Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[Si:2]([CH3:5])([CH3:4])[CH3:3].[I:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](I)[CH:8]=1>>[I:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Si:2]([CH3:5])([CH3:4])[CH3:3])[CH:8]=1
Reactant: C[Si](C)(C)Cl
Reactant: Ic1cccc(I)c1
Product: C[Si](C)(C)c1cccc(I)c1

Procedure:
1-Iodo-3-trimethylsilanyl-benzene is prepared in a manner analogous to the procedure described in examples 1 and 1a utilizing chlorotrimethylsilane and 1,3-diiodobenzene as the dihalo compound of formula (III).
Reaction SMILES: Cl.[CH:2]([O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([CH3:4])[CH3:3].C(N(CC)CC)C.[F:19][C:20]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33](=[O:40])[NH:32][N:31]=2)=[CH:25][C:21]=1[C:22](O)=[O:23].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[F:19][C:20]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33](=[O:40])[NH:32][N:31]=2)=[CH:25][C:21]=1[C:22]([N:9]1[CH2:10][CH2:11][CH:6]([O:5][CH:2]([CH3:4])[CH3:3])[CH2:7][CH2:8]1)=[O:23]
Reactant: CC(C)OC1CCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)OC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.6 %

Procedure:
A solution of 4-isopropoxypiperidine hydrochloride (120 mg, 0.67 mmol) and triethylamine (0.206 mL, 1.48 mmol), in N,N dimethylformamide (2 mL) was added in one portion to a stirred solution of 2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (1) (200 mg, 0.67 mmol), triethylamine (0.206 mL, 1.48 mmol) and O-Benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium hexafluorophosphate (381 mg, 1.01 mmol) in N,N dimethylformamide (2 mL) at 25° C. The resulting solution was stirred at 25° C. for 4 hours. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound (172 mg, 60.6% yield); 1H NMR (399.902 MHz, DMSO) δ 1.06-1.11 (6H, m), 1.21-1.46 (2H, m), 1.61-1.87 (2H, m), 3.04 (1H, t), 3.62 (2H, td), 3.70 (1H, quintet), 3.92-4.01 (1H, m), 4.07 (1H, q), 4.33 (2H, s), 7.19-7.25 (1H, m), 7.32-7.37 (1H, m), 7.38-7.44 (1H, m), 7.81-7.92 (2H, m), 7.96-8.00 (1H, m), 8.26-8.29 (1H, m), 12.58 (1H, s); m/z (LC-MS, ESI+), RT=1.98 (M+H 424.6).
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH2:14][NH:15]S(C(C)(C)C)=O)=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-:3])=[O:2].[ClH:22].O1CCOCC1>CO>[N+:1]([C:4]1[C:5]([CH2:14][NH2:15])=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)([O-:3])=[O:2].[ClH:22]
Reactant: CC(C)(C)S(=O)NCc1ccc2cccnc2c1[N+](=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NCc1ccc2cccnc2c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 2-methyl-propane-2-sulfinic acid (8-nitro-quinolin-7-ylmethyl)-amide (Intermediate 209) (402 mg, 1.31 mmol) in dry MeOH (10 ml) under a nitrogen atmosphere was cooled to 0° C. HCl in dioxane (4M, 1.7 ml, 6.9 mmol) was added and the mixture was stirred at 0° C. for 1 h and allowed to warm to room temperature overnight. The mixture was concentrated in vacuo and the residue was triturated with dry ether (10 ml). The solid was collected by filtration, washed with dry ether and dried at room temperature to give the title compound as an HCl salt (180 mg, 100%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNCC1
Reactant: N#Cc1ccc(F)cc1
Product: N#Cc1ccc(N2CCCCC2)cc1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 4-fluorobenzonitrile and piperidine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:19])=[CH:4][C:5]([N+:16]([O-])=O)=[C:6]([CH2:8][CH:9]2[NH:13][C:12](=[O:14])[NH:11][C:10]2=O)[CH:7]=1.[H][H]>CN(C)C=O.[Pt]>[Cl:1][C:2]1[C:3]([CH3:19])=[CH:4][C:5]2[N:16]=[C:10]3[NH:11][C:12](=[O:14])[NH:13][C:9]3=[CH:8][C:6]=2[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])c(CC2NC(=O)NC2=O)cc1Cl
Reactant: [H][H]
Agent: [Pt]
Solvent: CN(C)C=O
Product: Cc1cc2nc3[nH]c(=O)[nH]c3cc2cc1Cl
Yield: 85.6 %

