Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@@H:6]1[C@@H:10]([OH:11])[CH2:9][CH2:8][NH:7]1)=[O:5].CCN(C(C)C)C(C)C.[Cl:21][C:22]1[C:29]([CH3:30])=[C:28]([N:31]=[C:32]=[O:33])[CH:27]=[CH:26][C:23]=1[C:24]#[N:25]>C(Cl)Cl>[CH3:2][O:3][C:4]([C@@H:6]1[C@@H:10]([OH:11])[CH2:9][CH2:8][N:7]1[C:32]([NH:31][C:28]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([Cl:21])[C:29]=1[CH3:30])=[O:33])=[O:5]
Reactant: Cc1c(N=C=O)ccc(C#N)c1Cl
Reactant: COC(=O)[C@H]1NCC[C@@H]1O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1[C@@H](O)CCN1C(=O)Nc1ccc(C#N)c(Cl)c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
A solution of ester 1A (500 mg, 2.75 mmol) in dry CH2Cl2 (10 mL) was cooled to 0° C., treated with Hunig's base (0.53 mL, 3.04 mmol) and stirred at 0° C. for 30 min. The solution was treated with isocyanate 23E (505 mg, 2.62 mmol), and the resulting suspension was stirred at rt for 3 h. The insoluble solids were filtered off and the filtrate was partitioned between aqueous NH4Cl (6.0 mL) and CH2Cl2 (3×60 mL). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue and insoluble solids were combined and chromatographed (silica gel; EtOAc/hexane gradient) to yield the title compound (177.2 mg, 75.3%) as a white solid, mp 189-191° C. HPLC: 1.72 min (retention time) (Conditions: YMC S-5 C-18 (4.6×50 mm), eluting with 0-100% B, 4 min gradient. (A=90% H2O-10% CH3CN-0.1% TFA and B=10% H2O-90% CH3CN-0.1% TFA); Flow rate at 4 mL/min. UV detection at 220 nm). Chiral HPLC: retention time=22.2 min (100%); Conditions: AD (4.6×250 mm); Eluted with 20% isopropanol in heptane for 30 min at 1 mL/min. MS (ES) m/z 338 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH:7]1([N+:13]#[C-:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]=O>Cl(O)(=O)(=O)=O>[CH:7]1([NH:13][C:14]2[N:6]3[C:2]([S:3][CH:4]=[CH:5]3)=[N:1][C:21]=2[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Nc1nccs1
Reactant: [C-]#[N+]C1CCCCC1
Reactant: O=Cc1ccccn1
Agent: [O-][Cl+3]([O-])([O-])O
Product: c1ccc(-c2nc3sccn3c2NC2CCCCC2)nc1

Procedure:
Compound 12 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) 2-aminothiazole solution (0.1 M, MC), 0.575 ml (0.115 mmol) cyclohexylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 2-pyridinecarbaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: [P:1]([Cl:4])(Cl)Cl.[CH2:5]([O:9][C:10](=[O:17])[C:11]([CH2:15][OH:16])([CH2:13][OH:14])[CH3:12])[CH2:6][CH2:7][CH3:8].O.N#N>C1(C)C=CC=CC=1>[Cl:4][P:1]1[O:14][CH2:13][C:11]([CH3:12])([C:10]([O:9][CH2:5][CH2:6][CH2:7][CH3:8])=[O:17])[CH2:15][O:16]1
Reactant: ClP(Cl)Cl
Reactant: CCCCOC(=O)C(C)(CO)CO
Agent: N#N
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOC(=O)C1(C)COP(Cl)OC1
Reaction time: 1 h

