].OS(O)(=O)=O>CC(C)=O>[I:13]/[CH:2]=[CH:3]/[C:4]([C:6]1([CH3:12])[CH2:9][CH:8]([CH2:10][CH3:11])[CH2:7]1)=[O:5]
Reactant: [I-]
Reactant: CCC1CC(C)(C(=O)/C=C/Cl)C1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCC1CC(C)(C(=O)/C=C/I)C1
Yield: 108.7 %

Procedure:
A solution of 4.2 g of trans-1-chloro-3-(3-ethyl-1-methylcyclobutyl)-prop-1-en-3-one (prepared in Example 5A) and 10 g of anhydrous sodium iodide in 60 ml of acetone was refluxed with about 0.5 ml H2SO4 for 4 hr under an argon atmosphere. The solvent was removed by evaporation in vacuo. The residue was diluted with water and the aqueous mixture was extracted several times with ether. The combined ether extract was washed with aqueous sodium thiosulfate solution and then dried over anhydrous magnesium sulfate and evaporated in vacuo to yield 6.8 g of the title compound having the following physical characteristics:
Reaction SMILES: C(#N)C.F[C:5]1[C:14]([O:15][CH3:16])=[C:13]2[C:8]([C:9](=[O:24])[C:10]([C:21]([OH:23])=[O:22])=[CH:11][N:12]2[C@@H:17]2[CH2:19][C@@H:18]2[F:20])=[CH:7][CH:6]=1.Cl.C(N(CC)CC)C.C(O)(=O)C(O)=O.[NH:39]1[CH2:43][CH2:42][C@@H:41]([C:44]2([NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:46][CH2:45]2)[CH2:40]1>C(N(CC)CC)C>[C:50]([O:49][C:48]([NH:47][C:44]1([C@@H:41]2[CH2:42][CH2:43][N:39]([C:5]3[C:14]([O:15][CH3:16])=[C:13]4[C:8]([C:9](=[O:24])[C:10]([C:21]([OH:23])=[O:22])=[CH:11][N:12]4[C@@H:17]4[CH2:19][C@@H:18]4[F:20])=[CH:7][CH:6]=3)[CH2:40]2)[CH2:45][CH2:46]1)=[O:54])([CH3:53])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCNC2)CC1
Reactant: COc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1c(N2CC[C@@H](C3(NC(=O)OC(C)(C)C)CC3)C2)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
An acetonitrile solution (45 mL) containing 7-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (3 g), triethylamine hydrochloride (2.8 g), and boron trifluoride-tetrahydrofuran complex (2.84 g) was stirred at room temperature for 30 minutes. tert-Butyl {1-[(3R)-pyrrolidin-3-yl]cyclopropyl}carbamate oxalic acid salt (3.54 g) and triethylamine (5.71 mL) were further added to reaction mixture, followed by stirring for 10 hours at the same temperature. The solvent was evaporated under reduced pressure, and methanol (30 mL) was added to the residue. The mixture was refluxed for 12 hours, and the solvent was evaporated under reduced pressure. 80% Hydrated methanol (20 mL) was added to the residue, and the pH of the product was adjusted to 7 by use of 5N aqueous sodium hydroxide solution, followed by stirring at 60° C. for 30 minutes and at room temperature for 16 hours. The thus-produced crystals were recovered through filtration and dried, to thereby yield 4.79 g of the title compound (yield: 94%).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[C:3]([C:14]([O:16]CC)=O)[N:2]=1.[CH:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1>O>[C:22]1([CH2:25][CH2:26][NH:27][C:14]([C:3]2[N:2]=[CH:1][C:13]3[NH:12][C:11]4[C:6]([C:5]=3[CH:4]=2)=[CH:7][CH:8]=[CH:9][CH:10]=4)=[O:16])[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=1
Reactant: NCCc1ccccc1
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Solvent: O
Product: O=C(NCCc1ccccc1)c1cc2c(cn1)[nH]c1ccccc12
Yield: 95.2 %

