Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH:21]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH3:31])[NH:24][C:23]([CH2:32][O:33][CH2:34]C(O)=O)=[C:22]1[C:38]([O:40][CH2:41][CH3:42])=[O:39].N1C=CC=CC=1.C[C:50]1([CH3:58])[O:55][C:54](=[O:56])[CH2:53][C:52](=[O:57])O1>ClCCl>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH:21]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:25]([CH3:31])[NH:24][C:23]([CH2:32][O:33][CH2:34][C:52](=[O:57])[CH2:53][C:54]([O:55][CH2:50][CH3:58])=[O:56])=[C:22]1[C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CCOC(=O)C1=C(COCC(=O)O)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)COCC1=C(C(=O)OCC)C(c2cccc(Cl)c2Cl)C(C(=O)OC)=C(C)N1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 55.8 %

Procedure:
A solution of carbonyl diimidazole (5.20 g) and 2-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxy}acetic acid (14.00 g) in dichloromethane (200 ml) was stirred at room temperature under nitrogen for 2 hours and then added to a solution of pyridine (2.40 g) and 2,2-dimethyl-1,3-dioxane-4,6-dione (4.56 g) in dichloromethane (200 ml) over 8 minutes. The mixture was stirred at room temperature for 2.5 hours, washed successively with water, ice-cold 2.5M hydrochloric acid and saturated brine, dried over anhydrous magnesium sulphate and evaporated. The residue was dissolved in ethanol (200 ml) and the solution heated under reflux for 2.75 hours and evaporated. The residue was triturated with diethyl ether and the resulting solid collected washed with diethyl ether and dried to give the title compound (9.0 g), m.p. 99°-102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9]
Reactant: Oc1c(Cl)cccc1Cl
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Cl)c(O)c(Cl)c1
Temperature: 25 °C

Procedure:
To 31 g of 2,6-dichlorophenol in 120 ml acetic acid cooled in an ice bath is added over 5 minutes 50 ml of 70% nitric acid. After stirring an hour at room temperature, the mixture is purged with nitrogen, then poured into water, filtered; the product is washed with water and dried in vacuo to give 2,6-dichloro-4-nitrophenol. NMR (CD3OD): δ8.2(s).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]([C:15]2[CH:20]=[C:19]([OH:21])[C:18]([Cl:22])=[CH:17][C:16]=2[F:23])[C:6](=[O:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1)[CH3:2].[C:24](Cl)(=[O:28])[CH:25]([CH3:27])[CH3:26].N1C=CC=CC=1>C(OCC)C>[C:24]([O:21][C:19]1[CH:20]=[C:15]([N:5]2[C:6](=[O:14])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[N:9]=[C:4]2[O:3][CH2:1][CH3:2])[C:16]([F:23])=[CH:17][C:18]=1[Cl:22])(=[O:28])[CH:25]([CH3:27])[CH3:26]
Reactant: CCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(OC(=O)C(C)C)c(Cl)cc1F

Procedure:
using 2-ethoxy-1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-trifluoromethyl-6(1H)-pyrimidinone and isobutyryl chloride with pyridine in diethyl ether there is obtained {5-[2-ethoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-2-chloro-4-fluorophenyl} isobutyrate, 1NMR (CDCl3, 400 MHz): 7.38 ppm (d,1H), 7.13 ppm (d,1H), 6.58 ppm (s,1H), 4.50 ppm (m,2H), 2.87 ppm (m,1H), 1.35 ppm (d,3H), 1.34 ppm (d,3H), 1.31 ppm (t,3H);
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH3:3].S(Cl)([Cl:17])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:17])=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH3:3]
Reactant: CCCOCc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCOCc1ccc(C(=O)Cl)cc1

Procedure:
4-(Propoxymethyl)benzoic acid (1.4 g, 7.2 mmol) was mixed with thionyl chloride (1.3 g, 10.9 mmol), pyridine (0.1 ml) and toluene (3 ml), followed by reacting them at 80° C. for 2 hours, and distilling off superfluous thionyl chloride and toluene under reduced pressure, to obtain raw 4-(propoxymethyl) benzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][N:3]=1.[Br:11]Br>S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Ag+2]>[Br:11][C:8]1[CH:9]=[CH:10][C:5]2[S:4][N:3]=[C:2]([Cl:1])[C:6]=2[CH:7]=1
Reactant: BrBr
Reactant: Clc1nsc2ccccc12
Agent: [Ag+2]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Product: Clc1nsc2ccc(Br)cc12
Yield: 25.9 %

