Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:15]#[N:16])[CH2:8][CH2:9]CS([O-])(=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[ClH:19].[N:20]1([C:26]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[NH:34][C:33](=[O:38])[CH2:32][CH2:31]3)=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(N(CC)CC)C>[ClH:19].[C:15]([CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:8][CH2:9][N:23]1[CH2:24][CH2:25][N:20]([C:26]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[NH:34][C:33](=[O:38])[CH2:32][CH2:31]3)=[O:27])[CH2:21][CH2:22]1)#[N:16]
Reactant: N#CC(CCCS(=O)(=O)[O-])c1ccccc1
Reactant: O=C1CCc2cc(C(=O)N3CCNCC3)ccc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CC(CCN1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1)c1ccccc1
Reaction time: 0.5 h

Procedure:
3.8 Grams of 3-phenyl-3-cyanopropylmesylate was dissolved in 60 ml of dimethylformamide, then to this solution was added 4.0 g of sodium iodide and stirred at 60° C. to 70° C. for 30 minutes. Next, 5.8 g of 6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril hydrochloride and 5.5 ml of triethylamine were added thereto and heated at 70° C. to 80° C. for 5 hours. The solvent was removed by evaporation, to the residue thus obtained was added 5%-potassium carbonate aqueous solution, then the mixture was extracted with chloroforom. The extract was washed with water, and an aqueous solution saturated with sodium chloride, and dried with magnesium sulfate. After removal of the solvent by evaporation, the residue thus obtained was purified by means of a silica gel column chromatography (eluent: dichloromethane →dichloromethane:methanol =100:5), then the desired product was converted into a hydrochloride, recrystallized from ethanol-water to yield 2.0 g of 6-[4-(3-cyano-3-phenylpropyl)-1-piperazinylcarbonyl] -3,4-dihydrocarbostyril monohydrochloride. Colorless powdery substance. Melting point: 249° C.-251° C. (decomp.).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Cl)[N:11]=1.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: Clc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(COc2cccc(OCc3ccccc3)n2)cc1

Procedure:
Benzyl alcohol (5.1 g; 0.05 mols) was reacted with 2,6-dichloropyridine (3.5 g; 0.024 mols) utilizing sodium hydride (1.2 g) and, as solvent, dimethylformamide by the procedure of Example 1 above. Usual work up, chromatography and recrystallisation gave 2,6-dibenzyloxypyridine as a colorless solid (5.5 g; 81%). Melting point: 74° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[C:6]([CH3:9])[C:5]([O:10][CH2:11][O:12][CH2:13][CH3:14])=[CH:4][C:3]=1[CH:15]([OH:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].Br[CH2:23]Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:13]([O:12][CH2:11][O:10][C:5]1[CH:4]=[C:3]([CH:15]([OH:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:2]2[O:1][CH2:23][O:8][C:7]=2[C:6]=1[CH3:9])[CH3:14]
Reactant: ClCBr
Reactant: CCOCOc1cc(C(O)C(=O)OCC)c(O)c(O)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOCOc1cc(C(O)C(=O)OCC)c2c(c1C)OCO2
Yield: 43.5 %

Procedure:
By following Example 9 procedure, 0.19 g of ethyl 2-(2,3-dihydroxy-5-(ethoxymethoxy)-4-methylphenyl)-2-hydroxyacetate is reacted with 1.0 g of bromochloromethane and 0.65 g of cesium carbonate in DMF medium to get 0.086 g of title compound as syrup. IR (neat): 3481, 2978, 2928, 1739, 1492, 1435, 1397, 1365, 1255, 1209, 1117, 1058, 984, 936, 847, and 718 cm−1. 1H-NMR (CDCl3, 400 MHz): δ 6.51 (s, 1H, Ar. H), 5.96 (d, J=1.2 Hz, 1H, OCH2O), 5.92 (d, J=1.2 Hz, 1H, OCH2O), 5.17 (br. s., exch. with D2O, 1H, OH), 5.15 (d, J=1.6 Hz, 2H, ArOCH2O), 4.19-4.30 (m, 2H, OCH2OCH2CH3), 3.72 (q, J=6.8 Hz, 2H, COOCH2CH3), 2.10 (s, 3H, ArCH3), 1.25 (t, J=7.2 Hz, 3H, OCH2CH3), 1.23 (t, J=7.2 Hz, 3H, OCH2CH3). 13C NMR (CDCl3, 100 MHz): δ 173.04 (CO), 151.26 (C-6), 146.70 (C-1a), 139.58 (C-3a), 116.38 (C-4), 110.94 (C-7), 105.55 (C-5), 101.30 (C-2), 94.43 (OCH2O), 68.83 (CHOH), 64.29 (OCH2CH3), 62.17 (OCH2CH3), 15.09 (OCH2CH3), 14.04 (OCH2CH3), 8.96 (ArCH3)
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([N:7]([CH2:35][CH3:36])[C:8]1[CH:34]=[CH:33][C:11]([CH:12]=[N:13][N:14](CC2C=CC(C)=CC=2)[C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)[CH3:6].CO>C(Cl)Cl>[CH2:35]([N:7]([CH2:5][CH3:6])[C:8]1[CH:9]=[CH:10][C:11]([CH:12]=[N:13][NH:14][C:15](=[O:24])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:33][CH:34]=1)[CH3:36]
Reactant: CCN(CC)c1ccc(C=NN(Cc2ccc(C)cc2)C(=O)c2ccc(OC)cc2)cc1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)c1ccc(C=NNC(=O)c2ccc(O)cc2)cc1
Temperature: 0 °C
Yield: 54.2 %

