Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:14])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].N1C=CC=CC=1>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][C:15](=[O:17])[CH3:16])=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1-c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccccc1-c1ccc(Cl)cc1
Yield: 51.1 %

Procedure:
The title compound was prepared from 4′-chloro-1,1′-biphenyl-2-amine (3.5 g, 17.19 mmol), acetic anhydride (1.79 mL, 18.9 mmol), pyridine (3.2 mL, 39.5 mmol), and 4-(N,N-dimethylamino)pyridine (0.06 g, 0.52 mmol) according to the procedure and in the same manner as described in Example 60, step b. The crude product was purified by re-crystallization from a mixture of ethyl acetate-hexane to yield N-(4′-chloro-1,1′-biphenyl-2-yl)acetamide (2.16 g, 8.78 mmol, 51%) as a white solid;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[CH2:24]1COCC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]=[CH:18][CH:17]=[CH:16]4)([OH:12])[CH3:24])=[CH:9][N:10]=2)[N:7]=1
Reactant: O=C(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Reactant: C1CCOC1
Product: CC(O)(c1cc2cccnc2cc1F)c1cnc2ccc(Cl)nn12
Temperature: 25 °C
Yield: 95 %

Procedure:
To a solution of (6-chloroimidazo[1,2-b]pyridazin-3-yl)(7-fluoroquinolin-6-yl)methanone (2.93 g, 6.73 mmol) in THF (80 mL) was added MeMgl solution (4.48 mL, 13.45 mmol). The resulting solution was allowed to stir at reflux for 5 hrs. Then the reaction mixture was cooled to room temperature, quenched with water, washed with NH4Cl solution and extracted by CH2Cl2. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford 2.2 g (yield: 95%) title compound which was used to next step without further purification. LCMS (method B): [MH]+=343, tR=2.05 min.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH:23]3[CH2:27][CH2:26][N:25]([C:30](=[O:32])[CH3:31])[CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:20])=[O:21])=[N:11]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2CCNC2)c2cnccc12
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCC(n2c(Cn3nc(S(C)(=O)=O)c4ccncc43)nc3cc(Cl)ccc32)C1
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 1-{[5-chloro-1-(pyrrolidin-3-yl)-1H-benzimidazol-2-yl]methyl}-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine (30 mg, 0.07 mmol), acetic anhydride (0.1 mL) in 8 mL of DCM was added DMAP (3 mg, 0.025 mmol). The mixture was stirred for 1 h. Then 20 mL of DCM and then 10 mL of water was added. The organic phase was washed with water, NaHCO3 and dried over anhydrous Na2SO4. The solvent was evaporated to give the residue which purified by preparative-HPLC to afford the title compound (15 mg, yield: 50%) as a pale solid.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].[CH2:11]([O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25]([CH:29]=[O:30])=[CH:24][CH:23]=[C:22]2[N:31]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(=CC)C>C(O)(C)(C)C.S([O-])([O-])=O.[Na+].[Na+]>[CH2:11]([O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[C:25]([C:29]([OH:6])=[O:30])=[CH:24][CH:23]=[C:22]2[N:31]([CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)c2cc(OCc3ccccc3)ccc12
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: O=C(O)c1ccc(N(Cc2ccccc2)Cc2ccccc2)c2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A freshly prepared solution of sodium chlorite (16.8 g, 186 mmol) in a 20% aqueous solution of sodium dihydrogen phosphate (155 mL) was added to a solution of 6-(benzyloxy)-4-(dibenzylamino)-1-naphthaldehyde (prepared by the method described in WO 03/014064) (8.50 g, 18.6 mmol) and 2-methyl-2-butene (27.2 g, 41 mL, 387 mmol) in t-butanol (186 mL). The mixture was stirred vigorously at RT for 1 h. The reaction mixture was diluted with a saturated aqueous solution of sodium sulfite (150 mL) and stirred for 15 min. The mixture was concentrated and then partitioned between CH2Cl2 and water. The aqueous phase was separated and extracted with CH2Cl2. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a tan solid. This material was purified via column chromatography on silica gel (eluting with 0-50% EtOAc-hexane) to afford 6-(benzyloxy)-4-(dibenzylamino)-1-naphthoic acid as an orange brown solid. MS (ESI, pos. ion) m/z: 474.1 (M+H). Mass Calc'd for C32H27NO3: 473.
Reaction SMILES: [CH3:1][N:2]([S:12]([C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:14])=[O:13])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9](O)=O)[CH2:5][CH2:4]1.[C:19]1([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[C:27]([NH2:32])[CH:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][N:2]([S:12]([C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:14])=[O:13])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[NH:32][C:27]3[CH:26]=[C:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:30]=[CH:29][C:28]=3[N:31]=2)[CH2:5][CH2:4]1
Reactant: CN([C@H]1CC[C@H](C(=O)O)CC1)S(=O)(=O)C(C)(C)C
Reactant: Nc1ccc(-c2ccccc2)cc1N
Product: CN([C@H]1CC[C@H](c2nc3ccc(-c4ccccc4)cc3[nH]2)CC1)S(=O)(=O)C(C)(C)C

