Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][C:11]1([CH3:23])[O:22][CH:19]([CH:20]=[CH2:21])[CH:13]([CH:14]([OH:18])[CH2:15][C:16]#[N:17])[O:12]1.[CH3:24][O:25][CH2:26]Cl>C(OCC)C>[CH3:10][C:11]1([CH3:23])[O:22][CH:19]([CH:20]=[CH2:21])[CH:13]([CH:14]([O:18][CH2:24][O:25][CH3:26])[CH2:15][C:16]#[N:17])[O:12]1
Reactant: COCCl
Reactant: C=CC1OC(C)(C)OC1C(O)CC#N
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: C=CC1OC(C)(C)OC1C(CC#N)OCOC
Temperature: 0 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
Nine milliliters of diisopropylethylamine were added to 2.11 g of 4,5-(dimethylmethylenedioxy)-3-hydroxy-6-heptenenitrile, and 2 ml of methoxymethyl chloride was then added to the mixture gradually at 0° C. After stir-ring at 0° C. for 16 hours, the reaction mixture was diluted with 300 ml of diethyl ether, and washed with 1N hydrochloric acid, a saturated sodium hydrogen carbonate aqueous solution and a sodium chloride aqueous solution in sequence. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was filtered by a silica gel column to afford 2.28 g of 4,5-(dimethylmethylenedioxy)-3-methoxymethoxy-6-heptenenitrile having the following properties (yield 88 %).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5](=[O:13])[C:4]2[CH:14]=[C:15]([CH2:18][C:19]([O:21]C)=[O:20])[CH:16]=[CH:17][C:3]1=2.[Cl:23]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:23][C:17]1[C:3]2[N:2]([CH3:1])[CH2:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[C:5](=[O:13])[C:4]=2[CH:14]=[C:15]([CH2:18][C:19]([OH:21])=[O:20])[CH:16]=1
Reactant: COC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CN2C
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: CN1Cc2ccccc2C(=O)c2cc(CC(=O)O)cc(Cl)c21
Yield: 56.1 %

Procedure:
Methyl 5,6-dihydro-5-methyl-11-oxodibenz[b,e]azepine-2-acetate (2.0 g) was dissolved in chloroform (50 ml), and the solution was refluxed for 2 hours with the addition of N-chlorosuccinimide (1.4 g). The reaction mixture was treated in the same manner as described in Example 8 to obtain 5,6-dihydro-4-chloro-5-methyl-11-oxodibenz[b,e]azepine-2-acetic acid (1.2 g) having a melting point of 168.0°-170° C. (prismatic crystals).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:24][C:25]2[CH:26]=[N:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]([CH2:18][C:19]([O:21]CC)=[O:20])[CH2:16][N:17]=1)=[CH:9]2)[CH3:2].O1CCCC1.CO.[OH-].[K+]>O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([O:24][C:25]2[CH:26]=[N:27][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][CH:30]=2)[CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:14][CH:15]([CH2:18][C:19]([OH:21])=[O:20])[CH2:16][N:17]=1)=[CH:9]2)[CH3:2]
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OCC)c3[nH]2)S1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCOc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C3=NCC(CC(=O)O)S3)[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.5 %

Procedure:
To a mixture of ethyl [2-(7-ethoxy-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-5-yl]acetate (0.22 g), tetrahydrofuran (10 mL) and methanol (10 mL) was added a solution of potassium hydroxide (85%, 0.10 g) in water (5 mL). The mixture was stirred at room temperature for 15 h and then partitioned between ethyl acetate and aqueous citric acid solution. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated to give a light yellow amorphous solid, which was crystallized from ethyl acetate-hexane to give the title compound (186 mg, 90%) as light yellow crystals. MS 476 (MH+). mp 208-210° C.
Reaction SMILES: [CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:7]=[CH:6][C:5]=2[N:4]1[S:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=1)(=[O:26])=[O:25])[CH3:2].C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[CH2:1]([CH:3]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:17])[CH:15]=2)[C:10]2[CH:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:7]=[CH:6][C:5]=2[N:4]1[S:24]([C:27]1[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=1)(=[O:26])=[O:25])[CH3:2]
Reactant: CCC1c2cc(F)ccc2-c2cc(-c3ccccc3)ccc2N1S(=O)(=O)c1ccc(OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CCC1c2cc(F)ccc2-c2cc(-c3ccccc3)ccc2N1S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.3 %

