Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[NH:11][S:12]([C:15]1[CH:16]=[N:17][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:19][CH:20]=1)(=[O:14])=[O:13].C([O-])([O-])=O.[Na+].[Na+].[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][C:35]=1[C:42]([F:45])([F:44])[F:43]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[N:11]([CH2:38][C:37]1[CH:40]=[CH:41][C:34]([F:33])=[C:35]([C:42]([F:45])([F:43])[F:44])[CH:36]=1)[S:12]([C:15]1[CH:16]=[N:17][C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:19][CH:20]=1)(=[O:14])=[O:13]
Reactant: O=S(=O)(Nc1nc2ccccn2c1Cl)c1ccc(N2CCOCC2)nc1
Reactant: Fc1ccc(CBr)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(N2CCOCC2)nc1)N(Cc1ccc(F)c(C(F)(F)F)c1)c1nc2ccccn2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To a solution of compound 11-E (0.030 g, 0.049 mmol) in DMF (1 mL) was added Na2CO3 (0.015 g, 0.15 mmol) and 4-fluoro-3-trifluoromethylbenzyl bromide (0.014 g, 0.053 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water, and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography, eluting with a hexanes-EtOAc gradient to give Compound 90 as a yellow solid (0.008 g, 29%); MS m/z (M+H+) 570.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.I[C:17]1[C:18]([C:26]([F:29])([F:28])[F:27])=[N:19][NH:20][C:21]=1[NH:22][C:23](=[O:25])[CH3:24]>CN(C=O)C.[Cu]I.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([C:7]#[C:8][C:17]2[C:18]([C:26]([F:28])([F:29])[F:27])=[N:19][NH:20][C:21]=2[NH:22][C:23](=[O:25])[CH3:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: CC(=O)Nc1[nH]nc(C(F)(F)F)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Nc1[nH]nc(C(F)(F)F)c1C#Cc1ccccc1
Temperature: 85 °C
Yield: 73.1 %

Procedure:
A degassed solution of phenylacetylene (3.9 ml, 35 mmol) and Et3N (36 mL) in DMF (13.5 mL) was added to N-[4-iodo-3-(trifluoromethyl)-1H-pyrazol-5-yl]acetamide (4.5 g, 14 mmol), CuI (530 mg, 2.8 mmol) and PdCl2(PPh3)2 (980 mg, 1.4 mmol) under an atmosphere of N2. The reaction was then heated to 85° C. for 3.5 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography (silica gel, ethyl acetate/isohexane 1:9 to 1:0) yielding the title compound as a brown oil (3 g) which was used in the subsequent step.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:27])[CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[C:5]([CH3:28])[CH:4]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH3:36]>CN(C)C(=O)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:40]4[CH2:41][CH2:42][N:37]([CH2:35][CH3:36])[CH2:38][CH2:39]4)=[CH:4][C:5]=3[CH3:28])=[O:27])[C:12](=[O:26])[CH:13]=2)=[N:20][CH:21]=1
Reactant: CCN1CCNCC1
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccc(Cl)cn2)cc1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCN1CCN(Cc2ccc(C(=O)Cn3ccc(OCc4ccc(Cl)cn4)cc3=O)c(C)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-chloro-pyridin-2-ylmethoxy)-1H-pyridin-2-one (preparation 3b, 110 mg, 0.23 mmol) in N,N-dimethylacetamide (2 mL) is added Cs2CO3 (184 mg, 0.57 mmol) and N-ethylpiperazine (63 μL, 0.75 mmol). The reaction mixture is stirred overnight at room temperature. The mixture is purified via reverse phase HPLC chromatography (Gilson Xbridge C18 5 μm, gradient 5%→90% acetonitrile in water+0.3% NH4OH, 120 mL/min).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10](O)[CH3:11])=[CH:6][C:5]=1[N+:13]([O-:15])=[O:14].CCN(S(F)(F)[F:23])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([F:23])[CH3:11])=[CH:6][C:5]=1[N+:13]([O-:15])=[O:14]
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)c1ccc(C(C)O)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(C(C)F)cc1[N+](=O)[O-]
Temperature: -50 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
To a solution of 4-(1-hydroxy-ethyl)-2-nitro-benzoic acid methyl ester (1.09 g, 4.84 mmol) in DCM (15 mL) cooled at −50° C. was added dropwise a solution of DAST (0.734 mL, 5.32 mmol) in DCM (2 mL). The reaction was stirred at −50° C. for 2 h. Sat. aq NaHCO3 was added to reaction mixture and the solution was stirred at r.t. for 1 h. The aqueous phase was extracted with DCM (3×) and the combined organic phases were dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, hexanes to EtOAc/hexanes (4:6)) to give 4-(1-fluoro-ethyl)-2-nitro-benzoic acid methyl ester (0.60 g, 2.64 mmol, 56%). 1H-NMR (CDCl3, 300 MHz) 7.85 (s, 1H); 7.75 (d, J=7.9 Hz, 1H); 7.7.61 (d, J=7.3 Hz, 1H); 5.60-5.82 (qd, J=6.45, 47.2 Hz, 1H); 3.92 (s, 3H); 1.70 (dd, J=6.4, 23.7 Hz, 3H).
Reaction SMILES: Br[CH:2]1[CH2:4][CH2:3]1.[Mg].[O:6]=[C:7]1[C:16]2[CH:17]=[C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:20][C:15]=2[O:14][CH2:13][C:12]2[CH:11]=[CH:10][S:9][C:8]1=2.[Cl-].[NH4+]>C1COCC1>[CH:2]1([C:7]2([OH:6])[C:16]3[CH:17]=[C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][C:12]3[CH:11]=[CH:10][S:9][C:8]2=3)[CH2:4][CH2:3]1
Reactant: COC(=O)Cc1ccc2c(c1)C(=O)c1sccc1CO2
Reactant: BrC1CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc2c(c1)C(O)(C1CC1)c1sccc1CO2
Reaction time: 0.5 h
Yield: 79 %

