Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[C:5]([NH:7][CH2:8][CH2:9][CH2:10][S:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)=[O:6].C(N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[C:5]1(=[O:6])[C:4]2[C:3](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:2][N:7]1[CH2:8][CH2:9][CH2:10][S:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: O=C(NCCCSc1ccncc1)c1ccccc1CO
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2CN1CCCSc1ccncc1
Temperature: 25 °C
Yield: 78.8 %

Procedure:
To a solution of 1.51 g (5.0 mmol) of 4-[3-(2-hydroxymethylbenzoyl)aminopropylthio]pyridine and 2.09 ml (15.0 mmol) of triethylamine in 50 ml of methylene chloride, 0.77 ml (10.0 mmol) of methanesulfonyl chloride was added with stirring at room temperature, and the mixture was stirred at room temperature for 30 minutes. The mixture was washed with saturated aqueous sodium bicarbonate, water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethyl acetate) to give 1.12 g of the desired compound (78.9% yield, pale brown crystals), mp. 73°-74.5° C.
Reaction SMILES: [C:1](=O)([O:37]C1C=CC([N+]([O-])=O)=CC=1)[O:2][C@H:3]([CH2:18][C:19]1[CH:27]=[C:26]([CH3:28])[C:25]2[C:21](=[CH:22][N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[N:24]=2)[CH:20]=1)[C:4](=[O:17])[N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:7][CH2:6]1.[F:48][C:49]1[CH:50]=[CH:51][CH:52]=[C:53]2[C:58]=1[NH:57][C:56](=[O:59])[N:55]([CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)[CH2:54]2.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:48][C:49]1[CH:50]=[CH:51][CH:52]=[C:53]2[C:58]=1[NH:57][C:56](=[O:59])[N:55]([CH:60]1[CH2:65][CH2:64][N:63]([C:1]([O:2][C@H:3]([CH2:18][C:19]3[CH:27]=[C:26]([CH3:28])[C:25]4[C:21](=[CH:22][N:23]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:34])[CH3:36])[N:24]=4)[CH:20]=3)[C:4](=[O:17])[N:5]3[CH2:6][CH2:7][CH:8]([N:11]4[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]4)[CH2:9][CH2:10]3)=[O:37])[CH2:62][CH2:61]1)[CH2:54]2
Reactant: O=C1Nc2c(F)cccc2CN1C1CCNCC1
Reactant: Cc1cc(C[C@@H](OC(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3Cc4cccc(F)c4NC3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-oxo-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-2-yl 4-nitrophenyl carbonate (150 mg, 0.23 mmol) and 8-fluoro-3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (84.2 mg, 1.50 equiv) in dimethylformamide (1 mL) was added diisopropylethylamine (79 μL, 0.45 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated and purified by column chromatography to give 78 mg (45%) as a colorless film. Mass spec.: 776.58 (MH)+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:27])[CH2:21][S:22][CH2:23][CH2:24][CH2:25][OH:26])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:27])[CH2:21][S:22][CH2:23][CH2:24][CH2:25][O:26][C:28](=[O:30])[CH3:29])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CSCCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCCCSCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Yield: 87 %

Procedure:
Following a procedure similar to that described in Example 67(c), but using N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(3-hydroxypropylthio)acetamide [prepared as described in step (c) above] and acetic anhydride as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in an 87% yield.
Reaction SMILES: [CH:1]([NH:4][C:5](=O)[CH:6]([Cl:8])[Cl:7])([CH3:3])[CH3:2].Cl.P(Cl)(Cl)([Cl:13])=O>P(Cl)(Cl)(Cl)(Cl)Cl>[CH:1]([N:4]=[C:5]([Cl:13])[CH:6]([Cl:8])[Cl:7])([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)NC(=O)C(Cl)Cl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CC(C)N=C(Cl)C(Cl)Cl
Yield: 65 %