Procedure:
BBr3 (2 mL, 1.0 M solution in dichloromethane) was added dropwise to a cooled (0° C.) solution of 4-Methoxy-benzoic acid N′-(4-diethylamino-benzylidene)-N-(4-methyl-benzyl)-hydrazide (compound 2) (0.33 g, 0.00077 mol) in dried CH2Cl2 (5 mL) at −78° C. under Ar. After stirring for an additional hour at 0° C., the reaction mixture was warmed to room temperature and treated with 1:1 CH3OH:CH2Cl2 (10 mL) with cooling and stirred 2 hr at ambient temperature. Concentration of the mixture gave oil, which was purified by flash chromatography 9:1 CH2Cl2/MeOH to give the desired product as a solid 0.13 g in 41% yield, mp: 228.4° C. 1H NMR (CD3OD) δ 8.16 (s, 1H), 7.81 (d, 2H), 7.63 (d, 2H), 6.88 (d, 2H), 6.72 (d, 2H), 3.87 (d, 1H), 3.46 (q, 4H), 1.19 (t, 6H). 13C NMR (CD3OD) δ 162.2, 158.2, 147.1, 146.7, 126.3, 126.2, 120.7, 117.7, 111.9, 110.6, 108.0, 41.1, 8.6. Anal. Calcd for C18H21N3O2.¼H2O: C, 68.43; H, 6.70; N, 13.31. Found: C, 68.36; H, 6.99; N, 13.58.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:47])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH:14][C:15](=[O:46])[CH:16]([NH:28]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(NCC)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:47])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH:14][C:15](=[O:46])[CH:16]([NH2:28])[CH2:17][CH2:18][CH2:19][NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22]
Reactant: COC(=O)c1ccc(C(=O)OC)c(NC(=O)C(CCCNC(=O)OC(C)(C)C)NC(=O)OCC2c3ccccc3-c3ccccc32)c1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)OC)c(NC(=O)C(N)CCCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 125.8 %

Procedure:
The compound (236.0 mg) obtained in Example 14-1 was dissolved in anhydrous DMF (4.7 ml) and added with diethylamine (4.7 ml) and the whole was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (194.7 mg) as a colorless viscous solid.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)=[CH:4][C:5]#[N:6].Br[CH2:18][C:19](=O)[C:20]([F:23])([F:22])[F:21]>C1(C)C=CC=CC=1.C(O)(=O)C.C(OCC)(=O)C>[CH3:1][N:2]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:4]([C:5]#[N:6])=[C:3]1[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1
Reactant: CNC(=CC#N)c1ccc2ccccc2c1
Reactant: O=C(CBr)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cc(C#N)c1-c1ccc2ccccc2c1

