Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH2:2]([O:9][C:10]1[CH:35]=[CH:34][CH:33]=[CH:32][C:11]=1[CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[CH:41]([CH:43]([CH2:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]([O:61][CH3:62])=[O:60])=[CH:55][CH:54]=1)[CH2:44][CH2:45][CH2:46][CH2:47][C:48]([O:50][CH3:51])=[O:49])=O.O=C1CCCCC1C(OC(C)(C)C)=O.ClCC1C=CC(C(OC)=O)=CC=1>C1COCC1.O>[CH2:2]([O:9][C:10]1[CH:35]=[CH:34][CH:33]=[CH:32][C:11]=1[CH:12]=[CH:41][CH:43]([CH2:52][C:53]1[CH:54]=[CH:55][C:56]([C:59]([O:61][CH3:62])=[O:60])=[CH:57][CH:58]=1)[CH2:44][CH2:45][CH2:46][CH2:47][C:48]([O:50][CH3:51])=[O:49])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(COc2ccccc2C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)CCCCC(C=O)Cc1ccc(C(=O)OC)cc1
Agent: CC(C)(C)OC(=O)C1CCCCC1=O
Agent: COC(=O)c1ccc(CCl)cc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCCCC(C=Cc1ccccc1OCc1ccccc1)Cc1ccc(C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
At 0° C. and under argon, 343.4 mg (0.64 mmol) of 2-(benzyloxy)benzyl-triphenylphosphonium bromide from Ex. III are suspended in 20 ml of THF, and 0.48 ml of butyllithium (0.76 mmol, 1.6 M solution in hexane) is added. The deep-orange solution is stirred at 0° C. for 30 min, and a solution of 195 mg (0.64 mmol) of methyl 6-formyl-7-(4-methoxycarbonylphenyl)heptanoate (prepared analogously to Example I from t-butyl 2-oxocyclohexanecarboxylate and methyl 4-chloromethylbenzoate, cf. EP-A-0 341 551) in 15 ml of THF is added dropwise at this temperature. The mixture is stirred at 0° C. for 30 min. At 0° C., water is added, and the mixture is then warmed to room temperature and extracted with ethyl acetate. The organic phase is washed with sodium chloride solution, dried with magnesium sulfate and concentrated using a rotary evaporator. For purification, the substance was chromatographed on 40 g of silica gel 60 (particle size 0.040-0.063 mm) using the mobile phase petroleum ether/ether 4:1 to 1:1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[O:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][NH2:20])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:20][CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: NCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(NCCN2CCOCC2)c(Br)c1
Yield: 74 %