Procedure:
5-[(5-Chloro-4-methyl-2-nitrophenyl)methyl]-2,4-imidazolidinedione (2 g, 7 mmol) in dimethylformamide (30 mL) was hydrogenated over 5% platinum on carbon (0.4 g) at 55 psi until hydrogen uptake ceased. The mixture was heated on a steam bath for two hours, concentrated in vacuo and the residue treated with hot (90° C.) dimethyl sulfoxide. Filtration through infusorial earth and evaporation of the solvent afforded a solid which was washed with ether and suspended in boiling methanol. Filtration gave 1,3-dihydro-7-chloro-6-methyl-2Himidazo[4,5-b]quinolin-2-one (1.40 g, 84%) m.p.>360° C.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].I[C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12]>C(N(CC)CC)C.C(OCC)(=O)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][Si:2]([C:5]#[C:6][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12])([CH3:4])[CH3:3]
Reactant: N#Cc1cccc(I)c1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)C#Cc1cccc(C#N)c1
Reaction time: 0.07 h
Yield: 82.8 %

Procedure:
Add trimethylsilylacetylene (3.4 mL, 24.0 mmol) to a mixture of bis(triphenylphosphine)palladium (II) dichloride (766 mg, 1.1 mmol), copper (I) iodide (418 mg, 2.2 mmol) and 3-iodobenzonitrile (5 g, 21.8 mmol) in triethylamine (20 mL). Upon addition of the trimethylsilylacetylene an exothermic reaction occurs and after about 4 min the reaction mixture solidifies. Cool the reaction mixture for about 15 min, dilute with ethyl acetate (100 mL), filter through fluted filter paper using ethyl acetate and concentrate. Dissolve the residue in ethyl acetate (200 mL) and wash sequentially with an aqueous solution of 0.1 N hydrochloric acid and a saturated aqueous solution of sodium chloride. Dry (sodium sulfate), filter and concentrate. Purify the residue by silica gel chromatography, eluting with 0:100 to 5:95 ethyl acetate:hexanes, to give the title compound as a tan solid (3.6 g, 83%).
Reaction SMILES: CN(C)C=O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:14][CH3:15])=[C:11]([OH:13])[CH:12]=1.Br[CH2:17][CH2:18][Cl:19].C(=O)([O-])[O-].[K+].[K+]>O>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([O:14][CH3:15])=[C:11]([O:13][CH2:17][CH2:18][Cl:19])[CH:12]=1
Reactant: COc1ccc(Br)cc1O
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Br)cc1OCCCl
Temperature: 70 °C
Reaction time: 5 h
Yield: 103.4 %

Procedure:
To 1.2 L of N,N-dimethylformamide solution containing 159 g (0.79 mol) of 5-bromo-2-methoxyphenol (see WO 01019785) were added 340 g (2.37 mol) of 1-bromo-2-chloroethane and 120 g (0.868 mol) of potassium carbonate, and the mixture was stirred at 70° C. for 5 hours. Then, 220 g (1.53 mol) of 1-bromo-2-chloroethane and 80 g (0.58 mol) of potassium carbonate were additionally added thereto twice by dividing them to two portions during the reaction, and the mixture was further stirred for 7 hours. After completion of the reaction, the reaction mixture was poured into water, and extracted with toluene. The organic layer after separation was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 217 g of the title compound as a dark brownish solid substantially quantitatively.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=1.[CH2:21]=[O:22].[Na+].[Cl-]>C1COCC1>[CH3:12][O:13][C:14]1[N:15]=[C:16]([CH2:20][CH2:21][OH:22])[CH:17]=[CH:18][CH:19]=1
Reactant: COc1cccc(C)n1
Reactant: C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(CCO)n1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 37 %

