Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.Cl.[Cl:12][C:13]1[CH:14]=[N:15][C:16](=[O:19])[NH:17][CH:18]=1.C(N(CC)CC)C.[K+].[Br-]>ClCCl.CCOCC.CC(C)=O>[C:7]1([CH3:10])[CH:8]=[CH:9][C:4]([O:3][CH2:2][N:17]2[CH:18]=[C:13]([Cl:12])[CH:14]=[N:15][C:16]2=[O:19])=[CH:5][CH:6]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: Cc1ccc(OCCl)cc1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CCOCC
Product: Cc1ccc(OCn2cc(Cl)cnc2=O)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The title compound was prepared by adding a solution of 4-(chloromethoxy)toluene (see J.Appl. Chem. 3, 266(1953)) (10 mmol) in dichloromethane (10 ml) to a solution of 5-chloropyrimidin-2-one hydrochloride (10 mmol) and triethylamine (20 mmol) in dichloromethane (50 ml). The mixture was stirred at room temperature for 2 days. The product, 1.90 g (76%), consisted of the N- and O-isomers in the ratio 3:1. The N-isomer was isolated by its lower solubility in ether; m.p. 186° C. (acetone). (Found: C57.59; H4.65 Calc. for C12H11ClN2O2 : C57.49; H4.43) 1H NMR (CDCl3): δ 2.25 (Me), 5.74 (CH2), 6.8-7.3 (Ph), 7.80 and 8.50 (H-4 and H-6, respectively, J 3 Hz). IR (KBr): 1680 cm-1 (CO). MS [70 eV, m/z% rel. int.)[: 250 (7,M), 145 (31), 143 (100), 116 (28).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[O:10][C:9]2([CH3:20])[CH3:19])[CH:6]=[N:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[CH2:30]([OH:32])[CH3:31]>>[CH2:30]([O:32][CH2:2][C:3]1[N:7]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[O:10][C:9]2([CH3:20])[CH3:19])[CH:6]=[N:5][CH:4]=1)[CH3:31]
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1CCl
Reactant: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOCc1cncn1C1c2ccccc2C(=O)OC1(C)C

Procedure:
To a solution of 4-(5-chloromethyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one (0.150 g, 0.516 mmol), prepared as described in Example 18, in anhydrous ethanol (5 mL) is added diisopropylethyl amine (0.100 g, 0.77 mmol) and the mixture is stirred at reflux overnight. The mixture is purified by semi-preparative reverse phase HPLC to give 4-(5-ethoxymethyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one as a white solid; MS (ESI) m/z 301.0 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 1.26 (s, 3 H), 1.29 (t, J=6.1 Hz, 3 H), 1.54 (s, 3 H), 3.62 (br. s, 2 H), 4.70 (br. s, 2 H), 5.59 (s, 1 H), 7.02 (s, 1 H), 7.29 (br. s, 1 H), 7.52 (d, J=7.8 Hz, 1 H), 7.63 (td, J=7.8, 1.3 Hz, 1 H), 7.74 (td, J=7.6, 1.3 Hz, 1 H), 8.21 (dd, J=7.8, 1.3 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:7][C:6]=1[O:20][CH3:21].[SH:22][C:23]1[S:24][CH2:25][CH2:26][N:27]=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([O:20][CH3:21])=[CH:7][C:8]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([N:27]2[CH2:26][CH2:25][S:24][C:23]2=[S:22])=[O:19])=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COCOc1c(OC)cc(CCCCC(=O)O)cc1OC
Reactant: SC1=NCCS1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCOc1c(OC)cc(CCCCC(=O)N2CCSC2=S)cc1OC
Reaction time: 16 h
Yield: 97.6 %

Procedure:
To a solution of 0.88 g of 5-(4-methoxymethoxy-3,5-dimethoxyphenyl)pentanoic acid and 0.42 g of 2-mercaptothiazoline in 30 ml of dichloromethane were added 0.73 g of dicyclohexylcarbodiimide and 36 mg of 4-dimethylaminopyridine at room temperature followed by stirring for 16 hours. The reaction mixture was filtered with suction, and the filtrate washed with a 1N aqueous NaOH solution and then with saturated aqueous sodium chloride and dried over sodium sulfate. The solvent was removed by distillation, and the residue subjected to column chromatography on silica gel. From the fraction eluted with dichloromethane was obtained 1.15 g of N-[5-(4-methoxymethoxy-3,5-dimethoxyphenyl)pentanoyl)-thiazolidine-2-thione.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8].C(=O)([O-])[O-].[Na+].[Na+].C([N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])(OCC)=O.Cl>O.O1CCOCC1>[C:27]1(=[O:28])[N:23]([NH:8][C@H:7]([C:9]([OH:11])=[O:10])[CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:24](=[O:33])[C:25]2=[CH:32][CH:31]=[CH:30][CH:29]=[C:26]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: N[C@@H](Cc1cccs1)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)[C@H](Cc1cccs1)NN1C(=O)c2ccccc2C1=O
Temperature: 0 °C

