Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[NH:13][CH2:14][CH2:15][CH2:16][C:10]3=[N:9][C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.O=[CH:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[C:1]1([C:7]2[N:12]=[C:11]3[N:13]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:14][CH2:15][CH2:16][C:10]3=[N:9][C:8]=2[C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccccc2)NCCC3)cc1
Reactant: CCOC(=O)CCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccc(C)cc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Phenyl-2-p-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate F) (162 mg, 0.538 mmol) in dry DCE (1 ml) was treated with DIPEA (0.103 ml, 0.591 mmol) followed by ethyl 7-oxoheptanoate (185 mg, 1.075 mmol). The reaction mixture was stirred at RT for 10 minutes and sodium triacetoxyborohydride (570 mg, 2.69 mmol) was added. The resulting mixture was stirred at 60° C. for 16 hours. After cooling to RT, the mixture was slowly added to water (50 ml) and extracted with DCM (3×). The combined organic extracts were passed through a phase separating column and concentrated in vacuo. The resulting crude product was purified by chromatography on silica eluting with 0-10% EtOAc/iso-hexane to afford the title compound; LCMS; Rt 1.38 mins MS m/z 458 [M+H]+; Method 2minLC_v003
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.Cl[C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:23][CH3:24])=[C:15]([O:18][CH2:19][CH2:20][O:21][CH3:22])[CH:16]=2)[CH:11]=[C:10]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=2)[N:9]=1>>[CH3:24][O:23][C:14]1[CH:13]=[C:12]2[C:17](=[CH:16][C:15]=1[O:18][CH2:19][CH2:20][O:21][CH3:22])[C:8]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)=[N:9][C:10]([NH:25][C:26]1[CH:30]=[C:29]([CH3:31])[NH:28][N:27]=1)=[CH:11]2
Reactant: OC1CCOC1
Reactant: COCCOc1cc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2cc1OC
Product: COCCOc1cc2c(OC3CCOC3)nc(Nc3cc(C)[nH]n3)cc2cc1OC

Procedure:
Similar procedure as described in example 400 was used, starting from 3-hydroxy-tetrahydrofuran and [1-Chloro-6-methoxy-7-(2-methoxy-ethoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine to give [6-Methoxy-7-(2-methoxy-ethoxy)-1-(tetrahydro-furan-3-yloxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 415(MH+).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:21]=[CH:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][C:11]=3[CH:10]=2)O1.Cl[C:24]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:26][N:25]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:30]1([C:28]2[CH:29]=[CH:24][N:25]=[C:26]([C:9]3[CH:21]=[CH:20][C:19]4[C:18]5[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=5)[NH:12][C:11]=4[CH:10]=3)[CH:27]=2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Clc1cc(-c2ccccc2)ccn1
Reactant: CC1(C)OB(c2ccc3c(c2)[nH]c2ccccc23)OC1(C)C
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: c1ccc(-c2ccnc(-c3ccc4c(c3)[nH]c3ccccc34)c2)cc1
Temperature: 102.5 °C
Reaction time: 16 h

Procedure:
To a three-necked flask equipped with a magnetic stir bar was added 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-9H-carbazole (682 mg, 2.32 mmol, 1.1 eq), 2-chloro-4-phenylpyridine (400 mg, 2.11 mmol, 1.0 eq), Pd2(dba)3 (21 mg, 0.023 mmol, 0.01 eq), PCy3 (14 mg, 0.051 mmol, 0.024 eq) and K3PO4 (761 mg, 3.59 mmol, 1.7 eq). Then the flask was evacuated and back-filled with nitrogen, and the evacuation and back-fill procedure was repeated twice. Then solvent dioxane (8 mL) and water (3.8 mL) were added under the protection of nitrogen. The mixture was stirred in an oil bath at a temperature of 100-105° C. for 16 hours. Then the mixture was cooled to ambient temperature and diluted with ethyl acetate. The organic layer was separated and dried over sodium sulfate, and filtered, the filtrate was concentrated under reduced pressure and the residue was purified through column chromatography on silica gel using hexane and ethyl acetate (5:1-3:1-2:1) as an eluent to obtain the desired product, 2-(4-phenylpyridin-2-yl)-9H-carbazole, as a brown solid (675 mg in 99% yield). 1H NMR (DMSO-d6, 400 MHz): δ 7.20 (t, J=7.6 Hz, 1H), 7.41-7.45 (m, 1H), 7.51-7.61 (m, 4H), 7.68 (dd, J=4.8, 1.2 Hz, 1H), 7.96-7.98 (m, 2H), 8.05 (dd, J=7.6, 1.6 Hz, 1H), 8.18 (d, J=7.6 Hz, 1H), 8.24 (d, J=8.0 Hz, 1H), 8.31 (s, 1H), 8.35 (d, J=0.4 Hz, 1H), 8.77 (d, J=5.2 Hz, 1H), 11.37 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[OH-].[Na+].[C:13]1([S:19](Cl)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[C:13]1([S:19]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)n1ccc2cc(F)ccc21
Temperature: 25 °C
Yield: 93.3 %