Procedure:
3-Chlorobenzo[d]isothiazole (10 g, 59.0 mmol) was added to a solution of bromine (3.2 mL, 62.0 mmol) and silver sulfate (19.6 g, 63.0 mmol) in sulfuric acid (200 mL). The resulting brown mixture was allowed to stir at room temperature for 2h under nitrogen. The color slowly faded to pale yellow as a white precipitate formed. The precipitate was collected by vacuum filtration and triturated with hexanes to yield 5-bromo-3-chlorobenzo[d]isothiazole as a white solid (3.8 g). 1H NMR (300 MHz, CDCl3): 8.18 (s, 1H), 7.8 (d, 1H), 7.64 ppm (d, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]3[O:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO>[CH:10]12[O:15][CH:13]([CH2:12][CH2:11]1)[CH2:14][N:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:20]3[CH:21]=[CH:22][C:17]([NH2:16])=[CH:18][CH:19]=3)[N:7]=1)[CH2:9]2
Reactant: Nc1ccc(B(O)O)cc1
Reactant: Clc1nccc(N2CC3CCC(C2)O3)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2nccc(N3CC4CCC(C3)O4)n2)cc1
Yield: 82 %

Procedure:
3-(2-Chloro-pyrimidin-4-yl)-8-oxa-3-aza-bicyclo[3.2.1]octane (3, 564 mg, 2.5 mmol) and 4-aminophenylboronic acid, pinacol ester (602 mg, 2.75 mmol) are dissolved in toluene (25 mL) and EtOH (15 mL). A 2M solution of Na2CO3 is added (5 mL) and the mixture is degassed by leading a stream of nitrogen through the solution. Tetrakis(triphenylphosphine) palladium is added (144 mg, 5 mol %) and the mixture is heated under reflux for 48 hours. The mixture is diluted with EtOAc, washed with saturated NaHCO3, the organic phase is dried (MgSO4), filtered, and concentrated. The mixture is purified by silica gel chromatography using a gradient of ethyl acetate in hexanes (40-100%) to give 576 mg (2.04 mmol, 82%) of 4-[4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)pyrimidin-2-yl]aniline. RT 1.51, M+H=283.1
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:17]([OH:19])=O)[S:5][C:6]=1[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:47]([N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)([CH3:49])[CH3:48].CCN(CC)CC>C(Cl)Cl>[CH:47]([N:50]1[CH2:55][CH2:54][N:53]([C:17]([C:4]2[S:5][C:6]([C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH:10]=[CH:9][CH:8]=3)=[C:2]([CH3:1])[N:3]=2)=[O:19])[CH2:52][CH2:51]1)([CH3:49])[CH3:48]
Reactant: CC(C)N1CCNCC1
Reactant: Cc1nc(C(=O)O)sc1-c1cccc2ccccc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(C(=O)N2CCN(C(C)C)CC2)sc1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-methyl-5-naphthalen-1-yl-thiazole-2-carboxylic acid in methylene chloride (2 ml) is added BOP (44 mg, 0.10 mmol), isopropylpiperazine (13 mg, 0.10 mmol) and Et3N (20 mg, 0.20 mmol). The reaction mixture is stirred at rt for 2 hr. Solvent is removed and the resulting mixture is purified by PTLC to give the title compound. LC-MS M+1 380.03. 1H NMR δ (CDCl3) 7.90-7.96 (m, 2H), 7.68-7.72 (m, 1H), 7.46-7.56 (m, 4H), 4.51 (brs, 2H), 3.85 (brs, 2H), 2.77 (m, 1H), 2.67 (brs, 4H), 2.25 (s, 3H), 1.10 (d, 6H). LC-MS (M+1) 380.1.
Reaction SMILES: [H-].[Na+].C(OC([NH:10][C@H:11]1[CH2:16][CH2:15][C@@H:14]([CH2:17][OH:18])[CH2:13][CH2:12]1)=O)(C)(C)C.[CH2:19]1OCCOCCOCCOCCOC1.CI>C1COCC1>[CH3:19][O:18][CH2:17][C@@H:14]1[CH2:13][CH2:12][C@H:11]([NH2:10])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CO)CC1
Reactant: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC[C@H]1CC[C@@H](N)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (72 mg, 1.78 mmol, 60% by weight suspended in mineral oil) was washed three times with 10 mL portions of hexanes, and suspended in dry THF (12 mL). The suspension was cooled to 0° C. To this suspension, cis-(tert-butoxy)-N-[4-(hydroxymethyl)cyclohexyl]carboxamide (0.273 g, 1.20 mmol) and 15-crown-5 (0.250 mL, 1.25 mmol) were added. The reaction mixture was then stirred at 0° C. for about 30 min. Methyl iodide was then added dropwise (75 μL, 1.20 mmol). Since the reaction was not complete after overnight stirring at room temperature, the mixture was cooled to 0° C. and reacted with 100 mg of sodium hydride and 0.250 mL of 15-crown-5. After about 2 hours at room temperature, the reaction was complete. The reaction was quenched by the slow addition of water and the crude product was extracted with ethyl acetate. Purification was effected by column chromatography on silica gel using 20% ethyl acetate in hexanes as the eluent. ES-MS (m/z) 244. cis-(Tert-butoxy)-N-[4-(methoxymethyl)cyclohexyl]carboxamide was dissolved in ethanol (5 mL) and the solution was treated with 1 mL of acetyl chloride at room temperature. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the resulting solid was used without further purification. (79% yield) ES-MS (m/z) 144.
Reaction SMILES: C([O:5]O)(C)(C)C.[C:7]([O:11][C:12]([NH:14][C@H:15]([C@@H:23]([OH:27])[CH2:24][CH:25]=[CH2:26])[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>>[C:7]([O:11][C:12]([NH:14][C@H:15]([C@@H:23]([OH:27])[C@@H:24]([OH:5])[CH:25]=[CH2:26])[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:13])([CH3:9])([CH3:8])[CH3:10]
Reactant: C=CC[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OO
Product: C=C[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C

