Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)[NH:13][N:12]=2)=[CH:6][CH:5]=1.[O-:28][C:29]#[N:30].[K+].C(O)C.C(O)(=O)C>O>[Cl:27][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[N:17]=[CH:16][N:15]=[C:14]3[NH:13][N:12]=[C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([CH2:3][NH:2][C:29]([NH2:30])=[O:28])=[CH:5][CH:6]=4)[C:19]=23)[CH:26]=[CH:25][CH:24]=1
Reactant: N#C[O-]
Reactant: NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: NC(=O)NCc1ccc(Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1
Temperature: 20 °C

Procedure:
A mixture of 150 mg (0.391 mmol) of 3-(4-aminomethyl-phenylamino)-4-(3chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine hydrate (see Step 77.5), 95 mg (1.17 mmol) of potassium cyanate, 3 ml of ethanol, 3 ml of water and 0.0258 ml (0.451 mmol) of acetic acid is heated under reflux for 1 hour. After cooling to about 20° C., filtration and recrystallization of the filtration residue from methanol/water, 4-(3-chloro-phenylamino)-3-(4-{ureido-methyl}-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine is obtained; m.p. >280° C.; FAB-MS: (M+H)+=409.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH2:11].[CH2:12]=O.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(O)(=O)C>[NH2:11][C:5]1[C:4]2=[CH:3][C:2]([CH3:1])=[C:10]([CH2:12][N:17]3[CH2:18][CH2:19][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:16]3)[N:9]2[N:8]=[CH:7][N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C=O
Reactant: Cc1cc2c(N)ncnn2c1
Solvent: CC(=O)O
Product: Cc1cc2c(N)ncnn2c1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 105 %

Procedure:
A solution of 6-methylpyrrolo[2,1-f][1,2,4]triazin-4-amine (500 mg, 3.3 mmol; preparation described in PCT Int. Pat. Appl. WO 2007/056170) in acetic acid (8 ml) was treated with 37% aq. formaldehyde solution (328 μl, 4.04 mmol) and tert-butyl piperazine-1-carboxylate (754 mg, 4.04 mmol). The mixture was stirred at 60° C. overnight. After evaporation, the residue was taken up in ethyl acetate and washed with sat. aq. sodium hydrogencarbonate solution. The aqueous layer was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate and evaporated affording 1.2 g of the crude product which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Yield: 90.8 %