Procedure:
Trans-4-(N-methyl-tert-butylsulfonylamino)cyclohexanecarboxylic acid and 4-phenyl-1,2-phenylenediamine were allowed to undergo ring closure condensation under the same conditions as described in Example 1-3), followed by separatory purification on a collective thin-layer chromatograph (chloroform:methanol=10:1) to give the title compound.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:30])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH:15]1([CH2:14][CH:13]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=2)[C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([CH2:5][CH2:4][OH:3])[N:7]=2)=[O:30])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCOC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc(CCO)cs2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.2 %

Procedure:
A solution of {2-[3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester (prepared as in Example 3(B)(d), 120 mg, 0.26 mmol) in diethyl ether (500 μL) was cooled to 0° C. and then slowly treated with lithium aluminum hydride (15 mg, 0.39 mmol). The reaction mixture was allowed to warm to 25° C. where it was stirred for 1 h. After 1 h at 25° C., thin layer chromatography still indicated the presence of the starting material. An additional amount of lithium aluminum hydride (10 mg, 0.26 mmol) was added to the reaction mixture, and the reaction mixture was allowed to stir at 25° C. for 1 h. The reaction mixture was then slowly quenched by the dropwise addition of water (10 mL). The resulting mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/3 hexanes/ethyl acetate) afforded 3-cyclopentyl-N-[4-(2-hydroxyethyl)-thiazol-2-yl]-2-(4-methanesulfonyl-phenyl)-propionamide (20 mg, 18%) as a yellow foam: mp 84-87° C.; EI-HRMS m/e calcd for C20H26N2O4S2 (M+) 422.1334, found 422.1335.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[CH3:17].[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[CH3:17]
Reactant: COC(=O)c1cc(-c2c(C)cnn2C)c(Cl)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cnn(C)c1-c1cc(C(=O)O)sc1Cl
Temperature: 70 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To a 100 mL round-bottomed flask was added methyl 5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (106 mg, 0.39 mmol) in Tetrahydrofuran (THF) (2 mL). 6N NaOH (2 mL, 12.00 mmol) was added slowly and the reaction mixture stirred overnight at 70° C. The reaction was cooled to room temperature, partitioned between CHCl3 and H2O and the pH of the aqueous layer was adjusted to ˜3 by the addition of 6N HCl. The layers were separated, the organic layer dried over Na2SO4 and concentrated affording the desired compound (96 mg, 0.37 mmol, 95%): LC-MS (ES) m/z=257 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:16][CH2:17][C:18]([N:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([CH2:29][O:30][C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:40]=2[N:39]=[C:38]([CH3:41])[CH:37]=[C:36]3[O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=2)[C:23]=1[Cl:50])[CH3:21])=[O:19].ClC1C(COC2C3N=C(OC)N(CC4C=CC=CN=4)C=3C=CC=2)=C(Cl)C=CC=1N(C)C(=O)CNC(=O)CCC1C=CC(C(NCCOC)=O)=CC=1>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][C:13]([NH:16][CH2:17][C:18]([N:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([CH2:29][O:30][C:31]3[CH:32]=[CH:33][CH:34]=[C:35]4[C:40]=3[N:39]=[C:38]([CH3:41])[CH:37]=[C:36]4[O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)[C:23]=2[Cl:50])[CH3:21])=[O:19])=[O:15])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(CCC(=O)O)cc1
Reactant: Cc1cc(OCc2ccccn2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Agent: COCCNC(=O)c1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c3nc(OC)n4Cc3ccccn3)c2Cl)cc1
Product: CC(=O)Nc1ccc(CCC(=O)NCC(=O)N(C)c2ccc(Cl)c(COc3cccc4c(OCc5ccccn5)cc(C)nc34)c2Cl)cc1