Procedure:
An allylic oxidation using stoichiometric SeO2 and t-butyl hydroperoxide (Umbriet, M. A. and Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 5526) was performed on the resultant product of Example 50 to give the desired product after silica gel chromatography.
Reaction SMILES: [C:1](NCC(O)=O)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].C(N(CC)C(C)C)(C)C.[NH2:32][CH2:33][C:34]([NH:36][C:37]1[CH:51]=[CH:50][C:40]([CH2:41][NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:39][CH:38]=1)=[O:35]>CN(C=O)C>[C:45]([O:44][C:43]([NH:42][CH2:41][C:40]1[CH:39]=[CH:38][C:37]([NH:36][C:34](=[O:35])[CH2:33][NH:32][C:1](=[O:2])[O:3][CH2:4][CH:5]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11]3[C:6]2=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:51][CH:50]=1)=[O:49])([CH3:46])([CH3:47])[CH3:48]
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=O)CN)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(NC(=O)CNC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of Fmoc-Glycine (16 g, 54 mmol, 1.0 eq.) in dry DMF (160 mL) at 0° C. was added N,N-diisopropylethylamine (14 g, 108 mmol, 2.0 eq) and N N,N′,N′-Tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (16 g, 54 mmol, 1.0 eq). The mixture was stirred at 0° C. for 30 min and a solution of tert-butyl [4-(glycylamino)benzyl]carbamate (12 g, 54 mmol, 1.0 eq.) in dry DMF (50 mL) was added. The mixture was stirred at room temperature overnight poured into ice water (400 mL) and extracted with EtOAc (400 mL×2). The organic layer was washed with brine (200 mL×2), dried over Na2SO4 and concentrated in vacuum. The residue was re-crystallized from EtOAc (200 mL) and petroleum ether (400 mL) to afford #B118 (18 g, 66.6%) as a white solid. 1H NMR (400 Hz, DMSO-d6): δ 9.93 (s, 1H), 7.91 (d, 2H), 7.75 (d, 2H), 7.61 (m, 1H), 7.52 (d, 2H), 7.43 (m, 2H), 7.36 (m, 3H), 7.18 (d, 3H), 4.32 (d, 2H), 4.26 (m, 1H), 4.07 (d, 2H), 3.80 (d, 2H), 1.39 (s, 9H)
Reaction SMILES: [Na+].[CH2:2]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15][CH2:16][CH3:17])=[C:7]([C:18]([O-])=[O:19])[C:6]=1[C:21]([O-])=[O:22])[CH3:3].[Na+].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:28]([F:38])[CH:27]=1>C(O)(=O)C.O>[CH2:16]([O:15][C:8]1[C:7]2[C:18](=[O:19])[N:25]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:28]([F:38])[CH:27]=3)[C:21](=[O:22])[C:6]=2[C:5]([O:4][CH2:2][CH3:3])=[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)[CH3:17]
Reactant: CCOc1c(C(=O)[O-])c(C(=O)[O-])c(OCC)c2ccccc12
Reactant: CCOC(=O)Cc1ccc(N)cc1F
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2=O)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.5 %