Procedure:
2-Bromo-1-fluoro-4-nitrobenzene (1.0 g, 4.5 mmol), 2-morpholinoethanamine (0.77 g, 5.9 mmol) and potassium carbonate (1.571 g, 11.4 mmol) in DMSO (5 mL) were stirred at room temperature for 1.5 hours. The mixture was triturated with water, and 2-bromo-N-(2-morpholinoethyl)-4-nitroaniline (1.1 g, 72.8% yield) was collected via filtration. HPLC: Rt=0.61 min. (PHENOMENEX® Luna 5 micron C18 4.6×30 mm, 10-90% aqueous methanol containing 0.1% TFA, 2 min. gradient, flow rate=5 mL/min., detection at 254 nm). MS (ES): m/z=332.06 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:18]=[C:19]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:20]2[CH:25]=[N:24][N:23]([CH:26]([CH3:28])[CH3:27])[C:21]=2[N:22]=1.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:26]([N:23]1[C:21]2[N:22]=[C:17]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:18]=[C:19]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:20]=2[CH:25]=[N:24]1)([CH3:28])[CH3:27]
Reactant: CCOC(=O)c1cc(O)nc2c1cnn2C(C)C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(OS(=O)(=O)C(F)(F)F)nc2c1cnn2C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
Trifluoromethanesulfonic anhydride (5.23 g, 18.5 mmol) was added to a cooled solution of ethyl 6-hydroxy-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (4.2 g, 16.9 mmol) and pyridine (1.46 g, 18.5 mmol) in DCM (60 mL); and it was allowed to stirred at room temperature for 2 h. After completion of the reaction, saturated NaHCO3 solution (60 mL) was added to it and extraction was carried out using DCM (30 mL×3). The combined organic layers were washed with water (100 mL); brine (100 mL); dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was finally purified by silica gel column chromatography to provide pure the desired intermediate (5 g, 77.8% yield).
Reaction SMILES: C([O:4][C@@H:5]1[CH2:11][C@@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[C@:9]2([CH3:20])[C@@H:7]([O:8]2)[CH2:6]1)(=O)C.C([O-])([O-])=O.[K+].[K+].C(O)(=O)C>CO>[Si:13]([O:12][C@H:10]1[C@:9]2([CH3:20])[C@@H:7]([O:8]2)[CH2:6][C@H:5]([OH:4])[CH2:11]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(=O)O[C@H]1C[C@@H]2O[C@]2(C)[C@H](O[Si](C)(C)C(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](O)C[C@@H]2O[C@@]21C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
The compound of Example 16C (9.20 g, 30.6 mmol) was dissolved in 105 mL of methanol. K2CO3 (10.1 g, 72.1 mmol, 2.35 equivalents) was added and the reaction mixture was stirred at ambient temperature for 2 hours. 6.60 mL (115 mmol, 3.77 equivalents) of acetic acid were added to the reaction mixture; after mixing for 10 minutes, the solids were filtered off and rinsed with 40 mL of methanol. The combined filtrate and rinses were concentrated to a residue which was mixed with 106 mL of water. The layers were separated, and the aqueous layer was extracted three times with 50 mL of ethyl acetate. The combined organic layers were washed twice with 45 mL of brine, dried over MgSO4, filtered and concentrated to afford the titled compound (7.72 g, 98%).
Reaction SMILES: [O:1]=[C:2]1[N:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][C@H:21]([CH2:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31]([S:35]([CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])(=[O:37])=[O:36])[N:30]=[CH:29]4)[C:22](O)=[O:23])=[O:19])[CH2:14][CH2:13]2)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(N(CC)C(C)C)(C)C.[N:53]1([CH:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[N:53]1([CH:59]2[CH2:64][CH2:63][N:62]([C:22](=[O:23])[C@H:21]([NH:20][C:18]([N:15]3[CH2:16][CH2:17][CH:12]([N:11]4[CH2:10][C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[NH:3][C:2]4=[O:1])[CH2:13][CH2:14]3)=[O:19])[CH2:25][C:26]3[CH:27]=[C:28]4[C:32](=[CH:33][CH:34]=3)[N:31]([S:35]([CH2:38][CH2:39][Si:40]([CH3:43])([CH3:41])[CH3:42])(=[O:36])=[O:37])[N:30]=[CH:29]4)[CH2:61][CH2:60]2)[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1
Reactant: C1CCN(C2CCNCC2)CC1
Reactant: C[Si](C)(C)CCS(=O)(=O)n1ncc2cc(C[C@@H](NC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)C(=O)O)ccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCS(=O)(=O)n1ncc2cc(C[C@@H](NC(=O)N3CCC(N4Cc5ccccc5NC4=O)CC3)C(=O)N3CCC(N4CCCCC4)CC3)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.6 %

