Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].O1CCCC1.Cl[CH2:10][C:11]([N:13]([C:15]1[C:16](=[O:31])[C:17]2[C:22]([C:23](=[O:30])[C:24]=1[NH:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:14])=[O:12].O>O1CCCC1>[CH3:29][O:28][CH2:27][CH2:26][NH:25][C:24]1[C:23](=[O:30])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:31])[C:15]=1[N:13]([CH3:14])[C:11](=[O:12])[CH2:10][N:2]([CH3:3])[CH3:1]
Reactant: CNC
Reactant: COCCNC1=C(N(C)C(=O)CCl)C(=O)c2ccccc2C1=O
Solvent: O
Solvent: C1CCOC1
Product: COCCNC1=C(N(C)C(=O)CN(C)C)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2 M Dimethylamine/tetrahydrofuran solution (3.0 ml) was added to a solution of 2-chloro-N-[1,4-dihydro-3-(2-methoxyethyl)amino-1,4-dioxo-2-naphthalenyl]-N-methylacetamide (0.5 g) in tetrahydrofuran (30 ml) and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was crystallized from ethanol to give N-[1,4-dihydro-3-(2-methoxyethyl)amino-1,4-dioxo-2-naphthalenyl]-N-methyl-2-(dimethylamino)acetamide (0.19 g) as a brown powder.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[CH:4]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[C:15]([CH3:16])=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[C:24][Si](C)(C)C)[CH:18]=3)[NH:13][N:12]=2)=[O:10])[CH2:5]1)[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:29]([N:3]([CH2:1][CH3:2])[CH:4]1[CH2:8][CH2:7][N:6]([C:9]([C:11]2[C:15]([CH3:16])=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[CH:24])[CH:18]=3)[NH:13][N:12]=2)=[O:10])[CH2:5]1)[CH3:30]
Reactant: CCN(CC)C1CCN(C(=O)c2n[nH]c(-c3cccc(C#C[Si](C)(C)C)c3)c2C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cccc(-c2[nH]nc(C(=O)N3CCC(N(CC)CC)C3)c2C)c1
Reaction time: 1.5 h

Procedure:
A solution of 0.101 g (0.24 mmol) of (3-diethylamino-pyrrolidin-1-yl)-[4-methyl-5-(3-trimethylsilanylethynyl-phenyl)-1H-pyrazol-3-yl]-methanone in 2.4 ml THF at 0° C. was treated with 0.26 ml (0.26 mmol) of 1M tetrabutylammonium fluoride in THF. The reaction was stirred at this temperature for 1.5 h and then partitioned between water/Et2O (3×). The organic phases were washed with water, dried (Na2SO4) and evaporated to give 0.084 g (quant) of the title compound as yellow foam. MS: 351.3 (MH+).
Reaction SMILES: [C:1]1([O:11][CH2:12][CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[C:16]2[C:31]([O:33]CC)=[O:32])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O1CCOCC1>[Li+].[OH-]>[CH3:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:15]([CH2:14][CH2:13][CH2:12][O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:16]=1[C:31]([OH:33])=[O:32]
Reactant: CCOC(=O)c1c(-c2ccccc2C)c2ccccc2n1CCCOc1cccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccccc1-c1c(C(=O)O)n(CCCOc2cccc3ccccc23)c2ccccc12

Procedure:
A mixture of EXAMPLE 31D in 1N LiOH:dioxane (0.5 mL: 2 mL) was heated under microwave conditions (CEM Discover) at 130° C. for 30 minutes. The mixture was quenched with 1NHCl aqueous mixture (0.5 mL) and extracted with ethyl acetate. The extract was dried (Na2SO4), filtered, and concentrated. The concentrate was purified by reverse phase HPLC (Zorbax SB-C18, 20-100% acetonitrile/water/0.1% trifluoroacetic acid). 1H NMR (400 MHz, DMSO-d6) δ 12.73 (bs, 1H), 8.23 (d, 1H), 7.87 (d, 1H), 7.66 (d, 1H), 7.52 (m, 3H), 7.38 (t, 1H), 7.26 (m, 4H), 7.12 (m, 2H), 7.04 (m, 1H), 6.87 (d, 2H), 4.91 (t, 2H), 4.19 (t, 2H), 2.38 (m, 2H), 2.01 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:21][CH:20]=[CH:19][N:5]2[C:6](=[O:18])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[CH2:22]1[CH2:24][CH:23]1[CH2:25][O:26][C:27]1C=CC=CC=1C=O.[O-]CC.[Na+]>C(O)C>[CH2:22]1[CH2:24][CH:23]1[CH2:25][O:26]/[CH:27]=[CH:1]/[C:2]1[N:3]=[C:4]2[S:21][CH:20]=[CH:19][N:5]2[C:6](=[O:18])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][CH:9]=1
Reactant: O=Cc1ccccc1OCC1CC1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1c(-c2ccc(C(F)(F)F)cc2)c(/C=C/OCC2CC2)nc2sccn12
Yield: 47.6 %

