Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:9]#[N:10])=[CH:4][CH:3]=1.Cl[CH2:21][CH2:22][N:23]([CH3:25])[CH3:24].C(N(C(C)C)CCC(C1C=CC=CC=1)C#N)(C)C.ClCCN(C(C)C)C(C)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH2:11][CH2:12][N:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:15])[CH3:16])([CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[C:9]#[N:10])=[CH:6][CH:7]=1
Reactant: CN(C)CCCl
Reactant: CC(C)N(CCC(C#N)c1ccc(F)cc1)C(C)C
Agent: CC(C)N(CCC(C#N)c1ccccc1)C(C)C
Agent: CC(C)N(CCCl)C(C)C
Product: CC(C)N(CCC(C#N)(CCN(C)C)c1ccc(F)cc1)C(C)C

Procedure:
Substitution of equivalent quantities of α-(p-fluorophenyl)-α-[2-(diisopropylamino)ethyl]acetonitrile and 2-chloro-N,N-dimethylethylamine for α-[2-(diisopropylamino)ethyl]-α-phenylacetonitrile and 2-chloro-N,N-diisopropylethylamine called for respectively in the procedure of Example 2, Method B, there is obtained α-(p-fluorophenyl)-α-[2-(diisopropylamino)ethyl]-α-[2-(dimethylamino)ethyl]acetonitrile, as an oil.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:16][CH2:17][CH3:18])=[C:12]([CH:15]=1)[CH:13]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCOCC>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:16][CH2:17][CH3:18])=[C:12]([CH:15]=1)[CH:13]=[CH2:1]
Reactant: CCOc1ccc(Br)cc1C=O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=Cc1cc(Br)ccc1OCC
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
Methyltriphenylphosphonium bromide (1.09 g, 3.05 mmol) was added to a solution of potassium t-butoxide (0.5 g, 2.29 mmol) in THF (8 mL). The resulting reaction mixture turned bright yellow and was stirred for 40 min after which, it was cooled to −78° C. 5-bromo-2-ethoxybenzaldehyde was dissolved in THF (2 mL) and added to the reaction which was stirred for 2 h. The reaction was warmed to rt, diluted with ether and filtered through celite. The filtrate was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography eluting with 15% EtOAc/hexanes yielded 320 mg of the desired product: 1H NMR (500 MHZ, CDCl3) δ 7.58 (d, J=2.5 Hz, 1H), 7.31 (dd, J=6.4, 2.4 Hz, 1H), 6.96-7.04 (m, 1H), 6.74 (d, J=8.7 Hz, 1H), 5.77 (d, 1H), 5.32 (d, 1H), 4.03-4.07 (m, 2H), 1.45 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH2:16][NH2:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[S:27]([NH:17][CH2:16][C:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])([OH:18])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)(=[O:29])=[O:28]
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Product: O=S(=O)(NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl)c1cc(Cl)ccc1Cl

Procedure:
Following the procedure described in the preceeding examples but using 2-(2,4-dichlorophenyl)-3-amino-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and 2,5-dichlorobenzenesulfonylchloride, the title compound was obtained in a similar yield:
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C1C(C(OO)=O)=CC=CC=1.BrN1C(=O)CCC1=O.Cl.[CH2:34]([O:36][C:37](=[O:40])[CH2:38][NH2:39])[CH3:35].C(=O)([O-])O.[Na+]>C(O)C.C(OCC)(=O)C.C1C=CC=CC=1>[N+:12]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]=1[CH2:1][CH:38]([NH2:39])[C:37]([O:36][CH2:34][CH3:35])=[O:40])([O-:14])=[O:13]
Reactant: CCOC(=O)CN
Reactant: Cc1c([N+](=O)[O-])cccc1C(F)(F)F
Agent: Cl
Agent: O=C(OO)c1ccccc1
Agent: O=C([O-])O
Solvent: c1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(N)Cc1c([N+](=O)[O-])cccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 48 h

Procedure:
5.0 g (24.3 mmol) of 2-methyl-1-nitro-3-(trifluoromethyl)benzene was added to a mixture of 100 ml of benzene, 50 ml of perbenzoic acid and 5.6 g (32 mmol) of N-bromosuccinimide, and they were stirred at 80° C. for 2 days. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was dissolved in 50 ml of ethanol. 6.8 g (48.6 mmol) of glycine ethyl ester hydrochloride and 6.1 g (72.9 mmol) of sodium hydrogencarbonate were added to the obtained solution, and they were stirred at 70° C. for 6 hours. The solvent was evaporated. After the extraction with ethyl acetate, the extract was washed with 1 N hydrochloric acid. The obtained aqueous layer was made basic with 1 N sodium hydroxide. After the extraction with ethyl acetate, the obtained organic layer was washed with saturated aqueous sodium chloride solution and then dried. The solvent was evaporated to obtain the title compound.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].Cl[P:7](=[O:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O.O1CCOCC1>[NH2:2][O:3][P:7](=[O:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NO
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: NOP(=O)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h
Yield: 36 %

