Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:11]2[N:16]=[C:15]([O:17][CH3:18])[N:14]=[C:13]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH:12]=2)[CH:7]=[CH:8][C:9]=1[F:10].C(N(CC)CC)C.[CH3:37][O:38][CH2:39][C:40](Cl)=[O:41]>C(Cl)Cl>[F:10][C:9]1[CH:8]=[CH:7][C:6]([C:11]2[CH:12]=[C:13]([NH:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[N:14]=[C:15]([O:17][CH3:18])[N:16]=2)=[CH:5][C:4]=1[CH2:3][NH:2][C:40](=[O:41])[CH2:39][O:38][CH3:37]
Reactant: COc1ccc(CCNc2cc(-c3ccc(F)c(CN)c3)nc(OC)n2)cc1
Reactant: COCC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)NCc1cc(-c2cc(NCCc3ccc(OC)cc3)nc(OC)n2)ccc1F
Reaction time: 15 h

Procedure:
A solution of [6-(3-aminomethyl-4-fluoro-phenyl)-2-methoxy-pyrimidin-4-yl]-[2-(4-methoxy-phenyl)-ethyl]-amine [200 mg, 0.52 mmol, see example 27] and triethylamine (264 mg, 2.61 mmol) in DCM (5 mL) is treated with methoxyacetyl chloride (114 mg, 1.1 mmol) at 0° C. After 15 hours at 4° C. in a refrigerator, the mixture is quenched with water (10 mL) filtered through Chem-Elut. The filtrate is concentrated, and subjected to chromatography on silica gel eluting with 10% MeOH in DCM to give N-(2-fluoro-5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-2-methoxy-acetamide, which is treated with saturated solution of hydrogen chloride in EtOAc followed by lyophilization to afford N-(2-Fluoro-5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzyl)-2-methoxy-acetamide hydrochloride [190 mg, 74%, Example 28]. LCMS: RT=2.35 minutes, MS: 455 (M+H). IC50=9 nM
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.C([Li])CCC.[CH2:16]([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)[CH:17]=[CH2:18]>O1CCCC1.[Cl-].[Na+].O>[OH:25][C:22]1([C:3]2[S:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]=2[CH3:1])[CH2:23][CH2:24][N:19]([CH2:16][CH:17]=[CH2:18])[CH2:20][CH2:21]1
Reactant: Cc1csc2ccccc12
Reactant: C=CCN1CCC(=O)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCN1CCC(O)(c2sc3ccccc3c2C)CC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 83.1 %

Procedure:
Scheme IA, step A: To a solution of 3-methylbenzothiophene (2.863 g, 19.3 mmol) in tetrahydrofuran (80 mL) at −78° C. was added a solution of n-butyllithium (13.3 mL, 21.2 mmol, 1.6 M in hexanes). The solution was warmed to 0° C. for one hour then recooled to −78° C. A solution of 1-(2-propenyl)-4-piperidone (2.957 g, 21.2 mmol) in tetrahydrofuran was added dropwise and the mixture was warmed to 20° C. After stirring for 18 hours at 20° C. the mixture was diluted with brine and extracted 3 times with ethyl acetate. The combined organics were dried over sodium sulfate then filtered and evaporated. The residue was purified using silica gel chromatography (dichloromethane/5% methanol in dichloromethane gradient eluent) to give 4.61 g (83%) of the intermediate title compound as a white amorphous solid. FDMS m/e=288 (M++1).