Procedure:
A solution of Intermediate 5 (400 mg, 1.289 mmol), (2-cyclopropylmethoxy)benzaldehyde (356 mg, 2.025 mmol) and sodium ethoxide (183 mg, 2.108 mmol) in ethanol (20 ml) was refluxed for 15 h. The reaction mixture was concentrated, the residue extracted with ethyl acetate, washed with water and brine to afford crude solid which was purified by column chromatography to afford 241 mg of the desired compound as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.12-0.20 (m, 2H), 0.27-0.32 (m, 2H), 0.78-0.83 (m, 1H), 3.74 (d, J=6.9 Hz, 2H), 6.90-6.97 (m, 2H), 7.18-7.26 (m, 2H), 7.39 (d, J=6.9 Hz, 1H), 7.52 (d, J=4.8 Hz, 1H), 7.58 (d, J=7.8 Hz, 2H), 7.80 (d, J=7.5 Hz, 2H), 7.91-7.97 (m, 1H), 8.00 (d, J=4.5 Hz, 1H); ESI-MS (m/z) 469.22 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([CH3:22])=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([CH3:23])=[C:10]2[C:24]([O:26]CCC#N)=[O:25])=[C:5]([O:31][CH3:32])[CH:4]=1)#[N:2].[OH-].[Na+].C(OCC)C.O>COCCOC.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([CH3:22])=[N:16][C:17]=3[O:19][CH2:20][CH3:21])[NH:12][C:11]([CH3:23])=[C:10]2[C:24]([OH:26])=[O:25])=[C:5]([O:31][CH3:32])[CH:4]=1)#[N:2]
Reactant: CCOc1nc(C)cc2c1C(c1ccc(C#N)cc1OC)C(C(=O)OCCC#N)=C(C)N2
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Solvent: CCOCC
Product: CCOc1nc(C)cc2c1C(c1ccc(C#N)cc1OC)C(C(=O)O)=C(C)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
642 mg (2.52 mmol) of the compound from Example 26A are dissolved in 40 ml of 1,2-dimethoxyethane/water (3:1 v/v), mixed with 5.04 ml (5.04 mmol) of 1 N sodium hydroxide solution and stirred at room temperature overnight. The mixture is then mixed with 30 ml of diethyl ether and 30 ml of water, the organic phase is separated off, and the aqueous phase is adjusted to pH 4-5 with 1 N hydrochloric acid. The resulting suspension is stirred for 1 h, and the precipitated solid is then removed by filtration. The precipitate is washed with water and a little diethyl ether. Drying at 40° C. in vacuo results in 642 mg (67% of theory) of the title compound.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[CH3:15][N:16]([CH3:40])[C:17]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:22][CH2:21][C:20]([C:24]2[NH:32][C:31]3[CH:30]=[CH:29][N:28]=[CH:27][C:26]=3[C:25]=2[CH3:33])(O)[CH2:19][CH2:18]1.O.[OH-].[Na+]>CS(O)(=O)=O.C(Cl)Cl>[CH3:40][N:16]([CH3:15])[C:17]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:22][CH2:21][C:20]([C:24]2[NH:32][C:31]3[CH:30]=[CH:29][N:28]=[CH:27][C:26]=3[C:25]=2[CH3:33])=[CH:19][CH2:18]1
Reactant: Cc1c(C2(O)CCC(c3ccccc3)(N(C)C)CC2)[nH]c2ccncc12
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1c(C2=CCC(c3ccccc3)(N(C)C)CC2)[nH]c2ccncc12
Temperature: 77 °C
Reaction time: 3 h