Procedure:
2 g of ethyl β-carbolin-3-carboxylate and 5 g of β-phenethylamine are heated for 2 hours at 196° C. The cooled, partly crystallized mixture is treated with hot water which is decanted. The residue is recrystallized from xylene to form β-carbolin-3-carboxylic acid (2-phenylethyl)amide (2.5 g) of a melting point of 297°-298° C.
Reaction SMILES: C1(C)C=CC(S([C:10]2[C:21]3=[C:22]4[N:17]([CH2:18][CH2:19][CH2:20]3)[CH:16]=[C:15]([C:23]([OH:25])=[O:24])[C:14](=[O:26])[C:13]4=[CH:12][CH:11]=2)(=O)=O)=CC=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CS(C)=O.Cl>O>[N:28]1([C:10]2[C:21]3=[C:22]4[N:17]([CH2:18][CH2:19][CH2:20]3)[CH:16]=[C:15]([C:23]([OH:25])=[O:24])[C:14](=[O:26])[C:13]4=[CH:12][CH:11]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1
Reactant: Cc1ccc(S(=O)(=O)c2ccc3c(=O)c(C(=O)O)cn4c3c2CCC4)cc1
Reactant: C1CNCCN1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cn2c3c(c(N4CCNCC4)ccc3c1=O)CCC2
Yield: 17.3 %

Procedure:
19.1 g of 8-(p-toluenesulfonyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid and 12.9 g of piperazine were added to 200 ml of anhydrous dimethyl sulfoxide and the mixture was heated in an autoclave under flow of nitrogen at 10 atm. at a temperature of 150° to 160° C. for 18 hours while stirring. After completion of the reaction, the solvent and excess piperazine were removed under reduced pressure and a mixture of methanol and ethanol was added to the residue. The preicpitates formed were separated by filtration and washed with diethyl ether. The crystals thus-obtained were suspended in a mixture of 200 ml of water and 40 ml of a 10% aqueous hydrochloric acid solution and insoluble materials were removed by filtration. The filtrate was rendered neutral with saturated aqueous solution of sodium bicarbonate and purified through column chromatography using Amberlite LH-20 (a trade name for a product of Tokyo Organic Chemical Industries Ltd.) (eluent: water, ethanol). Recrystallization of the eluate from dimethylformamide gave 2.7 g of 8-(1-piperazinyl)-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as white needles having a melting point of 267° to 268° C.
Reaction SMILES: I[C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Li]CCCC.CN([CH:21]=[O:22])C>O1CCCC1>[CH:21]([C:2]1[C:3]([CH3:12])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8])=[O:22]
Reactant: Cc1cc(C)c(C(=O)O)cc1I
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C)c(C(=O)O)cc1C=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
To a stirred solution of 5-iodo-2,4-dimethylbenzoic acid (compound 1.3, 5.00 g, 18.1 mmol) in tetrahydrofuran (150 mL) under nitrogen at −78° C. was added n-BuLi (2.5 M in THF, 18 mL, 45 mmol) drop-wise. The mixture was stirred at −78° C. for 1 h and then DMF (5.3 mL, 68 mmol) was added drop-wise. The resulting mixture was stirred at −78° C. for 0.5 h and then carefully quenched by slow addition of water (50 mL). The pH of the mixture was adjusted to ˜3-4 with aqueous HCl (6 M) and then extracted with ethyl acetate (3×200 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:10-1:5) as the eluent to yield the title compound as a white solid (2.4 g, 74%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24].O>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][N:12]([CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CN1CCC(NC(=O)OC(C)(C)C)CC1
Reaction time: 1 h

Procedure:
4-(tert-butoxycarbonylamino)piperidine (1.2 g) and potassium carbonate (1.2 g) were suspended in dimethylformamide (20 mL), and then methyl bromoacetate (0.62 mL) was added. The reaction solution was stirred for one hour and water was added, followed by extraction with ethyl acetate. The organic layer was washed in turn with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the filtrate was concentrated. The residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1→0:1) to obtain the title compound (1.36 g) having the following physical properties.
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:37][CH2:38][C:39]1[CH:46]=[CH:45][C:42](C#N)=[C:41](F)[CH:40]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][C@H:2]1[C:3]([NH:37][CH2:38][C:39]1[CH:46]=[CH:45][CH:42]=[CH:41][CH:40]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Reactant: N#Cc1ccc(CN)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
To an ice cooled solution of Boc-Aze-OH (0.194 g, 0.96 mmol) in 5 mL of DMF was added TBTU (0.50 g, 9.6 mmol). After 30 min another solution, comprising 4-aminomethyl-2-fluorobenzonitrile (0.17 g, 0.81 mmol; see step (v) above) and diisopropylethyl amine (0.326 g, 2.53 mmol) in 7 mL of DMF was added. The resulting solution was stirred overnight at room temperature. The solvent was evaporated and the product was purified by preparative RPLC using CH3CN:0.1M NH4OAc (50:50). Freeze-drying gave 0.237 g (74%) of the desired sub-title compound.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:15][SiH:16]([CH:18]([SiH:22]([Cl:24])[Cl:23])[SiH:19]([Cl:21])[Cl:20])[Cl:17]>C1C=CC=CC=1>[Cl:15][Si:16]1([Cl:17])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[Si:19]([Cl:21])([Cl:20])[CH:18]1[SiH:22]([Cl:24])[Cl:23]
Reactant: Cl[SiH](Cl)C([SiH](Cl)Cl)[SiH](Cl)Cl
Reactant: C(#Cc1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: Cl[SiH](Cl)C1[Si](Cl)(Cl)C(c2ccccc2)C(c2ccccc2)[Si]1(Cl)Cl
Reaction time: 5 h
Yield: 12.3 %