Procedure:
To a solution of (R)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-3-[1-(2-trimethylsilanyl-ethanesulfonyl)-1H-indazol-5-yl]-propionic acid (554 mg, 0.88 mmol) and N,N-diisopropylethylamine (0.62 mL, 3.54 mmol) in methylene chloride (20 mL) was added a solution of 4-piperidinopiperidine (164 mg, 0.97 mmol) and PyBOP® (460 mg, 0.88 mmol) in methylene chloride (15 mL). The reaction mixture was stirred for 16 h at room temperature. It was then concentrated to approximately 2 mL and subjected to flash column chromatography using methylene chloride/methanol/triethylamine (94:5:1) as eluent to give 599 mg (87%) of the title compound as a white solid. 1H-NMR (CD3CN, 300 MHz) δ 8.37 (s, 0.5H), 8.36 (s, 0.5H), 8.02-7.96 (m, 1H), 7.74 (s, 0.5H), 7.71 (s, 0.5H), 7.55-7.46 (m, 1H), 7.21-7.12 (m, 2H), 6.97-6.92 (m, 1H), 6.79 (d, J=8.1 Hz, 1H), 5.71 (t, J=8.1 Hz, 1H), 5.00 (dd, J=15.0, 8.1 Hz, 1H), 4.63-4.51 (m, 1H), 4.39-4.29 (m, 1H), 4.29 (s, 2H), 4.10-3.96 (m, 3H), 3.46-3.40 (m, 2H), 2.92-2.70 (m, 8H), 2.58-2.37 (m, 5H), 1.74-1.40 (m, 13H), 0.80-0.74 (m, 2H), −0.04 (s, 9H). Mass spec.: 778 (MH)+.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([O:18][CH3:19])[CH:12]=1>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:13]([O:18][CH3:19])[CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(Br)ccc1O
Solvent: ClCCl
Product: COc1cc(Br)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred mixture of phenylboronic acid (1.20 g, 9.85 mmol) and 4-bromo-2-methoxyphenol (1.00 g, 4.92 mmol) in DCM (50.00 mL) was added cupric acetate (1.34 g, 7.39 mmol), powdered 4 A molecular sieves and TEA (3.43 mL, 24.6 mmol) at rt. The resulting mixture was then stirred at rt for 24 h at ambient atmosphere. The solvent was then removed under reduced pressure and the resulting residue was purified by flash chromatography (5% EtOAc in Hexane). 1H NMR (400 MHz, MeOD) δ ppm 3.81 (s, 3H), 6.84-6.95 (m, 3H), 7.01-7.15 (m, 2H), 7.25-7.36 (m, 3H).
Reaction SMILES: [CH2:1](O)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.C(N(CC)CC)C.S(Cl)([Cl:21])=O>C1C=CC=CC=1>[Cl:21][CH2:1][C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: OCc1ccc2c(c1)OCO2
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: ClCc1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 24 h
Yield: 99.9 %

Procedure:
Piperonyl alcohol (10 g, 65.7 mmol) was dissolved in benzene. Triethylamine (11 ml, 78.8 mmol) and thionyl chloride (11 ml, 131.4 mmol) were added dropwise thereto and was stirred for 24 hours at 0° C. The reaction mixture was extracted with sodium bicarbonate and ethyl acetate, the organic layer was separated, and dried over anhydrous magnesium sulfate to obtain 5-chloromethyl benzo[1,3]dioxol (11.2 g, yield 100%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11]([C:13]2[NH:14][C:15]([CH2:19][CH3:20])=[C:16]([Cl:18])[N:17]=2)=[O:12])[C@H:6]([O:21][CH3:22])[CH2:5]1)(=[S:3])[NH2:2].Br[CH2:24][C:25]([C:27]1([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:29][CH2:28]1)=O>>[Cl:18][C:16]1[N:17]=[C:13]([C:11]([NH:10][C@H:7]2[CH2:8][CH2:9][N:4]([C:1]3[S:3][CH:24]=[C:25]([C:27]4([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:29][CH2:28]4)[N:2]=3)[CH2:5][C@H:6]2[O:21][CH3:22])=[O:12])[NH:14][C:15]=1[CH2:19][CH3:20]
Reactant: CCOC(=O)C1(C(=O)CBr)CC1
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(N)=S)C[C@H]2OC)nc1Cl
Product: CCOC(=O)C1(c2csc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](OC)C3)n2)CC1