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:28]=[C:29]3[NH:35][CH2:34][C:33]4([CH2:40][CH2:39][O:38][CH2:37][CH2:36]4)[C:30]3=[N:31][CH:32]=2)[CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([N:35]1[C:29]3[C:30](=[N:31][CH:32]=[C:27]([N:24]4[CH2:25][CH2:26][O:21][CH2:22][CH2:23]4)[CH:28]=3)[C:33]3([CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH2:34]1)=[C:3]([CH3:20])[C:4]([N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19])=[N:5]2
Reactant: c1nc2c(cc1N1CCOCC1)NCC21CCOCC1
Reactant: Cc1c(N2CCCC2=O)nc2cc(F)cc(F)c2c1Br
Solvent: Cc1ccccc1
Product: Cc1c(N2CCCC2=O)nc2cc(F)cc(F)c2c1N1CC2(CCOCC2)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y using 1-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)pyrrolidin-2-one (60.0 mg, 0.180 mmol) and 6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] in toluene to give 1-(5,7-difluoro-3-methyl-4-(6′-(4-morpholinyl)-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-1′(2′H)-yl)-2-quinolinyl)-2-pyrrolidinone. 1H NMR (400 MHz, chloroform-d) δ ppm 7.61 (1H, d, J=2.3 Hz), 7.49 (1H, ddd, J=9.4, 2.5, 1.4 Hz), 6.95 (1H, ddd, J=11.8, 8.9, 2.5 Hz), 5.86 (1H, d, J=2.2 Hz), 4.19-4.31 (1H, m), 4.02-4.19 (4H, m), 3.84 (1H, d, J=9.2 Hz), 3.70-3.78 (4H, m), 3.56 (2H, qd, J=11.5, 2.5 Hz), 2.94-3.12 (4H, m), 2.64 (2H, t, J=8.0 Hz), 2.24-2.40 (4H, m), 2.17 (3H, s), 1.82 (1H, d, J=13.5 Hz), 1.69 (1H, dd, J=13.9, 2.2 Hz). Mass Spectrum (ESI) m/e=536.2 (M+1).
Reaction SMILES: [ClH:1].Cl.Cl.[CH2:4]([C:8]1[N:9]=[N:10][C:11]([O:28][CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:18]([NH2:20])[CH:19]=1)[CH2:5][CH2:6][CH3:7].[C:36]([Cl:39])(=[O:38])[CH3:37].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOCC>[ClH:39].[ClH:1].[CH2:4]([C:8]1[N:9]=[N:10][C:11]([O:28][CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:18]([NH:20][C:36](=[O:38])[CH3:37])[CH:19]=1)[CH2:5][CH2:6][CH3:7]
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(N)c1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
To a solution of 5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-phenylamine trihydrochloride (0.2 mmol, 110 mg) in DCM (1.0 mL) at 0° C. was added acetyl chloride (0.4 mmol, 29 μL), DIEA (0.4 mmol, 70 μL) and DMAP (5 mg). And the mixture was stirred at room temperature for 1 hour. It was then condensed in vacuo and the residue was purified by silica gel chromatography (DCM to DCM+10% 2N NH3 in MeOH) to give a colorless sticky solid, which was dissolved in DCM (1.0 mL), 2N HCl in ether (1.0 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to provide the title compound (61 mg). LCMS: m/z 482 [M+1]. 1H NMR (400 MHz, CDCl3): δ 8.43 (1H, s), 7.89 (1H, s), 6.97 (2H, s), 6.81 (1H, s), 5.60 (1H, bs), 4.37-4.43 (1H, m), 3.10-3.45 (4H, m), 2.90-2.95 (2H, m), 2.81 (3H, s), 2.35-2.61 (4H, m), 2.23 (3H, s), 1.25-1.87 (14H, m), 0.83 (3H, t).