Procedure:
68.70 g (0.50 mol) of phosphorus trichloride in 50 ml of toluene were added dropwise with vigorous stirring, in the course of 1 hour, to a solution of 95.15 g (0.50 mol) of 2,2-bis-hydroxymethylpropionic acid butyl ester in 250 ml of toluene at 5°-10° C. The reaction mixture was subsequently stirred for 1 hour without cooling in a water-jet vacuum, during which time a gentle flow of N2 was fed in; the solvent was then distilled off in vacuo (bath temperature=50° C./15-20 mm Hg), and the residue was purified by vacuum distillation. The product obtained was in the form of a colourless liquid; nD20 =1.4701; b.p. 113°-115° C./0.1 mm Hg.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][CH:4]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][O:1][CH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(CO)n1
Reactant: Clc1cccc(CBr)c1
Product: CC(C)(C)C(=O)Nc1cccc(COCc2cccc(Cl)c2)n1

Procedure:
This material was prepared in analogy to example 86 step A] from N-(6-hydroxymethyl-pyridin-2-yl)-2,2-dimethyl-propionamide (0.73 g) and 3-chlorobenzyl bromide as a yellow oil (0.75 g). MS (ESI): 332.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=O.[CH3:11][CH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:4]1[C:3]2[C:2]([N:1]=[C:15]3[C:16]=1[CH2:17][CH:12]([CH3:11])[CH2:13][CH2:14]3)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CC1CCC(=O)CC1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Nc1ccccc1C(=O)O
Product: CC1CCc2nc3ccccc3c(Cl)c2C1
Yield: 40 %

Procedure:
1.37 g (10 mmol) of 2-aminobenzoic acid and 1.23 ml (10 mmol) of 4-methylcyclohexanone were dissolved in 10 ml of phosphorus oxychloride and the reaction mixture was heated under reflux in a nitrogen atmosphere. After 3 h most of the phosphorus oxychloride was removed under vacuum. The remaining brown syrup was poured into a cold sodium bicarbonate (sat.) solution and washed once with chloroform. The yellow precipitate forming in the basic water solution was filtered (2-methyl-1,2,3,4-tetrahydro-9-(10H)-acridone, 46%). Following the procedure of Step 3 in Example 1, but substituting 2-methyl-1,2,3,4-tetrahydro-9-(10H)acridone for 9-(10H)acridone, gave 9-chloro-2-methyl-1,2,3,4-tetrahydroacridine (40%), which was reacted with 4-(4-methylpiperazin-1-yl)aniline (according to the procedure of Step 4 in Example 1), to afford the title compound with 39% yield (overall yield 7%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1)=[O:3].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>CC(C)=O>[C:2]([C:4]1[CH:12]=[CH:11][C:9]([O:10][CH2:20][CH2:21][CH2:22][Cl:23])=[C:6]([O:7][CH3:8])[CH:5]=1)(=[O:3])[CH3:1]
Reactant: ClCCCBr
Reactant: COc1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C(C)=O)ccc1OCCCCl

Procedure:
To a solution of 88.0 g (0.53 mole) of acetovanillone in 375 ml of acetone was added 69.1 g (0.5 mole) of K2CO3. The mixture was allowed to reflux for 30 min. A solution of 110.2 g (0.70 mole) of 1-bromo-3-chloropropane in 75 ml of acetone was added dropwise. The mixture was heated at reflux for 20 h. The mixture was filtered and the filtrate concentrated under vacuum. The residual oil was distilled. An oil which weighed 110 g was obtained at 141°-143° C.0.1 mm Hg. The oil crystallised upon standing.
Reaction SMILES: [PH:1](=[O:4])([OH:3])[OH:2].C([CH:8](C(C)C)[CH:9]1[NH:35][CH:10]1[C:11]1[N:15]=[CH:14][N:13]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]=1)(C)C.[N-:39]=[N+:40]=[N-:41].[Na+].[Cl-].[NH4+]>CO.O>[NH2:35][CH:9]([CH:10]([N:39]=[N+:40]=[N-:41])[C:11]1[N:15]=[CH:14][N:13]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:12]=1)[CH2:8][P:1]([O:3][CH:16]([CH3:23])[CH3:17])(=[O:2])[O:4][CH:9]([CH3:10])[CH3:8]
Reactant: [N-]=[N+]=[N-]
Reactant: O=[PH](O)O
Reactant: CC(C)C(C(C)C)C1NC1c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)OP(=O)(CC(N)C(N=[N+]=[N-])c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1)OC(C)C
Reaction time: 72 h
Yield: 162.1 %

