Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH2:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])(=[O:18])=[O:17])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([N:47]=[N+:48]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1.Cl>ClCCl>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([C:19]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[N+:47]=[N-:48])(=[O:17])=[O:18])=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Oc1ccc(S(=O)(=O)CS(=O)(=O)c2ccc(OC(=O)c3ccccc3)cc2)cc1)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=C(S(=O)(=O)c1ccc(OC(=O)c2ccccc2)cc1)S(=O)(=O)c1ccc(OC(=O)c2ccccc2)cc1
Reaction time: 0.08 h
Yield: 37 %

Procedure:
The bis(4-benzoyloxyphenylsulfonyl)methane in Synthesis Example 6, 10 g (0.019 mol), was dispersed in 200 g of dichloromethane. To the dispersion was added 5.6 g (0.029 mol) of p-toluenesulfonylazide which had been separately prepared. With stirring under ice cooling, 4.0 g (0.026 mol) of DBU was added to the dispersion, and after 5 minutes, 100 g of a 0.2N aqueous hydrochloric acid was added to stop reaction. The organic layer was separated and washed with 100 g of water. The organic layer was concentrated and 15 g of the residue was purified by silica gel column chromatography using dichloromethane as an elute. The thus obtained oily product was combined with 40 g of hexane for crystallization, followed by filtration and vacuum drying. There was obtained 4.0 g (yield 37%) of fine yellow crystals.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[S:11])[N:3]1[CH:12]([CH2:17][CH2:18][C:19]([O:21]C)=O)[C:13](OC)=[O:14].FC(F)(F)C([NH2:27])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl.O>[S:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2](=[O:1])[N:3]1[CH:12]1[CH2:17][CH2:18][C:19](=[O:21])[NH:27][C:13]1=[O:14]
Reactant: NC(=O)C(F)(F)F
Reactant: COC(=O)CCC(C(=O)OC)N1C(=O)c2ccccc2C1=S
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1CCC(N2C(=O)c3ccccc3C2=S)C(=O)N1
Temperature: 25 °C
Reaction time: 72 h
Yield: 63.4 %

Procedure:
A mixture of compound 208 (81 mg, 0.276 mmol), trifluoroacetamide (57 mg, 0.50 mmol), 1-hydroxybenzotriazole (145 mg, 1.07 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (200 mg, 1.04 mmol) and triethylamine (0.21 mL, 1.51 mmol) in CH2Cl2 (1.5 mL) was stirred at ambient temperature for 3 days. Water (10 mL) and CH2Cl2 (10 mL) were added. The dichloromethane layer was separated, washed with water, dried over Na2SO4 and evaporated under reduced pressure. Purification by chromatography, with EtOAc:CH2Cl2 (1:10) as the eluent, gave compound 212 (48 mg, 63%) as a red solid: mp 255° C.; 1H NMR (CDCl3) δ 8.00-7.98 (m, 1H), 7.80-7.71 (m, 3H), 5.63 (br, 1H), 2.98-2.70 (m, 3H), 2.18-2.15 (m, 1H); MS (CI/CH4) m/z 274 (M+); Anal. (C13H10N2O3S) C, H, N.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]2[CH2:14][C:9]1=[CH:10][N:11]2[C:15]1[N:20]2[CH:21]=[N:22][N:23]=[C:19]2[CH:18]=[C:17]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH3:32])[CH:25]=2)[N:16]=1)=O)(C)(C)C.Cl>O1CCOCC1.CO>[C@H:12]12[CH2:14][C@H:9]([NH:8][CH2:13]1)[CH2:10][N:11]2[C:15]1[N:23]2[N:22]=[CH:21][N:20]=[C:19]2[CH:18]=[C:17]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C@H:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH3:32])[CH:25]=2)[N:16]=1
Reactant: CC(Nc1cc(-c2cc3nncn3c(N3C=C4CC3CN4C(=O)OC(C)(C)C)n2)ccn1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@H](Nc1cc(-c2cc3ncnn3c(N3C[C@@H]4C[C@H]3CN4)n2)ccn1)c1ccccc1
Reaction time: 1 h