Procedure:
Compound 28 was prepared from 3-(4-acetamidophenyl)propanoic acid and 2-amino-N-(2,4-dichloro-3-(((2-methyl-4-(pyridin-2-ylmethoxy)quinolin-8-yl)oxy)methyl)phenyl)-N-methylacetamide in a as described for compound 1. MS (APCI) 700(M+), 1H NMR (CDCl3) 1.91 (s, 3H), 2.4-2.6 (m, 5H), 2.80-2.93 (m, 2H), 3.10 (s, 3H), 3.32-3.45 (m, 1H), 3.61-3.71 (m, 1H), 5.41 (s, 2H), 5.45-5.56 (m, 2H), 6.41-6.45 (m, 1H), 6.71 (s, 1H), 6.91-7.05 (m, 3H), 7.18-7.21 (m, 1H), 7.22-7.28 (m, 1H), 7.31-7.50 (m, 2H), 7.55-7.60 (m, 1H), 7.65-7.75 (m, 1H), 7.91-7.99 (m, 1H), 8.61-8.69 (m, 1H), 9.14 (s, 1H).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:20]=3[N:19]=[CH:18][C:17]([C:21]([F:24])([F:23])[F:22])=[CH:16]4)[CH2:7][CH2:6]2)[O:4]CC1.Cl>O1CCCC1>[F:23][C:21]([F:22])([F:24])[C:17]1[CH:18]=[N:19][C:20]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][C:11]=2[N:8]1[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]1
Reactant: FC(F)(F)c1cnc2c(N3CCC4(CC3)OCCO4)cccc2c1
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCN(c2cccc3cc(C(F)(F)F)cnc23)CC1
Temperature: 40 °C
Reaction time: 18 h
Yield: 66.6 %

Procedure:
A solution of 8-(1.4-dioxa-8-azaspiro[4.5]dec-8-yl)-3-(trifluoromethyl)quinoline (Step 3, 0.19 g) in tetrahydrofuran (3 mL) was treated with 2N aqueous HCl (1 mL) and then stirred at 40° C. for 18 hours. The mixture was cooled to room temperature and concentrated on a rotary evaporator. The residue was taken up in CH2Cl2, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated on a rotary evaporator to give 0.11 g of the desired product as a yellow oil; MS (ES) m/z (relative intensity); 295 (M+H)+ (100).
Reaction SMILES: [I:1][C:2]1[N:23]([S:24]([C:27]2[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=[CH:8][C:9]([C:10]3[S:14][C:13]([C:15]4([O:19]COC)[CH2:18][CH2:17][CH2:16]4)=[N:12][CH:11]=3)=[C:4]2[CH:3]=1.Cl>CO.O1CCCC1>[I:1][C:2]1[N:23]([S:24]([C:27]2[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=2)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=[CH:8][C:9]([C:10]3[S:14][C:13]([C:15]4([OH:19])[CH2:18][CH2:17][CH2:16]4)=[N:12][CH:11]=3)=[C:4]2[CH:3]=1
Reactant: COCOC1(c2ncc(-c3ccnc4c3cc(I)n4S(=O)(=O)c3ccc(C)cc3)s2)CCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3c(-c4cnc(C5(O)CCC5)s4)ccnc32)cc1
Temperature: 65 °C