Procedure:
3-(2-Thienyl)-L-alanine(2.24 g., 13.1 mmol.) was suspended in water/p-dioxane (20 ml./10 ml.) at room temperature under argon. Sodium carbonate (1.39 g.) was added and the mixture was stirred until homogeneous. N-Carbethoxyphthalimide (2.87 g.) was added, and the resulting mixture was stirred for 4.5 hours and then cooled to 0° C. The pH was adjusted to 1.5 with 6 N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed successively with 10% potassium bisulfate and brine, dried (sodium sulfate), filtered, and concentrated. The crude product was flash chromatographed (Merck silica gel) eluting with 1:1 ethyl acetate/hexane/1% acetic acid. The fractions containing clean desired product were combined, concentrated, azeotroped with ethyl acetate, and washed with water to remove the acetic acid. The organic layer was dried (sodium sulfate), filtered, and concentrated to give 2.70 g. of the title compound as a white crystalline product; m.p. 166°-168° C.; [α]D =-153.6° (c=0.46, methylene chloride). TLC (1% acetic acid in 1:1 ethyl acetate/hexane) Rf =0.5.
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([C:6](=O)[C:7](=[O:25])[N:8]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.NN>>[Br:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7](=[O:25])[N:8]2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Cc1c(Br)ccc2c1N(Cc1ccc(S(=O)(=O)N(C)C)cc1)C(=O)C2=O
Agent: NN
Product: Cc1c(Br)ccc2c1N(Cc1ccc(S(=O)(=O)N(C)C)cc1)C(=O)C2

Procedure:
Following the same procedure as described in example 10C, 4-(6-bromo-7-methyl-2,3-dioxo-2,3-dihydro-indol-1-ylmethyl)-N,N-dimethyl-benzenesulfonamide (0.392 g, 0.895 mmol) was treated with hydrazine to provide the crude title compound of 12B.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][N:7]1[C:16]2[C:15](=[O:17])[NH:14][C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=3[NH:11][C:10]=2[C:9]([CH3:22])=[CH:8]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:1][CH2:2][C:3]([N:11]1[C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[NH:14][C:15](=[O:17])[C:16]2[N:7]([CH3:6])[CH:8]=[C:9]([CH3:22])[C:10]1=2)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Cc1cn(C)c2c1Nc1ccccc1NC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cn(C)c2c1N(C(=O)CCl)c1ccccc1NC2=O
Yield: 68.9 %

Procedure:
A solution of 1.47 g of chloroacetyl chloride in 20 ml of dioxane is added dropwise with stirring to 1.9 g of 1,3-dimethyl-1,4,9,10-tetrahydropyrrolo[3,2-b][1,5]benzodiazepin-10-one, 5.5 g of powdered anhydrous potassium carbonate and 50 ml of dioxane in the course of 10 minutes at 50° C. The obtained mixture is stirred for several hours; precipitate is then filtered off, and the filtrate is concentrated to dryness. 1.75 g (69%) of the title compound of m.p. 267° to 269° C. (from acetonitrile) are obtained.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][CH:24]=[N:25][CH:26]=3)=[CH:17][CH:16]=2)[CH:7]=1.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:30]=1>C(N(CC)CC)C>[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([S:35]([N:13]([CH2:12][C:8]2[CH:7]=[C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:27])[CH:11]=[CH:10][CH:9]=2)[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[N:25][CH:24]=[N:23][CH:22]=3)=[CH:19][CH:20]=2)(=[O:37])=[O:36])[CH:30]=1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3cncnc3)cc2)c1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(O)CCc1cccc(CN(Cc2ccc(-c3cncnc3)cc2)S(=O)(=O)c2cccnc2)c1