Procedure:
To hydroxylamine hydrochloride (15.86 g, 228.2 mmol) in water (35 mL) cooled in an ice-salt bath was added 7.1 N aqueous sodium hydroxide (27.4 mL, 194.4 mmol) followed by 1,4-dioxane (100 mL). The solution was vigorously stirred for 15 min and then chlorodiphenylphosphine oxide (20.00 g, 84.52 mmol) was added as a solution in 1,4-dioxane (100 mL). The solution was stirred an additional 15 min as a white precipitate formed. The precipitate was collected and then suspended in cold (0°) 0.25 N aqueous sodium hydroxide (250 mL). The mixture was stirred for 1 h and then the solid was collected, washed with water (100 mL), and thoroughly dried under vacuum to afford the desired intermediate (7.09 g, 36%) as a white solid. 1H-NMR (300 MHz, DMSO-d6) 7.65-7.74 (m, 4H), 7.38-7.42 (m, 6H); 31P-NMR (DMSO-d6) 23.11 (br s, 1P).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][OH:22])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.C(OC(=O)CCC1C=NC(Br)=CC=1)C.FC1C=CC(B(O)O)=CC=1.C(N(CC)CC)C>C(Cl)Cl>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][O:22][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCc1ccc(-c2ccc(F)cc2)nc1
Agent: CCOC(=O)CCc1ccc(Br)nc1
Agent: OB(O)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCc1ccc(-c2ccc(F)cc2)nc1
Reaction time: 5 h

Procedure:
544.8 mg (4.75 mmol) of methanesulfonyl chloride were added dropwise with cooling to 1000 mg (4.32 mmol) of 3-(6-(4-fluorophenyl)pyridin-3-yl)propan-1-ol (prepared analogously to example 1a), starting from 3-(6-bromopyridin-3-yl)propionic acid ethyl ester and 4-fluorophenylboronic acid) and 656.3 mg (6.48 mmol) of triethylamine in 50 ml of methylene chloride. After 5 h at room temperature, the mixture was extracted with water, and the organic phase was separated and concentrated. Yield: 1.3 g (97%).
Reaction SMILES: I[C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.[Si:8]([O:15][C@@H:16]1[CH2:20][NH:19][C:18](=[O:21])[CH2:17]1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].CNCCNC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COC1CCCC1.C(OCC)(=O)C.[Cu]I>[Si:8]([O:15][C@@H:16]1[CH2:20][N:19]([C:2]2[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=2)[C:18](=[O:21])[CH2:17]1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: Cn1ccc(I)n1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CNC(=O)C1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: COC1CCCC1
Solvent: CCOC(C)=O
Product: Cn1ccc(N2C[C@@H](O[Si](C)(C)C(C)(C)C)CC2=O)n1
Yield: 87 %

Procedure:
A solution of 3-iodo-1-methyl-1H-pyrazole (1.7 g), (4S)-4-((tert-butyl(dimethyl)silyl)oxy)pyrrolidin-2-one (1.8 g), copper(I) iodide (315 mg), N1,N2-dimethylethane-1,2-diamine (0.36 mL) and tripotassium phosphate (3.5 g) in cyclopentyl methyl ether (34 mL) was stirred overnight at 120° C. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, water and 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 (ethyl acetate/hexane) to give the title compound (2.1 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:26]=[CH:25][C:12]([O:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([C:22]([O-:24])=[O:23])[CH2:18][CH2:17]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Na+].[F:28][CH:29]([F:46])[O:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[F:28][CH:29]([F:46])[O:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:3]=[N:4][C:5]([NH:8][C:9]3[CH:26]=[CH:25][C:12]([O:13][CH2:14][CH2:15][N:16]4[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]4)=[CH:11][CH:10]=3)=[N:6][CH:7]=2)=[CH:33][CH:32]=1
Reactant: CC1(C)OB(c2ccc(OC(F)F)cc2)OC1(C)C
Reactant: O=C([O-])C1CCN(CCOc2ccc(Nc3ncc(Br)cn3)cc2)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: C1COCCO1
Product: O=C(O)C1CCN(CCOc2ccc(Nc3ncc(-c4ccc(OC(F)F)cc4)cn3)cc2)CC1
Temperature: 150 °C