Procedure:
N-isopropyldichloroacetamide, 249.5 grams (2.94 mole), and 210 milliliters of phosphorous pentachloride, 306.5 grams (2.94 mole), was added and the mixture was stirred vigorously and heated at reflux until hydrogen chloride evolution ceased. The phosphorous oxychloride was stripped off at reduced pressure. Distillation at 4.5 millimeters gave 360 grams (65% yield) of N-isopropyldichloroacetimidoyl chloride, b.p. 63°-72° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]([N:16]2[CH2:21][C@H:20]([CH3:22])[N:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18][C@H:17]2[CH3:31])=[O:15])=[C:6]([CH2:8][C:9]([OH:11])=O)[CH:7]=1.Cl.CN(C)CCCN=C=NCC.[CH3:44][S:45]([NH2:48])(=[O:47])=[O:46].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][CH2:13][C:14]([N:16]2[CH2:21][C@H:20]([CH3:22])[N:19]([CH2:23][C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[CH2:18][C@H:17]2[CH3:31])=[O:15])=[C:6]([CH2:8][C:9]([NH:48][S:45]([CH3:44])(=[O:47])=[O:46])=[O:11])[CH:7]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CC(=O)O
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1CC(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.9 %

Procedure:
To a solution of (5-chloro-2-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-phenyl)-acetic acid (0.70 g, 1.44 mmol) was added 4-dimethylaminopyridine (0.26 g, 2.16 mmol), (3-(dimethylamino)propyl)ethyl carbodiimide hydrochloride (0.42 g, 2.16 mmol), methanesulfonamide (0.15 g, 1.58 mmol) and triethylamine (0.40 mL, 2.88 mmol). The reaction was stirred at ambient temperature for 18 hours. The reaction mixture was then diluted with dichloromethane and washed with 1 M aqueous hydrochloric acid. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel to give the title compound (0.34 g, LRMS: 526.2).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[CH:12]3)=[CH:4][CH:3]=1.[F:20][C:21]([F:32])([F:31])[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1.CC(C)([O-])C.[Na+]>O1CCOCC1.C[C@@H](P(C(C)(C)C)C(C)(C)C)[C]1[C](P(C2CCCCC2)C2CCCCC2)[CH][CH][CH]1.[CH]1[CH][CH][CH][CH]1.[Fe].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:20][C:21]([F:31])([F:32])[O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][C:2]2[N:7]=[N:6][C:5]([O:8][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[NH:15][C:14](=[O:19])[CH:13]=[CH:12]4)=[CH:4][CH:3]=2)=[CH:25][CH:24]=1
Reactant: O=c1ccc2cc(Oc3ccc(Cl)nn3)ccc2[nH]1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Agent: [Fe]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: O=c1ccc2cc(Oc3ccc(NCc4ccc(OC(F)(F)F)cc4)nn3)ccc2[nH]1
Temperature: 110 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
To a suspension of 6-((6-chloropyridazin-3-yl)oxy)quinolin-2(1H)-one (0.032 g, 0.117 mmol) in dioxane (2.0 mL) at room temperature was added 4-(trifluoromethoxy)benzylamine (0.091 mL, 0.585 mmol), (R)-(−)-1-[(S)-2-(Dicyclohexylphosphino)ferrocenyl]ethyldi-t-butylphosphine (3.28 mg, 5.85 μmol), palladium (II) acetate (1.313 mg, 5.85 μmol) and sodium-t-butoxide (0.014 mL, 0.164 mmol). The reaction mixture was stirred in a sealed tube at 110° C. overnight, then concentrated under vacuum to a yellow oil. This was purified by prep HPLC to yield 6-((6-((4-(trifluoromethoxy)benzyl)amino)pyridazin-3-yl)oxy)quinolin-2(1H)-one as a white solid (4 mg, 5%). 1H NMR (500 MHz, METHANOL-d4) δ ppm 7.96 (d, J=9.5 Hz, 2H), 7.67-7.34 (m, 8H), 6.68 (d, J=9.6 Hz, 1H), 4.59 (s, 2H). LCMS: R.T.=1.738 min; [M+H]+=429.08.
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][N:12]1[C:18](=[O:48])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:28][C:29]([N:31]1[CH2:35][C:34]([F:37])([F:36])[CH2:33][C@@H:32]1[C:38]([O:40]CC1C=CC=CC=1)=[O:39])=[O:30])=[O:10])C1C=CC=CC=1>C(O)C.[Pd]>[C:9]([C@H:11]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][N:12]1[C:18](=[O:48])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:28][C:29]([N:31]1[CH2:35][C:34]([F:37])([F:36])[CH2:33][C@@H:32]1[C:38]([OH:40])=[O:39])=[O:30])([OH:10])=[O:8]
Reactant: O=C(OCc1ccccc1)[C@H]1CC(F)(F)CN1C(=O)COc1ccccc1OCC(=O)N1CC(F)(F)C[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)[C@H]1CC(F)(F)CN1C(=O)COc1ccccc1OCC(=O)N1CC(F)(F)C[C@@H]1C(=O)O
Yield: 92.8 %