Procedure:
A stirred suspension of 6-ethyl-8-fluoro-5-[(4-methoxyphenyl)sulfonyl]-2-phenyl-5,6-dihydrophenanthridine (0.13 g, 0.26 mmol) and cyclohexene (0.48 mL, 4.8 mmol) was treated drop-wise at room temperature under nitrogen with a solution of 1 M boron tribromide in dichloromethane (1.6 mL, 1.6 mmol). After stirring for 20 hours at room temperature, the reaction was quenched by the drop-wise addition of a saturated, aqueous, sodium bicarbonate solution (300 mL), followed by extraction with dichloromethane (6×20 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a crude product. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:4 to 3:7 gradient), followed by re-crystallization from a mixture of ethyl acetate-hexane, to yield 4-[(6-ethyl-8-fluoro-2-phenylphenanthridin-5(6H)-yl)sulfonyl]phenol as a homogeneous solid (0.09 g, 71%), m.p. 207° C.;
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][C:18]([CH:20]1[CH2:22][CH2:21]1)=[O:19])=O)C1C=CC=CC=1.[N:23]1[C:32]2[C:27](=[N:28][C:29]([CH:33]=O)=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.N1CCCCC1>CC(O)C>[N:28]1[C:27]2[C:32](=[N:23][CH:24]=[CH:25][CH:26]=2)[CH:31]=[CH:30][C:29]=1[CH:33]=[C:15]1[NH:11][C:12]([NH:17][C:18]([CH:20]2[CH2:21][CH2:22]2)=[O:19])=[N:13][C:14]1=[O:16]
Reactant: O=Cc1ccc2ncccc2n1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C(NC(=O)C2CC2)=N1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: O=C1N=C(NC(=O)C2CC2)NC1=Cc1ccc2ncccc2n1
Temperature: 25 °C

Procedure:
To a mixture of 2-(cyclopropanecarbonyl-amino)-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (109.6 mg, 0.36 mmol), 1,5-naphthyridine-6-carboxaldehyde (47.4 mg, 0.30 mmol) and iPrOH (5.0 mL) in a 25-mL round bottom flask was added piperidine (0.05 mL) and the suspension was then heated under refluxing for 3.5 hrs to give a suspension. The reaction mixture was cooled to r.t. and the solid was collected by filtration, washed with MeOH, and ether to give cyclopropanecarboxylic acid (5-[1,5]naphthyridin-2-ylmethylene-4-oxo-4,5-dihydro-1H-imidazol-2-yl)-amide as a light brown solid, 32.6 mg (35.4%). HR-ES (+) m/e calcd. for C16H13N5O2: (M)+ 307.1069. Found: 307.1066.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:18]C[CH2:16]3)[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)#[N:20]>>[CH:15]([N:12]1[CH2:11][CH2:10][N:9]([CH2:8][C:5]2[N:6]=[CH:7][C:2]([C:24]3[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[CH:22][CH:23]=3)=[CH:3][CH:4]=2)[CH2:14][CH2:13]1)([CH3:16])[CH3:18]
Reactant: Brc1ccc(CN2CCN(C3CCC3)CC2)nc1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: CC(C)N1CCN(Cc2ccc(-c3ccc(C#N)cc3)cn2)CC1