Procedure:
A stirred mixture of diisopropyl(2RS,3RS)-2,3-epimino-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (2.6 g, prepared as described in Example 58), sodium azide (1.59 g), ammonium chloride (0.58 g) and methanol-water (8:1, 50 ml) was heated under reflux for six hours, then allowed to stand at room temperture for three days. Further quantities of sodium azide (0.80 g) and ammonium chloride (0.29 g) were added and the mixture heated for a further six hours. It was then filtered through silica, using chloroform as eluant, dried, evaporated and chromatographed on silica, using chloroform-hexane-methanol (15:3:1) as eluant, to give diisopropyl(2RS,3SR)-2-amino-3-azido-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (2.27 g) as a yellow oil. NMR (CDCl3): δ1.3(12H,m), 1.65-1.85(1H,m), 2.12-2.28(1H,m), 3.65(1H,m), 4.58(1H,d), 4.68(2H,m), 7.05-7.38(15H,m), 8.00(1H,s). Regiochemistry was confirmed by extensive NMR studies on acetylated material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:3]=1[CH:18]=O.CCN(CC)CC.[CH:27]1([NH2:30])[CH2:29][CH2:28]1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][C:3]=1[CH2:18][NH:30][CH:27]1[CH2:29][CH2:28]1
Reactant: NC1CC1
Reactant: O=Cc1cc(CCNC(=O)CC(F)(F)F)ccc1Cl
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(CC(F)(F)F)NCCc1ccc(Cl)c(CNC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
A mixture of N-[2-(4-chloro-3-formyl-phenyl)-ethyl]-3,3,3-trifluoro-propionamide (175 mg, 0.596 mmol), Et3N (0.125 mL, 0.896 mmol) and cyclopropylamine (0.063 mL, 0.90 mmol) in MeOH (2.00 mL) was heated to reflux for 4 h. The mixture was allowed to cool to rt, and NaBH4 (56.4 mg, 1.49 mmol) was added in portions. The mixture was stirred for 1 h, and aq. sat. NaHCO3 was added. The mixture was extracted with EtOAc several times, and the combined org. extracts were washed with brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (CH2Cl2/MeOH 95:5) yielded the title compound (130 mg, 65%). LC-MS: tR=0.65 min; ES+: 335.12.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][O:10][C:11](=[O:20])[C@:12]([N:17]=[C:18]=[O:19])([CH:14]([CH3:16])[CH3:15])N.[CH3:21][N:22]1CCOC[CH2:23]1>ClCCl>[CH3:9][O:10][C:11](=[O:20])[C@H:12]([CH:14]([CH3:16])[CH3:15])[NH:17][C:18]([N:22]([CH3:23])[CH2:21][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=1)=[O:19]
Reactant: c1ccncc1
Reactant: CN1CCOCC1
Reactant: COC(=O)[C@](N)(N=C=O)C(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)N(C)Cc1ccccn1)C(C)C
Reaction time: 2 h