Procedure:
0.47 g (0.0007 mol) (R)-1-[[2-[2-[(R)-2-Benzyloxycarbonyl-4,4-difluoropyrrolidin-1-yl]-2-oxo-ethoxyl]-phenoxy]acetyl]-4,4-difluoropyrrolidine-2-carboxylic acid benzyl ester in 20 ml ethanol were hydrogenated at room temperature and atmospheric pressure in the presence of 0.09 g 5% palladium/carbon. After completion of the reaction the catalyst was filtered off, the solvent was distilled off, and the residue was dissolved in dichloromethane. Evaporation gave 0.32 g (94%) (R)-1-[[2-[2-[(R)-2-carboxy-4,4-difluoropyrrolidin-1-yl]-2-oxo-ethoxyl]-phenoxy]acetyl]-4,4-difluoropyrrolidine-2-carboxylic acid as a light yellow foam. ISP-MS: 493 (MH)+; [α]D=+46.8° (c=1% in dimethylsulfoxide).
Reaction SMILES: CC1C=C(C2C=CC(OC(F)(F)F)=CC=2)SC=1CO.[F:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[C:24]([F:31])=[CH:23][C:22]=1[C:32]1[S:36][C:35]([CH2:37][O:38][Si](C(C)C)(C(C)C)C(C)C)=[C:34]([CH3:49])[CH:33]=1>>[F:20][C:21]1[CH:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[C:24]([F:31])=[CH:23][C:22]=1[C:32]1[S:36][C:35]([CH2:37][OH:38])=[C:34]([CH3:49])[CH:33]=1
Reactant: Cc1cc(-c2cc(F)c(C(F)(F)F)cc2F)sc1CO[Si](C(C)C)(C(C)C)C(C)C
Agent: Cc1cc(-c2ccc(OC(F)(F)F)cc2)sc1CO
Product: Cc1cc(-c2cc(F)c(C(F)(F)F)cc2F)sc1CO