Procedure:
P4O10 (approx. 1 g, two spatula-tips) was added to a solution of 4-dimethylamino-1-(3-methyl-1H-pyrrolo[3,2-c]pyridin-2-yl)-4-phenylcyclohexanol (600 mg, 1.72 mmol) in methanesulfonic acid (20 ml). The slightly pale brown-coloured solution was stirred at 77° C. (oil bath temperature) for 3 h. Water (10 ml) was added to the reaction mixture and this was rendered basic with sodium hydroxide solution (5 M). Methylene chloride (30 ml) was then added and the mixture was stirred for 10 min. The phases were separated. The aqueous phase was extracted with methylene chloride (3×35 ml). The combined organic phases were dried over sodium sulfate. The volatile constituents were then removed completely in vacuo. 425 mg of (±)-N,N-dimethyl-N-[4-(3-methyl-1H-pyrrolo[3,2-c]pyridin-2-yl)-1-phenylcyclohex-3-enyl]amine remained (dark brown solid, slightly contaminated).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([OH:22])[CH:18]=3)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:33][NH:34][C:35]([C:37]1[CH:42]=[C:41](Cl)[CH:40]=[CH:39][N:38]=1)=[O:36].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:33][NH:34][C:35]([C:37]1[CH:42]=[C:41]([O:22][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=2)[CH:21]=[N:20]3)[CH:40]=[CH:39][N:38]=1)=[O:36]
Reactant: CC(C)(C)c1cccc(Nc2cnc3cc(O)ccc3n2)c1
Reactant: CNC(=O)c1cc(Cl)ccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc3nc(Nc4cccc(C(C)(C)C)c4)cnc3c2)ccn1

Procedure:
The mixture containing 2-(3-tert-butyl-phenylamino)-quinoxalin-6-ol (1 eq), potassiumbis(trimethylsilyl)amide (4eq), was stirred in dimethylformamide for 30 min. at room temperature. To this mixture was added 4-chloro-pyridine-2-carboxylic acid methylamide (1 eq) and potassium carbonate (1.2 eq) and microwaved for 6 mins. at 170° C. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried, filtered and concentrated. Purification on Prep LC yielded the desired product.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].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>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: Brc1n[nH]c2ccccc12
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(-c2n[nH]c3ccccc23)cc1
Temperature: 100 °C
Yield: 5.4 %

Procedure:
A mixture of 3-bromo-1H-indazole (0.20 g, 1.0 mmol), 4-methoxyphenylboronic acid (0.228 g, 1.5 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.228 g, 0.1 mmol) in ethylene glycol dimethyl ether (5 mL) and 2.0 M sodium carbonate solution (6 mL) under nitrogen was heated at 100° C. for 18 hours. It was quenched by water and extracted with chloroform. The extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was then purified by chromatography (SiO2, 15-30% ethyl acetate/hexane) to provide the title compound (0.012 g, 5% yield): 1H NMR (CDCl3) δ 10.4 (br s, 1H), 8.01 (d, 1H), 7.92 (d, 2H), 7.46 (m, 2H), 7.22 (m, 1H), 7.06 (d, 2H), 3.89 (s, 3H); EI-MS (m/z) 224 [M]+.
Reaction SMILES: [OH:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl.[CH2:12](O)[CH3:13]>>[OH:1][C:2]1([C:8]([O:10][CH2:12][CH3:13])=[O:9])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: CCO
Reactant: O=C(O)C1(O)CCNCC1
Agent: Cl
Product: CCOC(=O)C1(O)CCNCC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
The 4-hydroxypiperidine-4-carboxylic acid (118 mg) obtained in the step (a) of Example 68 was dissolved in 1 N hydrochloric acid/ethanol (5 ml) solution, and the resulting solution was stirred at room temperature for 17 hours and then under reflux for 6 hours. The reaction mixture was concentrated to obtain crude ethyl 4-hydroxypiperidine-4-carboxylate. This crude ethyl 4-hydroxypiperidine-4-carboxylate was used in the following reaction without purification.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][C:3]=1[C:18]([NH:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[O:19].[Mn]([O-])(=O)(=O)=O.[Ba+2].[Mn]([O-])(=O)(=O)=O>ClCCl>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:4]=[C:3]1[C:18]([NH:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1)=[O:19]
Reactant: O=C(Nc1nccs1)C1=C(O)c2ccccc2N(c2ccccc2)C1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [Ba+2]
Solvent: ClCCl
Product: O=C(Nc1nccs1)c1cn(-c2ccccc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 86 %

