Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:19][CH2:18][CH2:17][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])=[O:4].[C:20]([O:24][C:25]([NH:27][C@H:28]([C:44](O)=[O:45])[CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])=[O:26])([CH3:23])([CH3:22])[CH3:21]>O.O1CCOCC1>[C:20]([O:24][C:25]([NH:27][C@H:28]([C:44]([N:1]1[CH2:19][CH2:18][CH2:17][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])=[O:4])=[O:45])[CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Reaction time: 2 h
Yield: 74 %

Procedure:
23 g (0.086 mol) of prolyl-arginine (2) are dissolved in 100 ml of water and to this solution under stirring there is added a solution of 53 g (0.1 mol) of pentafluorophenyl ester of tert.butyloxycarbonyl-Nε -benzyloxycarbonyl-lysine in 300 ml of dioxane. 2 hours thereafter the solvent is evaporated and the residue is dissolved in 150 ml of dimethylformamide and stirred at room temperature (20° C.) for 48 hours. Then dimethylformamide is evaporated to 1/3 of its volume and the solution is poured into one liter of ether. After 2 hours the resulting residue is filtered-off, washed on the filter with ether and dried in vacuum. After reprecipitation from a mixture ethylacetate-ethanol-ether (3:1:30) there are obtained 47 g (74%) of the product (3) having the following properties: M.p. 90° C., [α]D20 -39.0° (c 1.0; 10% CH3COOH); Rf =0.51 (A, "Eastman"), 0.82 (B, "Eastman"); EHis =0.34 (pH=2.4).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:11]=[CH:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4]
Reactant: COc1ccc(C=O)cc1
Reactant: COC(=O)c1cc(Cl)cn1N
Solvent: CO
Product: COC(=O)c1cc(Cl)cn1N=Cc1ccc(OC)cc1

Procedure:
Prepared according to the imine formation condition used in Example 18 step b) from 1-amino-4-chloro-1H-pyrrole-2-carboxylic acid methyl ester and 4-methoxy benzaldehyde in refluxing methanol for 12 h. 1H NMR (CDCl3, δ in ppm): 8.33 (s, 1H), 7.78 (d, 2H, J=8.8 Hz), 7.13 (d, 1H, J=2.2 Hz), 6.96 (d, 2H, J=8.8 Hz), 6.87 (d, 1H, J=1.8 Hz), 3.87 (s, 3H), 3.82 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[C:17]1([CH2:23][CH2:24][CH2:25][OH:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[O:26][CH2:25][CH2:24][CH2:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: OCCCc1ccccc1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(OCCCc2ccccc2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, 3-phenyl-1-propanol and DBU in dioxane. ES-MS m/e (%): 376 (M{81Br}+H+, 98), 374 (M{79Br}+H+, 100), 258 ([M{81Br}+H-BnCH═CH2]+, 55), 256 ([M{81Br}+H-BnCH ═CH2]+, 50).
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.CSC.[Cl:11][C:12]1[CH:30]=[CH:29][C:15]([O:16][C:17]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[O:21])([CH3:19])[CH3:18])=[CH:14][CH:13]=1.C[O-].[Na+]>C(#N)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2([C:17]([O:16][C:15]3[CH:14]=[CH:13][C:12]([Cl:11])=[CH:30][CH:29]=3)([CH3:19])[CH3:18])[CH2:5][O:21]2)=[CH:23][CH:24]=1
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(Oc1ccc(Cl)cc1)C(=O)c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CSC
Product: CC(C)(Oc1ccc(Cl)cc1)C1(c2ccc(Cl)cc2)CO1
Reaction time: 12 h
Yield: 53.9 %