Procedure:
The title compound was prepared using a method analogous to that used for the preparation of {3-methyl-5-[4-(trifluoromethoxy)phenyl]thien-2-yl}methanol (intermediate 118) using ({5-[2,5-difluoro-4-(trifluoromethyl)phenyl]-3-methylthien-2-yl}methoxy)(triisopropyl)silane (intermediate 119).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][N:38]([CH3:48])[C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:42]2[CH:43]=[CH:44][C:39]([N:38]([CH3:48])[CH3:37])=[CH:40][CH:41]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CN(C)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CN(C)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 60.6 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 43, 0.15 g, 0.28 mmol), 4-(dimethylamino)-phenyl boronic acid (0.12 g, 0.72 mmol) and dichlorobis(triphenylphosphine)palladium (II) (21 mg, 0.03 mmol) in dioxane (3 mL) was added an aqueous sodium carbonate solution (2 M, 0.36 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded {4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-dimethyl-amine (80 mg, 59%) as a white solid: LC/MS m/e calcd for C28H29N3O2S [M+H]+ 472.63, observed 472.2.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[C:30]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][C:35]1=[O:40])([CH3:33])([CH3:32])[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:30]([N:34]1[CH2:39][CH2:38][N:37]([CH2:18][C:13]2[N:14]([CH3:17])[C:15]3[C:11]([N:12]=2)=[C:10]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[N:9]=[C:8]([N:7]2[C:6]4[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=4[N:4]=[C:3]2[CH2:1][CH3:2])[N:16]=3)[CH2:36][C:35]1=[O:40])([CH3:33])([CH3:31])[CH3:32]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CC(C)(C)N1CCNCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)C)C(=O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.8 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.15 g, 0.39 mmol), 1-tert-butylpiperazin-2-one (0.072 g, 0.46 mmol) and 4 Å molecular sieves (0.4 g) in DCE (5 mL) was stirred for 4 h at room temperature. Sodium triacetoxyborohydride (0.163 g, 0.77 mmol) was added and the reaction mixture was stirred for 18 h at room temperature. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 5:95) to give 577 as a white solid (0.178 g, 87%). LCMS (Method I): RT=3.59 min, [M+H]+ 532.2 1H NMR (400 MHz, DMSO-d6): δ 8.03-7.98 (m, 1 H), 7.65-7.60 (m, 1 H), 7.26-7.21 (m, 2 H), 4.50-3.95 (m, 5 H), 3.83-3.79 (m, 6 H), 3.78 (m, 4 H), 3.27 (q, J=7.4 Hz, 2 H), 3.08 (s, 2 H), 2.69-2.64 (m, 2 H), 1.36 (s, 9 H), 1.34 (t, J=7.4 Hz, 3 H)
Reaction SMILES: Br[C:2]1[C:3]([O:13][CH3:14])=[N:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]=[CH:8][C:7]2=[O:12].C([O-])=O.[NH4+]>CO.[Pd]>[CH3:14][O:13][C:3]1[CH:2]=[C:11]2[C:6]([C:7](=[O:12])[CH:8]=[CH:9][NH:10]2)=[CH:5][N:4]=1
Reactant: COc1ncc2c(=O)cc[nH]c2c1Br
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1cc2[nH]ccc(=O)c2cn1
Temperature: 25 °C

Procedure:
8-Bromo-7-methoxy-1H-[1.6]naphthyridin-4-one (12 g, 33.5 mmol) was dissolved in anhydrous methanol (240 mL) and 10% Dry Pd/C (2.4 g) was added carefully in portions. This was followed by portionwise addition of ammonium formate (24 g) which caused an exotherm. The reaction mixture was heated to reflux for 1 h. The reaction mixture was cooled to RT, filtered through Celite, and washed with hot MeOH. The filtrate was concentrated and the residue purified by column chromatography on silica gel (230-400 mesh) eluting with ethyl acetate-methanol.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:21]=[CH:20][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:12]=2[CH2:13]O)=[CH:8][CH:7]=1.N1C=CC=CC=1.C1C=CC=CC=1>O>[Cl:3][CH2:13][C:12]1[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:11]=1[O:10][C:9]1[CH:20]=[CH:21][C:6]([CH3:5])=[CH:7][CH:8]=1
Reactant: Cc1ccc(Oc2ccc(C)cc2CO)cc1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(Oc2ccc(C)cc2CCl)cc1

Procedure:
36.5 Ml. of thionyl chloride are added dropwise at 10°-15° C. with stirring and cooling with ice to a solution of 110 g. of 2-(4-methyl-phenoxy)-5-methylbenzyl alcohol in 78 ml. of pyridine. The mixture is stirred for an additional 1 hour at 10° C. and then diluted with 200 ml. of benzene. Then, 200 ml. of water are carefully added dropwise with ice-cooling. The aqueous phase is separated and the organic phase washed successively with dilute hydrochloric acid, water and saturated sodium bicarbonate solution. The aqueous phases are each extracted once more with benzene. The combined benzene extracts are dried over sodium sulfate and evaporated to dryness in vacuo and there is obtained 3-chloromethyl-4-(4-methyl-phenoxy)-toluene as an oil.
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[N:21]3[C:16]([CH:17]=[N:18][C:19](O)=[N:20]3)=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[N:23]1([C:29]2[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][CH:34]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>>[C:1]([O:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[N:21]3[C:16]([CH:17]=[N:18][C:19]([NH:35][C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[CH:30]=4)=[N:20]3)=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OCc1cccc(-c2ccc3cnc(O)nn23)c1
Reactant: Nc1cccc(N2CCOCC2)c1
Product: CC(C)(C)OCc1cccc(-c2ccc3cnc(Nc4cccc(N5CCOCC5)c4)nn23)c1
Yield: 56.1 %