Procedure:
To a 0° C. solution of 5-fluoroindole (10 g, 74 mmol) and tetrabutyl ammonium hydrogen sulfate (3.8 g, 11 mmol) in 200 mL of toluene was added 200 mL 50% aqueous NaOH, followed by addition of benzene sulfonylchloride (14 mL, 111 mmol). The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was extracted with ethyl acetate and washed with 1 M HCl, aqueous sodium bicarbonate, water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The remaining residue was recrystallized from ethyl acetate and hexanes to afford 19 g (96% yield) of 1-benzenesulfonyl-5-fluoro-1H-indole as a white crystalline solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[CH2:19][CH3:20])(O)[CH2:9][CH2:10][CH2:11][OH:12])[CH3:2].Cl.O1CCCC1>C(O)C>[CH2:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[CH2:19][CH3:20])=[CH:9][CH2:10][CH2:11][OH:12])[CH3:2]
Reactant: CCc1ccsc1C(O)(CCCO)c1sccc1CC
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1ccsc1C(=CCCO)c1sccc1CC
Temperature: 50 °C
Yield: 69 %

Procedure:
This oil consisting of 1,1-bis(3-ethyl-2-thienyl)-1,4-dihydroxylbutan was mixed with 75 ml 2N hydrochloric acid solution, 75 ml tetrahydrofuran and 75 ml ethanol and heated at 50° C. for 18 h. The solution was evaporated and the resultant oil was purified by "flash" chromatography on silica gel (Art 9385) eluting with heptane/ethylacetate (5:1) to give 4,4-bis(3-ethylthien-2-yl)but-3-en-1-ol (5.4 g, 69%) as an oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][CH2:5][C:6]([OH:27])([CH2:22][O:23][C:24](=[O:26])[CH3:25])[CH:7]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[O:10])[N:8]=1.CCN(CC)CC.[N:35]([CH2:38][C:39](Cl)=[O:40])=[N+:36]=[N-:37]>C(Cl)Cl>[N:35]([CH:38]1[C:39](=[O:40])[N:8]2[CH:7]([C:9]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=3)=[O:10])[C:6]([OH:27])([CH2:22][O:23][C:24](=[O:26])[CH3:25])[CH2:5][S:4][C@:3]12[S:2][CH3:1])=[N+:36]=[N-:37]
Reactant: CSC1=NC(C(=O)OCc2ccc([N+](=O)[O-])cc2)C(O)(COC(C)=O)CS1
Reactant: [N-]=[N+]=NCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS[C@]12SCC(O)(COC(C)=O)C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N1C(=O)C2N=[N+]=[N-]
Temperature: 25 °C
Yield: 54.1 %