Procedure:
1.6M n-Butyllithium/hexane solution (282 mL, 451.96 mmol) was added dropwise to a solution of 2-methoxy-6-methylpyridine (50.60 g, 410.87 mmol) in THF (625 mL) over 1 hr at −78° C. under argon atmosphere. The reaction mixture was stirred at −78° C. for 45 min, paraformaldehyde (49.3 g, 1643.49 mmol) was added thereto at −78° C., and the mixture was stirred vigorously at room temperature for 3.5 hr. The reaction mixture was poured into ice water (1000 mL), and NaCl was added thereto to give a saturated solution. The saturated solution was extracted with a mixed solvent of ethyl acetate/THF (3:1) (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 8→50% ethyl acetate/hexane) to give 2-(6-methoxypyridin-2-yl)ethanol (23.22 g, 152 mmol, 37%) as a colorless oil.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)[CH2:6][CH2:5]2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[NH:8][CH:7]([CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:6][CH2:5]4)=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: Ic1ccc2c(c1)CCC(CN1CCCC1)N2
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Clc1ccc(-c2ccc(C#Cc3ccc4c(c3)CCC(CN3CCCC3)N4)nc2)cc1

Procedure:
Prepared according to general working method I from 6-iodo-2-pyrrolidin-1-ylmethyl-1,2,3,4-tetrahydro-quinoline (260 mg, 0.76 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (162 mg, 0.76 mmol).
Reaction SMILES: [BH4-].[Na+].[CH3:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]1=O.Cl>C1COCC1.CO>[CH3:3][C:4]1[CH2:12][C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][C:10]=2[C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: CC1Cc2c(cccc2-c2cnc3ccccc3c2)C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC1=Cc2cccc(-c3cnc4ccccc4c3)c2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
11.3 g (0.3 mol) of NaBH4 were added in portions at 0° C. to a solution of 64 g (0.23 mol) of 2-methyl-4-(3-quinolyl)-1-indanone in 600 cm3 of THF/methanol 2:1 and the mixture was stirred for 18 hours at room temperature. The reaction mixture was poured onto 1000 g of ice, admixed with concentrated aqueous HCl to a pH of 1 and extracted a number of times with Et2O. The combined organic phases were washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution. The solvent was removed under reduced pressure and the crude product was taken up in 1000 cm3 of toluene, admixed with 2 g of p-toluenesulfonic acid and heated under reflux for 2 hours using a water separator. The reaction mixture was washed 3 times with 150 cm3 of saturated aqueous NaHCO3 solution and the solvent was removed under reduced pressure. Chromatography on silica gel (hexane/ethyl acetate 20:1) gave 45 g (76%) of 2-methyl-7-(3-quinolyl)indene as a colorless oil.
Reaction SMILES: [C:1]([N:4]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][C@@H:5]1[C:10]1[C:15](F)=[CH:14][C:13]([NH:17][C:18]([C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)=O)=[C:12]([N+:26]([O-])=O)[CH:11]=1)(=[O:3])[CH3:2].[CH3:29][O:30][CH2:31][C:32]1[N:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1>>[C:1]([N:4]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][C@@H:5]1[C:10]1[C:15]([O:38][C:35]2[CH:36]=[N:37][C:32]([CH2:31][O:30][CH3:29])=[CH:33][CH:34]=2)=[CH:14][C:13]2[N:17]=[C:18]([C:20]3[CH:25]=[N:24][CH:23]=[CH:22][N:21]=3)[NH:26][C:12]=2[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1[C@@H](c2cc([N+](=O)[O-])c(NC(=O)c3cnccn3)cc2F)CC[C@@H]1C
Reactant: COCc1ccc(O)cn1
Product: COCc1ccc(Oc2cc3nc(-c4cnccn4)[nH]c3cc2[C@H]2CC[C@H](C)N2C(C)=O)cn1