Procedure:
Analogous to Example 1510b, 7-(3-tert-Butoxymethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol (109 mg, 0.37 mmol) and 3-Morpholin-4-yl-phenylamine (0.0818 g, 0.459 mmol) were reacted to afford [7-(3-tert-Butoxymethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(3-morpholin-4-yl-phenyl)-amine as an orange foam (95 mg, 56%). LCMS: 458 (M+H); 1H-NMR (DMSO-d6): 9.30 (s, 1H), 8.97 (s, 1H), 8.06 (s, 1H), 7.98 (d, 1H, J=7.74 Hz), 7.46 (t, 1H, J=7.74), 7.36 (d, 1H, 7.74 Hz), 7.30 (s, 1H), 7.28 (d, 1H, J=9.68 Hz), 7.15 (d, 1H, J=8.07 Hz), 7.12 (d, 1H, J=4.84 Hz), 6.95 (d, 1H, J=4.84 Hz), 4.48 (s, 2H), 3.65 (t, 4H, J=4.58 Hz), 2.95 (t, 4H, J=4.58 Hz), 1.22 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[CH3:18][O:19][C:20]1[CH:21]=[C:22](O)[CH:23]=[CH:24][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)C)=O)=O)(C)C>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([O:10][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([O:19][CH3:18])[CH:25]=2)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COc1cccc(O)c1
Reactant: COC(=O)[C@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@@H](Oc2cccc(OC)c2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.6 %

Procedure:
To an ice cold solution of (2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (1.15 g, 4.69 mmol) and 3-methoxyphenol (0.56 mL, 5.158 mmol) in THF (10 mL) is added triphenylphosphine (1.84 g, 7.03 mmol) followed by the dropwise addition of diisopropyl-azodicarboxylate (1.40 mL, 7.03 mmol). Warm to room temperature and stir for 18 h. Dilute the reaction with ethyl acetate and wash with 1 N HCl, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate) and purify (silica gel chromatography, eluting with dichloromethane/ethyl acetate mixtures) to give the title compound (0.57 g, 34%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([Cl:17])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=O)C.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O>[Cl:17][C:7]1[C:6]([CH2:4][OH:3])=[CH:11][N:10]=[C:9]2[N:12]([CH2:15][CH3:16])[N:13]=[CH:14][C:8]=12
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCn1ncc2c(Cl)c(CO)cnc21
Reaction time: 2 h