Procedure:
1-(5-Bromopyridin-2-ylmethyl)-4-isopropylpiperazine (1.163, 3.75 mmol) and 4-cyanophenyl-boronic acid (0.82 g, 5.6 mmol) were mixed with catalyst and reacted in the same manner as in example 18. The title compound was isolated as white crystals of the free amine. Yield: 241 mg (20%)
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C[Si](C)(C)N[Si](C)(C)C.[Na].[Br:32][C:33]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][C:34]=1[CH2:35]Br.CCOC(C)=O>C1COCC1.O>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:35][C:34]3[CH:37]=[C:38]([C:41]([F:42])([F:44])[F:43])[CH:39]=[CH:40][C:33]=3[Br:32])[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: FC(F)(F)c1ccc(Br)c(CBr)c1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1Br
Reaction time: 0.25 h

Procedure:
To (4S,5R)-5-(3,5-bis-trifluoromethyl-phenyl)-4-methyl-oxazolidin-2-one (0.246 g, 0.79 mmol) in THF (10 mL) at mom temperature was added sodium hexamethyldisilazane (1M in THF; 1.02 mL, 1.02 mmol), and the reaction was stirred for 15 minutes. 2-Bromo-5-(trifluoromethyl)benzyl bromide (0.250 g, 0.79 mmol) was added, and the reaction was stirred overnight at room temperature. The mixture was worked-up with EtOAc and H2O, and the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([O:13][Si](C(C)(C)C)(C)C)[CH2:10][C@H:9]1[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=O)(C)(C)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].O>ClCCl>[OH:13][C@H:11]1[CH2:12][NH:8][C@H:9]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH2:10]1.[C:28]([OH:30])([C:27]([F:32])([F:31])[F:26])=[O:29]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)CC[C@@H]1C[C@@H](O)CN1
Reaction time: 8 h

Procedure:
To a solution of 3-((2R,4R)-1-(tert-butoxycarbonyl)-4-{[tert-butyl(dimethyl)silyl]oxy}-pyrrolidin-2-yl)propanoic acid (5.1 g, 13.65 mmol) in dichloromethane (100 ml) at 0° C. were added trifluoroacetic acid (14 ml) and water (3 ml). The reaction mixture was allowed to warm up and stirred overnight. The reaction mixture was concentrated in vacuo to afford 3-[(2R,4R)-4-hydroxypyrrolidin-2-yl]propanoic acid as TFA salt (3.74 g). Yield: 100%
Reaction SMILES: OO.[C:3]([O:6][C:7](=O)[CH3:8])(=O)C.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:23])C(C)=C)=[CH:14][C:13]=1[C:24]([F:27])([F:26])[F:25])#[N:11]>O>[C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:7]2([CH3:8])[CH2:3][O:6]2)=[O:23])=[CH:14][C:13]=1[C:24]([F:25])([F:26])[F:27])#[N:11]
Reactant: C=C(C)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Agent: OO
Solvent: O
Product: CC1(C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)CO1
Reaction time: 0.5 h

Procedure:
10 ml of 30% aqueous hydrogen peroxide is heated to 35–40° C. 20 ml of acetic anhydride is added dropwise under cooling, so that the temperature does not exceed 40–50° C. 0.02 g of wolframic acid is added and the reaction mixture is stirred for 0.5 hours at 50–55° C. 3 grams of the amide (7) is added to the mixture portionwise and the reaction mixture is stirred for 6 hours at 50–55° C. The suspension is then cooled to 20–25° C. and poured, under stirring, into 100 ml of cold (0–5° C.) water. The suspension is stirred for 30 minutes and the solid is filtered off, washed by water and dried at 40–50° C. Yield: 2.44 g (76.5%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1N2CCN(CC2)C1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)([O-:23])=[O:22].O>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][O:12][S:30]([C:27]2[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:29][CH:28]=2)(=[O:31])=[O:32])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: O=[N+]([O-])c1ccc(CCO)cc1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CCOS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
To a stirred solution of 4-nitrobenzeneethanol (3.34 g, 20.0 mmol) and triethylenediamine (3.36 g, 30.0 mmol) in DCM (62.7 mL) at 0° C. was added 4-nitrobenzenesulfonyl chloride (4.97 g, 22.43 mmol) in portions over a 5 min period. The reaction mixture was then stirred at room temperature for 2 h. Water (50 mL) was added and the resulting mixture was stirred for 10 min. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the crude title compound (5.8 g, 82% yield) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C1COCC1>[Br-:14].[CH2:15]([N:11]1[CH:12]=[CH:13][N+:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[CH:10]1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCBr
Reactant: COc1ccccc1-n1ccnc1
Solvent: C1CCOC1
Product: CCCCCCn1cc[n+](-c2ccccc2OC)c1
Product: [Br-]