Procedure:
The title compound of Step A was prepared from 3-{3-[(4-pyrimidin-5-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, of Step A of Example 11t, and pyridine-3-sulfonyl chloride hydrochloride, of Preparation 2, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 9.20 (s, 1H), 9.06 (s, 1H), 8.92 (s, 2H), 8.81 (s, 1H), 8.80 (m, 1H), 7.46 (m, 3H), 7.26 (m, 2H), 7.15 (m, 1H), 7.06 (d, 1H), 6.91 (d, 1H), 6.86 (s, 1H), 4.42 (s, 2H), 4.37 (s, 2H), 3.65 (s, 3H), 2.82 (t, 2H), 2.50 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:12]([O-])=O)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]>CCO.CC(O)=O.[Fe]>[NH2:12][C:3]1[C:2]([Cl:1])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(Cl)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1cccc(Cl)c1N
Temperature: 25 °C
Yield: 8.2 %

Procedure:
Iron powder (1.94 g, 34.8 mmol) was added to the solution of methyl 3-chloro-2-nitrobenzoate (2.5 g, 111.6 mmol) in EtOH/HOAc (100 mL/100 mL) at room temperature, and then the suspension was refluxed under N2 for 2 hrs. After cooling down to room temperature, partial of the solvents was removed on rotary vacuum, the resulting residue was partitioned between H2O/EtOAc (200 mL/300 mL). The separated organic phase was washed with aqueous NaOH (1N, 50 mL), brine (50 mL), dried over MgSO4, and concentrated on rotary vacuum to afford the expected product as a tan oil (1.7 g, 79% yield) which became wax type solid standing on bench. The crude product was pure enough to be used in next step without further purification; 1H NMR (400 MHz, CDCl3) δ ppm 3.86 (s, 3 H), 6.25 (s, 2 H), 6.57 (t, J=7.93 Hz, 1 H), 7.39 (dd, J=7.81, 1.51 Hz, 1 H), 7.79 (dd, J=8.06, 1.51 Hz, 1 H); Mass spec. 185.95 (MH+), Calc. for C8H8ClNO2 185.02.
Reaction SMILES: [CH:1]1([S:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[C:9]#[N:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br.O>O1CCCC1>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:8]([S:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[C:9]#[N:10]
Reactant: BrCCCCCBr
Reactant: COc1ccc(C(C#N)SC2CCCCC2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(C#N)(CCCCCBr)SC2CCCCC2)cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 7.57 g of product from Example 82 in 180 ml of anhydrous tetrahydrofuran, under argon, is added 1.3 g of 50% sodium hydride in oil. The mixture is stirred at room temperature for 1 hour; followed by the addition of 10.6 ml of 1,5-dibromopentane and the stirring is continued for 4 hours at room temperature. The reaction mixture is poured into 450 ml of water and extracted with diethyl ether. The organic layer is washed with saturated sodium chloride, dried, filtered and concentrated in vacuo to give 23 g of a crude oil. The oil is purified by chromatography (silica gel: hexane to 10% ethyl acetate/hexane) to give 8.9 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([C:30]2[N:34]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:33]=[N:32][CH:31]=2)=[CH:25][CH:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:24]=[CH:25][C:26]([C:30]3[N:34]([CH2:35][C:36]([OH:38])([CH3:37])[CH3:39])[N:33]=[N:32][CH:31]=3)=[C:27]([CH3:29])[N:28]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Cc1nc(Cl)ccc1-c1cnnn1CC(C)(C)O
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1-c1cnnn1CC(C)(C)O

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (70 mg, 0.22 mmol) and 1-[5-(6-chloro-2-methylpyridin-3-yl)-1H-1,2,3-triazol-1-yl]-2-methylpropan-2-ol (60 mg, 0.22 mmol) as starting materials.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20].[O-]C1C=CC=CC=1.Cl>CC(C)=O.O>[CH2:20]([O:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=CCOc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99.7 %

Procedure:
To 5-fluoro-2-nitrophenol (10 g, 63.6 mmol), which had been dissolved in 100 ml of acetone, was added potassium carbonate (16.6 g, 120 mmol). The pale yellow solution immediately turned bright red in color. Allyl bromide (15.4 g, 11.0 ml, 127 mmol) was added and the stirring was continued at room temperature. A thick red precipitate formed and 2 ml of distilled water was added to help dissolve the phenoxide salt. The round bottomed flask was then fitted with a condenser and the suspension was refluxed under a nitrogen atmosphere for 17 hours. The suspension was cooled to room temperature and 2N HCl was slowly added with stirring until all the solid had dissolved. The organics were extracted with ethyl acetate, washed with water and saturated aqueous sodium bicarbonate solution. The combined extracts were dried over magnesium sulphate, filtered and concentrated on the rotary evaporator and vacuum line to yield 2-(2-propenyloxy)-4-fluoronitrobenzene as an orange/yellow oil (12.5 g, 100%). This product was used in the next step without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:13]C1C=CC(C[C@@H](C(O)=O)N)=CC=1.N[C@H](C(O)=O)CC[Se]C>>[F:13][NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: N[C@@H](Cc1ccc(F)cc1)C(=O)O
Agent: C[Se]CC[C@H](N)C(=O)O
Product: O=C(O)[C@H](Cc1ccccc1)NF
Reaction time: 21 h