Procedure:
A solution of 59.2 g (0.47 mol) of dimethyl sulphate and 32 g (0.517 mol) of dimethyl sulphide in 270 ml of acetonitrile is stirred at room temperature for 5 days. A solution of 87 g of 4-chlorophenyl 2-(p-chlorophenoxy)-prop-2-yl ketone in 80 ml of acetonitrile is then added dropwise at 20° to 25° C., in the course of approx. 2 hours. 28.7 g (0.53 mol) of sodium methylate are introduced at the same temperature, and the mixture is stirred for a further 12 hours and then concentrated. The residue is stirred overnight with a mixture of 200 ml of ethyl acetate and 150 ml of water. The organic phase is separated off, dried over sodium sulphate and concentrated in vacuo. 49 g (76% of theory) of crude 2-(4 chlorophenyl)-2-[2-(p-chlorophenoxy)-prop-2-yl]-oxirane are obtained, and this compound is directly reacted further. ##STR158## 52 g (0.3982 mol) of p-chlorophenol and 55 g (0.3982 mol) of potassium carbonate in 400 ml of toluene are heated under reflux for 2 hours in a water separator. The mixture is cooled to 40° C., and a solution of 2-bromo-prop-2-yl 4-chlorophenyl ketone in 170 ml of toluene is added dropwise. This reaction mixture is stirred for a further 5 hours at 100° C. and then cooled, water is added and the organic phase is separated off. This is washed with dilute sodium hydroxide solution and water, dried over sodium sulphate and concentrated. 87 g (85% of theory) of crude 4-chlorophenyl 2-(p-chlorophenoxy)-prop-2-yl ketone are obtained, and this compound is directly reacted further. ##STR159## 1 ml of hydrogen bromide/glacial acetic acid is added to 65.5 g (0.36 mol) of 4-chlorophenyl isopropyl ketone in 200 ml of chloroform, and 57.5 g (0.36 mol) of bromine are then added dropwise at 30° C. The mixture is stirred for a further 30 minutes at room temperature, and thereafter concentrated in vacuo. 86.6 g (92% of theory) of crude 2-bromo-prop-2-yl 4-chlorophenyl ketone are obtained, and this compound is directly reacted further.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12>>[CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[N:4]1[C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]2[C:12]1=[O:17]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Product: Cc1cc([N+](=O)[O-])ccc1N1C(=O)c2ccccc2C1=O
Yield: 83 %

Procedure:
A mixture of 10.0 g (65.7 mmole) of 2-methyl-4-nitroaniline and 10.7 g (72.3 mmole) of phthalic anhydride was heated in an oil bath with an initial temperature of 150°. As the temperature was raised slowly to 165°, the mixture melted and resolidified. The cooled mixture was triturated with 200 ml of dichloromethane and filtered, and the filtrate was washed successively with 3N aqueous hydrochloric acid, water, and 5% aqueous sodium hydroxide. The organic phase was dried over calcium chloride, treated with activated charcoal, filtered, and the filtrate concentrated in vacuo. The resultant solid was suspended in hot ethanol and, after cooling, was collected and dried, giving 15.4 g of N-(2-methyl-4-nitrophenyl)phthalimide. A portion (10.0 g) of the intermediate was hydrogenated in tetrahydrofuran containing 4 ml of concentrated aqueous hydrochloric acid using 5 psi hydrogen gas over 5% palladium on carbon. The filtered solution was concentrated to dryness and the resultant solid washed with methanol, giving 8.3 g of the title compound. The product thus isolated was used in subsequent reactions without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:6])(O)[C:3]#[N:4].[NH2:7][CH2:8][CH2:9][CH2:10][OH:11]>>[OH:11][CH2:10][CH2:9][CH2:8][NH:7][C:2]([CH3:6])([CH3:1])[C:3]#[N:4]
Reactant: NCCCO
Reactant: CC(C)(O)C#N
Product: CC(C)(C#N)NCCCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
To a neat solution of acetone cyanohydrin (930 mg, 10.9 mmol) at 0° C. was slowly added the 3-amino-1-propanol (861 mg, 11.5 mmol). The resulting solution was stirred at room temperature for 3 hrs and then evaporated under reduce pressure to give the desired compound 3 (1.1 g, 71%) which was directly used for the next step without purification.
Reaction SMILES: BrCCC1C=CC([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=CC=1.[C:26]([O:30][C:31]([NH:33][C:34]([CH3:52])([CH3:51])[CH2:35][C:36]([NH:38][C@@H:39]1[CH2:45][CH2:44][C:43]2[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=2[NH:41][C:40]1=[O:50])=[O:37])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[N+:23]([C:20]1[CH:19]=[CH:22][CH:17]=[CH:18][C:21]=1[C:22]1[CH:15]=[CH:10][C:11]([CH2:12][N:41]2[C:42]3[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=3[CH2:44][CH2:45][C@@H:39]([NH:38][C:36](=[O:37])[CH2:35][C:34]([NH:33][C:31](=[O:32])[O:30][C:26]([CH3:29])([CH3:27])[CH3:28])([CH3:52])[CH3:51])[C:40]2=[O:50])=[CH:18][C:17]=1[O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:10]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2-c2ccc(CCBr)cc2)cc1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3[N+](=O)[O-])c(Oc3ccccc3)c2)C1=O)NC(=O)OC(C)(C)C