Procedure:
In DMF (300 ml), 5-fluoro-2-nitrophenol (10.0 g, 63.7 mmol), benzyl bromide (10.9 g, 63.7 mmol) and potassium carbonate (13.2 g, 95.6 mmol) were stirred at 80° C. for 4 hours. After cooling, the reaction mixture was poured in water (200 ml), followed by extraction with ether (2×200 ml). The extract was washed with saturated brine (200 ml), dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane-ethyl acetate (4:1) eluate fractions, the title compound (14.3 g, 91.3%) was obtained as a pale yellow amorphous substance.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][C:11]=2[O:18][CH3:19])=[C:4]([CH3:20])[N:3]=1.C(N(CC)C(C)C)(C)C.[CH:30]([C:33]1[CH:38]=[C:37]([CH:39]([CH3:41])[CH3:40])[CH:36]=[C:35]([CH:42]([CH3:44])[CH3:43])[C:34]=1[S:45](Cl)(=[O:47])=[O:46])([CH3:32])[CH3:31].[Cl-].[Li+].CS([Cl:55])(=O)=O>O1CCCC1.O>[CH:42]([C:35]1[CH:36]=[C:37]([CH:39]([CH3:40])[CH3:41])[CH:38]=[C:33]([CH:30]([CH3:32])[CH3:31])[C:34]=1[S:45]([O:8][C:6]1[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][Cl:55])=[CH:12][C:11]=2[O:18][CH3:19])=[C:4]([CH3:20])[N:3]=[C:2]([NH2:1])[N:7]=1)(=[O:47])=[O:46])([CH3:43])[CH3:44]
Reactant: COc1cc(CO)ccc1Cc1c(C)nc(N)nc1O
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CCl)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C(C)C)cc(C(C)C)cc1C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
To a solution of 2-amino-5-(4-hydroxymethyl-2-methoxybenzyl)-6-methylpyrimidin-4-ol (5.0 g) and N,N-diisopropylethylamine (11.7 g) in tetrahydrofuran (50 g), 2,4,6-triisopropylbenzenesulfonyl chloride (8.3 g) was added and refluxed for 10 h. After cooling to RT, lithium chloride (2.3 g) was added to the reaction mixture and stirred for 0.5 h, methanesulfonyl chloride (4.2 g) was added over 0.25 h dropwise and the reaction mixture was stirred for 4 h at RT. To the reaction mixture, water (25 g) was added and extracted with ethyl acetate (25 g). The organic layer was washed with water (25 mL) and concentrated in vacuo. To the residue, toluene (20 g) was added and concentrated on vacuo to obtain a light brown solid. The solid was precipitated with toluene (30 g) to obtain sub-title compound (6.8 g). 1H-NMR (300 MHz, CDCl3) δ 7.17 (2H, s), 6.90-6.82 (3H, m), 5.16 (2H, brs), 4.55 (2H, s), 4.10 (2H, septet, J=6.8 Hz), 3.82 (3H, s), 3.81 (2H, s), 2.91 (1H, septet, J=6.8 Hz), 2.32 (3H, s), 1.25 (6H, d, J=7.2 Hz), 1.19 (12H, d, J=6.8 Hz)
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].[H-].[Na+].[CH2:9](Br)[CH:10]=[CH2:11]>CN(C=O)C.CCOCC>[CH2:11]([O:6][C:2]([CH3:3])([CH3:1])[C:4]#[CH:5])[CH:10]=[CH2:9]
Reactant: C#CC(C)(C)O
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C#CC(C)(C)OCC=C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
To stirred solution of 2-methylbut-3-yn-2-ol (7.33 ml, 75 mmol) in DMF (100 mL) was added 60% NaH (3.00 g, 75 mmol) at 0° C. After 30 min, the cold bath was removed stirred for 1 h at rt. To this was added allyl bromide (9.74 ml, 113 mmol) over 5 min and continued stirring for 16 h. Then, diluted with Et2O (250 mL), washed with water (5×50 mL), brine (50 mL), dried (MgSO4), filtered and concentrated to give yellow liquid (5.64 g). HNMR of this indicated it is 2:1 mixture of product and unreacted alcohol. This was used without purification. 1H NMR (500 MHz, CDCl3) δ 5.93-6.02 (m, 1H), 5.32 (qd, J=1.7, 17.2 Hz, 1H), 5.18 (qd, J=1.5, 10.4 Hz, 1H), 4.13 (td, J=1.4, 5.6 Hz, 2H), 2.45 (s, 1H), 1.52 (s, 6H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:42][CH2:41][C@H:40]([OH:43])[CH2:39]1.C(N(CC)C(C)C)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][CH2:36][N:38]5[CH2:42][CH2:41][C@H:40]([OH:43])[CH2:39]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Reactant: O[C@H]1CCNC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCN1CC[C@H](O)C1
Temperature: 25 °C
Yield: 14.3 %

Procedure:
A stirred solution of (1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea from Example 27B (102 mg, 0.194 mmol), (S)-3-pyrrolidinol (51 mg, 0.582 mmol), N,N-diisopropylethylamine (75 mg, 0.582 mmol) and tetrabutylammonium iodide (71 mg, 0.194 mmol) in dry N,N-dimethylformamide (5 mL) was heated at 60° C. for 20 h. After cooling to room temperature, the reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL) and the organic layer was separated, washed with brine (50 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by preparative HPLC (using a phenyl-hexyl reverse phase column, eluted with gradient of solvent B=0.05% HOAC/CH3CN and solvent A=0.05% HOAc/H2O). The combined fractions were washed with saturated aqueous NaHCO3 and the aqueous layer extracted with a mixture of 20% methanol in dichloromethane (2×50 mL). Concentration under reduced pressure afforded (S)-1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(3-(3-hydroxypyrrolidin-1-yl)propoxy)-6-methoxyquinazolin-4-yloxy)phenyl)urea as a colorless solid (16 mg, 14%). 1H NMR (300 MHz, CDCl3) δ 8.59 (brs, 1H), 7.68 (brs, 1H), 7.52-7.55 (m, 2H), 7.26-7.35 (m, 4H), 6.95 (m, 1H), 6.11 (s, 1H), 4.34-4.40 (m, 3H), 4.04 (s, 3H), 3.00-3.20 (m, 2H), 2.84 (m, 1H), 2.67-2.68 (m, 2H), 2.50 (m, 1H), 2.10-2.30 (m, 3H), 1.80 (m, 1H), 1.51 (m, 1H), 1.26 (s, 9H); LC-MS (ESI) m/z 577 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20]C(=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH3:28]>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH3:28]
Reactant: CC(Br)c1ccccn1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Product: CC(Sc1c(Cl)ccc2c1CCNCC2)c1ccccn1
Product: Cl

