Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:25](O)[CH2:26][OH:27].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:27]1[C:2]2([CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]([N:14]4[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]4=[O:24])=[CH:12][CH:13]=3)[CH2:4][CH2:3]2)[O:1][CH2:25][CH2:26]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)cc2)C(=O)O1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)OCCO4)cc2)C(=O)O1
Yield: 69 %

Procedure:
The compound was prepared by reacting (S)—N-{3-[4-(4-oxo-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.5 mmol), ethylene glycol (0.5 mmol), p-toluene sulfonic acid (0.3 mmol) in toluene and by purifying on silica gel column chromatography to provide title compound in 69% yield.
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH:14]([CH3:16])[CH3:15])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.[CH3:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:29]=2)[NH:24][N:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[CH:14]([N:12]([CH3:13])[C:11]1[C:2]([C:28]2[CH:29]=[C:30]3[C:25](=[CH:26][CH:27]=2)[NH:24][N:23]=[C:22]3[CH3:21])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2)([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Reactant: Cc1n[nH]c2ccc(B3OC(C)(C)C(C)(C)O3)cc12
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: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]nc(C)c4c3)c(N(C)C(C)C)nc2c1
Temperature: 95 °C
Reaction time: 4 h
Yield: 35.8 %

Procedure:
To a solution of methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (180 mg, 0.61 mmol) in 1,4-dioxane (1 mL) was added 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (440 mg, crude), K3PO4 (360 mg, 1.71 mmol), Pd(PPh3)4 (40 mg, 0.03 mmol) under nitrogen atmosphere. After stirring 4 h at 95° C., the reaction mixture was dissolved in water (50 mL), extracted with dichloromethane (3×30 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford a residue, which was purified by a silica gel column with 0.5% methanol in dichloromethane to afford methyl 3-(isopropyl(methyl)amino)-2-(3-methyl-1H-indazol-5-yl)quinoxaline-6-carboxylate as a light yellow solid (85 mg, 35%).
Reaction SMILES: [CH2:1]([N:3]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[CH:21]1[CH2:30][CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[CH:27]=2)[CH2:22]1)[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].Cl.[CH2:34]([N:36]([CH2:40][CH3:41])[CH2:37][CH2:38]Cl)[CH3:35]>>[CH2:34]([N:36]([CH2:40][CH3:41])[CH2:37][CH2:38][O:11][C:8]1[CH:7]=[CH:6][C:5]([C:4]([N:3]([CH2:1][CH3:2])[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH:21]2[CH2:30][CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:31][CH3:32])[CH:27]=3)[CH2:22]2)=[O:12])=[CH:10][CH:9]=1)[CH3:35]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Reactant: CCN(CC)CCCl
Agent: Cl
Product: CCN(CC)CCOc1ccc(C(=O)N(CC)c2cc(OC)ccc2C2CCc3cc(OC)ccc3C2)cc1
Yield: 72.5 %