Procedure:
A mixture of 1,4-bis(ethyloxy)-2,3-naphthalenedicarboxylic acid sodium salt (526 g, 1.51 mol) and ethyl (4-amino-2-fluorophenyl)acetate (539 g, 2.73 mol) in glacial acetic acid (5100 mL) was heated to reflux for 6 hours, with reaction progress monitored by 1H-nmr spectroscopy. The reaction mixture was allowed to cool to room temperature, stirred for 18 hours, diluted with water (14 L) and stirred for a further 30 minutes. The product was isolated by filtration, washed with water (5 L) and dried in a vacuum oven at 60° C. to give the desired product as an off-white solid (587 g, 84% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[S:10][C:11]=1[Cl:12].CCN(C(C)C)C(C)C.[NH2:26][C@@H:27]([CH2:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[CH2:28][N:29]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]1=[O:39].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:26][C@H:27]([CH2:28][N:29]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]2=[O:39])[CH2:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]2)=[O:15])[S:10][C:11]=1[Cl:12]
Reactant: Cn1ncc(Br)c1-c1cc(C(=O)O)sc1Cl
Reactant: N[C@@H](CC1CCCCC1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(Br)c1-c1cc(C(=O)N[C@@H](CC2CCCCC2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 32 %

Procedure:
To a solution of 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-2-thiophenecarboxylic acid (81 mg, 0.252 mmol), n,n-diisopropylethylamine (0.22 ml, 1.26 mmol) and 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (81 mg, 0.25 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (141 mg, 0.302 mmol) in one portion. The solution stirred at 25° C. for 12 h and was then partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 40% EtOAc in hexanes) yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-chloro-N-{(1S)-2-cyclohexyl-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-2-thiophenecarboxamide (47 mg, 0.080 mmol, 31.6% yield) as a clear oil: LCMS (ES) m/e 589, 591 (M, M+2)+.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][C:13]3[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+].C(O)C>O>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:12][C:13]3[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:9][CH:10]=1
Reactant: CCCCCCc1ccc2nc(-c3ccc(OC(C)=O)cc3)sc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCc1ccc2nc(-c3ccc(O)cc3)sc2c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 97.3 %

Procedure:
To 0.7 g (2.0 mM) of 2-(p-acetoxyphenyl)-6hexylbenzothiazole, 0.25 g (6.0 mM) of sodium hydroxide and 50 ml of ethanol, followed by stirring for 10 hours at room temperature. After the reaction, the reaction mixture was poured into water, and 2 ml of concentrated hydrochloric was added thereto to precipitate a crystal. The crystal was recovered by filtration and sufficiently washed with water, followed by drying to obtain 0.6 g of 2-(p-hydroxyphenyl)-6-hexylbenzothiazole (Yield: 96.5%).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=[O:3].[NH2:19][C@@:20]1([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][C:24](=[CH2:26])[C@@H:23]2[C@H:21]1[C@H:22]2[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)(O)[O-].[Na+]>O1CCCC1.O>[CH:17]1[C:18]2[CH:6]([CH2:5][O:4][C:2]([NH:19][C@@:20]3([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][C:24](=[CH2:26])[C@@H:23]4[C@H:21]3[C@H:22]4[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:3])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: C=C1C[C@@](N)(C(=O)OCC)[C@H]2[C@@H]1[C@@H]2C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=C1C[C@@](NC(=O)OCC2c3ccccc3-c3ccccc32)(C(=O)OCC)[C@H]2[C@@H]1[C@@H]2C(=O)OCC
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
Add solid 9-fluorenylmethyl chloroformate (3.15 g, 12.2 mmol) portion wise over 5 minutes to a stirred solution of diethyl (1S,2S,5R,6S)-2-amino-4-methylene-bicyclo[3.1.0]hexane-2,6-dicarboxylate (2.8 g, 11.1 mmol) and sodium bicarbonate (2.04 g, 24.3 mmol) in tetrahydrofuran (28 mL) and water (8.4 mL) cooled to 0-5° C. After 1 hour, add water (10 mL) and extract with ethyl acetate (50 mL). Wash the extract with brine solution (20 mL), dry, filter and evaporate to a pale yellow oil (6.5 g). Purify by flash chromatography eluting with ethyl acetate:iso-hexane (10:90 to 20:80) to give a viscous colorless oil (4.58 g). Repurify by flash chromatography eluting with ethyl acetate:iso-hexane (20:80) to give a white semi-solid foam of title compound (4.22 g, 80%). MS (m/z): 476 (M+1).
Reaction SMILES: [CH2:1](N(CC)CC)C.[CH2:8]([N:15]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@H:16]([C:18]([OH:20])=O)[CH3:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)=O.C(Cl)(Cl)(Cl)Cl.CC(C)(C)C(Cl)=O.C[Mg]Cl>O1CCCC1>[CH3:1][C:18]([CH:16]([N:15]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:17])=[O:20]
Reactant: C[C@@H](C(=O)O)N(Cc1ccccc1)Cc1ccccc1
Reactant: CCN(CC)CC
Agent: CC(C)(C)C(=O)Cl
Agent: C[Mg]Cl
Agent: O=C=O
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)C(C)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.75 h
Yield: 65 %