Procedure:
To a solution of sodium 1-(2-(4-(5-bromopyrimidin-2-ylamino)phenoxy)ethyl)piperidine-4-carboxylate 13 (0.05 mmol) in 1,4-dioxane (1.0 mL) is added 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7 (0.05 mmol), 3M Na2CO3 (0.15 mmol) and Pd(PPh3)4 (0.0025 mmol). The reaction is evacuated and backfilled with nitrogen twice then heated at 150° C. for 10 min. Purification by prep-HPLC (ACN gradient 10-70%) affords 1-(2-(4-(5-(4-(difluoromethoxy)phenyl)pyrimidin-2-ylamino)phenoxy)ethyl)piperidine-4-carboxylic acid A3. 1H NMR (400 MHz, d6-DMSO) δ 9.68 (s, 1H), 8.78 (s, 2H), 7.76 (d, J=8.8 Hz, 2H), 7.71 (d, J=9.2 Hz, 2H), 7.28 (t, J=74.0 Hz, 1H), 7.27 (d, J=8.4 Hz, 2H), 6.98 (d, J=8.8 Hz, 1H), 4.28 (t, J=4.8 Hz, 2H), 3.51 (m, 2H), 3.23 (m, 4H), 1.24 (t, J=7.2, 6H). MS (m/z) (M+1)+: 485.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:10]([OH:12])=[O:11])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(O[N:61]1[C:66](=[O:67])[CH2:65][CH2:64][C:62]1=[O:63])=[N+](C)C)C>C1COCC1>[O:63]=[C:62]1[CH2:64][CH2:65][C:66](=[O:67])[N:61]1[O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][C:15]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[C:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:38])[CH:8]=1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1C(=O)OC(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCOc1ccc(C(=O)ON2C(=O)CCC2=O)cc1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101.8 %

Procedure:
4-(14-tert-Butoxycarbonyl tetradecyloxy) isophthalic acid 3-tert-butyl ester (0.15 g, 0.28 mmol) was dissolved in THF (2 ml). DIEA (58 μl, 0.34 mmol) was added, and the solution was cooled to 0° C. TSTU (0.10 g, 0.28 mmol) was added. The reaction was stirred at 0° C. for 30 min and then at rt for 16 h. The sample was concentrated under vacuum to near dryness. AcOEt (20 ml) was added and the solution was washed with 0.2 N HCl and sat. NaHCO3 (3×5 ml each), dried over MgSO4 and concentrated to yield a residue (0.18 g). The residue was purified by flash chromatography (silica: AcOEt/heptane 3:7 (0.5 l), 1:1 (0.2 l)) yielding an oil with white solids (55 mg, 31%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(OP([CH2:29][C:30]#[N:31])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])=[CH:29][C:30]#[N:31])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(OC)cc(C(=O)c2ccccc2OC)c1
Reactant: CCOP(=O)(CC#N)OCC
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=CC#N)c2ccccc2OC)c1
Yield: 70.3 %