Procedure:
Synthesized from N-ethyl-4-hydroxy-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]benzamide (250 mg) and 2-diethylaminoethyl chloride hydrochloride (130 mg) according to an analogous synthetic method to Preparation Example 40, the title compound (223 mg) was obtained.
Reaction SMILES: [C:1]12[C:6](=O)[CH:5]=[C:4]([CH:8]=1)[C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]2=1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]12[CH2:8][C:4](=[CH:5][C:6]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]2=1
Reactant: O=C1C=C2C=C1c1ccccc12
Reactant: C1CCNCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C1=C2CC(=C1N1CCCCC1)c1ccccc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2-Benzobicyclo[2.2.1]hepteneone (0.5 g) was combined with piperidine (1 ml), p-toluenesulfonic acid (0.1 g), and toluene (25 ml) and heated to reflux for 20 hours. The solution was concentrated on a rotary evaporator and the residue was distilled on a Kugelrohr apparatus (120° C. at 0.05 mm Hg). The distillate was combined with glacial acetic acid (10 ml) and sodium cyanoborohydride (0.5 g) and stirred at room temperature for 12 hours. The solution was made basic by the addition of 10% sodium hydroxide in water. The resulting mixture was extracted with ether (3×50 ml) and the combined ether layers were dried over magnesium sulfate and concentrated on a rotary evaporator. The residue was distilled on a Kugelrohr apparatus (120° C. at 0.05 mm Hg) to provide the product as a colorless oil. Analytical data are reported in Table I.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][CH2:14][O:15][C:16]([CH3:18])=[O:17].[Cl:19][C:20]1[C:25]([CH:26]=[O:27])=[CH:24][CH:23]=[CH:22][N:21]=1>C1COCC1>[CH2:14]([O:15][C:16](=[O:17])[CH2:18][CH:26]([C:25]1[C:20]([Cl:19])=[N:21][CH:22]=[CH:23][CH:24]=1)[OH:27])[CH3:13]
Reactant: O=Cc1cccnc1Cl
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 14.5 mL diisopropylamine in 336 mL THF was added 49 mL n-BuLi (2.5 M in hexanes) at 0° C. The mixture was stirred at 0° C. for 15 min, cooled to −78° C. before 10 mL EtOAc were dropwise added. After another 30 min, a solution of 2-chloro-3-pyridine carboxaldehyde (84.8 mmol), dissolved in 84 mL THF, was added. The mixture was stirred at −78° C. for 30 min and then allowed to warm to RT. After stirring for 1.5 h, the reaction was quenched with sat. aq. NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification with CC (KP-SIL™ from Biotage) using Hept/EtOAc (10/1) to EtOAc gives the desired compound as yellow oil.
Reaction SMILES: C([O:3][C:4](=[O:26])[C@@:5]([CH3:25])([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:27][C:28]1[O:32][C:31]([C:33]2[S:34][CH:35]=[CH:36][CH:37]=2)=[N:30][C:29]=1[CH2:38][CH2:39]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH3:25][C@:5]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:39][CH2:38][C:29]2[N:30]=[C:31]([C:33]3[S:34][CH:35]=[CH:36][CH:37]=3)[O:32][C:28]=2[CH3:27])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:26]
Reactant: CCOC(=O)[C@](C)(Cc1ccc(O)cc1)Oc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Product: Cc1oc(-c2cccs2)nc1CCOc1ccc(C[C@](C)(Oc2ccc(C(F)(F)F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from (S)-3-(4-hydroxyphenyl)-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester (95% ee; Chiralpak AD separation, 8×27 cm, 10% IPA/heptane, 275 nm) and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester by the procedure described in Example 1.
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[C:10]([Cl:14])[CH:11]=[C:12]([CH3:13])[C:7]=2[O:6][CH2:5][CH2:4][CH2:3]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>>[Cl:14][C:10]1[CH:11]=[C:12]([CH3:13])[C:7]2[O:6][CH2:5][CH2:4][CH2:3][CH:2]([NH:1][S:16]([CH3:15])(=[O:18])=[O:17])[C:8]=2[CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(Cl)cc2c1OCCCC2N
Product: Cc1cc(Cl)cc2c1OCCCC2NS(C)(=O)=O

Procedure:
0.6 g of 5-amino-7-chloro-9-methyl-2,3,4,5-tetrahydro-1-benzoxepine (Example 10b) were reacted with methanesulfonyl chloride analogously to Example 10c. 0.6 g of 7-chloro-9-methyl-5-methylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine was obtained, m.p. 154-156° C. By subsequent alkylation with butyl iodide analogously to Example 11, 0.6 g of 5-(N-butyl-N-methylsulfonylamino)-7-chloro-9-methyl-2,3,4,5-tetrahydro-1-benzoxepine was obtained, m.p. 106-110° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:13]=1)[CH2:9][C:10]#[CH:11]>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:14]2[CH:13]=[C:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[O:16][N:15]=2)=[CH:22][CH:21]=1
Reactant: Brc1ccccn1
Reactant: C#CCCc1cc(-c2ccc(F)cc2)no1
Product: Fc1ccc(-c2cc(CCC#Cc3ccccn3)on2)cc1
Yield: 25000 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (40 mg, 0.26 mmol) and 5-but-3-ynyl-3-(4-fluoro-phenyl)-isoxazole (55 mg, 0.26 mmol). Reaction time: 2 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 9:1 to 7:3) to yield 19 mg (65 mmol, 25%) of 2-(4-(3-(4-fluorophenyl)isoxazol-5-yl)but-1-ynyl)pyridine as a white solid (M.P.=83-84° C.).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:9][S:8][C:7]=2[CH:17]=1.Cl[C:19]1[N:20]([CH3:32])[C:21](=[O:31])[CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][N:26]=2)[N:24]=1.C(N(CC)CC)C>O1CCCC1>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([CH:11]3[CH2:12][CH2:13][N:14]([C:19]4[N:20]([CH3:32])[C:21](=[O:31])[CH:22]=[C:23]([C:25]5[CH:30]=[CH:29][N:28]=[CH:27][N:26]=5)[N:24]=4)[CH2:15][CH2:16]3)=[CH:9][S:8][C:7]=2[CH:17]=1
Reactant: Fc1ccc2c(C3CCNCC3)csc2c1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCC(c3csc4cc(F)ccc34)CC2)nc(-c2ccncn2)cc1=O
Temperature: 90 °C
Reaction time: 6 h
Yield: 74.6 %