Procedure:
To 5-{7-[2-(1-phenyl-ethylamino)-pyridin-4-yl]-[1,2,4]triazolo[4,3-c)pyrimidin-5-yl}-2,5-diaza-bicyclo[2.2.1]heptene-2-carboxylic acid tert-butyl ester (0.022 g, 0.043 mmol) were added 4N HCl (1 mL) in dioxane and a few drops of methanol. After 1 h, the reaction was concentrated in vacuo and the residue was taken up in water and extracted with ethyl acetate. The aqueous layer was neutralized with saturated sodium bicarbonate and extracted with chloroform (3×). The combined organic extract was dried (K2CO3), filtered, and concentrated in vacuo to give the title compound as a golden yellow solid. MS (ES+): 413.1 [M+H]+, 411.2 [M−H]−.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][CH:13]([NH2:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:21][C:22]1[C:30]2[C:25](=[CH:26][C:27]([C:31](O)=[O:32])=[CH:28][CH:29]=2)[NH:24][CH:23]=1>>[Cl:21][C:22]1[C:30]2[C:25](=[CH:26][C:27]([C:31]([NH:20][CH:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:12][CH2:11][CH2:10][N:7]3[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]3)=[O:32])=[CH:28][CH:29]=2)[NH:24][CH:23]=1
Reactant: CC(C)N1CCN(CCCC(N)c2ccccc2)CC1
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Product: CC(C)N1CCN(CCCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccc2)CC1

Procedure:
Using coupling method A, crude 4-(4-isopropylpiperazin-1-yl)-1-phenylbutylamine (530 mg, 1.9 mmol) and 3-chloro-indole-6-carboxylic acid (376 mg, 1.9 mmol) afforded, after purification (SiO2: 10:10:1 hexane:EtOAc:isopropyl-amine), 184 mg (21%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH:9]1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]([O:20]C(N1CCC2(OCCO2)CC1)=O)(C)(C)[CH3:17].[Li]C(CC)C.CI>CN(CCN(C)C)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([O:20][CH2:16][CH2:17][O:14]2)[CH2:10][CH:9]1[CH3:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)OCCO2
Reactant: CC1CC(=O)CCN1C(=O)OC(C)(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: O
Solvent: CI
Product: CC1CC2(CCN1C(=O)OC(C)(C)C)OCCO2
Reaction time: 1 h

Procedure:
2-Methyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester. A solution of 1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (2.97 g) in TMEDA (2.2 mL) was cooled to −78° C. and sec-BuLi (1.8 M in THF, 13 mL) was added dropwise. The resulting yellow solution was aged at −78° C. for 1 h. Methyl iodide (1.5 mL) was added and the mixture was warmed from −78° C. to RT over 16 h. The reaction mixture was poured into water (800 mL) and extracted with EtOAc. The combined organic extracts were washed with H2O, brine, and dried over Na2SO4. Purification on SiO2 (330 g, 5 to 20% EtOAc/hexanes) provided 1.65 g of 7-methyl-1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester. Multiple aliquots of this ester were combined (2.29 g), treated with 5 mL of conc. HCl in 10 mL of dioxane, and heated at 65° C. for 6 h. The solvent was removed and the residue was dissolved in CH2Cl2 and treated with di-tert-butyldicarbonate (1.0 g). After 5 d, the mixture was diluted with satd. aq. NaHCO3 and H2O, and extracted with CH2Cl2. Purification on SiO2 (120 g, 5 to 15% EtOAc/hexanes) provided 1.40 g of the desired product as a white solid. 1H NMR (500 MHz, CDCl3): 4.69-4.59 (m, 1H), 4.21-4.12 (m, 1H), 3.30-3.20 (m, 1H), 2.66-2.57 (m, 1H), 2.47-2.36 (m, 1H), 2.32-2.23 (m, 1H), 2.22-2.15 (m, 1H), 1.42 (s, 9H), 1.11 (d, J=7.1 Hz, 3H).
Reaction SMILES: [N:1]([CH:4]([CH:10]([C:12]1[C:13]([Cl:18])=[N:14][CH:15]=[CH:16][CH:17]=1)[OH:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:2]=[N-:3].[C:19]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20].N1C=CN=C1>CN(C)C=O>[N:1]([CH:4]([CH:10]([O:11][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:25])[CH3:24])[C:12]1[C:13]([Cl:18])=[N:14][CH:15]=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:2]=[N-:3]
Reactant: CCOC(=O)C(N=[N+]=[N-])C(O)c1cccnc1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)C(N=[N+]=[N-])C(O[Si](C)(C)C(C)(C)C)c1cccnc1Cl