Procedure:
Prepared from 4'-bromoethyl-2-(4-nitrophenoxy) -1,1'-biphenyl and 3-t-butoxycarbonylamino-3-methyl -N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3-(R) -yl]-butanamide (Example 57, Step A) by the procedure described in Example 69, Step D. 1NMR (200 MHz, CDCl3): 1.32 (s,6H), 1.38 (s,9H), 1.78 (m,1H), 2.3-2.7 (m,5H), 4.47 (m,1H), 4.75 (d,15 Hz,1H), 5.13 (d,15 Hz,1H), 6.63 (d,7 Hz,1H), 6.75 (d,8 Hz,2H), 7.05-7.50 (m,/11H), 7.97 (s,1H), 7.98 (d,8 Hz,2H).
Reaction SMILES: C1C=CC(C(Cl)(C2C(Cl)=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH:22]([C:44]([O:46][CH2:47][CH:48]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:54]2[C:49]1=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:45])[C@H:23]([C:41]([OH:43])=[O:42])[CH2:24][CH2:25][N:26](C(OC(C)(C)C)=O)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].CCN(C(C)C)C(C)C>C(Cl)Cl>[NH:22]([C:44]([O:46][CH2:47][CH:48]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:54]2[C:49]1=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:45])[C@H:23]([C:41]([OH:43])=[O:42])[CH2:24][CH2:25][NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28]
Reactant: CC(C)(C)OC(=O)N(CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)C(=O)OC(C)(C)C
Agent: Clc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O

Procedure:
To 3 g of 2-chlorotrityl chloride resin with 1.3 mmol/g substitution (Novabiochem, 01-64-0114) in 30 ml of dry DCM in 30 ml reaction vessel for solid phase synthesis, 2.577 g (5.85 mmol, 1.5 eq) of Fmoc-Dab(diBoc)-OH (Mw=440.5, (Fmoc-(N-γ-Boc)-L-α,γ-diaminobutyric acid, AnaSpec, 28246) and 2.23 ml (12.87 mmol, 3.3 eq) of DIPEA (Aldrich, Mw=129.2, d=0.74) were added.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[F:9][C:10]([F:17])([F:16])[C:11](OCC)=[O:12].O>ClCCl>[F:9][C:10]([F:17])([F:16])[C:11]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])=[O:12]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCCCCCCO
Solvent: ClCCl
Solvent: O
Product: O=C(NCCCCCCO)C(F)(F)F
Reaction time: 8 h

Procedure:
6-aminohexanol (11.7 g; 100 mmol) is dissolved in dry dichloromethane (100 mL) and drop wise added ethyl trifluoroacetate (15 g; 105 mmol) in dry dichloromethane (50 mL) (˜30 min), and the mixture is stirred overnight. Water (10 ml) is added, and the mixture is stirred for 30 min. The solution is washed with water (2×100 mL), dried (Na2SO4), and concentrated. The residue is redissolved in acetonitrile (100 μL) and concentrated. The residue is placed on vacuum overnight, and a white crystalline solid is obtained. Yield 19 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=[S:9])[NH2:8])=[CH:3][CH:2]=1.Br[CH:11]([C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[C:18]1([C:17]2[N:8]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[S:9][C:11]=2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(Br)C(=O)c1ccccc1
Reactant: NC(=S)c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccncc2)nc1-c1ccccc1
Temperature: 25 °C
Yield: 56.8 %