Procedure:
A mixture of 1.61 g (7.2 mmol) of 2-(N-methylamino)methyl)pyridine dihydrochloride and 1.14 g (7.2 retool) of α-isocyanato-valine methyl ester in 40 ml of dichloromethane was treated with 2 ml (18 mmol) of 4-methylmorpholine. After being stirred for 2 h, the solution was partitioned between dichloromethane and water, dried over Na2SO4, and concentrated. Chromatography on silica gel using 2% methanol in chloroform provided 1.94 g (96%) of the desired compound (Rf 0.32, 5% methanol in chloroform) as a colorless oil.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:11][C:10](=[O:12])[NH:9][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:7]=1[C:20]([OH:22])=O.[C:23]1([CH:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:30][CH2:31][NH2:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C.Cl>ClCCl>[C:33]1([CH:29]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:30][CH2:31][NH:32][C:20]([C:7]2[CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[NH:9][C:10](=[O:12])[NH:11][C:6]=2[CH2:5][O:4][CH2:3][CH2:2][Cl:1])=[O:22])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C1NC(COCCCl)=C(C(=O)O)C(c2cccc(Cl)c2)N1
Reactant: NCCC(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C1NC(COCCCl)=C(C(=O)NCCC(c2ccccc2)c2ccccc2)C(c2cccc(Cl)c2)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
139 mg (0.417 mmol) of 6-(2-chloroethoxymethyl)-4-(3-chlorophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and 106 mg (0.500 mmol) of 3,3-diphenylpropylamine were dissolved in 10 ml of dichloromethane. 120 mg (0.626 mmol) of WSC hydrochloride was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=50/1) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:12](I)=[CH:11][CH:10]=[C:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].[CH:18]([Sn](CCCC)(CCCC)CCCC)=[CH2:19]>C1(C)C=CC=CC=1.CCOCC.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.C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C>[Cl:1][C:2]1[C:12]([CH:18]=[CH2:19])=[CH:11][CH:10]=[C:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5]
Reactant: CCNC(=O)c1c([Si](C)(C)C)ccc(I)c1Cl
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C=Cc1ccc([Si](C)(C)C)c(C(=O)NCC)c1Cl
Reaction time: 24 h
Yield: 21.3 %

Procedure:
To a solution of the compound of Example 239 (0.382 g, 1.0 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.02 mmol) and 2.6-di-t-butyl-4-methylphenol (1.5 mg) in toluene (10 mL) was added vinyltributyltin (0.349 g, 1.1 mmol). The light yellow solution was heated at reflux for 24 h, additional tetrakis(triphenylphosphine)palladium(0) (15 mg) was added, and reflux was continued for 24 h. The cool mixture was diluted with ether, filtered through Celite, concentrated and purified by RC (ethyl acetate/hexanes). The product was further purified by recrystallization from pentane to afford the title compound as white needles (0.060 g, 21%). m.p. 127°-128° C.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][NH:6][C:7]([C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:11][N:10]=1)=[O:8])C.CO.O.O[Li].O>C1COCC1>[CH2:21]([O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:12]1[O:11][N:10]=[C:9]([C:7]([NH:6][CH2:5][C:4]([OH:28])=[O:3])=[O:8])[CH:13]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)CNC(=O)c1cc(-c2ccccc2OCc2ccccc2)on1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CNC(=O)c1cc(-c2ccccc2OCc2ccccc2)on1
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a stirred solution of 5-(2-benzyloxy-phenyl)-isoxazole-3-carboxylic acid (0.7 g, 0.00237 mol) in DMF (4 mL) was added DIPEA (1.226 g, 0.00948 mol), HOBt (0.4 g, 0.0029 mol) and EDCI.HCl (0.57 g, 0.0029 mol) at ambient temperature. After 5 minutes glycine ethyl ester hydrochloride (0.347 g, 0.0024 8 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the resulting precipitate was isolated by filtration. Purification by column chromatography using silica gel 60-120 mesh (65% ethyl acetate in hexane) afforded 0.66 g (73%) of {[5-(2-benzyloxy-phenyl)-isoxazole-3-carbonyl]-amino}-acetic acid ethyl ester. To a stirred solution of {[5-(2-benzyloxy-phenyl)-isoxazole-3-carbonyl]-amino}-acetic acid ethyl ester (0.65 g, 0.00171 mol) in a mixture of THF (10 mL), methanol (5 mL) and H2O (5 mL) was added LiOH.H2O (0.215 g, 0.00512 mol) at ambient temperature. The resulting mixture was stirred overnight. Volatiles were removed by evaporation and the residue was diluted with water acidified with concentrated HCl. The resulting precipitate was isolated by filtration and dried to afford 0.56 g of {[5-(2-benzyloxy-phenyl)-isoxazole-3-carbonyl]-amino}-acetic acid. LCMS: 353.11 (M+1)+, 60.4%.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].O>O1CCCC1>[Si:15]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: OCCCCCCCBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCCCCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of 7-bromoheptanol (50 g, 25.6 mmole) and imidazole (4.2 g, 61.5 mmole) in dry tetrahydrofuran (80 ml) was added t-butyldimethylsilyl chloride (4.6 g, 30.8 mmole) dropwise during 1 hour at room temperature. Then the reaction mixture was stirred overnight at room temperature. When the reaction was completed, water was added to the reaction solution which was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (n-hexane:ethyl acetate=20:1) to give 5.7 g (yield: 72%) of the title compound as a colorless oil.
Reaction SMILES: [OH-].[K+].CS(C)=O.[NH:7]1[CH:11]=[CH:10][CH:9]=[CH:8]1.Br[CH2:13][C:14]([O:16]CC)=[O:15]>O>[N:7]1([CH2:13][C:14]([OH:16])=[O:15])[CH:11]=[CH:10][CH:9]=[CH:8]1
Reactant: c1cc[nH]c1
Reactant: CCOC(=O)CBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)Cn1cccc1
Reaction time: 1 h