Procedure:
A procedure similar to that described in Preparation 49 was repeated, except that 3.90 g of ethyl 2-azido-3-(2-chloropyridin-3-yl)-3-hydroxypropionate (prepared as described in Preparation 76), 8.6 g of t-butyldimethyl-silyl chloride, 10 g of imidazole and 80 ml of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 8:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 5.6 g of the title compound having Rf=0.31 (on silica gel thin layer chromatography using a 3:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:14]([NH2:16])=O)=[CH:11][NH:12][CH:13]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:26]2)=CC=1.CCCCCC.C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([C:14](=[S:26])[NH2:16])=[CH:11][NH:12][CH:13]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1c[nH]cc1-c1cccc(Cl)c1Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: NC(=S)c1c[nH]cc1-c1cccc(Cl)c1Cl
Yield: 104.8 %

Procedure:
A mixture of 4-(2,3-dichlorophenyl)pyrrole-3-carboxamide (0.98 g, 3.8 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (0.77 g, 1.9 mmol) in tetrahydrofuran is heated at reflux for 75 minutes, cooled and concentrated in vacuo to obtain a residue. Chromatography of the residue using silica gel and a 1:1 hexane/ethyl acetate mixture gives the title product as a yellow solid (0.54 g, mp 128°-132° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[O:14][N:13]=[CH:12][CH:11]=1.[Na]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]([CH2:11][C:12]#[N:13])=[O:14]
Reactant: Fc1cc(-c2ccno2)c(Cl)cc1Cl
Agent: [Na]
Solvent: CCO
Product: N#CCC(=O)c1cc(F)c(Cl)cc1Cl
Yield: 93.5 %

Procedure:
23.2 g (0.1 mole) of 5-(2,4-dichloro-5-fluorophenyl)-isoxazole are added in portions to a solution of 2.3 g (0.1 g atom) of sodium in 100 ml of absolute ethanol in the course of about 30 minutes while cooling with ice and stirring. The mixture is then stirred at room temperature for 1 hour, the alcohol is distilled off in vacuo, the residue is dissolved in about 1 liter of warm water, the solution is extracted twice with methylene chloride, the aqueous phase is acidified to pH=4 with 10 percent strength hydrochloric acid (~38 ml) and the precipitate is filtered off cold with suction and dried in vacuo at 50° C. 21.7 g (93%) of 2,4-dichloro-5-fluoro-benzoylacetonitrile of melting point 98°-99° C. are obtained.
Reaction SMILES: [CH3:1][C:2]([CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)(=[O:6])=[O:5])[CH3:3].[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:23]([N:20]1[CH2:21][CH2:22][CH:17]([C:2]([CH3:1])([S:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=2)(=[O:5])=[O:6])[CH3:3])[CH2:18][CH2:19]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C1CCNCC1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)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: CC(C)(C1CCN(C(=O)c2ccccc2)CC1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 10 ml vial was added 4-(1-methyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperidine (33 mg, 0.098 mmol), benzoic acid (10 mg, 0.082 mmol), Bop reagent (43.5 mg, 0.098 mmol), diisopropylethyl amine (0.029 ml, 0.164 mmol) and 2 ml dimethylformamide. The resulting solution was stirred at room temperature for 10 minutes. LC-Mass showed clean desired product. The reaction mixture was diluted with 1 ml dimethyl sulfoxide, 1 ml water and 0.03 ml of trifluoroacetic acid. This mixture was loaded on a reverse phase column and purified on HPLC eluted with water/acetonitrile gradient solvent. Desired fraction was collected and lyophilized to give the title compound as a fluffy white solid.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:16][CH2:17][CH:18]([OH:20])[CH3:19]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:16]([CH2:17][CH:18]([OH:20])[CH3:19])[C:5]=32)=[CH:10][CH:9]=1
Reactant: O=CCC1Cc2ccc(Cl)cc2C1=O
Reactant: CC(O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(O)Cn1ccc2c1-c1cc(Cl)ccc1C2
Reaction time: 0.75 h
Yield: 61.5 %