Procedure:
Replacement of phenylalanine residues in a protein with p-fluoro-L-phenylalanine (F-Phe) can be implemented for the structural analysis of the protein by19F NMR8, 9. However, as with selenomethionine substitution, F-Phe substitution is cytotoxic. We followed the expression of the CspA in a manner analogous to that demonstrated for selenomethionine EnvZB. CspA was expressed with pColdI(SP4)cspA for 21 hr with and without the addition of F-Phe (FIG. 4A). The addition of F-Phe did not adversely affect CspA production in the SPP system. We then affinity purified the 86-residue CspA product and used mass spectroscopy to determine the extent of F-Phe substitution (FIGS. 4B,C). Although the endogenous Phe biosynthesis was not inhibited in the present SPP system, substantial incorporation of F-Phe (approximately 60 to 70% of total Phe residues) was observed, indicating that toxic F-Phe can be efficiently incorporated into a protein without affecting its yield.
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][CH2:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([N+:18]([O-])=O)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.[Pd]>[Si:5]([O:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:11]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:13]=1)[NH2:18])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(N)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl(dimethyl){[3-nitro-5-(trifluoromethyl)benzyl]oxy}-silane (3.70 g, 11.00 mmol) in EtOAc (100 mL) was added Pd (300 mg, 10% on carbon). The reaction mixture was allowed to stir at rt overnight under an atmosphere of hydrogen. The reaction mixture was filtered through a pad of Celite and washed with EtOAc. The solvents were evaporated to give 3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-5-(trifluoromethyl)aniline (3.32 g, 95. LCMS: (FA) ES+ 306.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[N+](C1C=CC=CC=1)([O-])=O.[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>O.O1CCCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2[CH:17]=[CH:16][C:14]([NH:15][C:33](=[O:36])[CH:34]=[CH2:35])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C=CC(=O)Cl
Reactant: Nc1ccc(S(=O)(=O)c2ccc(O)cc2)cc1
Solvent: O=[N+]([O-])c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: C=CC(=O)Nc1ccc(S(=O)(=O)c2ccc(O)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-(4'-hydroxyphenylsulfonyl)aniline (23.3 g), pyridine (9.4 g) and nitrobenzene (1 ml) is added to 400 ml of tetrahydrofuran. To the ice-cooled solution, 9.0 g of acrylic acid chloride is added dropwise and stirred for 30 min. The stirred mixture is added to 2,000 ml of water and the precipitating crystal is separated by filtration. The resulting crystal is recrystallized with ethanol to obtain the end compound in an amount of 28.5 g. The structure of this compound is verified by IR, NMR and mass spectra.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.O(CCCCCO)C1C=CC=CC=1.[NH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C([O-])([O-])=O.[K+].[K+]>>[O:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[N:3]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1cncc(OCCCCCOc2ccccc2)n1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: OCCCCCOc1ccccc1
Agent: [K+]
Product: c1ccc(OCCCCCOc2cncc(N3CCNCC3)n2)cc1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-[(5-phenoxypentyl)oxy]pyrazine (2.06 g, 7.03 mmol; obtained according to the procedure of example 50, step 1, starting from 5-phenoxy-1-pentanol*), piperazine (1.88 g, 21.8 mmol) and K2CO3 (0.97 g, 7.03 mmol). The yield of the title compound was 1.15 g (48%) which was obtained as a white solid. Purity 100% (HPLC). MS m/z 343 (M+H)+. HRMS m/z calcd for C19H26N4O2 (M)+ 342.2056, found 342.2054. *Described in. J. Org. Chem. 1968, 33, 2271-2284.
Reaction SMILES: COC([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([CH2:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:10][CH:11]=2)[CH2:6]1)=O.[OH-].[Na+]>CO>[C:19]1([S:16]([CH2:15][C:9]2[CH:8]=[C:7]3[C:12]([CH2:13][CH2:14][NH:5][CH2:6]3)=[CH:11][CH:10]=2)(=[O:18])=[O:17])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)N1CCc2ccc(CS(=O)(=O)c3ccccc3)cc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=S(=O)(Cc1ccc2c(c1)CNCC2)c1ccccc1
Yield: 99.3 %