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]([N:22]([C:29](=[O:31])[CH3:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH:13]2[CH3:32])=[O:11])=[CH:6][CH:5]=1.[Li].O>CO>[C:29]([N:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C@H:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]([C:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:33])=[O:2])=[CH:9][CH:8]=2)=[O:11])[C@@H:13]([CH3:32])[CH2:14]1)(=[O:31])[CH3:30]
Reactant: COC(=O)c1ccc(C(=O)N2c3ccccc3C(N(C(C)=O)c3ccccc3)CC2C)cc1
Agent: [Li]
Solvent: O
Solvent: CO
Product: CC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(C(=O)O)cc2)c2ccccc21
Yield: 103.3 %

Procedure:
A solution of 4-[4-(Acetyl-phenyl-amino)-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl]-benzoic acid methyl ester (50 mg) and lithium hydroxyde (0.283 mmol) in methanol (2 ml) and water (1 ml) was stirred at room temperature overnight. After addition of water, the mixture was washed with dichloromethane. The aqueous layer was acidified and then extracted using ethyl acetate. The organic layer is separated and dried over sodium sulfate. The solvent was removed to give the title compound (50 mg).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:24][CH2:25][C@H:26]([OH:46])[C:27]4[CH:36]=[CH:35][C:34]([O:37]CC5C=CC=CC=5)=[C:33]5[C:28]=4[CH:29]=[CH:30][C:31](=[O:45])[NH:32]5)=[CH:18][CH:17]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>ClCCl.CO.[Pd]>[C:1]1([C:7]2[CH:8]=[C:9]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][NH:24][CH2:25][C@H:26]([OH:46])[C:27]4[CH:36]=[CH:35][C:34]([OH:37])=[C:33]5[C:28]=4[CH:29]=[CH:30][C:31](=[O:45])[NH:32]5)=[CH:20][CH:21]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(Nc2ccc(CCNC[C@H](O)c3ccc(OCc4ccccc4)c4[nH]c(=O)ccc34)cc2)cc1-c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(Nc2ccc(CCNC[C@H](O)c3ccc(O)c4[nH]c(=O)ccc34)cc2)cc1-c1ccccc1

Procedure:
The free base form of compound 1 was prepared from the protected intermediate PP. To a solution of N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-benzyloxy-2(1H)-quinolinon-5-yl)ethylamine (PP) prepared by the process of Examples 1 and 2 (43.0 g, 70 mmol) in 50% dichloromethane/methanol (200 mL) was added 20% palladium on carbon (8.6 g). The reaction was stirred vigorously under one atmosphere of hydrogen for 18 h. The solids were filtered off over Celite and washed with 50% dichloromethane/methanol (4×25 mL). The combined filtrates were evaporated to dryness to give compound 1 (38 g, purity 92% by HPLC ratio) as a gray solid.
Reaction SMILES: [C:1]([NH:9][C:10]([N:12]1[C:16]2([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([Br:36])[CH:31]=3)[CH2:17][N:18]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:19][CH:15]2[CH2:14]O1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C>C(O)(=O)C.[Zn]>[C:1]([NH:9][C:10]1[S:11][CH2:14][CH:15]2[CH2:19][N:18]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])[CH2:17][C:16]2([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Br:36])[CH:31]=2)[N:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(=S)N1OCC2CN(C(=O)OCc3ccccc3)CC21c1cccc(Br)c1)c1ccccc1
Agent: CC(C)=C(Cl)N(C)C
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C(NC1=NC2(c3cccc(Br)c3)CN(C(=O)OCc3ccccc3)CC2CS1)c1ccccc1
Yield: 102.4 %

Procedure:
To a solution of benzyl 1-(benzoylcarbamothioyl)-6a-(3-bromophenyl)-3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole-5-carboxylate (1.9 g, 3.3 mmol) in acetic acid (30 mL) is added powered zinc (2.0 g, 30 mmol). The resultant suspension is sonicated for 2 hours before being filtered through a pad of diatomaceous earth. The diatomaceous earth pad is washed with ethyl acetate. The combined filtrates are concentrated to dryness then diluted with ethyl acetate (100 mL) and washed with saturated sodium bicarbonate (100 mL). The aqueous layer is re-extracted with ethyl acetate (50 mL) and chloroform (50 mL). The combined organic layers are dried over magnesium sulfate, filtered, and concentrated. The residue is then dissolved in dichloromethane (30 mL) and treated with 1-chloro-N,N,2-trimethylpropenylamine (1.0 mL, 7.6 mmol). The resultant solution is stirred at ambient temperature for 3.3 hours and concentrated to dryness. The residue is purified by silica gel flash chromatography, eluting with gradient of ethyl acetate/dichloromethane (0 to 40%) to give the title compound (1.86 g, 100%). ES/MS (m/e): (79Br/81Br) 550/552 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:17])[CH:13]=[CH:12]2)[CH3:5].