Procedure:
A solution of 2.08 g of (RS)-2-(2-oxoethyl)-6-chloro-1-indanone and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 30 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 3:7). 1.52 g (61%) of (RS)-1-(7-chloro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil which was used directly in the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([OH:18])=O)[N:13]=2)=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O[NH:51][C:52](=[NH:54])[CH3:53]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]3[O:18][N:54]=[C:52]([CH3:53])[N:51]=3)[N:13]=2)=[N:6][CH:7]=1
Reactant: CC(=N)NO
Reactant: O=C(O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(CCc2csc(Nc3ncc(Br)cc3Oc3ccccc3)n2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
To a mixture of 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoic acid (0.100 g, 0.238 mmol), DIEA (0.0456 mL, 0.262 mmol) in 5 mL DMF at ambient temperature was added N-((dimethylamino)fluoromethylene)-N-methylmethanaminium hexafluorophosphate (V) (0.0628 g, 0.238 mmol). The mixture was stirred for 30 minutes at ambient temperature and then N-hydroxyacetamidine (0.0194 g, 0.262 mmol) was added in one portion and the reaction was heated at 110° C. overnight. The reaction was then cooled to ambient temperature and EtOAc was added and the organic layer washed with water (2×10 mL), dried over Na2SO4 and concentrated to a residue that was purified on silica gel eluting with 25% EtOAc/Hexanes to give 5 the title compound (0.067 g, 61.4% yield). 1H NMR (d6 DMSO) δ 2-29 (s, 3H), 3.04 (t, 7.6 Hz, 2H), 3.26 (t, J=7.6 Hz, 2H), 6.74 (s, 1H), 7.11 (d, J=7.8 Hz, 2H), 7.21 (t, J=7.3 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 2H), 8.22 (d, J=2.0 Hz, 1H), 11.00 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][CH2:7][CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[C:23]([C:25]([OH:32])([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])#[CH:24]>>[OH:32][C:25]([CH2:29][CH2:30][CH3:31])([CH2:26][CH2:27][CH3:28])[C:23]#[C:24][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][O:6][CH2:7][CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19]
Reactant: O=C1c2ccccc2C(=O)N1CCOCc1cccc(Br)c1
Reactant: C#CC(O)(CCC)CCC
Product: CCCC(O)(C#Cc1cccc(COCCN2C(=O)c3ccccc3C2=O)c1)CCC

Procedure:
Sonogashira coupling of 2-(2-(3-bromobenzyloxy)ethyl)isoindoline-1,3-dione and 4-ethynylheptan-4-ol following the method described in Example 12 gives 2-(2-(3-(3-hydroxy-3-propylhex-1-ynyl)benzyloxy)ethyl)isoindoline-1,3-dione.
Reaction SMILES: [F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][C:6]=1[F:14].[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[F:1][CH:2]([F:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:22][S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])[CH3:12])=[CH:7][C:6]=1[F:14]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(OCC(F)F)c(F)c1
Product: CC(N[S@](=O)C(C)(C)C)c1ccc(OCC(F)F)c(F)c1
Yield: 84 %