Procedure:
A solution of crude p-nitrobenzyl 2-methylthio-5-hydroxy-5-acetoxymethyl-5,6-dihydro-4H-1,3-thiazine-4-carboxylate (6.31 g., 15.23 mMol) in andydrous CH2Cl2 (75 ml.) is cooled to -78° C. under a N2 atmosphere. Et3N (2.97 ml., 21.3 mMol) is added to the stirring solution followed by dropwise addition of a solution of azidoacetyl chloride (1.85 ml., 21.2 mMol) in CH2Cl2 (20 ml.). The resulting solution is allowed to warm slowly to room temperature. The solution is washed with H2O (3x) and brine, dried with MgSO4, filtered, and concentrated in vacuo to a dark, reddish-brown, viscous oil (7.3 g.). This material is purified by chromatography on silica gel (140 g.). Elution of the column with 10% EtOAc/Oh provides p-nitrobenzyl 7-azido-6-methylthio-3-hydroxy-3-acetoxymethyl-cepham-4-carboxylate (4.10 g.) as a dark oil: ir (CHCl3) 2.91, 4.72, 5.58, 5.73, 6.20, 6.55, and 7.39μ; nmr (CDCl3)δ 2.13 (s, 3, COCH3), 2.23 (s, 3, SCH3), 2.83, 3.63 (ABq, 2, J=14Hz, SCH2), 4.17 (s, 1, OH), 4.30, 4.57 (ABq, 2, J=12Hz, CH2OAc), 4.87 (s, 2, H4 and H7), 5.37 (s, 2, CH2Ar), and 7.60, 8.25 (ABq, 4, J=9Hz, ArH); mass spectrum m/e 497 (M+), 469, 454, 422, 414, 368, 354, 341, 311, 299, 278, 261, and 136.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[CH:3]=1.C([Li])CCC.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([C:27]2[C:39](=[O:40])[N:38]([CH2:41][CH3:42])[C:30]3[N:31]=[C:32](S(C)=O)[N:33]=[CH:34][C:29]=3[CH:28]=2)[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1.C(OCC)(=O)C.O>C1COCC1>[CH3:26][O:25][C:23]1[CH:22]=[C:21]([C:27]2[C:39](=[O:40])[N:38]([CH2:41][CH3:42])[C:30]3[N:31]=[C:32]([NH:1][C:2]4[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[CH:3]=4)[N:33]=[CH:34][C:29]=3[CH:28]=2)[CH:20]=[C:19]([O:18][CH3:17])[CH:24]=1
Reactant: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(S(C)=O)nc21
Reactant: COc1cc(N)cc(OC)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(Nc3cc(OC)nc(OC)c3)nc21
Temperature: -10 °C
Reaction time: 8 h
Yield: 50.6 %

Procedure:
To a −78° C. solution of 3.0 g (19.5 mmol) of 4-amino-2,6-dimethoxypyridine in 75 mL of THF was added dropwise 10.6 mL (17.0 mmol) of 1.6 M n-butyllithium in hexanes. The reaction solution was stirred for 15 minutes at which time 1.8 g (4.9 mmol) of 6-(3,5-dimethoxy-phenyl)-8-ethyl-2-methylsulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one was added in small portions as a solid. The reaction mixture was allowed to warm slowly to −10° C. then remain at −10° C. overnight. The reaction mixture was poured into ethyl acetate/water/3.5 mL 6N HCl. The mixture is shaken and separated. The organic phase was washed with a saturated solution of sodium bicarbonate, twice with water, and brine, then dried over magnesium sulfate, filtered, and concentrated to a solid yellow residue. The solid was triturated under 25 mL of 1:15:10 methanol/chloroform/ethyl acetate and filtered to give a yellow solid that is crystallized from 300 mL of acetonitrile to give 1.15 g (51%) of the titled compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([NH2:12])[CH3:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[CH2:22][CH:21]2[C:23](O)=[O:24])=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([NH:12][C:23]([CH:21]3[CH2:22][CH:20]3[C:17]3[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][CH:18]=3)=[O:24])[CH3:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CC(N)c1ccc2c(c1)CCO2
Reactant: O=C(O)C1CC1c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(NC(=O)C1CC1c1ccc(Cl)cc1)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
A mixture of 1-(2,3-dihydro-benzofuran-5-yl)-ethylamine (0.1 mmol), 2-(4-Chloro-phenyl)-cyclopropanecarboxylic acid (0.1 mmol), EDAC.HCl (0.2 mmol), DMAP (0.2 mmol), and triethylamine (0.4 mmol) in dichloromethane (2 mL) was stirred at room temperature overnight. The reaction mixture was purified by flash chromatography eluting with 50% hexanes in ethyl acetate to give the title compound (23 mg) as a solid.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[NH:7][CH:8]=[N:9]2)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:22]=1[CH2:23]Cl>CN(C)C(=O)C>[CH2:1]([NH:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH2:23][C:22]1[C:25]([F:29])=[CH:26][CH:27]=[CH:28][C:21]=1[Cl:20])[CH:2]=[CH2:3]
Reactant: Fc1cccc(Cl)c1CCl
Reactant: C=CCNc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: C=CCNc1ncnc2c1ncn2Cc1c(F)cccc1Cl
Yield: 58 %