[Se](=O)=[O:19]>O1CCOCC1.O>[CH3:1][O:2][CH2:3][CH:4]([O:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH:17]=[O:19])[CH:13]=[CH:12]2)[CH3:5]
Reactant: O=[Se]=O
Reactant: COCC(C)Oc1cccc2ccc(C)nc12
Solvent: C1COCCO1
Solvent: O
Product: COCC(C)Oc1cccc2ccc(C=O)nc12
Yield: 82.5 %

Procedure:
To 8-(1-methoxypropan-2-yloxy)-2-methylquinoline (1.0 g, 4.32 mmol) in dioxane/water (10/1 mL) was added selenium dioxide (0.576 g, 5.19 mmol) and the reaction was heated to reflux for 2 hours. The reaction was concentrated to dryness and the residue purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 8-(1-methoxypropan-2-yloxy)quinoline-2-carbaldehyde (874 mg, 82.4% yield) as a solid
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])[CH2:6][CH2:7][CH3:8].[N+]([O-])(O)=O.S(=O)(=O)(O)O>S(=O)(=O)(O)O>[N+:1]([C:12]1[CH:11]=[C:10]([C:5](=[O:9])[CH2:6][CH2:7][CH3:8])[CH:15]=[CH:14][CH:13]=1)([O-:4])=[O:2]
Reactant: CCCC(=O)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCCC(=O)c1cccc([N+](=O)[O-])c1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
Concentrated nitric acid (40 ml) was added cautiously with cooling to concentrated sulphuric acid (100 ml) maintaining a temperature of −5° C. Another solution of butyrophenone (59.2 g, 0.47 mol) in concentrated sulphuric acid (140 ml) was made up with shaking, keeping the temperature at −5° C. (+/−5° C.). The former nitric acid/sulphuric acid solution was added portionwise over 45 min to the latter solution of ketone in sulphuric acid keeping the temperature at −10° C.+/−5° C. during the addition and for a subsequent 30 min. The reaction mixture was poured onto crushed ice (1.5 1) and then extracted with diethyl ether (200 ml and then 3×100 ml). The combined organic extracts were washed with water and then aqueous saturated sodium hydrogen carbonate solution and dried (MgSO4) before concentrating in vacuo. The crude yellow oil crystallised after 16 h and was then purified by chromatography on silica gel (1 kg) eluting with hexane:diethyl ether (9:1) to give the title compound as a white solid (9.1 g, 10%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[N:6]1.Br[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=1>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[C:18]([NH:19][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)=[CH:17][CH:16]=[C:15]([CH3:20])[N:14]=2)=[O:12])=[N:6]1
Reactant: Fc1cccc(Br)c1
Reactant: COCCn1ccc(NC(=O)c2nc(C)ccc2N)n1
Product: COCCn1ccc(NC(=O)c2nc(C)ccc2Nc2cccc(F)c2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid [1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-amide in accordance with the general method of example, step using 1-Bromo-3-fluorobenzene instead of 3-bromopyridineto yield the final compound as a yellow oil, MS (ISP): m/e=370.3 (M+H+).
Reaction SMILES: [CH:1]1([CH2:6][N:7]([C:10]2[N:15]=[C:14]3[CH:16]=[CH:17][N:18]([CH3:19])[C:13]3=[CH:12][C:11]=2[C:20]#N)[CH2:8][CH3:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl.C(N(CC)CC)C.ClC(OCC)=[O:34].[BH4-].[Na+]>COC(O)C.C1COCC1.CCO>[CH:1]1([CH2:6][N:7]([C:10]2[N:15]=[C:14]3[CH:16]=[CH:17][N:18]([CH3:19])[C:13]3=[CH:12][C:11]=2[CH2:20][OH:34])[CH2:8][CH3:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)Cl
Reactant: CCN(CC1CCCC1)c1nc2ccn(C)c2cc1C#N
Agent: COC(C)O
Agent: Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCO
Product: CCN(CC1CCCC1)c1nc2ccn(C)c2cc1CO