Procedure:
According to the general synthesis procedure, 10.40 mmol (1,812 g) 1-(2-methoxyphenyl)imidazole and 11.44 mmol (1,889 g, 1.65 ml) 1-bromohexane are dissolved in 5 ml THF and heated for 5 h to 80° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH2:7][CH3:8])[NH:4][N:3]=1.[C:9]1([CH:15]([C:21](OCC)=[O:22])[C:16](OCC)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(N(CCCC)CCCC)CCC.[OH-].[Na+]>[CH2:7]([C:5]1[N:6]=[C:2]2[N:1]=[C:16]([OH:17])[C:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:21]([OH:22])[N:3]2[N:4]=1)[CH3:8]
Reactant: CCc1nc(N)n[nH]1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Product: CCc1nc2nc(O)c(-c3ccccc3)c(O)n2n1
Reaction time: 0.5 h

Procedure:
A solution of 5.00 g 3-amino-5-ethyl-1,2,4-triazole and 15.00 g diethyl phenylmalonate in 18 ml N,N-dibutylbutan-1-amine is stirred at 185° C. over night. The solution is diluted with 5N NaOH solution, the resulting mixture is stirred for 30 min. The aqueous layer is washed with diethylether, acidified at 0° C. with concentrated HCl until precipition of the product is complete. The precipitate is collected by filtration to yield the product, which is used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[CH2:12]([OH:15])[C:13]#[CH:14]>COCCOC.C(N(CC)CC)C.ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[NH2:8][C:6]1[CH:7]=[C:2]([C:14]#[C:13][CH2:12][OH:15])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1cc(Br)ccc1[N+](=O)[O-]
Reactant: C#CCO
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: Nc1cc(C#CCO)ccc1[N+](=O)[O-]
Reaction time: 48 h
Yield: 82.9 %

Procedure:
A suspension of bromoarene 2 (447 mg g; 2.06 mmol); tetrakis(triphenylphosphine) palladium(0) (145 mg, 0.12 mmol) and copper(I)iodide (143 mg, 0.75 mmol) in degassed ethyleneglycol dimethylether (2.5 mL) and triethylamine (1.5 mL), was stirred at room temperature under nitrogen in the dark for 10 min and then treated with neat prop-2-yn-1-ol (0.7 mL, 12 mmol) (or any other alkyne of choice, 5 eq.), and the mixture stirred under the same conditions for 48 h, diluted with dichloromethane (50 mL), filtered through a celite pad and concentrated. Purification by flash chromatography (eluent 50 to 75% AcOEt in hexane) afforded compound 72 (328 mg, 83% yield).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.[C:22]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.C(OCC)(=O)C>[OH:1][C@@H:2]1[C@@H:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:22])=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccc(O)cc2)[C@@H](O)C1
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.7 %