Procedure:
To a suspension of pyridine-4-carbothioamide (2.9 g, 21 mmol) in ethanol (150 mL) was added ethyl 2-bromo-3-oxo-3-phenylpropanoate (5.9 g, 22 mmol), and the mixture was heated under reflux for 8 hr. The reaction solution was allowed to cool to room temperature, and the solid was collected by filtration, washed with diethyl ether, dried, suspended in ethyl acetate (250 mL), and washed with saturated aqueous sodium bicarbonate solution (150 mL×2). The combined aqueous layer was extracted with ethyl acetate (100 mL×2). The combined organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was washed with diethyl ether, and collected by filtration to give the title compound (3.7 g, 57%) as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[C:4]2[N:5]([C:19]([C:22](O)=[O:23])=[CH:20][N:21]=2)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:8]=1.O[NH:28][C:29](=[NH:40])[C:30]1[CH:35]=[CH:34][C:33]([S:36](=[O:39])(=[O:38])[NH2:37])=[CH:32][CH:31]=1>>[F:26][C:2]([F:1])([F:25])[C:3]1[C:4]2[N:5]([C:19]([C:22]3[O:23][N:40]=[C:29]([C:30]4[CH:31]=[CH:32][C:33]([S:36]([NH2:37])(=[O:38])=[O:39])=[CH:34][CH:35]=4)[N:28]=3)=[CH:20][N:21]=2)[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:11][CH:10]=2)[CH:8]=1
Reactant: O=C(O)c1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)cc1
Product: NS(=O)(=O)c1ccc(-c2noc(-c3cnc4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)cc5)cn34)n2)cc1

Procedure:
The title compound was prepared from 8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-3-carboxylic acid (example C.32) (187 mg, 0.5 mmol) and N-hydroxy-4-sulfamoyl-benzamidine [CAS-No. 4476-10-2] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane) as a yellow solid (143 mg, 52%). MS (EI) 553.1 [(M)+]; mp 292° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10].[OH-:14].[Na+]>CCO.O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]([NH2:10])=[O:14]
Reactant: [OH-]
Reactant: N#Cc1cccc(C2OCCO2)c1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)c1cccc(C2OCCO2)c1
Yield: 69.6 %

Procedure:
To a solution of 3-(1,3-dioxolan-2-yl)-benzonitrile (5.86 g) in a mixture of EtOH (140 mL) and H2O (60 mL) was added sodium hydroxide (6.46 g) and the mixture was heated under reflux for 2 hours. The solvent was evaporated under reduced pressure and the aqueous layer was extracted with CH2Cl2. The organic phase was washed with water, dried over Na2SO4, filtered and evaporated to give the title compound (4.5 g) as a white solid.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:16][C:17]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([N:12]1[CH2:13][CH2:14][C:15]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[N:9][C:10]=2[CH2:11]1)=[O:20]
Reactant: c1ccc(-n2nnc3c2CCNC3)cc1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccc(Cl)c1Cl)N1CCc2c(nnn2-c2ccccc2)C1
Reaction time: 8 h
Yield: 75.6 %

Procedure:
A solution of 1-phenyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine (17 mg, 0.085 mmol) and 2,3-dichlorobenzoic acid (18 mg, 0.093 mmol) in DCM (8 ml) was treated with Et3N (35 μL, 0.25 mmol) followed by HATU (38 mg, 0.1 mmol). The reaction was stirred overnight, then concentrated to minimum volume and purified on 16 g SiO2 with 0-3.5% NH3 in MeOH/CH2Cl2 to give 24 mg (75%) of 5-[(2,3-dichlorophenyl)carbonyl]-1-phenyl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine. MS (ESI): mass calcd. for C18H14Cl2N4O, 372.0; m/z found, 373.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.63-7.42 (m, 5H), 7.38-7.17 (m, 2H), 5.23-4.88 (m, 1H), 4.54 (q, J=15.7 Hz, 1H), 4.23 (dt, J=13.2, 5.5 Hz, 1.0H), 4.10-4.00 (m, 1.0H), 3.65-3.48 (m, 1H), 3.03 (t, J=5.7 Hz, 1H), 3.00-2.74 (m, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](OS(C(F)(F)F)(=O)=O)=[CH:5][C:4]=1[O:17][CH3:18])=[O:2].[Si]([O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(C(C)(C)C)(C)C>>[OH:26][C:27]1[CH:32]=[CH:31][C:30]([C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[C:4]([O:17][CH3:18])[CH:5]=2)=[CH:29][CH:28]=1
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)ccc1C=O
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Product: COc1cc(-c2ccc(O)cc2)ccc1C=O