Procedure:
Hydrosilation of diphenylacetylene with tris(dichlorosilyl)methane in the presence of H2PtCl6 /IPA. Into the same apparatus as described in Example 1 were place 3.39 g of diphenylacetylene, 5.91 g of tris(dichlorosilyl)methane, 40 ml of dried benzene, and 100 μl of a 0.1 M H2PtCl6 /IPA solution to form a mixture. The mixture was stirred for 5 hours at reflux temperature and then the solvent removed at atmospheric pressure. The residue was vacuum distilled at 67 Pa to yield a mixture comprising 7.51 g of 1,1,3,3-tetrachloro-2-dichlorosilyl-4,5-diphenyl-1,3-disilacyclopentane (TCD-GC area of 12.3%) and 1,1,3,3 -tetrachloro-2-(1,2-dichloro-2,3-diphenyl- 1 -sila-2-propenyl)-4,5-diphenyl-1,3-disilacyclopentane (TCD-GC area 74%). 1,1,3,3-Tetrachloro-2-dichlorosilyl4,5-diphenyl-1,3-disilacyclopentane=1H-NMR (CDCl3, ppm): 1.72 (d, 3.4 Hz, 1H, SiCHSi), 3.47-3.53 (m, 2H, CHPh), 5.8 (d, 3.5 Hz, 1H, SiH), 7.15-7.28 (m, 10 H, ArH). 1,1,3,3-Tetrachloro-2-(1,2-dichloro-2,3-diphenyl-1 -sila-2-propenyl)-4,5-diphenyl-1,3-disilacyclopentane=1H-NMR (CDC13, ppm): 1.73(s, 1H, SiCHSi), 3.52-3.55 (m, 2H, CHPh), 7.12-7.50 (m, 21H, C=CHPh and ArH).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][OH:10])=[CH:3][CH:2]=1.[C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH:12]=[CH2:13]>CO>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][O:10][CH2:13][CH2:12][C:11]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:3][CH:2]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: OCCCc1ccncc1
Solvent: CO
Product: CC(C)(C)OC(=O)CCOCCCc1ccncc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
Triton B (40% methanol solution, 0.5 ml) was concentrated under reduced pressure, and 4-pyridinepropanol (10.2 g, 74.5 mmol) was added thereto. After 15 minutes, tert-butyl acrylate (9.59 g, 74.8 mmol) was added to the mixture, and the mixture was stirred at room temperature for 6 hrs. The reaction mixture was subjected to a silica gel column chromatography, eluted with hexane-ethyl acetate (1:1, v/v) to give the titled compound (17.1 g, 86%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11](C(O)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:22][C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:24]1[CH:25]=[CH:26][CH:27]=[N:28][C:23]=1[CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: ClCc1ncccn1
Reactant: O=C(O)N1CCN(c2ccc(O)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cnc(COc2ccc(N3CCNc4ccccc43)cc2)nc1
Temperature: 100 °C