Procedure:
The entitled compound was obtained as a pale yellow oily substance in the same method as in Example 595 (step 9) or in accordance with the method or by combining it with an ordinary method but using N-(4-((2R,5S)-1-acetyl-5-methylpyrrolidin-2-yl)-5-fluoro-2-nitrophenyl)pyrazine-2-carboxamide obtained in Example 595 (step 8) and 6-(methoxymethyl)pyridin-3-ol.
Reaction SMILES: [NH2:1][C:2]1[C:11](I)=[C:10]([C:13]2[N:17]([CH3:18])[N:16]=[N:15][C:14]=2[CH3:19])[C:9]([Cl:20])=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:21]>[Pd].C(O)(=O)C.CO>[NH2:1][C:2]1[CH:11]=[C:10]([C:13]2[N:17]([CH3:18])[N:16]=[N:15][C:14]=2[CH3:19])[C:9]([Cl:20])=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:21]
Reactant: Cc1nnn(C)c1-c1c(Cl)c2c(c(N)c1I)CCNC2=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nnn(C)c1-c1cc(N)c2c(c1Cl)C(=O)NCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 178.8 %

Procedure:
Two batches were prepared by the following method: a mixture of 5-amino-8-chloro-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-6-iodo-3,4-dihydroisoquinolin-1(2H)-one (293f, 2.9 g, 6.9 mmol each batch) and palladium on carbon (2.9 g) in glacial acetic acid (29 mL) and methanol (290 mL) was stirred under a hydrogen balloon at room temperature overnight. The combined reaction mixtures were filtered through celite, and the filter pad washed with methanol (300 mL). The filtrate was concentrated and the residue purified by silica gel chromatography (eluting with 10:1 dichloromethane/methanol) affording 5-amino-8-chloro-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (293g, 3.6 g, 65% combined yield) as yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 8.12 (s, 1H), 6.82 (s, 1H), 3.75 (s, 3H), 3.29-3.28 (m, 2H), 2.70-2.67 (m, 2H), 2.07 (s, 3H). MS: 292 [M+1].
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Br:34][C:35]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:36]=1[CH:37]=[N:38][NH:39][C:40]2=[O:45].[N:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:49]=[CH:48][C:47]=1[CH2:56][CH2:57]O>C1COCC1.O>[Br:34][C:35]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:36]=1[CH:37]=[N:38][N:39]([CH2:57][CH2:56][C:47]1[CH:48]=[CH:49][C:50]3[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:46]=1)[C:40]2=[O:45]
Reactant: OCCc1ccc2ccccc2n1
Reactant: O=c1[nH]ncc2c(Br)cccc12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: O=c1c2cccc(Br)c2cnn1CCc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To a mixture of PPh3 (699 mg, 2.67 mmol) in THF (50 mL) and DIAD (198 mg, 0.98 mmol), 5-bromo-2H-phthalazin-1-one (300 mg, 1.33 mmol) and then 2-quinolin-2-yl-ethanol from example a1 (254 mg, 1.46 mmol) were added dropwise at 15° C. under nitrogen. The mixture was stirred at room temperature overnight. Water was added and the mixture was extracted with EtOAc. The organic phase was washed with HCl (1 N). The aqueous phase was basified and extracted with DCM. The organic phase was washed with a NaHCO3-solution, dried over Na2SO4, filtered and concentrated. The crude product was recrystallized from EA and dried to give the title compound as bright beige solid (300 mg, 59.2% yield).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9].[CH3:18]I>>[CH3:17][O:16][C:12]1[CH:11]=[C:7]([CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][O:1][CH3:18])[C:13]=1[O:14][CH3:15])[C:8]([OH:10])=[O:9]
Reactant: COc1cc(C(=O)O)cc(CCCO)c1OC
Reactant: CI
Product: COCCCc1cc(C(=O)O)cc(OC)c1OC
Yield: 69 %