Procedure:
The title compound was prepared by reacting trifluoro-methanesulfonic acid 4-formyl-3-methoxy-phenyl ester (11.0 mmol) with 4-tert-butyl-dimethylsilyoxyphenyl-boronic acid (3.50 g, 13.86 mmol) according to Method B to yield 880 mg (35%, over two steps) of yellowish solid: mp 159-161° C.; 1H NMR (DMDO-d6): δ 4.01 (3H, s), 6.89 (2H, d, J=8.62 Hz), 7.31 (1H, d, J=8.16 Hz), 7.36 (1H, d, J=1.15 Hz), 7.66 (2H, d, J=8.63 Hz), 7.72 (1H, d, J=8.09 Hz), 9.80 (1H, s), 10.34 (1H, s); mp 159-161° C.; IR 1660 cm−1; MS (ESI) m/z 227 (M−H)−, 229 (M+H)+.
Reaction SMILES: [Cl-:1].[CH:2]1([C:8]2([CH2:28][N:29]3[C:33]([CH3:35])([CH3:34])[CH2:32][O:31][C:30]3=[O:36])[CH2:13][CH2:12][N:11]([C:14]([C@@H:16]3[C@H:20]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[CH2:19][NH2+:18][CH2:17]3)=[O:15])[CH2:10][CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:37][C:38]([CH3:40])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl-:1].[CH:2]1([C:8]2([CH2:28][N:29]3[C:33]([CH3:34])([CH3:35])[CH2:32][O:31][C:30]3=[O:36])[CH2:9][CH2:10][N:11]([C:14]([C@H:16]3[C@H:20]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=4)[CH2:19][NH+:18]([CH:38]([CH3:40])[CH3:37])[CH2:17]3)=[O:15])[CH2:12][CH2:13]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(C)=O
Reactant: CC1(C)COC(=O)N1CC1(C2CCCCC2)CCN(C(=O)[C@H]2C[NH2+]C[C@H]2c2ccc(F)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)[NH+]1C[C@@H](C(=O)N2CCC(CN3C(=O)OCC3(C)C)(C3CCCCC3)CC2)[C@H](c2ccc(F)cc2)C1
Temperature: 0 °C
Yield: 120.3 %

Procedure:
A solution of the product of step E (100 mg; 0.1916 mmol) in methylene chloride (100 mL) was converted to the free-base by washing with saturated sodium bicarbonate. The organic phase was washed with brine, dried (Na2SO4), filtered and the volatiles were removed in vacuo. The residue was dissolved in methylene chloride (2 mL) and cooled to 0° C. Acetone (111 mg; 0.14 mmol) was added, followed by acetic acid (57 mg; 0.9579 mmol) and sodium triacetoxyborohydride (0.575 mmol). The reaction mixture was stirred and allowed to warm to room temperature over 36 h at which time the reaction was quenched with saturated sodium bicarbonate. After extracting three times with methylene chloride, the organic solution was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to provide the crude residue which was purified on silica gel (93:7 methylene chloride/methanol (contaiing 10% v/v ammonium hydroxide). The product was dissolved in ethyl acetate (2 mL) and converted to the hydrochloride salt by addition of a saturated solution of hydrogen chloride in ethyl acetate (2 mL). The reaction mixture was maintained at ambient temperature for 30 min at which time the volatiles were removed in vacuo. The solid was triturated to high purity with diethyl ether which furnished 95 mg of the title compound as the hydrochloride salt [MS: m/z 528 (MH+)].
Reaction SMILES: C[O-].[Na+].[CH:4]1([O:9][C:10]2[CH:11]=[C:12]([CH:18]([CH2:32][C:33]3[O:34][CH:35]=[C:36]([CH3:38])[N:37]=3)[C:19]#[C:20][C:21]3[CH:22]=[N:23][C:24]([NH:27]C(=O)CC)=[N:25][CH:26]=3)[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH2:8][CH2:7][CH2:6][CH2:5]1.O>CO>[NH2:27][C:24]1[N:23]=[CH:22][C:21]([C:20]#[C:19][CH:18]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:10]([O:9][CH:4]3[CH2:8][CH2:7][CH2:6][CH2:5]3)[CH:11]=2)[CH2:32][C:33]2[O:34][CH:35]=[C:36]([CH3:38])[N:37]=2)=[CH:26][N:25]=1
Reactant: CCC(=O)Nc1ncc(C#CC(Cc2nc(C)co2)c2ccc(OC)c(OC3CCCC3)c2)cn1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(C#Cc2cnc(N)nc2)Cc2nc(C)co2)cc1OC1CCCC1
Yield: 64 %