Procedure:
Triethylamine (8.85 mmol, 1.24 mL) was added under an argon atmosphere to a stirred solution of N,N-dibenzylalanine (8.85 mmol, 2.38 g) in tetrahydrofuran (THF) (53.0 mL) at -30° C. (dry ice/CCl4 bath). Trimethyl acetyl chloride (8.85 mmol, 1.42 mL) was then added dropwise via syringe and the turbid solution was allowed to stir at -30° C. for 30 minutes before dropwise addition of a solution of methylmagnesium chloride in THF (3.0M, 1.07 eq., 9.5 mmol, 3.23 mL) over 10 minutes. The solution was stirred for 45 minutes and then quenched with saturated solution of NH4Cl (5.0 mL). The solution was extracted with Et2O, the organic extracts washed with brine, dried over MgSO4, and filtered. The solvent was evaporated in vacuo and the residue was subjected to flash column chromatography on silica gel with 8:1 hexanes/ethyl acetate to isolate a pure product in 65% yield. Colorless oil; Rf =0.43 (7:1 hexanes/ethyl acetate) 1H NMR (300.15 MHz) δ1.19 (d, J=5.4 Hz, 3H), 2.25 (5, 3H), 3.39 (q, J=6.9 Hz, 1H), 2.57 (AB quartet, δA =3.33, δB =3. JAS=13.8 Hz, 4H), 7.19-7.43 (m, 10H); 13C NMR (75.5 MHz 7.1, 27.7, 54.6, 62.9, 27.2, 128.5, 128.8, 139.3, 210.8; IR (Neat) 1710 cm-1 ; MS (low resolution) m/e 268 M+H 22%), 224 (MeCHNBn2, 100%); HRMS for C18H22NO: 268-1709 (calc'd 268-1676); Anal: calc'd for C18H21NO: C 80.68, H 7.92, N 5.24; Found: C 80.79, H 7.95, N 5.17.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccc(N3CCCCC3)cc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cc(N3CCCCC3)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted 1-Methyl-7-piperidin-1-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:9][CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:13]1[C:14]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][S:19][C:15]=2[N:16]=[CH:17][N:18]=1>C1COCC1.O>[C:22]1([C:21]2[C:14]3[C:13]([O:11][CH2:10][CH2:9][N:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)=[N:18][CH:17]=[N:16][C:15]=3[S:19][CH:20]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Clc1ncnc2scc(-c3ccccc3)c12
Reactant: OCCN1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(-c2csc3ncnc(OCCN4CCCCC4)c23)cc1
Reaction time: 0.17 h
Yield: 71.4 %

Procedure:
Sodium hydride (8 mg, 0.16 mmol) was suspended in dry THF (0.5 mL). To this was added 2-(1-piperidyl)ethanol (16 μL, 0.12 mmol) and the reaction stirred for 10 min until effervescence had ceased. Then 4-chloro-5-phenyl-thieno[2,3-d]pyrimidine (20 mg, 0.08 mmol) in dry THF (0.5 mL) was added and the reaction left to stir at room temperature for 72 hrs. The reaction mixture was diluted with water and extracted with DCM. The organic layers were concentrated and the residue purified by preparative TLC (eluent 10% MeOH in DCM) to give 5-phenyl-4-[2-(1-piperidyl)ethoxy]thieno[2,3-d]pyrimidine as a yellow oil (19.4 mg, 72%). LCMS RT=3.03 min. M+1=340.
Reaction SMILES: [CH2:1](I)[CH3:2].[CH2:4]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[C:14]([CH2:21][CH3:22])[CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:4]([O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([O:18][CH2:1][CH3:2])=[O:17])=[C:14]([CH2:21][CH3:22])[CH:13]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCI
Reactant: CCc1cc(OCc2ccccc2)ccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCc2ccccc2)cc1CC

Procedure:
Ethyl iodide (0.268 mL) was added to a suspension of 4-benzyloxy-2-ethylbenzoic acid (0.572 g) and potassium carbonate (0.617 g) in N,N-dimethylformamide (5.6 mL) at room temperature with stirring. The mixture was stirred at 50° C. for 1.5 hrs and at room temperature for 13 hrs, and then water was added. The mixture was extracted with ethyl acetate. The organic layer was washed with water, an aqueous solution of sodium chloride and brine successively, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (0.635 g).