Procedure:
To a solution of 5-(2-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(1-(methoxymethoxy)cyclobutyl) thiazole (Example 107B) (1.273 g, 2.138 mmol) in methanol (10.8 mL) and tetrahydrofuran (10.8 mL) was added 10% aqueous hydrochloric acid solution (6.61 mL, 21.38 mmol). The reaction mixture was heated to 65° C. for 3 hours. The reaction was partitioned between ethyl acetate (50 mL) and water (50 mL). The layers separated, and the aqueous layer was extracted with additional ethyl acetate (2×50 mL). The combined organics were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound. MS APCI(+) m/z 552.54 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:12]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)#[N:13].C[Si](C)(C)[N-][Si](C)(C)C.[K+]>>[C:12]([C:14]1([C:2]2[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)#[N:13]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: COCOc1cccnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: COCOc1cccnc1C1(C#N)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
2-Chloro-3-methoxymethoxy-pyridine (Tetrahedron 58 (2002), 309-314) (2 g, 11.5 mmol) and tert-butyl 4-cyanopiperidine-1-carboxylate (1.6 g, 7.7 mmol) were reacted in the presence of potassium hexamethyldisilazide (9.2 mmol) using the method in example 8-1 to afford the desired product: tert-Butyl 4-cyano-4-[3-(methoxymethoxy)pyridin-2-yl]piperidine-1-carboxylate: 1H NMR δ (ppm) (CDCl3): 8.21 (1H, d, J=4.6 Hz), 7.53 (1H, d, J=8.3 Hz), 7.27-7.23 (1H, m), 5.31 (2H, s), 4.20 (2H, br s), 3.55 (3H, s), 3.28 (2H, br s), 2.35 (2H, s), 2.10 (2H, br s), 1.47 (9H, s).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([O:12]COC)[CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH:16]=[O:17])[CH2:6][O:7]2.Cl>CC(C)=O>[F:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH:16]=[O:17])[CH2:6][O:7]2
Reactant: COCOc1cc(F)c2c(c1)OCC(C=O)=C2
Agent: Cl
Solvent: CC(C)=O
Product: O=CC1=Cc2c(F)cc(O)cc2OC1
Yield: 77.7 %

Procedure:
5-Fluoro-7-(methoxymethoxy)-2H-chromene-3-carbaldehyde (1.5 g) was dissolved in acetone (25 mL), and 1 M HCl (20 mL) was added thereto, followed by heating and refluxing for 5 hours. The reaction liquid was concentrated and the residue was dissolved in EtOAc, washed with water and brine, and dried over MgSO4, and the filtrate was concentrated. The residue was washed with chloroform to obtain 5-fluoro-7-hydroxy-2H-chromene-3-carbaldehyde (0.95 g) as a yellow powder.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6](/[CH:8]=[C:9]1\[CH2:10][N:11]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:13][C:14]\1=[O:15])=[O:7])[CH3:4]>>[CH2:3]([O:5][C:6](/[CH:8]=[C:9]1\[CH2:10][N:11]([C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:12][CH2:13][CH:14]\1[OH:15])=[O:7])[CH3:4]
Reactant: CCOC(=O)/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1=O
Agent: [BH4-]
Agent: [Na+]
Product: CCOC(=O)/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
After the portionwise addition of 1.48 g (39.1 mmol) of sodium borohydride to a 150 ml methanolic solution of 16.6 g (39.1 mmol) of (E)-3-ethoxycarbonylmethylidene-1-triphenylmethyl-4-piperidone under ice cooling, the resulting mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure. The concentrate was extracted with 50 ml of water and 150 ml of ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure, whereby 16.8 g (yield: 100%) of (E)-3-ethoxycarbonylmethylidene-4-hydroxy-1-triphenylmethylpiperidine were obtained as a brown oil. 200 ml of tetrahydrofuran and 6.70 g (35.2 mmol) of p-toluenesulfonic acid monohydrate were added to the resulting product and the resulting mixture was stirred at 50° C. for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure. The resulting solid was washed with toluene, whereby 10.8 g (yield: 86.6%) of the p-toluenesulfonate salt of 3-ethoxycarbonylmethylidene-4-hydroxypiperidine were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:13]([CH3:14])=[CH:12][CH2:11][CH2:10][CH:9]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+].C(O)(C(F)(F)F)=O.CCOC(C)=O>C(Cl)Cl>[C:6]([N:8]1[C@@H:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:10][CH2:11][CH2:12][C@@H:13]1[CH3:14])([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CCCCCCCCCCCC1CCC=C(C)N1C(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCC[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.8 %