Procedure:
An anhydrous THF (50 mL) solution of bromocyclopropane (8.3 mL) was added dropwise to a metal magnesium (2.5 g), while heating. After the termination of dropwise addition, an anhydrous THF (20 mL) was added thereto, and the mixture was refluxed under heating for an additional 2 hours. Thereafter, the reaction mixture was allowed to air-cool, and this solution was added dropwise to an anhydrous THF (30 mL) solution of methyl (4-oxo-4,10-dihydro-9-oxa-3-thiabenzo[f]azulen-6-yl)acetate (10.0 g) previously chilled in an ice bath. After stirring the mixture for 30 minutes, an aqueous saturated ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, and thereafter dried over anhydrous sodium sulfate. The solvents were distilled off under a reduced pressure, and the residue obtained was purified by silica gel column chromatography (hexane-ethyl acetate=5:1), to give 9.0 g (79%) of the captioned compound as an oily product.
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:15]([OH:17])=O)[N:12]([CH3:14])[CH:13]=2)=[CH:5][CH:4]=1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[CH3:34][NH:35][O:36][CH3:37]>C(Cl)Cl>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([C:15]([N:35]([CH3:34])[O:36][CH3:37])=[O:17])[N:12]([CH3:14])[CH:13]=2)=[CH:7][CH:8]=1
Reactant: Cn1cc(-c2ccc(Br)cc2)nc1C(=O)O
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [Na]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1nc(-c2ccc(Br)cc2)cn1C
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
To a solution of ethyl 4-(4-bromophenyl)-1-methyl-1H-imidazole-2-carboxylate (1.66 g, 5.37 mmol) in MeOH (38 mL) was added 1N NaOH solution (19 mL). The reaction turned cloudy white and was stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo and pumped under high vacuum overnight to give the sodium salt of 4-(4-bromophenyl)-1-methyl-1H-imidazole-2-carboxylic acid as a white solid. The sodium salt of 4-(4-bromophenyl)-1-methyl-1H-imidazole-2-carboxylic acid was dissolved in anhydrous CH2Cl2 (40 mL) under nitrogen at −15° C. (ice/methanol bath) and N-methylmorpholine (1.1 equiv, 5.91 mmol) was added followed by isobutyl chloroformate (1.1 equiv, 5.91 mmol). The reaction mixture was stirred at −15° C. for 15 minutes and then N,O-dimethylhydroxylamine hydrochloride (1.0 equiv, 5.37 mmol) was added. The reaction was allowed to warm to room temperature and was stirred for 17 hours. The reaction was quenched with H2O (10 mL). The product was extracted using EtOAc (3×30 mL) and the combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated in vacuo. Purification by silica gel chromatography (Analogix IF280, 20-100% EtOAc/hexanes) afforded the title compound as a tan solid (32%). ESMS [M+H]+: 324.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][C:14]=3[N:15]=2)[CH:7]=[CH:8][C:9]=1Cl)([O-:3])=[O:2].[S:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1>>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:16][C:14]=3[N:15]=2)[CH:7]=[CH:8][C:9]=1[C:28]1[CH:29]=[CH:30][S:26][CH:27]=1)([O-:3])=[O:2]
Reactant: OB(O)c1ccsc1
Reactant: O=[N+]([O-])c1cc(-c2nc3cc(-c4ccccc4)ccc3o2)ccc1Cl
Product: O=[N+]([O-])c1cc(-c2nc3cc(-c4ccccc4)ccc3o2)ccc1-c1ccsc1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-4-chlorophenyl)-5-phenylbenzoxazole (177 mg, 0.51 mmol) and thiophene-3-boronic acid (97 mg, 0.76 mmol) the subtitle compound was obtained (150 mg, 74%). 1H NMR (DMSO) δ 8.67(d, 1H), 8.48(dd, 1H), 8.12(d, 1H), 7.91(m, 2H), 7.83(m, 1H), 7.79–7.77(m, 4H), 7.51(m, 2H), 7.40(t, 1H), 7.22(dd, 1H).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[S:11](=[O:20])(=[O:19])[N:10]=2)=[C:5]([OH:21])[C:4]2[S:22][CH:23]=[CH:24][C:3]1=2.[S:25]1[C:29]([CH:30]=O)=[CH:28][N:27]=[CH:26]1>CN(C)C(=O)C>[O:19]=[S:11]1(=[O:20])[C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[NH:14][C:9]([C:6]2[C:7](=[O:8])[N:2]([N:1]=[CH:30][C:29]3[S:25][CH:26]=[N:27][CH:28]=3)[C:3]3[CH:24]=[CH:23][S:22][C:4]=3[C:5]=2[OH:21])=[N:10]1
Reactant: Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: O=Cc1cncs1
Solvent: CC(=O)N(C)C
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc2n1N=Cc1cncs1
Temperature: 25 °C