Procedure:
3,4-Dimethoxy-5-(3-methoxypropyl)benzoic acid was prepared from 3-(3-hydroxypropyl)-4,5-Dimethoxybenzoic acid (Example 10, Step 1) and methyl iodide by following Method I in 69% yield. The product was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH2:19][CH2:20][NH:21][CH2:22]3)=[CH:5][CH:4]=[N:3]1.O=C1N([S:33]([NH:36][C:37]2[N:42]=[CH:41][CH:40]=[CH:39][N:38]=2)(=[O:35])=[O:34])CCO1.C(N(CC)CC)C>C(#N)C>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:10]=[CH:9][C:8]=2[C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH2:19][CH2:20][N:21]([S:33]([NH:36][C:37]2[N:42]=[CH:41][CH:40]=[CH:39][N:38]=2)(=[O:35])=[O:34])[CH2:22]3)=[CH:5][CH:4]=[N:3]1
Reactant: O=C1OCCN1S(=O)(=O)Nc1ncccn1
Reactant: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1cccc2c1CCNC2
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1cccc2c1CCN(S(=O)(=O)Nc1ncccn1)C2
Temperature: 130 °C
Yield: 41.7 %

Procedure:
A microwave vial was charged with 5-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (Intermediate O, 55.90 mg, 0.156 mmol), 2-oxo-N-(pyrimidin-2-yl)oxazolidine-3-sulfonamide (Intermediate Q, 96 mg, 0.391 mmol), and acetonitrile (587 μl) to give a suspension. Triethylamine (218 μl, 1.564 mmol) was added resulting in the formation of a yellow solution. The vial was sealed and heated in a microwave reactor for 30 min at 130° C. The mixture was concentrated, then chromatographed on a 12 g silica gel column with 0 to 10% MeOH/DCM to provide 5-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (33.42 mg, 0.065 mmol) as a light-yellow solid. [M+H]+=515.2. 1H NMR (400 MHz, DMSO-d6) δ ppm=11.19 (br. s., 1H), 8.48 (d, J=4.9 Hz, 2H), 7.88 (dd, J=1.4, 8.1 Hz, 1H), 7.83 (br. s, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.22 (d, J=2.0 Hz, 1H), 7.20-7.10 (m, 2H), 7.03 (t, J=4.8 Hz, 1H), 6.89 (dd, J=1.3, 7.4 Hz, 1H), 5.88 (d, J=1.9 Hz, 1H), 4.62-4.49 (m, 2H), 3.59-3.52 (m, 1H), 3.48 (s, 3H), 3.23 (ddd, J=4.3, 8.0, 12.4 Hz, 1H), 2.59 (ddd, J=4.9, 8.3, 16.1 Hz, 1H), 2.28-2.19 (m, 1H).
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][CH:6]=1.[C:20]([C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[O:24][CH2:25][CH:26]1[O:28][CH2:27]1)#[N:21]>C(O)(C)C>[C:20]([C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[O:24][CH2:25][CH:26]([OH:28])[CH2:27][NH:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:9][CH:10]=1)#[N:21]
Reactant: CC(C)(N)CNc1ccc(C2=NNC(=O)CC2)cc1
Reactant: N#Cc1ccccc1OCC1CO1
Solvent: CC(C)O
Product: CC(C)(CNc1ccc(C2=NNC(=O)CC2)cc1)NCC(O)COc1ccccc1C#N
Reaction time: 24 h