Procedure:
The title compound is prepared in 84% yield (1.44 g, colorless oil) from 1-(4-(2,2-difluoroethoxy)-3-fluorophenyl)ethanone (1.16 g, 5.31 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide by the similar manner in Step-4 of Amine-1.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]O.[Br:6][C:7]1[C:12](O)=[C:11]([Br:14])[C:10]([Br:15])=[C:9]([Br:16])[C:8]=1[Br:17].[OH-].[Na+].ClC[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1>O>[Br:6][C:7]1[C:12]([CH:1]([O:2][CH:3]([C:4]2[C:11]([Br:14])=[C:10]([Br:15])[C:9]([Br:16])=[C:8]([Br:17])[C:7]=2[Br:6])[C:22]2[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[C:11]([Br:14])[C:10]([Br:15])=[C:9]([Br:16])[C:8]=1[Br:17]
Reactant: Oc1c(Br)c(Br)c(Br)c(Br)c1Br
Reactant: Cc1ccc(CCl)cc1
Reactant: COCCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C(OC(c2ccc(C)cc2)c2c(Br)c(Br)c(Br)c(Br)c2Br)c2c(Br)c(Br)c(Br)c(Br)c2Br)cc1

Procedure:
600 ml. of methyl glycol, 97.75 g (0.2 mole) of pentabromophenol, 8 g (0.2 mole) of sodium hydroxide in 8 ml of water, and 28.12 g (0.2 mole) of 1-chloromethyl-4-methyl-benzene were reacted in the manner previously described. At 65° C. the reaction perceptibly commenced. The ether crystallized in long needles during the refluxing of the mixture. Yield: 96 g (81%), M.P. 194° C. 10 g recrystallized from 300 ml of methoxyethyl chloride had a melting point of 200°-202° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH:6]=[CH:7][C:8]=1[CH2:9]N1C=CN=N1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[O:33][C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[N:36]=2)=[CH:28][C:27]=1[O:41][CH3:42].[NH:43]1[CH:47]=[C:46]([C:48]([O:50][CH3:51])=[O:49])[N:45]=[CH:44]1>>[O:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=[C:32]1[C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:45]2[C:46]([C:48]([O:50][CH3:51])=[O:49])=[CH:47][N:43]=[CH:44]2)=[C:27]([O:41][CH3:42])[CH:28]=1.[O:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:43]2[CH:47]=[C:46]([C:48]([O:50][CH3:51])=[O:49])[N:45]=[CH:44]2)=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1CBr
Reactant: COC(=O)c1c[nH]cn1
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1Cn1ccnn1
Product: COC(=O)c1cn(Cc2ccc(-c3nc4ccccc4o3)cc2OC)cn1
Product: COC(=O)c1cncn1Cc1ccc(-c2nc3ccccc3o2)cc1OC

Procedure:
Utilizing the general procedure outlined for 2-[3-methoxy-4-(1H-1,2,3-triazol-1-ylmethyl)phenyl]-1,3-benzoxazole, reaction of 2-[4-(bromomethyl)-3-methoxyphenyl]-1,3-benzoxazole (300 mg, 1.0 mmol) and methyl 4-imidazole carboxylate (126 mg, 1.0 mmol) afforded methyl 1-[4-(1,3-benzoxazol-2-yl)-2-methoxybenzyl]-1H-imidazole-5-carboxylate and methyl 1-[4-(1,3-benzoxazol-2-yl)-2-methoxybenzyl]-1H-imidazole-4-carboxylate as colorless solids. Methyl 1-[4-(1,3-benzoxazol-2-yl)-2-methoxybenzyl]-1H-imidazole-5-carboxylate: 1H NMR (CDCl3, 300 MHz) δ 7.73–7.80 (m, 4H), 7.57–7.60 (m, 1H), 7.34–7.38 (m, 2H), 7.15 (d, 1H), 5.58 (s, 2H), 4.00 (s, 3H), 3.83 (s, 3H). MS (ESI) 364 (M+H)+. Methyl 1-[4-(1,3-benzoxazol-2-yl)-2-methoxybenzyl]-1H-imidazole-4-carboxylate: 1H NMR (CDCl3, 300 MHz) δ 7.75–7.84 (m, 3H), 7.57–7.64 (m, 3H), 7.34–7.38 (m, 2H), 7.18 (d, 1H), 5.17 (s, 2H), 3.97 (s, 3H), 3.86 (s, 3H). MS (ESI) 364 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]=1[CH2:10]Br)=[O:4].[CH3:16][NH:17][CH3:18].C1COCC1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]=1[CH2:10][N:17]([CH3:18])[CH3:16])=[O:4]
Reactant: CNC
Reactant: COC(=O)c1oc2ccccc2c1CBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1oc2ccccc2c1CN(C)C
Reaction time: 1.5 h
Yield: 56.2 %