Procedure:
The product of Example 268D (0.115 g, 0.30 mmol) was reacted with 1,3-thiazole-5-carbaldehyde (0.35 g, 3.0 mmol) in N,N-dimethylacetamide (3 mL) in a sealed tube at 140° C. for 80 minutes in a microwave reactor. The reaction was cooled to 25° C. and concentrated under vacuum. The resulting residue was triturated with 0.1 M HCl (20 mL) and filtered to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]#[CH:12])=[CH:7][C:5]([NH2:6])=[C:4]([F:13])[CH:3]=1.[CH:14]12[CH2:19][CH:18]1[CH2:17][NH:16][CH:15]2[C:20](O)=[O:21].C[Al](C)C.O>C(Cl)Cl>[Cl:1][C:2]1[C:8]([O:9][CH2:10][C:11]#[CH:12])=[CH:7][C:5]([NH:6][C:20]([CH:15]2[NH:16][CH2:17][CH:18]3[CH:14]2[CH2:19]3)=[O:21])=[C:4]([F:13])[CH:3]=1
Reactant: O=C(O)C1NCC2CC21
Reactant: C#CCOc1cc(N)c(F)cc1Cl
Agent: C[Al](C)C
Solvent: O
Solvent: ClCCl
Product: C#CCOc1cc(NC(=O)C2NCC3CC32)c(F)cc1Cl
Temperature: 5 °C
Yield: 35.7 %

Procedure:
To a mixture of 2.36 g (11.79 mmol) of 4-chloro-2-fluoro-5-(2-propynyl)oxyaniline and 1.5 g (11.79 mmol) of (±)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid in methylene chloride (150 mL) stirred under nitrogen and cooled to 5° C. was added trimethylaluminum dropwise (2.0M, 11.8 mL, 23.58 mmol). The resultant mixture was stirred at room temperature for 48 h. Water (100 mL) was added dropwise at ice-bath temperature. The solid inorganic material which formed was filtered, and the filtrate was dried (MgSO4) and evaporated under reduced pressure to dryness. Flash chromatography on silica gel yielded 1.3 g of the product of Step F as a tan solid; m.p. 113°-115° C. IR (mineral oil, cm-1): 1687.1 (C=O); 2123.5 (C≡C).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:19]([OH:21])=O)=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2].S(Cl)([Cl:24])=O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([C:19]([Cl:24])=[O:21])=[CH:15][C:16]=3[C:17]=2[N:18]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(C(=O)O)cc3c2n1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncc2[nH]c3ccc(C(=O)Cl)cc3c2n1