Procedure:
2.6 g of 6-[4-(2-amino-2-methylpropylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone and 1.5 g of -(2-cyanophenoxy)-2,3-epoxypropane obtained in Example 1, (3) were dissolved in 20 ml of isopropanol, and heated with stirring for 24 hours. The solution was then worked up in the same way as in Example 1, (5). Recrystallization from dichloromethane-ether gave 2.93 g of 6-[4-[2-[3-(2-cyanophenoxy)-2-hydroxypropylamino]-2-methylpropylamino]phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2C(C)C)=[C:4](NCC2C=CC(OC)=CC=2)[N:3]=1.[H-].[Na+].I[CH:27]([CH3:29])[CH3:28].O>CN(C=O)C>[CH:27]([C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[CH:4][N:3]=1)([CH3:29])[CH3:28]
Reactant: CC(C)I
Reactant: COc1ccc(CNc2nc(Cl)nc3c2ncn3C(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ncc2[nH]cnc2n1
Reaction time: 0.5 h
Yield: 89 %

Procedure:
Preparation of 2-chloro-6-(4-methoxybenzylamino)-9-isopropylpurine (2) 2-chloro-6-(4-methoxybenzylamino)purine was suspended in dry DMF (5 ml) and treated with sodium hydride, 60% dispersion (82 mg, 2.06 mmol). The suspension was stirred for 30 min over which time it became a clear yellow/green solution. 2-Iodopropane (0.280 mL, 1.7 eq.) was added over 5 min and the resultant solution stirred for 2 days. Water was added and the solution and extracted with ethyl acetate. The organic layer was evaporated to give the product isopropyl purine (Yield=508 mg, 89%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=3)[N:14]=[C:13]([CH3:22])[C:12]=2[CH3:23])=[C:4]([O:24][CH3:25])[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)O1>>[Cl:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([CH3:22])[C:12]([CH3:23])=[C:11]2[N:8]1[C:9]2[C:5](=[C:4]([O:24][CH3:25])[CH:3]=[C:2]([C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)[CH:10]=2)[CH:6]=[CH:7]1
Reactant: COc1cc(Br)cc2c1ccn2-c1c(C)c(C)nc2ccc(Cl)cc12
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Product: COc1cc(-c2ccncc2)cc2c1ccn2-c1c(C)c(C)nc2ccc(Cl)cc12

Procedure:
Prepared according to procedure W using 4-(6-bromo-4-methoxy-1H-indol-1-yl)-6-chloro-2,3-dimethylquinoline (0.4 g, 0.962 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.3946 g, 1.92 mmol) to give 6-chloro-4-(4-methoxy-6-(4-pyridinyl)-1H-indol-1-yl)-2,3-dimethylquinoline as a white solid: 1H NMR (500 MHz, DMSO-d6) δ ppm 8.50 (2H, dd, J=4.6, 1.5 Hz), 8.09 (1H, d, J=8.8 Hz), 7.74 (1H, dd, J=8.9, 2.3 Hz), 7.64 (2H, dd, J=4.5, 1.6 Hz), 7.57 (1H, d, J=3.2 Hz), 7.07 (1H, s), 6.86-6.93 (3H, m), 4.07 (3H, s), 2.77 (3H, s), 2.05 (3H, s); Mass Spectrum (ESI) m/e=414.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](O)[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[N:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][OH:23]>C(O)CC>[OH:23][CH2:22][CH2:21][CH2:20][NH:19][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[N:3]=[CH:2][CH:7]=1
Reactant: CCCOc1ccccc1-c1nc(O)cc(Cl)n1
Reactant: NCCCO
Solvent: CCCO
Product: CCCOc1ccccc1-c1nccc(NCCCO)n1

Procedure:
A stirred solution of 4-chloro-6-hydroxy-2-(2-propoxyphenyl)pyrimidine (0.66 g) and 3-amino-1-propanol (0.56 g) in n-propanol was heated under reflux for 16 hours. The cooled reaction mixture was evaporated under reduced pressure to yield an oil which was partitioned between chloroform (20 ml) and water (20 ml). The chloroform layer was separated from the aqueous layer which was extracted with chloroform (2×10 ml) and the combined chloroform layers were washed with water, dried (magnesium sulphate) and evaporated under reduced pressure. The residue was recrystallised from isopropanol:diethyl ether to yield the title compound, 0.54 g, m.p. 147.5°-148.5° C.