Procedure:
To a solution of (3R,4R)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (490 mg, 1.67 mmol, procedure from WO 2000/63173) in DMF (6 mL) was added K2CO3 (577 mg, 4.2 mmol) followed by methyl iodide (0.52 mL, 8.4 mmol) at rt. The mixture was stirred at rt for 18 h. It was then diluted with 50 mL ethyl acetate and the solids were removed by filtration. The solvent was then evaporated under vacuum and the residue was purified via silica gel chromatography (hexanes-100% EtOAc) to yield (3R,4R)-tert-butyl 3-hydroxy-4-(4-methoxyphenyl)piperidine-1-carboxylate (450 mg, 88% yield). LCMS (method T) RT 3.068 min, m/z 306.3 (M−H)−; 1H NMR (500 MHz, chloroform-d) δ 7.15 (d, J=8.7 Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 4.40-4.30 (m, 1H), 4.25-4.05 (m, 1H), 3.78 (s, 3H), 3.64-3.52 (m, 1H), 2.77-2.66 (m, 1H), 2.65-2.51 (m, 1H), 2.45 (br. s., 1H), 2.26-2.10 (m, 1H), 1.76 (d, J=2.7 Hz, 1H), 1.71-1.60 (m, 1H), 1.48 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:14]=3[N:15]=2)[C:7](F)=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:22]([NH2:25])[CH2:23][CH3:24]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:14]=3[N:15]=2)[C:7]([NH:25][CH2:22][CH2:23][CH3:24])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCCN
Reactant: COc1ccc2oc(-c3cc([N+](=O)[O-])ccc3F)nc2c1
Product: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(OC)ccc2o1