Procedure:
In a procedure analogous to that of Example 9, by using 1.75 g of 6-allylaminopurine, 1.38 g of potassium carbonate, 50 ml of N,N-dimethylacetamide and 3.58 g of 2-chloro-6-fluorobenzyl chloride, there was obtained 1.84 g of 6-allylamino-9-(2-chloro-6-fluorobenzyl)purine as colorless needles (yield: 58%), m.p. 163°-164° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]=[C:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][OH:17]>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12]([N:14]([CH2:18][CH2:19][OH:20])[CH2:15][CH2:16][OH:17])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCNCCO
Reactant: O=C=NCCOCc1ccccc1
Solvent: ClCCl
Product: O=C(NCCOCc1ccccc1)N(CCO)CCO
Temperature: 25 °C
Yield: 74.2 %

Procedure:
To 3-benzyloxypropionic acid (129.6 g) in ether (310 ml) and N,N-dimethylformamide (4 ml) was added thionyl chloride (155 ml). The solution was refluxed for 2 hours, and solvents and excess thionyl chloride were removed by evaporation in vacuo. Yield 132 g of 3-Benzyloxypropionic acid chloride as an oil. To an ice cooled solution of the thus prepared acid chloride (132 g) in acetone (450 ml) was added a cold solution of sodium azide (48.5 g) in water (200 ml) at 5° C. After additional stirring at 5° C. for 30 minutes, the mixture was poured into water and toluene, and the aqueous phase was extracted twice with toluene. The combined organic phases were washed with brine. After drying (magnesium sulfate) the solution was heated slowly to 85° C. on a steam bath until evolution of nitrogen ceased. The solvent was removed in vacuo leaving 108.4 g of 2-benzyloxyethylisocyanate as an oil. A mixture of 2-benzyloxy-ethylisocyanate (10 g) and diethanolamine (5.72 g) in dichloromethane (60 ml) was refluxed for 2.5 hours. After cooling to room temperature, the solution was washed with brine. Drying (magnesium sulfate) and evaporation of the solvent yielded 11.4 g of N-(2-benzyloxyethyl)-N',N'-di-(2-hydroxyethyl)-urea as an oil. A solution of the urea derivative (11.4 g) in dichloromethane (55 ml) was cooled to 5° C., and thionyl chloride (8.3 ml) was added at a temperature below 10° C. After the addition the mixture was refluxed for 1 hour and then left over night at room temperature. The solution was washed with cold sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in 1,1,1-trichloroethane and refluxed for 3 hours. After cooling the solution was washed with sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated in vacuo, yielding 6.6 g of the title compound 22a as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[Cu]C#N.[CH3:22][C:23]1[CH2:28][CH:27]([CH3:29])[CH2:26][C:25](=[O:30])[C:24]=1[C:31]([O:33][CH3:34])=[O:32].[Cl-].[NH4+].[OH-].[NH4+]>C(OCC)C>[C:8]1([C:4]2[CH:3]=[C:2]([C:23]3([CH3:22])[CH2:28][CH:27]([CH3:29])[CH2:26][C:25](=[O:30])[CH:24]3[C:31]([O:33][CH3:34])=[O:32])[CH:7]=[CH:6][CH:5]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Brc1cccc(-c2ccccc2)c1
Reactant: COC(=O)C1=C(C)CC(C)CC1=O
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: COC(=O)C1C(=O)CC(C)CC1(C)c1cccc(-c2ccccc2)c1
Temperature: -90 °C
Reaction time: 0.33 h