Procedure:
0.3 g of the tent-Butyl ester of 4-(4-hydroxyphenyl)-3,4-dihydro-2H-quinoxaline-1-carboxylic acid is placed in 4.6 ml of dimethylformamide under nitrogen. 0.167 g of 2-(chloromethyl)pyrimidine and 0.508 g of potassium carbonate are added. The reaction medium is heated at 100° C. for 4 h. 0.254 g of potassium carbonate is added and heating is maintained for 1 h 30. After hydrolysis, the reaction medium is extracted with ethyl acetate until the aqueous phase has been completely extracted. The organic phases are combined, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to dryness. The crude product obtained is chromatographed on silica gel, elution being carried out with a gradient of methanol in dichloromethane varying from 0% to 9/1. 0.095 g of 1-[4-(pyrimidin-2-ylmethoxy)phenyl]-1,2,3,4-tetrahydro-quinoxaline is obtained.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:5][CH:4]=1.Br.C(O)(=O)C>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCCCCCCC(=O)O)cc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)CCCCCCCCc1ccc(O)cc1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
A mixture of 55.7 gms 9(4-methoxyphenyl)nonanoic acid, 640 ml 48% HBr and 640 ml acetic acid was refluxed for 7 hours and cooled to room temperature overnight. The solution was diluted with a large excess of water, whereupon a solid precipitated. The solid was filtered off, re-suspended in water, and filtered again. It was dissolved in ether, washed four times with water, and the organic phase was dried over MgSO4 overnight. The drying agent was filtered off and the solvent removed in vacuo to give a solid which was recrystallized from toluene to give 31.8 gms (58%) 9(4-hydroxyphenyl)nonanoic acid, m.p. 103°-5°.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=3)=[CH:13][C:12]([CH:23]([F:25])[F:24])=[N:11]2)=[CH:6][CH:5]=1)(O)=[O:2].S(Cl)([Cl:28])=O>>[Cl:28][C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=3)=[CH:13][C:12]([CH:23]([F:25])[F:24])=[N:11]2)=[CH:6][CH:5]=1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: CSc1ccc(-c2cc(C(F)F)nn2-c2ccc(C(=O)O)cc2)cc1
Product: CSc1ccc(-c2cc(C(F)F)nn2-c2ccc(C(=O)Cl)cc2)cc1

Procedure:
A mixture of 1-(4-carboxyphenyl)-3-(difluoromethyl) -5-[4-(methylthio)phenyl]pyrazole (2 g) and thionyl chloride (20 ml) was refluxed for 3 hours, and concentrated in vacuo, giving 1-[4-(chloroformyl)phenyl]-3-(difluoromethyl)-5-[4-(methylthio)phenyl]pyrazole. A solution of diethyl malonate (1.4 g) and ethanol (0.3 ml) in diethyl ether (15 ml) was added dropwise to a stirred mixture of magnesium (0.16 g), ethanol (0.2 ml) and carbon tetrachloride (0.36 ml) in diethyl ether (5 ml). The resulting mixture was refluxed for 1 hour. A solution of the above acid chloride in tetrahydrofuran (15 ml) was added dropwise to the mixture. The mixture was stirred at ambient temperature for 1 hour and refluxed for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. A mixture of the residue (4 g), acetic acid (40 ml), and 20% sulfuric acid (20 ml) was refluxed for 3.5 hours and then concentrated. The residue was dissolved in ethyl acetate, and the solution was washed with water, dried, and concentrated. The residue was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (4:1) to give crystals of 1-(4-acetylphenyl)-3-(difluoromethyl)-5-[4-(methylthio)phenyl]pyrazole (0.4 g).
Reaction SMILES: [CH2:1]([O:19][CH:20]1[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23][CH:22]([CH2:64][OH:65])[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].O[C:67]1[CH:74]=[CH:73][C:70]([CH:71]=[O:72])=[CH:69][CH:68]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:1]([O:19][CH:20]1[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23][CH:22]([CH2:64][O:65][C:67]2[CH:74]=[CH:73][C:70]([CH:71]=[O:72])=[CH:69][CH:68]=2)[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(CO)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc(C=O)cc2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reaction time: 0.67 h

Procedure:
(3,4,5-Tris-octadecyloxy-cyclohexyl)-methanol (283 mg, 308 μmol), 4-hydroxy-benzaldehyde (56 mg, 459 μmol), and triphenylphosphine (121 mg, 461 μmol) were dissolved in dehydrated THF (5.5 mL), DIED (93.3 μL, 472 μmol) was added, and the mixture was stirred for 40 minutes. 4-Hydroxy-benzaldehyde, triphenylphosphine, and DIED (each 153 μmol) were added, and the mixture was stirred overnight. Triphenylphosphine and DIED (each 306 μmol) were added, and the mixture was stirred for 2.5 hours. THF was evaporated, and 90% aqueous acetonitrile (6 ml) was added to the residue to allow crystallization. The crystals were collected by filtration and thoroughly washed with acetonitrile to give crude crystals of 4-(3,4,5-tris-octadecyloxy-cyclohexylmethoxy)-benzaldehyde. The crude crystals were purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to give the object compound (130 mg, 127 μmol, 41%).
Reaction SMILES: Br.[NH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[C:11](Cl)[N:10]=1.[OH-].[Na+]>COCCO.O>[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[C:11]([N:2]2[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)[N:10]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: C1CNCCN1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCO
Product: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Temperature: 75 °C