Procedure:
A mixture of 2-methoxycarbonyl-7-phenylsulfonylmethyl-1,2,3,4-tetrahydroisoquinoline (21.5 g, 6.2 mmol), sodium hydroxide (20 g, 0.5 mol) and methanol (250 ml) was heated at reflux for 64 h. The mixture was cooled and evaporation in vacuo, then the residue was partitioned between water (100 ml) and dichloromethane (5×50 ml). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give the title compound as a colourless solid (1.77 g, 99%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10](I)=[N:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][N:20](C=O)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[C-]#N.[C-]#N.[Zn+2].O>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:19]#[N:20])=[N:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Cn1nc(I)c2cccnc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C-]#N
Solvent: O
Product: CC(C)(C)OC(=O)Cn1nc(C#N)c2cccnc21
Temperature: 90 °C
Reaction time: 0.08 h

Procedure:
A 250 mL flask was charged with (3-iodo-pyrazolo[3,4-b]pyridin-1-yl)-acetic acid tert-butyl ester (15.0 g), PdCl2(dppf) (3.0 g), Zn(CN)2 (4.96 g), DMF (200 mL) and H2O (14 mL). The flask containing the resultant suspension was degassed and backfilled with nitrogen gas repeatedly for 5 minutes, followed by addition of Pd2(dba)3 (3.85 g) to the reaction mixture. The reaction mixture was heated under N2 at 90° C. for 16 h, cooled to room temperature, diluted with H2O (800 mL) and filtered. The collected solid was washed with toluene (10 mL) to provide (3-cyano-pyrazolo[3,4-b]pyridin-1-yl)-acetic acid tert-butyl ester as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH:12]=[C:13]2[C:18]3=[N:19][C:20]4[C:21]([CH3:27])=[CH:22][CH:23]=[CH:24][C:25]=4[CH:26]=[C:17]3[C:16](=[O:28])[O:15][C:14]2=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].NC1C=C(OC)C(OC)=CC=1.N1C=CC=CC=1>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH:12]=[C:13]([C:14]([OH:15])=[O:29])[C:18]3[N:19]=[C:20]4[C:21]([CH3:27])=[CH:22][CH:23]=[CH:24][C:25]4=[CH:26][C:17]=3[C:16]2=[O:28])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(NC=C2C(=O)OC(=O)c3cc4cccc(C)c4nc32)cc1OC
Agent: COc1ccc(N)cc1OC
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COc1ccc(-n2cc(C(=O)O)c3nc4c(C)cccc4cc3c2=O)cc1OC
Reaction time: 8 h
Yield: 78.3 %

Procedure:
A mixture of 19 (0.23 g), 4-aminoveratrole (0.46 g), pyridine (15 mL) and triethylamine (1 mL) was heated under reflux for 8 h (dissolution occurred during the heating). The reaction mixture was allowed to stand at −10° C. overnight and the resulting precipitate was collected by filtration and washed with a little cold acetone to give the product as a yellow solid (0.18 g, 78%), mp 297-298° C. (after forming needles->285° C.). 1H NMR (d6-DMSO): δ 2.73 (s, 3H, CH3), 3.78 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 7.12 (s, 2H), 7.23 (s, 1H), 7.67 (t, 1H, J=7.4 Hz, H-8), 7.95 (d, 1H, J=6.7 Hz), 8.23 (d, 1H, J=8.2 Hz), 8.45 (s, 1H), 9.50 (s, 1H, H-10), 15.98 (br s, 1H, COOH).
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17]Cl)[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(=O)(O)[O-:21].[Na+]>O1CCCC1.O>[N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17][OH:21])[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: Cc1cc(CCl)c(O)c(-n2nc3ccccc3n2)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CO)c(O)c(-n2nc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.5 %

Procedure:
To a suspension of 2-(2H-Benzotriazol-2-yl)-6-chloromethyl-4-methyl-phenol (20.0 g, 73 mmol) in a mixture of tetrahydrofuran and water (180 g, 5:1) sodium bicarbonate (9.2 g, 110 mmol) is added. The reaction mixture is stirred at room temperature for 5 hours and evaporated to dryness. The crude product is purified by column chromatography (ethyl acetate/heptane 1:4) to yield 9.6 g of 2-(2H-Benzotriazol-2-yl)-6-hydroxymethyl-4-methyl-phenol.