Procedure:
To a stirred solution of 1.34 g (3.81 mmol) of 1-(tert-Butoxycarbonyl)-6-methyl-2-n-undecyl-1,2,3,4-tetrahydropyridine in 260 mL of CH2Cl2 was added 1.44 g (22.86 mmol) of sodium cyanoborohydride. After being stirred 15 minutes at room temperature, the heterogeneous solution was cooled to −42° C. and TFA (3.7 mL, 38.10 mmol) was added slowly dropwise. After being stirred for 4 h at −42° C., the cold bath was removed, and the reaction mixture was immediately quenched with 190 mL of a saturated aqueous NaHCO3/THF mixture (50:50). The aqueous phase was extracted with CH2Cl2 (2×40 mL) and the combined organic extracts were washed with water and brine. The organic phase was dried with K2CO3, filtered through Celite, and evaporated to give the crude product. Column chromatography using 5% EtOAc in hexanes gave 0.9 g (67%) of the product as a clear colorless oil. 1H NMR (300 MHz) d 3.97-3.84 (m, 1H), 3.83-3.74 (m, 1H), 1.92-1.28 (m, 8H), 1.46 (s, 9H), 1.25 (br s, 18H), 1.22 (d, 3H), 0.89 (t, 3H); 13C NMR (75 MHz) 155.3 (s), 78.7 (s), 51.6 (s), 46.9 (s), 34.3 (s), 31.7 (s), 29.6 (s), 29.5 (s), 29.3 (s), 28.4 (s), 27.2 (s), 26.8 (s), 23.2 (s), 22.7 (s), 20.8 (s), 14.0 (s), 13.6 (s) ppm. FT-IR (neat) 2924, 2854, 2691, 1468, 1394, 1368, 1178, 1091 cm−1.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]1[CH2:24][C@H:23](OS(C)(=O)=O)[CH2:22][N:21]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:37][C:38]1[C:46]2[C:41](=[N:42][CH:43]=[N:44][C:45]=2[NH2:47])[NH:40][N:39]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[NH2:47][C:45]1[N:44]=[CH:43][N:42]=[C:41]2[N:40]([C@@H:23]3[CH2:22][N:21]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[C@H:20]([CH2:19][O:18][Si:1]([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:24]3)[N:39]=[C:38]([I:37])[C:46]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@@H](n2nc(I)c3c(N)ncnc32)C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(2S,4S)-tert-butyl 2-((tert-butyldiphenylsilyloxy)methyl)-4-(methylsulfonyloxy)pyrrolidine-1-carboxylate (389 mg) obtained in Step 2 above, 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (188 mg), and potassium carbonate (363 mg) were suspended in DMF (4.0 ml), followed by stirring overnight at 80° C. Ethyl acetate and water were added thereto to separate the organic layer. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless, oily substance (191 mg). Physical properties: m/z [M+H]+ 699.1
Reaction SMILES: [CH2:1]([NH:4][C:5]([CH:7]([CH3:31])[CH2:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[C:16]2[CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][C:21]=2[O:29][CH3:30])=[CH:11][CH:10]=1)=[O:6])[CH2:2][CH3:3].[C:32]1([S:38]([NH2:41])(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:30][O:29][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:20]=1[CH2:19][C:16]1[C:17]2[C:12](=[CH:11][CH:10]=[C:9]([CH2:8][CH:7]([C:5](=[O:6])[NH:4][CH2:1][CH2:2][CH3:3])[CH3:31])[CH:18]=2)[CH:13]=[CH:14][CH:15]=1)[C:24]([NH:41][S:38]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:40])=[O:39])=[O:25]
Reactant: CCCNC(=O)C(C)Cc1ccc2cccc(Cc3ccc(C(=O)O)cc3OC)c2c1
Reactant: NS(=O)(=O)c1ccccc1
Product: CCCNC(=O)C(C)Cc1ccc2cccc(Cc3ccc(C(=O)NS(=O)(=O)c4ccccc4)cc3OC)c2c1

Procedure:
Using a similar procedure to that described in Example 2.h., except starting from 4-[7-[2-(propylcarbamoyl)propyl]naphth-1-ylmethyl]-3-methoxybenzoic acid and benzenesulfonamide, the title compound was obtained (83%) as a colorless solid; mp 214.0°-217.5° C., MS(CI), m/e=559(M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)c(Cl)c1
Reactant: Nc1n[nH]cc1-c1ccccn1
Product: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc2c(-c3ccccn3)cnn12
Yield: 54.5 %

Procedure:
Reaction of 1-(3,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (285 mg, 1.0 mmol), prepared from commercially available 3,4-dichloro-acetophenone according to general procedure A, and 3-amino-4-(2-pyridinyl)-pyrazole [CAS No. 493038-87-2; prepared from 2-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (160 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (223 mg, 55%). MS (ISP) 409.2 [(M+H)+]; mp 188° C.