Procedure:
A solution of 3-bromobiphenyl (403 μL) in diethyl ether (4 mL) was stirred at −90° C. and treated slowly with n-butyllithium (1.6 M in hexanes, 1.5 mL). The resulting mixture was stirred at −90° C. for 20 min, and then transferred via a cannula to a stirred suspension of copper (I) cyanide (98 mg) in diethyl ether (1 mL) at −78° C. The mixture was stirred for 10 min at −78° C. and then warmed to 0° C. Once at the prescribed temperature, a solution of methyl 2,4-dimethyl-6-oxocyclohex-1-enecarboxylate (100 mg) in diethyl ether (1 mL) was added and the resulting mixture was warmed to rt over 30 min. Once at the prescribed temperature, the mixture was stirred at rt for 3 h. At the conclusion of this period, the mixture was treated with a 9:1 mixture of saturated aqueous ammonium chloride/ammonium hydroxide (10 mL). The resulting mixture was stirred for 10 min and then extracted three times with diethyl ether. The combined organic layers were washed with saturated aqueous ammonium chloride and saturated sodium chloride, dried over sodium sulfate and concentrated under vacuum to yield a residue. The residue was purified by chromatography on silica gel, eluting with 10% ethyl acetate/hexanes, to provide methyl (2RS,4RS)-2-(3-phenylphenyl)-2,4-dimethyl-6-oxocyclohexanecarboxylate (131.5 mg). Mass spectrum m/z 359.34 (M+Na+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[O:9][CH:10]=1)[CH3:2].Cl.Cl[CH2:21][C:22]1[N:23]=[CH:24][S:25][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:21][C:22]3[N:23]=[CH:24][S:25][CH:26]=3)=[CH:13][CH:12]=2)[O:9][CH:10]=1)[CH3:2]
Reactant: ClCc1cscn1
Reactant: CCOC(=O)Cc1coc(-c2ccc(O)cc2)n1
Agent: Cl
Product: CCOC(=O)Cc1coc(-c2ccc(OCc3cscn3)cc2)n1

Procedure:
The title compound is prepared in a manner substantially similar to Intermediate 16 from [2-(4-Hydroxy-phenyl)-oxazol-4-yl]-acetic acid ethyl ester (See Intermediate 64) and 4-(chloromethyl)thiazole hydrochloride except KI (2 eq.) is also added. MS (m/e): 345.2 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]3)=[O:22])[C:9]=2[CH3:30])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:24][CH2:25][CH:26]([NH:29][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:27][CH2:28]3)=[O:22])[C:9]=2[CH3:30])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(C(=O)N2CCC(N)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)N2CCC(NS(C)(=O)=O)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Yield: 73 %

Procedure:
1-{[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}piperidin-4-amine (20 mg, 0.043 mmol, 1 eq.), triethylamine (0.02 mL, 0.129 mmol, 3 eq.), and the methanesulfonyl chloride (0.007 mL, 0.086 mmol, 2 eq.) were stirred in dichloromethane (2 mL) for 16 h. The reaction was concentrated in vacuo. The crude material was purified by column chromatography 0-100% ethyl acetate/hexanes to yield 17 mg (74%) of desired product. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.60 (dd, J=14.60, 7.06 Hz, 2H) 2.05-2.36 (m, 5H) 2.93-3.10 (m, 3H) 3.35-3.76 (m, 2H) 4.45 (br. s., 2H) 4.71 (br. s., 1H) 7.07 (d, J=7.91 Hz, 2H) 7.15 (d, J=7.72 Hz, 1H) 7.20-7.35 (m, 3H) 7.45 (s, 1H); [M+H]+ 541.3.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH:12]([C:20](=[O:22])[CH3:21])C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH2:12][C:20](=[O:22])[CH3:21]
Reactant: CC(=O)C(C(=O)OC(C)(C)C)c1c([N+](=O)[O-])ccc(O)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Cc1c([N+](=O)[O-])ccc(O)c1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 30.7 %