Procedure:
3-Bromomethylbenzofuran-2-carboxylic acid methyl ester (269 mg, 1 mmol) was dissolved in anhydrous DMF and added 2M dimethylamine/THF solution (1.5 ml, 3 mmol). After 1-2 h, the reaction was diluted with EtOAc and washed twice with saturated NaHCO3 (aq.) and brine. The organic extract over was dried over Na2SO4 and then concentrated in vacuo. The crude was purified on a silica gel column (5% MeOH in dichloromethane) to give 3-dimethylaminomethylbenzofuran-2-carboxylic acid methyl ester (131 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[N:25]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=[N:26]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:29]1[N:25]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][O:19]2)[N:26]=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: Clc1ccc2c(cc(Br)n2Cc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Clc1ccc2c(cc(-c3ccnn3C3CCCCO3)n2Cc2ccccc2)n1
Temperature: 25 °C

Procedure:
A mixture of 1-benzyl-2-bromo-5-chloro-1H-pyrrolo[3,2-b]pyridine (0.088 g, 0.27 mmol, from Step 2), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.084 g, 0.30 mmol, Aldrich) and Na2CO3 (0.14 g, 1.4 mmol) in 1,2-dimethoxyethane (3 mL) and water (0.5 mL) was degassed by a stream of nitrogen through the solution for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.027 mmol, Strem) was added, the vial was capped and heated to reflux for 15 minutes. After cooling to room temperature, the mixture was partitioned between 10% sodium thiosulfate solution and EtOAc. The aqueous layer was extracted three times with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated. Flash chromatography, eluting with 25% EtOAc in hexanes afforded product. Yield: (75 mg, 68%).
Reaction SMILES: [C@@H:1]12[CH2:7][NH:6][C@@H:5]1[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[CH2:2]2.[Br:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23](Br)[CH:24]=1>>[Br:18][C:19]1[CH:24]=[C:23]([N:6]2[CH2:7][C@@H:1]3[C@H:5]2[CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:2]3)[CH:22]=[N:21][CH:20]=1
Reactant: Brc1cncc(Br)c1
Reactant: O=C(OCc1ccccc1)N1C[C@@H]2CN[C@@H]2C1
Product: O=C(OCc1ccccc1)N1C[C@@H]2CN(c3cncc(Br)c3)[C@@H]2C1
Yield: 47 %

Procedure:
The product of Example 52D (230 mg, 1.0 mmol) and 3,5-dibromopyridine were processed as described in Example 1E. The crude product was purified by chromatography (SiO2, ethyl acetate, Rf 0.2) to provide the title compound (180 mg, 47% yield). 1H NMR (MeOH-d4, 300 MHz) δ 3.20 (dd, J=12.5, 4.0 Hz, 1H), 3.30 (m, 2H), 3.40 (m, 1H), 3.64 (dd, J=7.8, 3.4 Hz, 1H), 3.95-4.10 (m, 3H), 4.75 (m, 1H), 5.15 (m, 2H), 7.05 (t, J=2.1 Hz, 1H), 7.24 (m, 3H), 7.35 (m, 2H), 7.70 (d, J=2.3 Hz, 1H), 7.93 (d, J=1.7 Hz, 1H); MS (DCI/NH3) m/z 390 (M+2+H)+, 388 (M+H)+.