Procedure:
A solution of β-(methylamino)-2-naphthaleneacrylonitrile (2.5 g, 0.012 mol) in toluene and acetic acid is treated dropwise with 3-bromo-1,1,1-trifluoro-2-propanone (2.3 g, 0.012 mol) at room temperature, heated at reflux temperature for 6 hours, cooled and diluted with ethyl acetate. The organic phase is washed sequentially with water and 5N NaOH, dried (Na2SO4) and concentrated in vacuo to give a brown oil residue. The residue is flash chromatographed (silica gel, hexanes/ethyl acetate, 80/20) to give the title compound as a yellow solid, mp 134° C., identified by mass spectral, IR and NMR analyses.
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][C:8]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:19][C:20]([N:22]1[CH2:26][C@@H:25]([F:27])[CH2:24][C@H:23]1[CH2:28][O:29][C:30]1[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][CH:31]=1)=[O:21].[OH-].[Na+]>C1COCC1>[F:1][C:2]1[C:10]2[O:9][C:8]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:19][C:20]([N:22]1[CH2:26][C@@H:25]([F:27])[CH2:24][C@H:23]1[CH2:28][O:29][C:30]1[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:38][CH:39]=1)=[O:21]
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@H](F)CN2C(=O)Cc2ccc3nc(Nc4ccccc4C)oc3c2F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)N3C[C@@H](F)C[C@H]3COc3ccc(C(=O)O)cc3)c(F)c2o1
Temperature: 25 °C
Reaction time: 14 h
Yield: 82.6 %

Procedure:
Methyl 4-((2S,4S)-1-(7-fluoro-2-(2-methylphenylamino)-6-benzoxazolylacetyl)-4-fluoro-2-pyrrolidinylmethoxy)benzoate (490 mg, 0.915 mmol) was dissolved in THF (40 ml). To the resulting solution was added 0.25N NaOH (40 ml), followed by stirring at room temperature for 14 hours. The reaction mixture was distilled under reduced pressure to remove the solvent. The residue was acidified with 1N HCl, followed by extraction with a chloroform/methanol (10/1) mixture. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column (silica gel: 50 g), whereby from chloroform/methanol (20/1) eluate fractions, the title compound (394 mg, 83%) was obtained as a colorless amorphous substance.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:9]=[CH:10][C:5]2=[C:4]([N:17]2[CH2:23][CH:22]3[O:24][CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[N:3]=1.[C:25]([NH:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:27])[CH3:26].C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[CH:19]12[O:24][CH:22]([CH2:21][CH2:20]1)[CH2:23][N:17]([C:4]1[N:3]=[C:2]([C:32]3[CH:33]=[CH:34][C:29]([NH:28][C:25](=[O:27])[CH3:26])=[CH:30][CH:31]=3)[N:7]=[C:6]3[N:8]([CH:11]4[CH2:16][CH2:15][CH2:14][CH2:13][O:12]4)[N:9]=[CH:10][C:5]=13)[CH2:18]2
Reactant: Clc1nc(N2CC3CCC(C2)O3)c2cnn(C3CCCCO3)c2n1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCCCO4)c3n2)cc1

Procedure:
6-Chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidine (21 mmol) is taken up as a suspension in dry ethyl acetate (50 mL). Following the addition of 4-toluenesulfonic acid monohydrate (25 mg), the mixture is heated to 60° C. and 3,4-dihydro-2H-pyran (2.5 mL) is added in drops. The reaction mixture is maintained at 60° C. for 18 hours and is then concentrated under reduced pressure. The residue is purified by flash silica gel chromatography. Following concentration of fractions, 6-chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine is obtained. 6-Chloro-4-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (3.1 mmol) is coupled to 4-acetamidophenylboronic acid (0.83 g, 4.6 mmol) with tetrakis(triphenylphosphine) palladium (0) (2.5 mol %), 2 M aqueous sodium carbonate solution, and ethylene glycol dimethyl ether (DME) and under microwave irradiation (175 C, 10 min). Following an aqueous workup and flash chromatography, N-{4-[4-(8-Oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenyl}-acetamide is obtained. N-{4-[4-(8-Oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenyl}-acetamide (1.2 mmol) is taken up in dioxane (5 mL), treated with 4 M hydrogen chloride in dioxane (5 mL), and allowed to stir at room temperature for 3 days. The slurry is concentrated and purified by reverse phase preparative high performance liquid chromatography, employing a Phenomenex Prodigy 250 mm×21.2 mm 5 μm column and a 5% acetonitrile/95% water/0.1% trifluoroacetic acid to 100% acetonitrile gradient over 40 minutes. After concentration, N-{4-[4-(8-Oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-phenyl}-acetamide is provided.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].[OH-].[Na+]>C(O)(=O)C>[CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH:7][CH2:12][CH2:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(N)cc1
Reactant: C=CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOC(=O)CCNc1ccc(CC)cc1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution of 4-ethyl aniline (10.0 g) in acetic acid (25 mL) was added ethyl acrylate (10.8 g). The mixture was heated to 80° C. for 2 hours. Additional ethyl acrylate (1.0 mL) was added, and the mixture was again heated to 80° C. for 1 hour. The mixture was allowed to cool to room temperature and stir for two days. Sodium hydroxide (8N) was added until the pH equaled 9. The mixture was partitioned between dichloromethane and water and the combined organics were washed once with 1N sodium hydroxide, once with brine, dried with sodium sulfate, filtered, and concentrated. The mixture was chromatographed using a 20% ethyl acetate in heptane solvent solution. A mixture of the mono and di ester product (19.5 g) were obtained (1:1 mixture). MS (ESI+) for C13H19NO2 m/z 221.99 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([OH:14])[CH:8]=2)=[O:4].Cl.Cl[C:17]1[S:18][C:19]2[C:20]([N:25]=1)=[N:21][CH:22]=[CH:23][CH:24]=2.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][C:17]1[S:18][C:19]3[C:20]([N:25]=1)=[N:21][CH:22]=[CH:23][CH:24]=3)[CH:8]=2)=[O:4]
Reactant: Clc1nc2ncccc2s1
Reactant: COC(=O)c1cc2ccc(O)cc2[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(=O)c1cc2ccc(Oc3nc4ncccc4s3)cc2[nH]1
Temperature: 60 °C
Yield: 52.7 %