Procedure:
To a suspension of sodium methoxide (0.12 g, 2.2 mmol) in methanol (20 mL) was added (+/-)-3-(3-cyclopentyloxy-4-methoxyphenyl)4(4-methyloxazol-2-yl)-1-(2-propionamidopyrimidin-5-yl)but-1-yne (0.29 g, 0.60 mmol). The mixture was heated at reflux for 1 h (forming a solution) and was cooled. Water was added and the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and the solvent was evaporated and gave the titled compound (64%) as an off-white solid, mp 103-105° C. Anal (C24H26N4O3 ·0.6 H2O) calcd: C, 67.15, H, 6.39, N, 13.05; C, 67.07, H, 6.22, N, 12.67.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]([OH:15])=[O:14])[CH:7]=[CH:6]2.[Si](C=[N+]=[N-])(C)(C)[CH3:17]>C1C=CC=CC=1.CO>[CH3:17][O:14][C:13]([C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)=[O:15]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1ccc2cc(C(=O)O)ccc2c1
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1ccc2cc(OC)ccc2c1
Reaction time: 1 h
Yield: 81 %

Procedure:
To a stirred solution of 6-methoxy-2-naphthoic acid (10.0 g, 49.5 mmol) in benzene:MeOH (4:1, 200 mL) at 0° C. was added TMS diazomethane (29.7 mL, 2.0 M in hexnae, 59.4 mmol) dropwise. After initial addition of reagent, TLC showed reaction was not quite complete, so another 4 mL of TMS diazomethane added. The reaction was then stirred for 1 h before total completion. After concentration, the residue was recrystallized from MeOH:H2O to afford the product (8.67 g, 81%) as a solid; 1H NMR (DMSO-d6) δ3.85 (s, 3H), 3.87 (s, 3H), 7.22 (dd, J=2.6, 9.0 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H), 7.85-7.92 (m, 2H), 8.00 (d, J=9.0 Hz, 1H), 8.51 (s, 1H); mass spectrum [(+) ESI], m/z 217 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][S:6][C:7]1[CH:8]=[C:9]([O:15][CH3:16])[C:10]([O:13][CH3:14])=[N:11][CH:12]=1.BrCC1C=C([F:28])C=C(Cl)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([F:28])[CH:19]=1)[CH2:5][S:6][C:7]1[CH:8]=[C:9]([O:15][CH3:16])[C:10]([O:13][CH3:14])=[N:11][CH:12]=1
Reactant: Fc1cc(Cl)cc(CBr)c1
Reactant: COc1cc(SCc2cccc(Cl)c2)cnc1OC
Product: COc1cc(SCc2cc(F)cc(Cl)c2)cnc1OC

Procedure:
Prepared as described for 5-(3-chlorobenzylthio)-2,3-dimethoxypyridine (Intermediate 8) but using 1-(bromomethyl)-3-chloro-5-fluorobenzene instead of 1-(bromomethyl)-3-chlorobenzene.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH2:17][C:16]2=[O:27])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[Pd]>[N:24]1[CH:25]=[CH:26][C:21]([N:18]2[CH2:19][CH2:20][N:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[C:16](=[O:27])[CH2:17]2)=[CH:22][CH:23]=1
Reactant: O=C1CN(c2ccncc2)CCN1c1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CN(c2ccncc2)CCN1c1ccc(O)cc1

Procedure:
To a solution of the product of step (i) (1.1 g) in a mixture of methanol (500 ml) and tetrahydrofuran (100 ml) was added 30% palladium-on-charcoal catalyst (300 mg) and the mixture stirred in an atmosphere of hydrogen at ambient temperature and pressure until all the starting material had been consumed. After removal of the catalyst by filtration, the solvent was evaporated in vacuo to give 4-[4-(4-pyridyl)piperazin-2-one-1-yl]phenol as a colourless solid, essentially one spot by tlc, which was used without further purification or characterisation.