Procedure:
Prepared by the method of Example 54a), from 2-(3-nitro-6-fluorophenyl)-5-methoxybenzoxazole (674 mg, 2.0 mmol) and propylamine (492 μL, 6.0 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.
Reaction SMILES: [CH3:1][Si:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([O:18]C(=O)OC)[CH:9]=1.C[O-].[Na+].CC(O)=O>CO>[CH3:1][Si:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([OH:18])[CH:9]=1
Reactant: COC(=O)Oc1cc(OCOCC[Si](C)(C)C)c2ccccc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[Si](C)(C)CCOCOc1cc(O)cc2ccccc12
Temperature: 5 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
5.82 g (16.7 mmol) of carbonic acid methyl ester 4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-yl ester was dissolved in 100 ml of methanol and cooled down to 5° C.; 3.4 ml=3.30 g (18.4 mmol) of sodium methoxide (5.4 molar in MeOH) was added and the reaction mixture then warmed up to room temperature. After one hour, it was poured into crashed ice, the pH was adjusted to 5-6 with AcOH (1N) and the reaction mixture subsequently extracted twice with MeCl2; the organic phases were washed with water, dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (SiO2, gradient of n-heptane/MeCl2) to give 4.23 g of 4-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ol as light brown oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[CH:4][C:3]=1[C:7]([OH:9])=O.P(Cl)(OCC)(OCC)=O.[NH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]2[S:29][C:28]3[N:30]=[CH:31][CH:32]=[N:33][C:27]=3[N:26]([CH2:34][O:35][CH3:36])[C:25]=2[CH:37]=1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:36][O:35][CH2:34][N:26]1[C:25]2[CH:37]=[C:21]([CH2:20][NH:19][C:7]([C:3]3[CH:4]=[N:5][O:6][C:2]=3[CH3:1])=[O:9])[CH:22]=[CH:23][C:24]=2[S:29][C:28]2[N:30]=[CH:31][CH:32]=[N:33][C:27]1=2
Reactant: Cc1oncc1C(=O)O
Reactant: COCN1c2cc(CN)ccc2Sc2nccnc21
Agent: CCOP(=O)(Cl)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCN1c2cc(CNC(=O)c3cnoc3C)ccc2Sc2nccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
A solution of 520 mg of 5-methyl-1,2-oxazole-4-carboxylic acid and 0.75 ml of triethylamine in tetrahydrofuran (10 ml) was ice-cooled. After adding 0.8 ml of diethyl chlorophosphate, the resulting mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added 5 ml of a solution of 750 mg of 8-aminomethyl-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]-benzothiazine in tetrahydrofuran and the resulting mixture was stirred at room temperature for 1.5 hours. Next, the reaction mixture was distributed into ethyl acetate and an aqueous solution of ammonium chloride. The organic layer was extracted, washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 520 mg of N-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)-5-methyl-1,2-oxazole-4-carboxamide. Further, the product was treated by the same method as the one of Example 434 to thereby give 310 mg of the title compound as yellow crystals.
Reaction SMILES: C(OC([N:8]1[C@H:12]([C:13](=[O:25])[NH:14][C@H:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[CH2:11][C@H:10]([NH:26][C:27]2[CH:36]=[C:35]3[C:30]([CH2:31][C@@H:32]([C:44](=[O:56])[NH:45][C@H:46]4[C:55]5[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=5)[CH2:49][CH2:48][CH2:47]4)[N:33](C(OC(C)(C)C)=O)[CH2:34]3)=[CH:29][CH:28]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C@H:46]1([NH:45][C:44]([C@@H:32]2[CH2:31][C:30]3[C:35](=[CH:36][C:27]([NH:26][C@H:10]4[CH2:11][C@@H:12]([C:13](=[O:25])[NH:14][C@H:15]5[C:24]6[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=6)[CH2:18][CH2:17][CH2:16]5)[NH:8][CH2:9]4)=[CH:28][CH:29]=3)[CH2:34][NH:33]2)=[O:56])[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:49][CH2:48][CH2:47]1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(N[C@H]3C[C@@H](C(=O)N[C@@H]4CCCc5ccccc54)N(C(=O)OC(C)(C)C)C3)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@H]1CCCc2ccccc21)[C@@H]1Cc2ccc(N[C@@H]3CN[C@H](C(=O)N[C@@H]4CCCc5ccccc54)C3)cc2CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
To a solution of (S)-tert-butyl 7-(((3S,5S)-1-(tert-butoxycarbonyl)-5-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-3-yl)amino)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (150 mg, 0.20 mmol) in CH2Cl2 (2.2 mL) was added TFA (303 μL, 3.93 mmol). The resulting solution was stirred at room temperature for 1 h. Additional TFA (303 μL, 3.93 mmol) was added. The reaction mixture was stirred for 2 h, then quenched carefully with sat. aq. NaHCO3 solution and poured into a separatory funnel containing EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (3×). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (111 mg, 100%) as a tan solid. MS (ESI+) m/z 564.4 (M+H)+.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1>>[C:2]1([S:1][C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: Sc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(O)c1ccc(Sc2ccccc2)cc1
Yield: 95.7 %

Procedure:
The conditions to prepare Reference Example 32 cl384847 are used with 6.0 g of mercaptobenzene, 12.22 g of potassium t-butoxide and 13.15 g of 4-bromobenzoic acid to give 12.0 g of the desired product as a solid, m.p. 101°-103° C.; M+H=231.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:7][O:8][CH2:9][Br:10]>CC(C)=O.O>[Br-:10].[CH3:7][O:8][CH2:9][N+:2]1([CH3:1])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CN1CCCC1
Reactant: COCBr
Solvent: O
Solvent: CC(C)=O
Product: COC[N+]1(C)CCCC1
Product: [Br-]
Temperature: 15 °C
Reaction time: 4 h

Procedure:
A 17.0 g quantity of N-methylpyrrolidine was dissolved in 160 g of dehydrated acetone (up to 0.1% in water content), followed by nitrogen replacement. To the solution was added dropwise 24.6 g of bromomethyl methyl ether (reagent, product of Tokyo Kasei Co., Ltd.) at 5° C. over a period of 1.5 hours. The mixture was stirred at 5 to not higher than 15° C. for 4 hours to terminate the reaction. The reaction mixture was filtered, and the resulting solids were washed with 160 g of acetone, and dried in a vacuum, affording 30.9 g of the desired product (white solid).