Procedure:
To a stirred solution of 6.67 g of 1,2-dihydro-4-hydroxy-1-phenyl-N-(2-thiazolyl)-3-quinolinecarboxamide in 100 ml of dichloromethane was added, dropwise, a solution of 26.7 g of barium permanganate in 500 ml of dichloromethane. After stirring for six hours at room temperature the solution was filtered and evaporated. Recrystallization of the residue from chloroform yielded 5.70 g (86%) of 1,4-dihydro-4-oxo-1-phenyl-N-(2-thiazolyl)-3-quinolinecarboxamide, m.p. 290° C.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[F:21])[CH:9]=[CH:10][C:11]=1[OH:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:43]1([CH:46]([C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59]O)[CH:54]=2)[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:45][CH2:44]1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH:43]1([CH:46]([C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][O:12][C:11]3[CH:10]=[CH:9][C:8]([C:13]4[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=4[F:21])=[CH:7][C:6]=3[CH2:5][CH2:4][CH2:3][C:2]([CH3:23])([CH3:22])[CH3:1])[CH:54]=2)[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:45][CH2:44]1
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Reactant: COc1ccc(F)c(-c2ccc(O)c(CCCC(C)(C)C)c2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)cc2CCCC(C)(C)C)c1)C1CC1
Yield: 78.5 %

Procedure:
To a solution of 3-(4,4-dimethylpentyl)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-ol (280 mg) in THF (5.0 mL) were added triphenylphosphine (348 mg), ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (330 mg) and a 40% solution of diethyl azodicarboxylate in toluene (600 μL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (380 mg) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9](Cl)[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=2[F:18])=[CH:4][N:3]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([S:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[C:10]2[C:15]([F:16])=[CH:14][CH:13]=[C:12]([F:17])[C:11]=2[F:18])=[CH:4][N:3]=1
Reactant: Fc1ccc(S)cc1
Reactant: Cc1cc(Br)ncc1C(Cl)c1c(F)ccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(Br)ncc1C(Sc1ccc(F)cc1)c1c(F)ccc(F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
To a solution of 2-bromo-5-[chloro(2,3,6-trifluorophenyl)methyl]-4-methylpyridine (4.65 g, 13.3 mmol) in N,N-dimethylformamide (70 ml), 4-fluorobenzenethiol (1.41 ml, 13.3 mmol) and then potassium carbonate (2.02 g, 14.6 mmol) were added in an argon atmosphere at 0° C., and the resulting mixture was stirred for 4 hours at room temperature. Ethyl acetate and water were added to the reaction mixture at 0° C., the organic layer was separated, and then the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=19:1 was concentrated under reduced pressure, and the resulting residue was washed with hexane, and then was collected by filtration, to obtain the title compound (5.17 g, 11.7 mmol, 88%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=3)=[C:6]2[N:5]=[CH:4][N:3]=1.I([O-])(=O)(=O)=[O:20].[Na+].O>CO>[OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:18])=[O:20])=[CH:13][CH:12]=3)=[C:6]2[N:5]=[CH:4][N:3]=1
Reactant: CSc1ccc(-c2cnn3c(O)ncnc23)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CS(=O)c1ccc(-c2cnn3c(O)ncnc23)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 65.7 %

Procedure:
To a suspension of 4-hydroxy-8-(4-methylthiophenyl)pyrazolo[1,5-a]-1,3,5-triazine (258 mg) and sodium metaperiodate (430 mg) in methanol (20 ml) is added water (0.5 ml), and the mixture is stirred at room temperature for 40 hours. The insoluble material is separated by filtration, washed with water and dried to give the title compound (180 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].Cl[C:28]1[N:29]=[CH:30][C:31]2[CH:36]=[CH:35][N:34]([CH:37]([CH2:40][CH3:41])[CH2:38][CH3:39])[C:32]=2[N:33]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.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:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:28]3[N:29]=[CH:30][C:31]4[CH:36]=[CH:35][N:34]([CH:37]([CH2:40][CH3:41])[CH2:38][CH3:39])[C:32]=4[N:33]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Reactant: CCC(CC)n1ccc2cnc(Cl)nc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCC(CC)n1ccc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc21
Temperature: 100 °C
Yield: 89.9 %