Procedure:
Use a method similar to the General Procedure 7, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and (±)-2-(1-bromoethyl)-pyridine to give, after deprotection by a method similar to the General Procedure 1-4, the title compound as a white solid. MS (APCI+) m/z: 319 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([N:10]2[CH2:13][CH:12]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11]2)[S:8][CH:9]=1)=[N+]=[N-].[C:32]1([C:37](Cl)=[O:38])[S:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C>CO.[OH-].[Pd+2].[OH-]>[Si:15]([O:14][CH:12]1[CH2:13][N:10]([C:7]2[S:8][CH:9]=[C:5]([CH2:4][NH:1][C:37]([C:32]3[S:36][CH:35]=[CH:34][CH:33]=3)=[O:38])[N:6]=2)[CH2:11]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1cccs1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CN=[N+]=[N-])cs2)C1)(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)[Si](OC1CN(c2nc(CNC(=O)c3cccs3)cs2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
1-(4-Azidomethyl-1,3-thiazol-2-yl)-3-t-butyldiphenylsilyloxyazetidine (2.47 g, 5.50 mmol) (obtained as described in Reference Example 62(1)) in methanol (120 ml) was subjected to catalytic hydrogenation in the presence of 20% palladium hydroxide (2.47 g) at room temperature. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. The residue was dissolved in methylene chloride (115 ml). To the mixture were added thenoyl chloride (0.71 ml, 6.60 mmol) and triethylamine (0.92 ml, 6.60 mmol), and the mixture was stirred at room temperature for 1 hour. After checking the completion of the reaction, the mixture was distilled under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-[4-(thiophene-2-carbonylamino)methyl-1,3-thiazol-2-yl]azetidine (1.88 g, yield 64%) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[H-].[Na+].CS(O[CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24])(=O)=O>C1COCC1.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH:7][CH2:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24]
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: COCCCCOS(C)(=O)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCCCNc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
5-Fluoro-2-nitroaniline (1.0 g) was dissolved in THF (20 ml), sodium hydride (60% in oil, 384 mg) was added, and the mixture was stirred at room temperature for 30 min. 4-Methoxybutyl methanesulfonate (1.28 g) was added, and the mixture was heated under reflux with stirring for 15 hr. The reaction mixture was cooled to room temperature and saturated brine was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (30:70) was concentrated under reduced pressure to give the object product (494 mg).
Reaction SMILES: Br.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12](=[NH:15])[N:11]([CH2:16][C:17](OC)=O)[N:10]=1.O=P(Cl)(Cl)[Cl:23]>ClC1C=CC=CC=1>[Cl:23][C:17]1[N:15]=[C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[F:2])=[N:10][N:11]2[CH:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)Cn1nc(-c2ccccc2F)ccc1=N
Agent: Br
Solvent: Clc1ccccc1
Product: Fc1ccccc1-c1ccc2nc(Cl)cn2n1
Temperature: 120 °C
Yield: 85.5 %