Procedure:
To a solution of 4-(6-fluorobenzo[b]thiophen-3-yl)piperidine hydrochloride (200 mg, 0.74 mmol) and 2-chloro-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (160 mg, 0.70 mmol) in tetrahydrofuran (10 mL) was added triethylamine (212 mg, 2.1 mmol). The mixture was stirred at 90° C. for 6 h. The solvent was evaporated off in vacuo and the residue was treated with water and chloroform. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. Recrystallization from ethyl acetate gave 2-[4-(6-fluorobenzo[b]thiophen-3-yl)piperidin-1-yl]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (220 mg, 96%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)=[O:4].Br[C:15]1[CH:16]=[N:17][N:18]2[CH:23]=[C:22]([C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)[CH:21]=[N:20][C:19]=12.CN(C=O)C.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.O>[CH3:29][N:27]1[CH:28]=[C:24]([C:22]2[CH:21]=[N:20][C:19]3[N:18]([N:17]=[CH:16][C:15]=3[C:8]3[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=3)[CH:23]=2)[CH:25]=[N:26]1
Reactant: Cn1cc(-c2cnc3c(Br)cnn3c2)cn1
Reactant: COC(=O)c1ccc(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: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2cnn3cc(-c4cnn(C)c4)cnc23)cc1
Temperature: 85 °C

Procedure:
[4-(Methoxycarbonyl)phenyl]boronic acid (0.5 g, 2.77 mmol) was added to 3-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine (0.7 g, 2.52 mmol). DMF (12.5 mL) and 1M Na2CO3 (3.8 mL) were added. The mixture was evacuated and flushed with nitrogen under stirring, then Pd(Ph3P)4 (0.15 g, 0.13 mmol) was added in a counter flow of nitrogen. The reaction mixture was heated to 85° C. for 16 h, cooled, and poured into a 5-fold excess of water. The solids were filtered and dried to give crude methyl 4-[6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]benzoate: LC/MS [M+H]=334.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:9][CH2:10][NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[OH-].[K+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[CH2:9][CH2:10][NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NCCC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NCCC(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1

Procedure:
A mixture of 4.25 g. of p-[[3,3-bis(p-chlorophenyl)propyl]amino]benzoic acid, ethyl ester, 2.85 g. of potassium hydroxide, and 50 ml. of 95% ethanol is heated at 75° C. for 26 hours, cooled, diluted with 150 ml. of water, and adjusted to pH 5 with 37% hydrochloric acid. The solid is collected, dried, and crystallized twice from isopropanol, giving 2.88 g. of the desired product as tan crystals, m.p. 213°-215° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([N:6]1[C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[C:8]([I:15])=[CH:7]1)[CH3:5].CI.[CH3:19]C(C)([O-])C.[K+]>C1COCC1>[I:15][C:8]1[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:14]=2[N:6]([C:4]([CH3:19])([CH3:5])[C:3]([O:2][CH3:1])=[O:16])[CH:7]=1
Reactant: COC(=O)C(C)n1cc(I)c2cnccc21
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)(C)n1cc(I)c2cnccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37 %

Procedure:
To a solution of 2-(3-iodo-pyrrolo[3,2-c]pyridine-1-yl)-propionic acid methyl ester (Preparation 57, 13.1 g, 39.7 mmol) in THF (15 mL) was added methyl iodide (2.96 mL, 47.6 mmol) followed immediately by a 1M solution of potassium tertbutoxide in THF (5.34 g, 47.6 mmol) and the reaction was stirred at room temperature for 15 minutes. The reaction was quenched with water, and the remaining THF removed in vacuo. The residue was extracted with EtOAc, dried and concentrated in vacuo to afford the title compound as a yellow solid (5.1 g, 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[N:11][N:10]=1.N#N.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:21])[C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[N+:11]([O-:32])[N:10]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: N#N
Solvent: ClCCl
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)n[n+]([O-])cc2c1
Yield: 30.4 %