Procedure:
To a mixture of potassium hydroxide (16.7 g) and dry DMSO (150 mL), pyrrole (5 g) was added dropwise at 20-25° C., with stirring under nitrogen atmosphere. Stirring was continued for 1 hr at 20-25° C. Ethyl bromoacetate (24.5 g) was added dropwise at 20-25° C. and stirring was continued for 2 hr. In the reaction mixture (150 mL) DM water was added and pH was made acidic (pH=3) with 20% HCI (50 mL). The reaction mixture was extracted with diethyl ether (2×100 mL). The combined organic extract was washed with DM water (100 mL), saturated brine (100 mL) and dried over Na2SO4. The solvent was evaporated to obtain pyrrol-1-yl-acetic acid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)[C:10]#[N:11])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:22]1([O:28][CH2:29][CH2:30][CH2:31][Br:32])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Br-:32].[C:10]([C:9]([C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[C:4]12[CH2:7][CH2:8][N+:1]([CH2:31][CH2:30][CH2:29][O:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([CH2:6][CH2:5]1)[CH2:2][CH2:3]2)#[N:11]
Reactant: BrCCCOc1ccccc1
Reactant: N#CC(c1cccs1)(c1cccs1)C12CCN(CC1)CC2
Product: N#CC(c1cccs1)(c1cccs1)C12CC[N+](CCCOc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 71.7 %

Procedure:
Following the general procedure outlined in Example 7, 1-azabicyclo[2.2.2]oct-4-yl(di-2-thienyl)acetonitrile (0.1073 g, 0.3412 mmol) and 3-bromopropyl phenyl ether (0.070 mL, 0.444 mmol) in 2CH3CN/3CHCl3 (6.5 mL) were reacted to give the desired product (0.1296 g, 72.0%). EI-MS m/z 449 (M+) Rt (2.17 min).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].C([C:10]1C=[CH:13][N:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][N:16]=2)[CH:11]=1)(O)=O>ClCCl>[ClH:4].[Cl:4][C:2]([C:1]1[CH:10]=[CH:11][N:12]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][N:16]=2)[CH:13]=1)=[O:3]
Reactant: O=C(O)c1ccn(-c2nccc3ccccc23)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cl
Product: O=C(Cl)c1ccn(-c2nccc3ccccc23)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
0.4 mL (4.5 mmol) of oxalyl chloride is added at 20° C. under an argon atmosphere to 0.58 g (2.2 mmol) of 3-carboxy-1-(isoquinol-1-yl)-1H-pyrrole dissolved in 45 mL of dichloromethane. After stirring at 20° C. for 0.5 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give 0.65 g of 3-chlorocarbonyl-1-(isoquinol-1-yl)-1H-pyrrole hydrochloride in the form of a beige-coloured solid which is used directly in the following step.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[NH:4][CH2:5][CH:6]([OH:9])[CH2:7][N:8]=1.S(Cl)([Cl:14])=O.[C:16](O)(=[O:18])[CH3:17]>C(O)C>[ClH:14].[C:16]([O:9][CH:6]1[CH2:5][NH:4][C:3]([C:2]([F:1])([F:10])[F:11])=[N:8][CH2:7]1)(=[O:18])[CH3:17]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)O
Reactant: OC1CN=C(C(F)(F)F)NC1
Solvent: CCO
Product: CC(=O)OC1CN=C(C(F)(F)F)NC1
Product: Cl
Yield: 0.8 %