Procedure:
The same operation as in Example (22b) was performed using cis(±)-N-(1-carbamothioyl-3-methoxypiperidin-4-yl)-4-chloro-5-ethyl-1H-imidazole-2-carboxamide obtained by the method described in Example (65c) (40 mg, 0.12 mmol) and ethyl 1-(bromoacetyl)cyclopropanecarboxylate obtained according to a method known in the literature (Heterocycles, 63, 3, 2004, 699-706) (60 mg, 0.26 mmol), to obtain 23.5 mg of the title compound as a colorless oily substance (42%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[CH3:24][N:25]([CH2:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[CH3:26].[OH-].[Na+]>CN(C=O)C.CO>[CH3:26][N:25]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([NH:32]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:11]\2=[CH:10][CH:9]=[CH:8][CH:7]=3)/[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[CH:33][CH:34]=1)[CH3:24]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: COc1ccc(C(Cl)=C2C(=O)N(C(C)=O)c3ccccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(/C(Nc2ccc(CN(C)C)cc2)=C2/C(=O)Nc3ccccc32)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(4-methoxyphenyl)-methylidene)-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[N:6][CH:5]=1.[Li+].[OH-]>C1COCC1.O>[Cl:10][C:9]1[C:4]([C:3]([OH:12])=[O:2])=[CH:5][N:6]=[C:7]([Cl:11])[CH:8]=1
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnc(Cl)cc1Cl
Reaction time: 18 h

Procedure:
4,6-Dichloro-nicotinic acid methyl ester (27.3 g, 133 mmol) was dissolved in THF (150 mL). LiOH (3.53 g, 147 mmol), dissolved in H2O (25 mL), was added dropwise and the reaction was allowed to stir for 18 h. The volatiles were removed in vacuo. The resultant residue was diluted with H2O (100 mL) and acidified with 6 N HCl while swirling at 0° C. The solution was brought to a pH of 2.0 and a yellow precipitate formed. The mixture was allowed to stand at 0° C. for 1 h then filtered to afford 4,6-dichloro-nicotinic acid as a yellow solid (20.6, 81%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([OH:14])[CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Cl.Cl[C:23]1[S:24][C:25]2[C:26]([N:31]=1)=[N:27][CH:28]=[CH:29][CH:30]=2>CC#N>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([O:14][C:23]3[S:24][C:25]4[C:26]([N:31]=3)=[N:27][CH:28]=[CH:29][CH:30]=4)[CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: Clc1nc2ncccc2s1
Reactant: COC(=O)c1cc2ccc(O)cc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1cc2ccc(Oc3nc4ncccc4s3)cc2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.4 %

Procedure:
To a solution of 6-hydroxy-benzo[b]thiophene-2-carboxylic acid methyl ester (0.18 g, 0.9 mmol) in MeCN (9 mL) was added Cs2CO3 (0.6 g, 1.8 mmol), 2-chloro-thiazolo[4,5-b]pyridine hydrochloride (0.18 g, 0.9 mmol) and the reaction mixture was stirred (rt, 3 h). The reaction mixture was filtered and concentrated in vacuum to provide the title compound as pink solid (0.18 g, 60%). MS (ESI): mass calcd. for C11H10N2O3S2, 342.0; m/z found, 343.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.58 (dd, J=4.8, 1.6, 1H), 8.12-8.00 (m, 3H), 7.92 (d, J=8.8, 1H), 7.46 (dd, J=8.8, 2.2, 1H), 7.24-7.18 (m, 1H), 3.96 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:15][CH2:16][C:17](Cl)=[O:18].Cl>ClC(Cl)C>[Cl:15][CH2:16][C:17]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2)=[O:18]
Reactant: O=C(Cl)CCl
Reactant: O=C1Cc2ccccc2N1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=C1Cc2cc(C(=O)CCl)ccc2N1
Temperature: 45 °C
Yield: 97.6 %