Procedure:
(3,5-Dimethoxyphenyl)-(2-methoxyphenyl)methanone (1.22 g, 4.48 mmol), cyanomethylphosphonic acid diethyl ester (1.41 ml, 8.96 mmol) in anhydrous THF (30 ml), and lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 9.00 ml, 9.00 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified via flash column chromatography (10% EtOAc in hexane gradient to 30% EtOAc in hexane in about 30 min.) to give 3-(3,5-Dimethoxy-phenyl)-3-(2-methoxy-phenyl)-acrylonitrile as an off-white solid (0.93 g, 70%); mp, 82-84° C.: 1HNMR (CDCl3) 7.39-6.90 (m, 8H, Ar), 6.57 (d, J=2 Hz, 2H, Ar), 6.51-6.48 (m, 2H, Ar), 6.42 (d, J=2 Hz, 2H, Ar), 5.89 (s, 2H, double bond protons of the two isomers), 3.78 (s, 6H, 2OCH3), 3.75 (s, 6H, 2OCH3), 3.74 (s, 6H, 2OCH3); 13C NMR (CDCl3) δ 160.9, 160.7, 160.2, 159.9; 157.7, 140.6, 140.3, 131.6, 131.2, 130.9, 128.0, 126.2, 120.9, 120.7, 118.0, 117.6, 111.8, 107.1, 105.8, 101.9, 98.0, 97.3, 55.8, 55.6, 55.6; Anal. Calcd. For C18H17NO3: C, 73.20; H, 5.80; N, 4.74. Found: C, 73.08; H, 5.85; N, 4.78.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[N:24]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]=[C:26]([CH3:28])[CH:27]=1)=[O:4].COC([C@H]1C[C@@H](S(C2C=CC=CC=2C(F)(F)F)(=O)=O)CN1C1N(CCC2C=CC=CC=2)N=C(C)C=1)=O.[OH-].[Li+].CC1C=C(N2C[C@H](S(C3C=CC=CC=3C(F)(F)F)(=O)=O)C[C@@H]2C(O)=O)N(CCC2C=CC=CC=2)N=1>>[CH3:28][C:26]1[CH:27]=[C:23]([N:6]2[CH2:7][C@H:8]([S:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:20])([F:22])[F:21])(=[O:12])=[O:11])[CH2:9][C@H:5]2[C:3]([OH:4])=[O:2])[N:24]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]=1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1CCc1ccccc1
Agent: COC(=O)[C@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C)nn1CCc1ccccc1
Agent: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@@H]2C(=O)O)n(CCc2ccccc2)n1
Agent: [Li+]
Product: Cc1cc(N2C[C@H](S(=O)(=O)c3ccccc3C(F)(F)F)C[C@H]2C(=O)O)n(CCc2ccccc2)n1

Procedure:
In analogy to the procedure described in example 253e, a mixture of (2S,4R)-1-(5-methyl-2-phenethyl-2H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester and (2R,4R)-1-(5-methyl-2-phenethyl-2H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give a mixture of the title compound and (2R,4R)-1-(5-methyl-2-phenethyl-2H-pyrazol-3-yl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid as yellow oil which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([N:8]1[Si:12]([CH3:14])([CH3:13])[CH2:11][CH2:10][Si:9]1([CH3:16])[CH3:15])([CH3:7])[C:3]#[C:4][CH2:5][OH:6].[K].[CH3:18][Si]([NH-])(C)C.CI>O1CCCC1.O>[CH3:18][O:6][CH2:5][C:4]#[C:3][C:2]([N:8]1[Si:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][Si:12]1([CH3:13])[CH3:14])([CH3:1])[CH3:7]
Reactant: CC(C)(C#CCO)N1[Si](C)(C)CC[Si]1(C)C
Reactant: C[Si](C)(C)[NH-]
Agent: [K]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: COCC#CC(C)(C)N1[Si](C)(C)CC[Si]1(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
4-Methyl-4-(2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopent-1-yl)pent-2-yn-1-ol (2.55 g) in dry tetrahydrofuran (30 ml) was cooled to −10° C. under an atmosphere of nitrogen with stirring and potassium bis(trimethylsilylamide (2.09 g) in dry tetrahydrofaran (25 ml) was added over 5 minutes then the mixture was stirred at −(10 to 5)° C. for 0.75 hours. Methyl iodide (1.49 g) in tetrahydrofuran (10 ml) was added over 5 minutes and the mixture was allowed to warm to ambient temperature over 2 hour then stored for 18 hours. The mixture was diluted with water and extracted with ethyl acetate (three times). The extracts were combined, washed with water, dried over magnesium sulphate and evaporated under reduced pressure to give 1-(1-methoxy-4-methylpent-2-yn-4-yl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane as a yellow liquid. This liquid was stirred with dilute aqueous hydrochloric acid (30 ml) for 0.25 hours, washed with diethyl ether (twice) and the aqueous acidic phase separated then evaporated under reduced pressure. The residue was evaporated under reduced pressure with toluene (twice) to remove any water, dissolved in dichloromethane and dried over magnesium sulphate then evaporated under reduced pressure to give 4-amino-1-methoxy-4-methylpent-2-yne hydrochloride, 0.66 g, as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:30][O:31][CH2:32][CH3:33])[N:14]([CH2:15][C:16]3([OH:29])[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[ClH:34]>C(O)C>[ClH:34].[ClH:34].[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:30][O:31][CH2:32][CH3:33])[N:14]([CH2:15][C:16]3([OH:29])[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(O)CCNCC1
Temperature: 65 °C