Procedure:
2-Trifluoromethyl-5-hydroxy-1,4,5,6-tetrahydropyrimidine (111 mmol) was dissolved in glacial acetic acid (100 ml) with stirring, and thionyl chloride (8.1 ml, 111 mmol) was added dropwise. The resulting solution was refluxed 19 hours, then evaporated to dryness in vacuo. The residue was taken up in water (50 ml), the pH adjusted to 9 (sat. Na2CO3), and extracted with chloroform. The chloroform was dried (MgSO4) and evaporated in vacuo to 2 g (90%) crude product as a clear red oil identified by 400 MHz nmr. The oil was converted to its HCl salt in anhydrous ethanol with addition of 1M HCl in ether. Unreacted starting material, as the hydrochloride, was collected and the mother liquor evaporated, treated with aqueous base and extracted with chloroform again. Chromatography (silica 60, chloroform/methanol) gave 440 mg crude product as an oil that was again converted to its hydrochloride salt in ethanol. After evaporation of solvents the crude HCl salt was recrystallized from ethanol/ether to yield 242 mg (0.8%) tan crystals, mp 197°-199° C. 400 MHz nmr confirmed the product calculated: C 34.09, H 4.09, N 11.36; found: C 34.13, H 4.14, N 11.50.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:26]=[CH:25][C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].Cl>CN(C)C=O.O.C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]=[N:10][C:11]2[CH:26]=[CH:25][C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)CCCCOc1ccc(N=Nc2ccc(C#N)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: N#Cc1ccc(N=Nc2ccc(OCCCCC(=O)O)cc2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
6.47 g (0.018 mol) of ethyl 5-[4-(4-cyanophenylazo)phenoxy]-pentanoate was dissolved in a mixture of 130 mL of dimethylformamide and 41 mL of water in a 500 mL one-neck round flask fitted with a magnetic stirring bar and a reflux condenser by heating to 90° C. while stirring on an oil bath. 3.9 g (0.098 mol) of NaOH was added through the condenser. Stirring and heating were continued for 1 h after which the reaction mixture was left for cooling to room temperature. The reaction mixture was then diluted with 200 mL of water and acidified with 5.5 N HCl until pH 1.5. The precipitated crude orange product was isolated by filtration. The precipitate was dissolved in 90 mL of hot ethanol and left overnight. After filtration and vacuum drying for 22 h at 50° C. 4.61 g (yield 7.9%) of 5-[4-(4-cyanophenylazo)phenoxy]-pentanoic acid was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[O:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[C:27](O)=[O:28]>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:27]([CH:23]4[CH2:24][CH2:25][CH2:26][O:22]4)=[O:28])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: O=C(O)C1CCCO1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Product: Cc1ccc(NC(=O)C2CCCO2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′biphenyl-3-yl)tetrahydrofuran-2- carboxamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4- carboxamide and tetrahydrofuran-2-carboxylic acid. using method D. NMR; δH [2H6]—DMSO 9.65,(1H, s), 8.61,(1H, t), 7.91,(2H, d), 7.63-7.60,(2H, m), 7.41,(2H, d), 7.22,(1H, d), 4.36,(1H, m), 3.97,(1H, q), 3.81,(1H, q), 3.16,(2H, t), 2.17,(4H, m), 1.97,(1H, m), 1.84,(2H, m), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.12 min, MH+379.