Procedure:
To a solution of methyl 2-(3-(2-fluorophenyl)-6-iminopyridazin-1(6H)-yl)acetate hydrobromide (0.5 g, 1.46 mmol) in chlorobenzene (20 mL) is added POCl3 (7.30 mmol). The reaction mixture is heated at 120° C. for 4 hours, cooled, concentrated under reduced pressure to dryness and sat. aqueous NaHCO3 (25 mL) is added. The mixture is extracted with CH2Cl2 (3×20 mL). Organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude product is purified via silica chromatography (hexanes to EtOAc) to afford the title compound (0.309 g, 85%) as a white solid: Rf 0.39 (1:4 EtOAc:hexanes); LCMS (m/z)=248.2, 250.2 [M+H]+, tR=2.51 min.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH3:10])=[C:4]([N+:11]([O-])=O)[CH:3]=1.[Cl-].[NH4+]>C(O)C.O.CCOC(C)=O.[Fe]>[Br:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH:9][CH3:10])=[C:4]([NH2:11])[CH:3]=1
Reactant: CNc1c([N+](=O)[O-])cc(Br)nc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CNc1c(N)cc(Br)nc1Cl
Temperature: 140 °C

Procedure:
To a solution of 6-bromo-2-chloro-N-methyl-4-nitropyridin-3-amine 2.59 (1 g, 3.75 mmol) in ethanol (10 ml) was added Fe powder (1.05 g, 18.7 mmol) and a solution of ammonium chloride (1 g, 18.8 mmol) in water (3 mL). The mixture was heated in microwave at 140° C. for 30 min. The mixture was then diluted with EtOAc, filtered and evaporated to give 6-bromo-2-chloro-N3-methylpyridine-3,4-diamine 2.59-A, which was used in the next step without purification.
Reaction SMILES: [CH2:1](I)C.[NH2:4][CH2:5][CH2:6][CH2:7][C@:8]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:12]([C:13](=[O:18])[C@@H:14]([O:16][CH3:17])[CH3:15])[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[S:9]1>>[NH2:4][CH2:5][CH2:6][CH2:7][C@:8]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:12]([C:13](=[O:18])[C@@H:14]([O:16][CH2:17][CH3:1])[CH3:15])[N:11]=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[S:9]1
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cccc(F)c2)S[C@@]1(CCCN)c1ccccc1
Reactant: CCI
Product: CCO[C@@H](C)C(=O)N1N=C(c2cccc(F)c2)S[C@@]1(CCCN)c1ccccc1

Procedure:
Prepared as described in Example 64 using ethyl iodide in place of methyl iodide. MS (+) m/z 416 (M+1) detected; 1H NMR (400 MHz, 10:1 CDCl3:CD3OD) δ 7.39 (m, 7H), 7.30 (m 1H), 7.20 (m, 1H), 4.85 (br q, 1H, J=6.3 Hz), 3.68-3.53 (m, 2H), 3.27 (m, 1H), 3.11 (m, 2H), 2.58 (m, 1H), 2.21 (m, 1H), 1.72 (m, 1H), 1.47 (d, 3H, J=6.3 Hz), 1.24 (m, 3H). Stereochemistry was assigned by inference from (S)-1-((S)-2-(3-aminopropyl)-5-(3-fluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.
Reaction SMILES: Br[C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH:7]([C:6]1[CH:9]=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:3]=[CH:4][C:5]=1[OH:10])=[O:8]
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: COCCOC
Product: O=Cc1cc(-c2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 17 h
Yield: 78.3 %

Procedure:
In an atmosphere of argon, 496 g (2.46 mol) of 5-bromosalicylaldehyde, 361 g (2.96 mol) of phenylboronic acid, 57 g (49.0 mmol) of tetraxis(triphenylphosphine)palladium(0), 8.6 L of DME and 784 g of sodium carbonate/3.7 L of water were charged, and subjected to heating under reflux with stirring for 17 hours. After cooling the resultant to room temperature, 3 L of toluene was added, and then an aqueous layer was removed. An organic layer was washed with water, and dried with magnesium sulfate. The solvent was distilled off under a reduced pressure. The crystals were purified by silica gel chromatography, whereby 382 g of 3-formyl-4-hydroxybiphenyl was obtained (yield: 78%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16](Br)=[CH:15][C:14]=3[C:20]([F:23])([F:22])[F:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)[O:28]1.C([O-])(=O)C.[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([OH:28])=[CH:15][C:14]=3[C:20]([F:23])([F:22])[F:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(Br)cc3C(F)(F)F)[C@@H]2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(O)cc3C(F)(F)F)[C@@H]2C1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 93.2 %