Procedure:
Piperazine hydrobromide (168.0 g., 1.006 mole) was added to a suspension of 4-amino-2-chloro-6,7-dimethoxyquinazoline (241.0 g., 1.006 mole) in 2-methoxyethanol (3.6 l.) and the mixture was stirred at reflux for 1.25 hours. The precipitate was separated by filtration, washed with hot 2-methoxyethanol and dried. The material then was added to a stirred solution of sodium hydroxide (81.0 g., 2.01 mole) in water (3 l.) and the mixture was heated to 75° C. The mixture then was cooled to 40° C., filtered, and the insoluble precipitate washed with water and dried. The material was triturated under refluxing absolute ethanol (6.0 l.) and the mixture was filtered. The filtrate was evaporated to dryness to yield the title compound, 180.0 g. (62%), m.p. 224°-228° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.C(O)(=O)C.[Br:13]Br>>[Br:13][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: Nc1ccc(F)cn1
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1ncc(F)cc1Br

Procedure:
To a solution of 5-Fluoro-pyridin-2-ylamine (3.00 g, 26.8 mmol) in acetic acid (30.0 mL, 528 mmol) at 80° C. was added bromine (5.50 mL, 107 mmol) in acetic acid (5.50 mL, 96.7 mmol). The temperature was maintained for one hour. The reaction was poured over ice, neutralized, and extracted with EtOAc. The organic layer was purified with ISCO silica gel chromatography to afford 3-bromo-5-fluoro-pyridine-2-ylamine. 6-Fluoro-8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 3-bromo-5-fluoro-pyridine-2-ylamine in a manner analogous to Steps 2a-b to afford a white solid (80%). MP=243-246° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.97 (s, 1H), 7.99 (d, J=8.5 Hz, 1H), 6.28 (bs, 2H). MS=231.0 (MH)+. 105b) 6-Fluoro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine prepared from 8-Bromo-6-fluoro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine and (4-Methylsulfonylphenyl)boronic acid in a manner analogous to Step 2c to afford a tan solid (45%). MP=226-234° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.00 (s, 1H), 8.43 (d, J=7.8 Hz, 2H), 8.06-8.00 (m, 3H), 6.27 (bs, 2H), 3.28 (s, 3H). MS=307.0 (MH)+. 105c) [6-Fluoro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-bis-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was formed from 6-fluoro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine and 1-(3-bromo-phenyl)-4-methyl-piperazine in a manner analogous to Step 2d and was isolated as a yellow solid (14% yield). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.32 (m, 2H), 8.10 (d, J=7.8 Hz, 2H), 7.70 (d, J=9.4 Hz, 1H), 7.55 (s, 1H), 7.49-7.46 (m, 1H), 7.40-7.35 (m, 2H), 7.17-7.13 (m, 2H), 7.01 (s, 1H), 6.71 (d, J=8.0 Hz, 1H), 6.54 (d, J=8.0 Hz, 1H), 3.31 (bm, 4H), 3.18 (bm, 4H), 3.12 (s, 3H), 2.62 (bm, 4H), 2.58 (bm, 4H), 2.40 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:21]([O:25][C:26]([N:28]([CH2:30][C:31](O)=[O:32])[CH3:29])=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:5]2[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:31](=[O:32])[CH2:30][N:28]([C:26]([O:25][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:27])[CH3:29])[N:3]=[CH:4]2)=[CH:12][CH:13]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CC(C)(C)c1ccc(Cn2cnc(N)c2C(N)=O)cc1
Product: CN(CC(=O)Nc1ncn(Cc2ccc(C(C)(C)C)cc2)c1C(N)=O)C(=O)OC(C)(C)C
Yield: 80 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 17, using 2.50 g (9.18 mmol) of 4-amino-1-(4-t-butylbenzyl)-5-imidazole carboxamide which was prepared in the same manner as in Example 57 and 2-(N-t-butyloxycarbonyl-N-methylamino)acetic acid instead of 3-pyridylacetic acid hydrochloride to obtain 3.27 g of 1-(4-t-butylbenzyl)-4-(2-(N-t-butyloxycarbonyl-N-methylamino)acetylamino)-5-imidazolecarboxamide (yield 80%).