Temperature: 130 °C
Reaction time: 60 h

Procedure:
A solution of 5-[N-(cyclopentylmethyl)-N-ethylamino]-methyl-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile (0.30 g, 1.06 mmol) in methoxyethanol (6 mL) is treated with 5N NaOH aq. (6 mL). The reaction mixture is stirred at 130° C. for 60 hours. After cooling to room temperature, the mixture is acidified with 1N HCl. The mixture is extracted with CH2Cl2, dried over sodium sulfate and concentrated in vacuo. To a solution of the obtained residue in THF (5 mL) is added triethylamine (0.14 mL, 1.00 mmol) and ethyl chloroformate (0.10 mL, 1.00 mmol) at room temperature. After stirring for 1 h, the resulting precipitate is removed by filtration, and the filtrate is concentrated in vacuo. To a solution of the residue in EtOH (3 mL) is added sodium borohydride (41 mg, 1.08 mmol) at 0° C. After stirring for 1 h, the reaction is quenched with H2O. The mixture is extracted with EtOAc and washed with brine. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by silica-gel column chromatography to give {5-[N-(cyclopentylmethyl)-N-ethylamino]-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl}methanol as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[S:10][CH:9]=2)=[CH:3][CH:2]=1.[H-].[Na+].S(OC)(O[CH3:23])(=O)=O>CN(C)C=O>[CH3:23][N:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[C:8]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[S:10][CH:9]=1
Reactant: c1cnc2scc(Nc3ccncc3)c2c1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccncc1)c1csc2ncccc12
Temperature: 0 °C
Yield: 70.6 %

Procedure:
A solution of 3-(4-pyridinylamino)thieno[2,3-b]pyridine (4 g) in 25 mL of dimethylformamide was added to an ice-cooled suspension of sodium hydride (60% oil dispersion, 0.85 g, washed with heptane) in 5 mL of dimethylformamide. After anion formation was completed a solution of dimethyl sulfate (2.4 g) in 5 mL of dimethylformamide was added. After one hour the reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride, and then was dried (anhydrous magnesium sulfate), filtered and evaporated to 4 g of a solid. Elution through silica with 10% methanol in ethyl acetate via flash column chromatography afforded 3 g of a solid, m.p. 143°-145° C. Recrystallization from acetonitrile afforded 2.1 g of crystals, m.p. 150°-152° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9](O)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C1(=O)O[CH2:16][CH2:15][O:14]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[OH:14][CH2:15][CH2:16][C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]2[C:8]=1[N:7]=[CH:6][CH:5]=[CH:4]2
Reactant: Oc1ccc(Cl)c2cccnc12
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OCCc1ccc(Cl)c2cccnc12
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A mixture of 5-chloro-8-hydroxyquinoline (1 mmol, 180 mg), ethylene carbonate (2 mmol, 180 mg) and Cs2CO3 (0.6 mmol, 195 mg) in dry DMF (10 mL) was stirred vigorously at 120° C. for 3 h. DMF was evaporated under high-vacuum and the residue was dissolved in water (15 mL), extracted twice with dichloromethane (15 mL), and the residue left after evaporation of dichloromethane was chromatographed over silica gel (eluent: 4:1 hexanes-EtOAc). A biege colored solid was obtained (174 mg, 78%).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][C:40](O)=[O:41])=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C@@H:47]([CH3:50])[CH2:48][OH:49].Cl.NCC(N)=O>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:41])[NH:46][C@@H:47]([CH3:50])[CH2:48][OH:49])=[CH:35][CH:36]=3)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: C[C@H](N)CO
Agent: Cl
Agent: NCC(N)=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)N[C@@H](C)CO)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 1 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and (S)-2-amino-1-propanol instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole and glycinamide hydrochloride, respectively.