Procedure:
To a solution of tert-butyl 2-(2-fluoro-3-hydroxy-6-nitrophenyl)-3-oxobutanoate (7.89 g) in dichloromethane was added trifluoroacetic acid (11.2 g) and the mixture stirred at ambient temperature for 20 hours. The mixture was concentrated to a thick paste and toluene (14 ml) added and the mixture distilled on a rotary evaporator (77 mbar, bath 40° C.). Further toluene (14 ml) was added and the mixture distilled. Sodium hydroxide (7.4% w/w, 20 ml) was added and the lower aqueous layer separated and washed with toluene (18 ml). The aqueous layer was diluted with water (20 ml) and warmed to 40° C. Acetic acid (13 ml) was added followed by sulphuric acid (20% w/w, 20 ml). The mixture was cooled to 0° C. and further water (43 ml) added. The mixture was cooled to −5° C. and left overnight. The solid was filtered and washed with water (24 ml). The solid was dried in a vacuum oven to give 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (1.65 g, 30.7%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([CH3:25])([CH3:24])[O:18][SiH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[B:26](OC(C)C)([O:31]C(C)C)[O:27]C(C)C.C([N-]C(C)C)(C)C.[Li+]>O1CCCC1>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[B:26]([OH:31])[OH:27].[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([CH3:25])([CH3:24])[O:18][SiH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)(C)OC(=O)n1ccc2cc(C(C)(C)O[SiH2]C(C)(C)C)ccc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: OB(O)c1cc2ccccc2[nH]1
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
5-(tert-Butyl-dimethyl-silanyloxymethyl)-indole-1-carboxylic acid tert-butyl ester (8b) (5.89 g, 16.3 mmol) was stirred in tetrahydrofuran (80 mL) and triisopropyl borate (4.18 g, 5.13 mL, 22.2 mmol) was added, and the reaction mixture was cooled to −5° C. To this was added the previously described lithiumdiisopropyl amide solution drop wise keeping the temperature between −5° C. and 0° C. After addition the reaction was stirred at −5° C. for 30 mins and then allowed to attain ambient temperature. The reaction mixture was concentrated in vacuo to yield crude indole-2-boronic acid-5-(tert-Butyl-dimethyl-silanyloxymethyl)-indole-1-carboxylic acid tert-butyl ester, which was dissolved in tetrahydrofuran (100 mL). Water (20 mL), potassium carbonate (6.17 g, 44.6 mmol), 3-iodo-5-nitro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyridin-2-one, intermediate (6a) (5.87 g, 14.8 mmol) in tetrahydrofuran (20 mL) and [1,1′-Bis(diphenylphosphino)ferrocene)]dichloropalladium(II), complex with dichloromethane (0.605 g, 5 mol %) were added. The red suspension was degassed for 10 minutes and then heated at 60° C. for 2 hours. The reaction mixture was cooled and was partitioned between ethyl acetate (200 mL) and aqueous saturated sodium bicarbonate solution (200 mL). The organic layer was separated and the aqueous was extracted with a further portion of ethyl acetate. The combined ethyl acetate layers were washed with brine, dried (Na2SO4), filtered through a plug of celite and concentrated in vacuo. The resultant crude product was purified by flash chromatography on SiO2 eluting with hexane—15% ethyl acetate/hexane (gradient) to afford the desired title compound as a yellow solid, 8.44 g, 90%.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH:9]2[CH2:11][CH:3]1[CH:4]1[CH:8]2[CH2:7][CH2:6][CH2:5]1.[CH3:12][O-:13].[Na+].O>C1CCCCC1>[CH:12]([C:9]1[CH:8]=[CH:4][C:3]([CH:11]=[C:10]2[CH:9]3[CH2:11][CH:3]([CH:4]4[CH:8]3[CH2:7][CH2:6][CH2:5]4)[C:2]2=[O:1])=[CH:2][CH:10]=1)=[O:13]
Reactant: O=C1CC2CC1C1CCCC21
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: O
Product: O=Cc1ccc(C=C2C(=O)C3CC2C2CCCC32)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A suspension of 40 mmol (6.3 g) of 8-ketotricyclo[5.2.1.02,6 ]decane and 60 mmol of sodium methoxide (11 g of a 30% solution) in 50 ml of cyclohexane are stirred at 50° C. for 30 minutes. 50 mmol (9.0 g) of terephthalaldehyde monodimethyl acetal are then added dropwise and the mixture is refluxed for 1 hour. It is then cooled to room temperature and 100 ml of water are added.