Procedure:
A solution of 1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (1 g, 3.13 mmoles), prepared as described in example 5, in dry CH2Cl2 (15 ml), under stirring and N2 at room temperature, was added with m-chloroperbenzoic acid (0.81 g, 4.7 mmoles). After 1 hour the mixture was washed with 10% NaOH and water, anhydrified and brought to dryness. The residue was flash chromatographed (eluent: ethyl acetate 100%, then ethyl acetate/CH3OH 8:2) to give a solid which was crystallised from acetic acid/ethyl acetate to give 0.32 g of the title compound (yield: 31%). m.p.>230° C.
Reaction SMILES: I[C:2]1[C:10]2[O:9][C:8](=[O:11])[N:7]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[CH:5]=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1.[C:23]([C:25]1[CH:26]=[C:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH:28]=[CH:29][CH:30]=1)#[CH:24]>>[N+:20]([C:4]1[CH:3]=[C:2]([C:24]#[C:23][C:25]2[CH:26]=[C:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH:28]=[CH:29][CH:30]=2)[C:10]2[O:9][C:8](=[O:11])[N:7]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[CH:5]=1)([O-:22])=[O:21]
Reactant: C[Si](C)(C)CCOCn1c(=O)oc2c(I)cc([N+](=O)[O-])cc21
Reactant: C#Cc1cccc(NC(=O)OC(C)(C)C)c1
Product: CC(C)(C)OC(=O)Nc1cccc(C#Cc2cc([N+](=O)[O-])cc3c2oc(=O)n3COCC[Si](C)(C)C)c1

Procedure:
The desired compound was prepared according to the procedure of Example B5, step C, using 7-iodo-5-nitro-3-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-benzoxazol-2(3H)-on and tert-butyl (3-ethynylphenyl)carbamate as the starting materials in quantitative yield. LCMS for C26H31N3O7SiNa (M+Na)+: m/z=548.0.
Reaction SMILES: [CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([CH3:32])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([CH3:33])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[F:35]C1(C2C=CC(C#N)=CC=2)CCNCC1.Cl>>[CH:1]1([C:5]2[C:26]([C:27]3[NH:31][C:30]([CH3:32])=[N:29][N:28]=3)=[CH:25][C:8]([C:9]([N:11]3[CH2:12][CH2:13][C:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=4)([F:35])[CH2:15][CH2:16]3)=[O:10])=[C:7]([CH3:33])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Reactant: N#Cc1ccc(C2(F)CCNCC2)cc1
Agent: Cl
Product: Cc1nnc(-c2cc(C(=O)N3CCC(F)(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile (compound 152), using compound 11.2 HCl salt instead of compound 1.5. m/z (ES+) 458 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 13.66 (s, 1H), 7.66 (d, 2H), 7.51 (d, 3H), 7.38 (s, 1H), 4.72 (d, 1H), 4.30 (br s, 1H), 3.46 (br s, 1H), 3.16 (dd, 1H), 3.04-2.78 (m, 2H), 2.38 and 2.36 (2 singlets, amide rotamers, ArCH3, 3H), 2.35-2.27 (m, 3H), 2.22-1.82 (m, 6H), 1.81-1.56 (m, 3H).
Reaction SMILES: C1(S(CC2C(C(OCC)=O)=C(O)C([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=CC=2)(=O)=O)C=CC=CC=1.Br[C:29]1[C:30]([O:50][CH3:51])=[C:31]([C:36]([CH2:39][S:40]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([OH:49])[CH:44]=2)(=[O:42])=[O:41])=[CH:37][CH:38]=1)[C:32]([O:34][CH3:35])=[O:33]>>[O:25]1[CH:26]=[CH:27][C:23]([C:29]2[C:30]([O:50][CH3:51])=[C:31]([C:36]([CH2:39][S:40]([C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([OH:49])[CH:44]=3)(=[O:42])=[O:41])=[CH:37][CH:38]=2)[C:32]([O:34][CH3:35])=[O:33])=[CH:24]1
Reactant: COC(=O)c1c(CS(=O)(=O)c2cccc(O)c2)ccc(Br)c1OC
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Product: COC(=O)c1c(CS(=O)(=O)c2cccc(O)c2)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 3-bromo-6-(3-hydroxybenzenesulphonylmethyl)-2-methoxybenzoate (Intermediate 141)
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[C:9]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)(=[O:11])[CH3:10]>>[C:9]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([O:2][C:1]2[CH:8]=[CH:7][C:5]([O:6][C:17](=[O:18])[C:16]3[CH:20]=[CH:21][C:13]([O:12][C:9](=[O:11])[CH3:10])=[CH:14][CH:15]=3)=[CH:4][CH:3]=2)=[O:18])=[CH:15][CH:14]=1)(=[O:11])[CH3:10]
Reactant: Oc1ccc(O)cc1
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Product: CC(=O)Oc1ccc(C(=O)Oc2ccc(OC(=O)c3ccc(OC(C)=O)cc3)cc2)cc1