Procedure:
To a stirring degassed solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (435 mg, 1.0 mmol), bis(pinacolato)diboron (279 mg, 1.1 mmol), and potassium acetate (294 mg, 3.0 mmol) in dry DMF (5.0 mL) was added palladium(II) acetate (6.7 mg, 0.03 mmol). The reaction was heated to 80° C. for 2 h and then cooled to room temp. The reaction was quenched with water and extracted with EtOAc (3×5 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to a brown oil. The oil was dissolved in THF (5 mL) and acetic acid (0.05 mL) and treated with hydrogen peroxide (0.25 mL). The reaction was stirred for 15 min and then quenched with st. aq. NaHSO3. The reaction was extracted with EtOAc (3×5 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to a brown oil. The oil was purified by flash chromatography (silica gel, 0–70% EtOAc in hexanes) to give 347 mg of the desired product as a pale yellow solid. MS (ESI) 373 (M+H).
Reaction SMILES: [CH:1](=[C:5]1[CH2:10][CH2:9][CH2:8][NH:7][C:6]1=[O:11])[CH2:2][CH2:3][CH3:4].CO>[Ir].ClCCl>[CH2:1]([CH:5]1[CH2:10][CH2:9][CH2:8][NH:7][C:6]1=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC=C1CCCNC1=O
Agent: [Ir]
Solvent: ClCCl
Solvent: CO
Product: CCCCC1CCCNC1=O
Yield: 90.2 %

Procedure:
This example describes the preparation of I where n=2 and R1=n-propyl. In a nitrogen-filled glove box, a Fisher-Porter tube was charged with iridium catalyst prepared as in Example 1 (8 mg, 0.010 mmol) and 3-(butylidene)-2-piperidone (150 mg, 1.0 mmol). Methanol (2 mL) and dichloromethane (2 mL) were added and the system was flushed 4 times with hydrogen and pressured to 60 psi (0.5 Mpa) H2. After 18 h the reaction mixture was filtered through a short pad of silica. The solvent was removed at reduced pressure to afford 3-butyl-2-piperidone (140 mg, 93%) as a white crystalline solid. Chiral gas chromatographic analysis (Rt-GammaDex SA column, 130° C. for 5 min, then programmed to 200° C. at 10°/min) indicated that conversion was 95% and the enantiomeric excess was 90%. 13C NMR: δ 14.24, 21.27, 22.85, 26.04, 29.25, 31.36, 40.96, 42.38, 176.02; 1H NMR: δ 0.91 (t, J=7, 3H), 1.22-1.58 (m, 6H), 1.70 (m, 1H), 1.79-2.00 (m, 3H), 2.24 (m, 1H), 3.29 (m, 2H), 7.25 (br s, 1H).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Si:13]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[C:28]([Cl:36])[C:27]=1[NH2:37])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C1COCC1>N1C=CC=CC=1>[Si:13]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:26]2[C:35]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[N:29]=[C:28]([Cl:36])[C:27]=2[N:37]=[C:1]1[OH:2])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)OCCCCNc1c(N)c(Cl)nc2ccccc12
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCCn1c(O)nc2c(Cl)nc3ccccc3c21
Temperature: 80 °C
Yield: 52.1 %

Procedure:
1,1′-Carbonyldiimidazole (32.6 g, 201 mmol) was added to a solution of N4-[4-(tert-butyldimethylsilanyloxy)butyl]-2-chloroquinoline-3,4-diamine (50.96 g, 134.1 mmol), THF (250 mL), and pyridine (250 mL), and the reaction was heated at 80° C. overnight and allowed to cool. The volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (600 mL), and the resulting solution was washed sequentially with brine (2×400 mL) and water (2×400 mL) and then concentrated under reduced pressure. The resulting solid was triturated with diethyl ether (1 L), collected by filtration, washed with diethyl ether (800 mL), and dried under vacuum for 30 minutes to provide 28.39 g of 1-[4-(tert-butyldimethylsilanyloxy)butyl]-4-chloro-1H-imidazo[4,5-c]quinolin-2-ol as a white solid.