Reaction SMILES: C([Li])CCC.[Cl-].[CH3:7][O:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]([C:40]2[C:41]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=3)=[N:42][N:43]([CH2:53][CH3:54])[C:44]=2[NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:37][CH:38]=O)=[CH:32][CH:31]=1.C([O-])(O)=O.[Na+]>CCOC(C)=O.C1COCC1>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]([C:40]2[C:41]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][N:56]=3)=[N:42][N:43]([CH2:53][CH3:54])[C:44]=2[NH:45][C:46](=[O:52])[O:47][C:48]([CH3:50])([CH3:51])[CH3:49])[CH2:37][CH:38]=[CH:7][O:8][CH3:9])=[CH:32][CH:31]=1
Reactant: CCn1nc(-c2ccccn2)c(C(CC=O)c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCn1nc(-c2ccccn2)c(C(CC=COC)c2ccc(Br)cc2)c1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 82.1 %

Procedure:
n-Butyllithium (1.6 M solution in hexanes, 0.980 mL, 1.57 mmol) was added dropwise over about 10 min to a slurry of (methoxymethyl)triphenylphosphonium chloride (0.550 g, 1.60 mmol) and THF (3.00 mL) under N2 at about −78° C. After about 5 min, the reaction vessel was transferred to an ice water bath. After stirring for about 10 min at about 0° C., the dark red reaction mixture was cooled to about −78° C. A solution of tert-butyl (4-(1-(4-bromophenyl)-3-oxopropyl)-1-ethyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl)carbamate (0.161 g, 0.168 mmol) and THF (1.50 mL) was added over about 5 min. After about 5 min, the reaction mixture was transferred to an ice bath. After about 1 h, saturated aqueous NaHCO3 (5 mL) and EtOAc (5 mL) were added respectively. The ice bath was removed. The layers were separated and the aqueous layer was extracted with EtOAc (5 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel using a gradient of 10-50% EtOAc in heptane. The fractions containing product were combined and concentrated under reduced pressure to afford tert-butyl (4-(1-(4-bromophenyl)-4-methoxybut-3-en-1-yl)-1-ethyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl)carbamate (0.0726 g, 0.138 mmol, 82%) as an ivory solid. Compound was about a 2.2:1 mixture of olefin isomers. LC-MS (Table 1, Method g) Rt=2.83 min; m/z 527 and 529 (M+H)+(Major) and Rt=2.87 min; m/z 527 and 529 (M+H)+ (Minor).
Reaction SMILES: N#N.[Cl:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([Cl:11])[C:5]=1[C@H:12]([O:14][C:15]1[C:16]2[O:24][CH:23]=[C:22](Br)[C:17]=2[CH:18]=[N:19][C:20]=1[NH2:21])[CH3:13].[C:26]([N:30]1[CH2:35][CH:34]=[C:33]([Sn](C)(C)C)[CH2:32][CH2:31]1)([CH3:29])([CH3:28])[CH3:27].CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1>C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO.C(N(CC)CC)C.CN(C=O)C>[C:26]([N:30]1[CH2:31][CH:32]=[C:33]([C:22]2[C:17]3[CH:18]=[N:19][C:20]([NH2:21])=[C:15]([O:14][C@@H:12]([C:5]4[C:6]([Cl:11])=[CH:7][CH:8]=[C:9]([F:10])[C:4]=4[Cl:3])[CH3:13])[C:16]=3[O:24][CH:23]=2)[CH2:34][CH2:35]1)([CH3:29])([CH3:28])[CH3:27]
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: CC(C)(C)N1CC=C([Sn](C)(C)C)CC1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: N#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C(C)(C)C)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 115 °C

Procedure:
In a two necked RB flask (50 mL), equipped with a N2 in let, a water condenser, and a magnetic stirrer, were placed 7-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-3-bromofuro[3,2-c]pyridine-6-amine (230 mg, 0.55 mmol), 1-tert-Butyl-1,2,3,6-tetrahydro-4-(trimethylstannyl)pyridine (240 mg, 0.79 mmol), tris(dibenzylideneacetone)dipalladium(0) (100 mg), tri-O-tolylphosphine (26 mg), DMF (10 mL) and triethylamine (1.0 mL). This reaction mixture was heated at 114-116° C. for 4 h. The TLC (10% MeOH in DCM) indicated that the starting material was consumed. From the reaction mixture DMF was removed under reduced pressure, water was added to the residue, and the mixture was extracted with DCM. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was purified on silica gel column chromatography eluting with 2-5% methanol in dichloromethane to give the title compound. 1H NMR (CDCl3, 300 MHz): δ=1.19 (s, 9H), 1.81 (d, J=6.6 Hz, 3H), 2.42 (br, m, 2H), 2.80 (m, 2H), 3.40 (br, m, 2H), 4.75 (br, 2H), 6.22 (br, 1H), 6.50 (m, 1H), 7.05 (t, J=8.4 Hz, 1H), 7.25 (m, J=8.4 Hz, 1H), 7.34 (s, 1H), 8.23 (s, 1H). EI-MS 478/480 (MH+).