Procedure:
To a solution 6-hydroxy-1H-indole-2-carboxylic acid methyl ester (4.0 g, 21 mmol) and 2-chloro-thiazolo[4,5-b]pyridine hydrochloride (4.3 g, 21 mmol) in MeCN:DMF (4:1, 250 mL) was added Cs2CO3 (13.8 g, 42 mmol) and the reaction mixture was heated (60° C., 4 h). The reaction mixture was cooled (rt) and partitioned between EtOAc (300 mL) and saturated NH4Cl (200 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2×200 mL). The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using MeOH (0.2 M NH3):DCM (0-15%) to provide the title compound as a brown solid (3.6 g, 53%). MS (ESI): mass calcd. for C16H11N3O3S, 325.1; m/z found, 326.0[M+H]+. 1H NMR (400 MHz, DMSO-d6): 12.18 (s, 1H), 8.52 (dd, J=4.8, 1.7, 1H), 8.39 (dd, J=8.0, 1.7, 1H), 7.82 (d, J=8.7, 1H), 7.53 (d, J=2.2, 1H), 7.34 (dd, J=8.0, 4.8, 1H), 7.26 (dd, J=2.2, 0.9, 1H), 7.19 (dd, J=8.7, 2.2, 1H), 3.88 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[CH3:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([NH2:32])=[CH:29][CH:30]=2)[CH:25]=[N:24]1.CCN(C(C)C)C(C)C.CCOC(C)=O>O1CCOCC1.O>[Cl:1][C:2]1[N:3]=[C:4]([NH:32][C:28]2[CH:27]=[C:26]3[C:31](=[CH:30][CH:29]=2)[N:23]([CH3:22])[N:24]=[CH:25]3)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Cn1ncc2cc(N)ccc21
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc5c(cnn5C)c4)nc(Cl)nc32)cc1
Yield: 86.9 %