Procedure:
To a solution of tert-butyl 4-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-hydroxypiperidine-1-carboxylate (0.720 g, 1.62 mmol, prepared as described in Example 4) in ethanol (10 mL) was added 4.3 M HCl in ethanol (2 mL). The solution was heated at 65° C. for 1.5 h. After the mixture cooled to rt, a solid was isolated by filtration. The solid was washed with diethyl ether and dried under reduced pressure at 100° C. to afford 4-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidin-4-ol dihydrochloride as a 0.5 hydrate and as a white solid, mp>260° C. MS (APCI) m/z 356 (M+H)+; Anal. calcd for C19H25N5O2.2HCl.0.5 H20: C, 52.18; H, 6.45; N, 16.01. Found: C, 52.32; H, 6.40; N, 15.90.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([O:27][CH2:28][CH2:29][NH:30]C(OC(C)(C)C)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([O:27][CH2:28][CH2:29][NH2:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:38]
Reactant: Cc1cc(F)ccc1-c1nc(OCCNC(=O)OC(C)(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(F)ccc1-c1nc(OCCN)nc2c1ccc(=O)n2-c1c(F)cccc1F

Procedure:
The product of Example 130 (1 g, 1.9 mmol) was dissolved in CH2Cl2 (8 mL) and stirred under Ar in an ice bath. A chilled solution of 25% TFA in CH2Cl2 (40 mL) was added, and the mixture was stirred for 45 min at 0° C. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and a saturated NaHCO3 solution. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 0-10% MeOH/CH2Cl2 gave the title compound as a white-amorphous solid. mp 96-99°, LC MS in/z=427 (MH+) Retention time=1.52 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:8].[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].B(O)O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:5]2[CH:4]=[CH:3][C:2]([C:29]3[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=3)=[CH:16][C:6]=2[C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:20][CH:21]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: OBO
Solvent: COCCOC
Solvent: O
Product: O=C(Nc1cccnc1)c1cc(-c2ccncc2)ccc1OCc1ccc(F)cc1
Temperature: 80 °C

Procedure:
To a solution of 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}-N-3-pyridinylbenzamide (may be prepared as described in Example 59; 150 mg, 0.37 mmol) in 1,2-dimethoxyethane (5 ml) was added 4-pyridinylboronic acid (68.9 mg, 0.561 mmol), sodium carbonate (198 mg, 1.87 mmol) and bis(triphenylphosphine)palladium(II) chloride (15.74 mg, 0.02 mmol), followed by water (1 ml). The reaction was heated at 80° C. overnight. The reaction mixture was then placed in a microwave vial with another 0.5 eq of boronic acid and 5% catalyst and heated at 120° C. for 25 minutes. The solvent was removed in vacuo, redissolved in 1:1 DMSO/methanol and purified by MDAP to yield the title compound as white solid. 56 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[NH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:14]=O>C(O)=O>[CH3:14][N:12]=[S:10]([CH3:13])([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:11]
Reactant: CS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: C=O
Solvent: O=CO
Product: CN=S(C)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 100 °C
Reaction time: 22 h

Procedure:
500 mg (2.5 mmol) of (RS)—S-(4-nitrophenyl)-S-methyl sulfoximide in 4 ml of formaldehyde (aqueous, 37%) and 20 ml of formic acid (98-100%) are stirred in an open flask at 100° C. After 22 hours, the solvent is evaporated, mixed again with 4 ml of formaldehyde (aqueous, 37%) and 20 ml of formic acid (98-100%) and stirred for another 22 hours at 100° C. Residue from the solvent is drawn off in a rotary evaporator. The remaining residue is dissolved with 2N HCl and extracted from DCM. The aqueous phase is made basic with NaHCO3 and extracted from DCM. The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. 448 mg (2.1 mmol, corresponding to 85% of theory) of the product is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[F:17])[C:6]=2[CH:18]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30](B(O)O)=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[N:7]1[C:6]2[CH:18]=[C:2]([C:30]3[N:26]([C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)[N:27]=[CH:28][CH:29]=3)[CH:3]=[CH:4][C:5]=2[N:9]=[CH:8]1
Reactant: Fc1ccc(-n2cnc3ccc(Br)cc32)c(F)c1
Reactant: OB(O)c1ccnn1-c1ccc(F)cc1
Product: Fc1ccc(-n2nccc2-c2ccc3ncn(-c4ccc(F)cc4F)c3c2)cc1

Procedure:
The title compound, light brown solid (69 mg, 55%), MS (ISP) m/z=391.5 [(M+H)+], mp 152° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(2,4-difluoro-phenyl)-1H-benzo[d]imidazole (intermediate K) (100 mg, 324 μmol) and 1-(4-fluoro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate A) (79.9 mg, 388 μmol).