Procedure:
Using the procedure described above, this compound was prepared from hydroquinone and 4-acetoxybenzoic acid. The crude product was recrystallized from methyl isobutyl ketone (18 ml/g) giving white platelets with a m.p. of 185.0° C. to 186.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[I:9]N1C(=O)CCC1=O>C(O)(=O)C>[Br:8][C:6]1[CH:7]=[C:2]([NH2:1])[C:3]([I:9])=[N:4][CH:5]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cncc(Br)c1
Solvent: CC(=O)O
Product: Nc1cc(Br)cnc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
3-Amino-5-bromopyridine (13.8 g, 79.8 mmol) was dissolved in acetic acid (440 mL) and placed under a nitrogen atmosphere. N-Iodosuccinimide (16.15 g, 71.8 mmol) was charged to the reaction which was stirred at room temperature overnight. The reaction was concentrated and the residue partitioned between EtOAc (200 mL) and saturated aqueous sodium hydrogen carbonate (200 mL). The layers were separated and the organic phase was washed with saturated aqueous sodium hydrogen carbonate (200 mL). The aqueous phase was extracted with EtOAc (3×200 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated. Chromatography (silica; 1.4 Kg packed in 70% DCM:30% heptane, eluting with 70-100% DCM in heptane) gave the title compound (11.5 g). 1H NMR (270 MHz, CDCl3): 7.83 (1H, m), 7.04 (1H, m), 4.33 (2H, br s).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([N+:18]([O-])=O)=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:3]=1.[NH:27]1[CH:31]=[CH:30][N:29]=[CH:28]1>C(Cl)(Cl)Cl>[NH2:18][C:5]1[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:3][C:2]([N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1c(Cl)nc(-c2ccccc2)c([N+](=O)[O-])c1C(=O)OCC
Reactant: c1c[nH]cn1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(-n2ccnc2)nc(-c2ccccc2)c(N)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.8 %

Procedure:
A mixture of 0.379 g of 2-chloro-3,4-diethoxycarbonyl-5-nitro-6-phenylpyridine, 0.21 g of imidazole and 15 ml of chloroform was heated under reflux for 8 hours. After the reaction mixture was concentrated, the residue was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After the solvent was distilled off, 5 ml of acetic acid and 0.5 g of reduced iron were added to the residue, and the mixture was stirred at room temperature for 4 hours. After an aqueous solution of sodium hydrogencarbonate was added for neutralization, extraction with ethyl acetate was conducted. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over sodium sulfate, followed by filtration with a small amount of silica gel. The filtrate was concentrated under reduced pressure, to give 0.342 g of the title compound as a yellow oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.ClC1C=C(C(OO)=[O:20])C=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N+:7]([O-:20])[CH:6]=[CH:5]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1ccc2cnccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
To a solution of 51.0 g (245.1 mmol) of 6-bromo-isoquinoline (3) in 800 ml of dichloromethane were added under mechanical stirring 90.6 g (367.6 mmol) of 3-chloro-benzenecarboperoxoic acid (70%). After stirring for 4 h at room temperature and standing overnight, saturated sodium hydrogen carbonate-solution was added until two clear layers were obtained. The dichloromethane solution was separated and washed with saturated NaCl-solution. The aqueous layers were extracted with a chloroform/isopropanol (3:1) mixture and the organic layers were combined, washed again with saturated NaCl-solution, dried over magnesium sulfate and evaporated. The obtained crude product (53.0 g) was used without further purification. Rt=0.89 min (Method C). Detected mass: 226.2 (M+H+).