Procedure:
2-Oxindole (6.7 g) was added to a stirred suspension of 23 g of aluminum chloride in 30 mL of dichloroethane in an ice bath. Chloroacetyl chloride (11.3 g) was slowly added and hydrogen chloride gas was evolved. After ten minutes of stirring, the reaction was warmed to 40-50° C. for 1.5 hours. The mixture was cooled to room temperature and poured into ice water. The precipitate was collected by vacuum filtration, washed with water and dried under vacuum to give 10.3 g (98%) of 5-chloroacetyl-2-oxindole as an off-white solid.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[CH:8]1)[C:2]#[CH:3].[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1I>>[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[C:3]#[C:2][CH2:1][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[CH:8]1
Reactant: Cc1cccc(C)c1I
Reactant: C#CCOCCn1cnc2c(N)nc3ccccc3c21
Product: Cc1cccc(C)c1C#CCOCCn1cnc2c(N)nc3ccccc3c21
Yield: 8 %

Procedure:
Using the general method of Example7, 1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine (0.50 g, 1.88 mmol) was reacted with 2,6-dimethyl iodobenzene (0.61 g, 2.63 mmol). The crude product was purified by column chromatography eluting with 95/5 dichloromethane/methanol to provide 0.056 g of 1-(2-{[3-(2,6-dimethylphenyl)-2-propynyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a solid, m.p. 200-201° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][C:9]([CH3:13])=[CH:8]2.C(=O)([O-])[O-].[Na+].[Na+]>Br>[CH3:13][C:9]1[CH:10]=[N:11][C:12]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[CH:4][C:3]=2[OH:2]
Reactant: COc1cccc2cc(C)cnc12
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cnc2c(O)cccc2c1
Temperature: 122 °C
Yield: 33.7 %

Procedure:
47% HBr (10 ml) was added to 8-methoxy-3-methylquinoline (Intermediate 29) (500 mg, 2.80 mmol) and heated at 122° C. for 18 h. The reaction was cooled to room temperature, the pH adjusted with sodium carbonate solution to pH=7 and extracted with DCM. The organic phase was dried (Na2SO4) and concentrated in vacuo to give the title compound (150 mg, 83%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[CH2:33]([O:35][C:36]1[CH:37]=[C:38]([CH:48]=[C:49]([O:52][CH2:53][CH3:54])[C:50]=1I)[CH2:39][C:40]1[C:41]([NH2:47])=[N:42][C:43]([NH2:46])=[N:44][CH:45]=1)[CH3:34].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[NH2:46][C:43]1[N:42]=[C:41]([NH2:47])[C:40]([CH2:39][C:38]2[CH:37]=[C:36]([O:35][CH2:33][CH3:34])[C:50]([C:2]3[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=3)=[C:49]([O:52][CH2:53][CH3:54])[CH:48]=2)=[CH:45][N:44]=1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1I
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1-c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-Bromo-benzonitrile (186 mg; 1 mmol), bis(pinacolato)diboron (279 mg; 1.1 mmol), potassium acetate (294 mg; 3 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium(II) (PdCl2(dppf)) (46 mg; 0.06 mmol) are stirred in dimethylformamide (6 ml; dried over a molecular sieve) at a bath temperature of 80° C. for 3 hours while gassing with argon. After cooling to room temperature, dimethylformamide (20 ml; dried over a molecular sieve), tetrakis-triphenylphosphine-palladium (90 mg; 0.078 mmol), 5-(3,5-diethoxy-4-iodo-benzyl)-pyrimidine-2,4-diamine (example 1) (331 mg; 0.8 mmol) and a 2 M aqueous potassium phosphate solution (4 ml) are added. The reaction mixture is stirred for approx. 1.5 hours at 80° C., cooled to room temperature and concentrated. The residue obtained is chromatographed over silica gel (100 g) with methylene chloride/methanol/NH4OH (19/1/0.05)0.61 mg (20%) 4′-(2,4-diamino-pyrimidin-5-ylmethyl)-2′,6′-diethoxy-biphenyl-4-carbonitrile are obtained as a beige powder.
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH:7]=[CH:6][C:5]=1[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])=[CH:20][N:19]=1)=[O:17]>C(O)C>[Br:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH:7]=[CH:6][C:5]=1[CH2:15][CH:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][Si:25]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:32]([CH3:33])[CH3:34])=[CH:20][N:19]=1)[OH:17]
Reactant: CC(C)[Si](Oc1ccc(C(=O)Cc2ccc(OCC3CC3)cc2Br)nc1)(C(C)C)C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)[Si](Oc1ccc(C(O)Cc2ccc(OCC3CC3)cc2Br)nc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
Sodium borohydride (0.109 g) was added to a solution of 2-[2-bromo-4-(cyclopropylmethoxy)phenyl]-1-(5-{[tris(1-methylethyl)silyl]oxy}pyridin-2-yl)ethanone (1.50 g) in ethanol (10 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate and water, and the organic layer was separated. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (1.210 g).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:4]=2[N:5]([CH3:21])[C:6](=[O:20])[CH:7]([CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[N:8]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1.[Cl-].[Li+].O.[OH-].[Cs+]>[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.O.O1CCOCC1>[NH2:27][C:28]1[N:29]=[CH:30][C:31]([C:2]2[C:3]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:4]=3[N:5]([CH3:21])[C:6](=[O:20])[CH:7]([CH2:9][C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:11]=3)[N:8]=2)=[CH:32][CH:33]=1
Reactant: CN1C(=O)C(Cc2ccc3ccccc3c2)N=C(Cl)c2cc(Cl)ccc21
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: [Pd]
Agent: [Cl-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CN1C(=O)C(Cc2ccc3ccccc3c2)N=C(c2ccc(N)nc2)c2cc(Cl)ccc21
Temperature: 100 °C
Yield: 30.5 %