Procedure:
10.02 g. of 4-Chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (0.04 mol.) are dissolved in 100 ml. of anhydrous tetrahydrofuran. Nitrogen is passed through the flask and while stirring and cooling with tap water, 1.14 g. of lithium aluminium hydride is added a bit at a time in order to keep the reaction temperature at about 25°C. Stirring is continued for an additional two hours at room temperature. The reaction mixture is allowed to stand over night. Then 3 N-hydrochloric acid (60 ml) is added and the mixture is evaporated in vacuo. The residue is dissolved in water, neutralized with aqueous sodium hydroxide (10%) to pH 7 and extracted several times with ether. The combined etheral extracts are dried with sodium sulfate, evaporated and the residual oil (6.7 g. (79%)) is distilled in vacuo, b.p. 0.4 mm 137°-140°, providing a quickly crystallizing oil. The compound is recrystallized from hexane, to yield the 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-methanol, m.p. 56°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24](=[O:28])[N:23]([CH3:29])[CH:22]=2)[C:9]2[CH:10]=[N:11][N:12]([CH:17]([CH3:19])[CH3:18])[C:13]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[CH:10]=[N:11][N:12]([CH:17]([CH3:18])[CH3:19])[C:13]=3[C:14](=[O:16])[N:20]2[C:21]2[CH:26]=[C:25]([CH3:27])[C:24](=[O:28])[N:23]([CH3:29])[CH:22]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(NC(c2ccc(Cl)cc2)c2cnn(C(C)C)c2C(=O)O)cn(C)c1=O
Solvent: CCOC(C)=O
Product: Cc1cc(N2C(=O)c3c(cnn3C(C)C)C2c2ccc(Cl)cc2)cn(C)c1=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-((4-chlorophenyl)((1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)amino)methyl)-1-isopropyl-1H-pyrazole-5-carboxylic acid (Step 36.5). tR: 4.31 min (HPLC 1); tR: 0.97 min (LC-MS 2); ESI-MS: 397 [M+H]+ (LC-MS 2); Rf=0.22 (EtOAc); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47-1.56 (m, 6H) 1.91 (s, 3H) 3.34 (s, 3H) 4.73-4.87 (m, 1H) 6.09 (s, 1H) 7.18-7.25 (m, 2H) 7.32-7.38 (m, 3H) 7.40 (s, 1H) 7.71 (d, J=2.7 Hz, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([S:11]([O:14][C:15]3[CH:16]=[C:17]([CH:34]=[C:35]([CH3:37])[CH:36]=3)[O:18][CH2:19][CH2:20][CH2:21][O:22][N:23]3C(=O)C4=CC=CC=C4C3=O)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[BH4-].[Na+].Cl.[OH-].[Na+]>C(O)C.O.O1CCCC1>[CH:1]1[C:10]2[C:5](=[C:6]([S:11]([O:14][C:15]3[CH:16]=[C:17]([CH:34]=[C:35]([CH3:37])[CH:36]=3)[O:18][CH2:19][CH2:20][CH2:21][O:22][NH2:23])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: Cc1cc(OCCCON2C(=O)c3ccccc3C2=O)cc(OS(=O)(=O)c2cccc3cnccc23)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCCCON)cc(OS(=O)(=O)c2cccc3cnccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
To a solution of N-[3-[3-(5-isoquinolinylsulfonyloxy)-5-methylphenoxy]propoxy]phthalimide (570 mg, 1.1 mmol), as prepared in the preceding step, in ethanol (20 mL), tetrahydrofuran (10 mL), and water (10 mL) was added sodium borohydride (230 mg, 6.0 mmol). The reaction mixture was stirred at ambient temperature overnight. The mixture was acidified (pH 1-2) with 2 N HCl and heated at 50° C. for 2 hours. After cooling to room temperature, 2 N NaOH was added to adjust the pH to 8-9. The mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine (50 mL) and dried over Na2SO4. After removing the solvent, the residue was purified by flash column chromatography (ethyl acetate) to give the title compound as a colorless oil (110 mg, 26%). 1H-NMR (300 MHz, CDCl3) δ9.42 (s, 1H), 8.81 (d, J=6.1 Hz, 1H), 8.54 (d, J=6.1 Hz, 1H), 8.33 (m, 2H), 7.67 (t, J=7.8 Hz, 1H), 6.55 (s, 1H), 6.28 (s, 1H), 6.23 (s, 1H), 3.81 (t, J=6.3 Hz, 2H), 3.74 (t, J=6.1 Hz, 2H), 2.15 (s, 3H), 1.94 (m, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C19H20N2O5S: 389.1 (M+H), 411.1 (M+Na). Found: 389.3, 411.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:22])([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[SH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[S:21][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])([OH:22])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc(F)ccc2S)CC1
Reactant: Cc1ccccc1I
Product: Cc1ccccc1Sc1ccc(F)cc1C1(O)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Prepared from 4-hydroxy-4-(2-mercapto-5-fluoro-phenyl)-piperidine-1-carboxylic acid tert-butyl ester and 1-iodo-2-methyl-benzene.