Procedure:
To a mixture of 4-(4-amino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (133 mg, 0.48 mmol) and sodium tert-butoxide (57.6 mg, 0.6 mmol) in 1,4-dioxane (0.5 mL) is added a solution of 2-chloro-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine (90 mg, 0.4 mmol) in 1,4-dioxane (1.0 mL), Pd2(dba)3 (18.3 mg, 0.02 mmol) and BINAP (25 mg, 0.04 mmol). The mixture is degassed, and heated at 100° C. for 3 h. The mixture is cooled to room temperature, diluted with EtOAc, and filtered through celite. The filtrate is concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2, EtOAc:Hexane=1:1) to give 167 mg of 4-{4-[7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH2:15][O:16][CH3:17])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])[NH2:5].[C:18](Cl)(Cl)=[O:19]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:5]=[C:18]=[O:19])[CH:6]=[C:7]([CH2:15][O:16][CH3:17])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14]
Reactant: COCc1cc(N)cc(Cl)c1OCCCC#N
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: COCc1cc(N=C=O)cc(Cl)c1OCCCC#N
Temperature: 25 °C
Yield: 99.6 %

Procedure:
3-Chloro-4-(3-cyanopropyloxy)-5-methoxymethylaniline (2.55 g) in toluene (20 ml) was dropwise added to a toluene solution containing 10 g of phosgene at 10° to 20° C. The resulting mixture was gradually heated and, after being refluxed for 30 minutes, cooled to room temperature. The solvent was removed by distillation under reduced pressure to give 3-chloro-4-(3-cyanopropyloxy)-5-methoxymethylphenyl isocyanate (2.80 g). The thus obtained crude substance was added to a toluene solution (50 ml) containing triethylamine (1.0 g) and isopropanol (1.0 g). The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give isopropyl N-[3-chloro-4-(3-cyanopropyloxy)-5-methoxymethylphenyl]carbamate (Compound No. 6) (2.70 g) in a yield of 79.2%. nD20.0 1.5196.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[CH2:32]([O:31][C:29]([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][N:6]1[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=[C:2]1[CH3:1])=[O:30])[CH3:33]
Reactant: Cc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: CCOC(=O)CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CCCCCCCn1c(C)nc(-c2ccccc2)c1-c1ccccc1
Yield: 71.8 %

Procedure:
2-Methyl-4,5-diphenylimidazole (2.5 g) (J. Org. Chem., 1937, 2,328) was reacted with sodium hydride (0.62 g) and ethyl 8-bromooctanoate (3.36 g) in a method similar to Example 12. Chromatography on silica gel eluted with a dichloromethane:ethanol gradient gave 1-(7-ethoxycarbonyl-heptyl)-2-methyl-4,5-diphenylimidazole (3.1 g, 72.1%) as an oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:21][C:22]1[C:26](B2OC(C)(C)C(C)(C)O2)=[C:25]([C:36]2([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[CH2:38][CH2:37]2)[O:24][N:23]=1>CO.O1CCOCC1.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:42]([O:41][C:40]([NH:39][C:36]1([C:25]2[O:24][N:23]=[C:22]([CH3:21])[C:26]=2[C:2]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:38][CH2:37]1)=[O:46])([CH3:45])([CH3:44])[CH3:43]
Reactant: Cc1noc(C2(NC(=O)OC(C)(C)C)CC2)c1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Cl)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cl)ccc1-c1c(C)noc1C1(NC(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 85.6 %

Procedure:
A re-sealable vial containing methyl 2-bromo-5-chlorobenzoate (0.205 g, 0.822 mmol), Pd(Ph3P)4 (0.042 g, 0.036 mmol), and anhydrous potassium phosphate, tribasic (0.275 g, 1.296 mmol) was evacuated and purged with N2 (g) (3×). To the solids was added a solution of tert-butyl 1-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazol-5-yl)cyclopropylcarbamate (0.236 g, 0.648 mmol) in MeOH (2×1 mL, 2 mL total) and 1,4-Dioxane (2×1 mL, 2 mL total). The suspension was evacuated and purged with N2 (g) (3×), the vial was sealed, and the contents heated to 80° C. LC-MS analysis indicated complete conversion to desired product with in 4 h. After 4 h, the reaction mixture was cooled to room temperature and filtered over Celite. The filter cake was washed with MeOH (3×) and the filtrate was concentrated to give a brown oil. The oil was purified on Biotage system (5% EtOAc:95% Hexanes to 30% EtOAc:70% Hexanes, then isocratic 30% EtOAc:70% Hexanes). The product methyl 2-(5-(1-(tert-butoxycarbonylamino)cyclopropyl)-3-methylisoxazol-4-yl)-5-chlorobenzoate (0.226 g, 0.555 mmol, 86% yield) was isolated as a clear oil. LC/MS m/z 407 [M+H]+.