Procedure:
5,7-Dichloro-1-methyl-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (0.40 g, 1.04 mmol), 2-aminopyridine-5-boronic acid pinacol ester (0.28 g, 1.25 mmol) and lithium chloride (0.13 g, 3.1 mmol) were added to 1,4-dioxane (4 mL). Nitrogen was bubbled into solution as reagents were added. Tetrakis(triphenylphosphine) palladium(0) (0.12 g, 0.10 mmol) was added followed by cesium hydroxide monohydrate (0.53 g, 3.1 mmol) and water (1 mL). After bubbling through nitrogen for 5 minutes the reaction was heated to 100° C. for 1 h under a nitrogen atmosphere. The mixture was cooled to ambient temperature, diluted with ethyl acetate (25 mL), washed with water (2×20 mL), brine (20 mL), dried with sodium sulfate, decanted then concentrated in the presence of silica. Chromotography eluting with a gradient of 30-100% ethyl acetate in hexanes provided 5-(6-aminopyridin-3-yl)-7-chloro-1-methyl-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (140 mg, 30% yield). 1H NMR (300 MHz, d6-DMSO) δ 3.47 (m, 2H) 3.75 (m, 1H), 6.43 (m, 1H), 6.50 (s, 2H), 7.27 (m, 1H), 7.40-7.67 (m, 6H), 7.75-7.82 (m, 4H), 7.92 (m, 1H); ESI m/z measured 441.1487 [M+H]+. calculated 441.1482.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:15][C:16]1[CH:17]=[C:18]([NH2:23])[CH:19]=[CH:20][C:21]=1[F:22].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.FC(F)(F)C(O)=O>[F:15][C:16]1[CH:17]=[C:18]([NH:23][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc(F)c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(NC2CCNCC2)cc1F

Procedure:
Was synthesised in the same way as (A) from 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (3.59 g, 18.0 mmol), 3,4-difluoro-phenylamine (1.16 g, 9.0 mmol) and sodium triacetoxyborohydride (5.34 g, 25.2 mmol) in dichloromethane (40 ml) and acetic acid (3.1 ml). The deprotection was run in dichloromethane (37 ml) and trifluoro acetic acid (18 ml). Yield 1.26 g, 66%