Procedure:
A solution of 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (275 mg, 0.804 mmol), 1-methyl-indazol-5-ylamine (118 mg, 0.803 mmol) and DIEA (0.350 mL, 2.01 mmol) in dioxane (7 mL) was stirred at 110° C. for 20 h. EtOAc and H2O were added. The organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 2-chloro-N-(1-methyl-1H-indazol-5-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (316 mg).
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][N:6]1[CH2:28][CH2:27][C:9]2[N:10]([CH2:18][CH:19]([OH:26])[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][C:16]=3[C:8]=2[CH2:7]1)C.Cl>C(O)C.[OH-].[Na+]>[OH:26][CH:19]([C:20]1[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=1)[CH2:18][N:10]1[C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][C:16]=2[C:8]2[CH2:7][N:6]([CH2:5][C:4]([OH:29])=[O:3])[CH2:28][CH2:27][C:9]1=2
Reactant: CCOC(=O)CN1CCc2c(c3cc(C)ccc3n2CC(O)c2ccncc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc2c(c1)c1c(n2CC(O)c2ccncc2)CCN(CC(=O)O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(8-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol (200 mg, 0.651 mmol) in acetonitrile (4 mL), potassium carbonate (270 mg, 1.953 mmol) and bromo-acetic acid ethyl ester (163 mg, 0.977 mmol) were added and the reaction mixture was stirred at RT for 1 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×30 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated to yield [5-(2-hydroxy-2-pyridin-4-yl-ethyl)-8-methyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl]-acetic acid ethyl ester (220 mg). To a solution of [5-(2-hydroxy-2-pyridin-4-yl-ethyl)-8-methyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl]-acetic acid ethyl ester (120 mg, 0.305 mmol) in ethanol (2 mL), 1N NaOH (3 mL) was added and the reaction mixture stirred at RT for 1 h. The progress of reaction was monitored by LCMS. The reaction mixture was neutralized with aq HCl. The solvent was removed under reduced pressure and the residue diluted with 90% MeOH in DCM and filtered. The filtrate was concentrated and residue was purified by reverse phase HPLC to yield [5-(2-hydroxy-2-pyridin-4-yl-ethyl)-8-methyl-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl]-acetic acid. 1H NMR (CD3OD, formate salt) δ (ppm): 8.42 (d, 2H), 7.4 (d, 2H), 7.2 (d, 2H), 6.9 (d, 1H), 5.03 (t, 1H), 4.6 (bs, 1H), 4.57 (bs, 2H), 4.3 (m, 2H), 3.8 (s, 2H), 3.7 (bs, 2H), 3.0 (m, 1H), 2.3 (s, 3H). Separation by chiral HPLC provides enantiomers II-65a-b.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[O:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[CH2:28][C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O.O>[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[CH2:28][C:29]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[O:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:30]
Reactant: Cc1ccc(F)c(CC(=O)O)c1
Reactant: Nc1nccc2occ(-c3ccc4c(c3)CCN4)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(F)c(CC(=O)N2CCc3cc(-c4coc5ccnc(N)c45)ccc32)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 93.6 %

Procedure:
A mixture of 3-(2,3-dihydro-1H-indol-5-yl)furo[3,2-c]pyridin-4-amine (150 mg, 0.440 mmol), 2-fluoro-5-methylphenylacetic acid (78 mg, 0.464 mmol), HATU (185 mg, 0.487 mmol), and Hunig's base (0.31 mL, 1.775 mmol) in N,N-Dimethylformamide (DMF) (3 mL) was stirred at room temperature for 4 days. Water (10 mL) was added, the mixture was stirred for about an hour, and the precipitate was collected by vacuum filtration. The solid was dried in the vacuum oven overnight to give 3-{1-[(2-fluoro-5-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-4-amine (174 mg, 0.412 mmol, 94% yield) as a beige solid. LC/MS (ES) m/z=402 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.27 (t, J=8.34 Hz, 2H), 3.89 (s, 2H), 4.29 (t, J=8.46 Hz, 2H), 5.53 (s, 2H), 6.93 (d, J=6.06 Hz, 1H), 7.03-7.18 (m, 3H), 7.30 (d, J=8.08 Hz, 1H), 7.40 (s, 1H), 7.86 (d, J=5.81 Hz, 1H), 7.92 (s, 1H), 8.13 (d, J=8.08 Hz, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O1CC[CH2:19][CH2:18]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[CH2:3]([N:10]1[CH2:15][CH2:14][CH:13]([C:18]#[CH:19])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: C1CCOC1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Product: C#CC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
Ethyl triphenylphosphonium bromide (25 g) was suspended in tetrahydrofuran (100 ml), followed by the addition of 60% sodium hydride (2.68 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction solution was ice-cooled again, followed by the addition of 1-benzyl-4-piperidone (11.55 g), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a colorless oil (6.08 g, yield; 52%).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([B:25]3[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]3)=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=O)(C)(C)C.C(OCC)C>O1CCOCC1.ClCCl>[ClH:1].[NH:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([B:25]3[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]3)=[CH:21][CH:20]=2)=[CH:17][N:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1(C)OB(c2ccc(-c3cnc([C@@H]4CCCN4)[nH]3)cc2)OC1(C)C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A solution of hydrogen chloride in 1,4-dioxane (4 N, 75 mL) was added to a solution of (S)-2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (7.0 g, 15.9 mmol) in dichloromethane (50 mL). Gas evolution was observed. After 30 minutes, a solid formed. After 1.5 hours, the resulting solid was isolated by filtration with diethyl ether washing. Any residual solvent was removed under reduced pressure to provide (S)-2-pyrrolidin-2-yl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazole hydrochloride (5.6 g, 95%) as an off-white solid.