Procedure:
184 mg of 8-hydroxycarbonyl-5H-pyrimido[5,4-b]indole-2-carboxylic acid ethyl ester (Example 18) is refluxed for 3 hours in 5 ml of thionyl chloride with one drop of dimethylformamide. After concentration, the mixture is further reacted without any purification.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]2[O:8][C:9]([CH2:11][CH3:12])=[CH:10][C:6]=2[CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:20]O>>[CH2:11]([C:9]1[O:8][C:7]2[CH:13]=[CH:14][C:4]([C:1]([O:3][CH3:20])=[O:2])=[CH:5][C:6]=2[CH:10]=1)[CH3:12]
Reactant: CCc1cc2cc(C(=O)O)ccc2o1
Reactant: CO
Agent: O=S(=O)(O)O
Product: CCc1cc2cc(C(=O)OC)ccc2o1

Procedure:
5-Carboxy-2-ethylbenzo[b]furan (2.48 g) and concentrated sulfuric acid (0.30 g) were stirred with heating in methanol (50 ml) at 60° C. for 16 hr. The reaction mixture was concentrated and chloroform mixture was added. The mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate. The chloroform layer was separated, dried over magnesium sulfate and concentrated to give the objective compound (2.40 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[C:14](Cl)(=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:16]([O:15][C:14]([NH:1][C@@H:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4])=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
To a solution of (S)-2-aminobutanoic acid (11.2 g, 109 mmol) in THF (200 mL) and a 2 M aqueous sodium carbonate solution (65.2 ml, 130 mmol) was added dropwise at 0° C. benzyl carbonochloridate (17.06 mL, 119 mmol). After stirring at room temperature for 16 hours, the reaction mixture was extracted with H2O/TBME, the aqueous layer was acidified with HCl (2M in H2O) until pH=2 and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated to give the title compound (22.8 g, 77%) as a colorless oil. The product was used in the next step without further purification. LC-MS: [M−H] 236.2; Rt 0.76 min; (LCMS method 1).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[NH:16][C:17]([CH:19]1[CH:24]2[CH2:25][CH:21]3[CH:22]([C:23]2=[O:26])[CH:20]13)=O.C(O)(C)C.[OH-].[K+]>O>[O:26]=[C:23]1[CH:22]2[CH:20]3[CH:21]2[CH2:25][CH:24]1[CH:19]3[C:17]1[NH:16][C:3]2[C:4](=[O:15])[N:5]([CH2:12][CH2:13][CH3:14])[C:6](=[O:11])[N:7]([CH2:8][CH2:9][CH3:10])[C:2]=2[N:1]=1
Reactant: CCCn1c(N)c(NC(=O)C2C3CC4C(C3=O)C42)c(=O)n(CCC)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCn1c(=O)c2[nH]c(C3C4CC5C(C4=O)C53)nc2n(CCC)c1=O
Temperature: 25 °C

Procedure:
5-Oxo-tricyclo[2.2.1.02,6]heptane-3-carboxylic acid (6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-pyrimidin-5-yl)-amide (360 mg) from step 1 was taken in 1:1 isopropanol:water (5 ml) and KOH (84 mg) was added. The reaction mixture was refluxed for one and half-hour. After cooling the reaction mixture to room temperature, iPrOH was removed by rotavap. The aqueous layer was neutralized with 2N HCl and extracted with ethyl acetate (3×50 ml). The combined organic layer was washed with water and brine and dried over Na2SO4. After concentration, the crude product was purified by silica gel chromatography, eluting with ethyl acetate:hexane (1:1). Yield (75 mg) Mass (ES+ 343).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClCCl.O>[Cl:6][C:7]1[C:8]([CH2:9][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:11][CH:12]=[CH:13][C:14]=1[OH:15]
Reactant: C1CCNC1
Reactant: O=Cc1cccc(O)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Oc1cccc(CN2CCCC2)c1Cl
Yield: 54.6 %

Procedure:
Pyrrolidine (71.3 mL, 855 mmol) was added to a solution of intermediate 12, 2-chloro-3-hydroxybenzaldehyde (103 g, 658 mmol) in dichloromethane (1 L). The reaction mixture was cooled on ice bath, and sodium triacetoxyborohydride (209.3 g, 987 mmol) was added in portions under stirring. The reaction mixture was stirred for 12 h at room temperature. Water (500 mL) and concentrated HCl were added to attain pH˜2. The organic layer was separated. The aqueous one was extracted with CH2Cl2 (2×400 mL), then with EtOAc (400 mL). The organic layers were discarded. The aqueous fraction was alkalized with K2CO3 to pH˜10, and the product was extracted with CHCl3 (3×500 mL). The organic layer was dried with Na2SO4 and evaporated in vacuo. The obtained crystals were separated by filtration from Et2O/hexane mixture (1:1) and coevaporated with dioxane to give the title compound (76 g, 55%, 359 mmol). LCMS data: 214 and 212 (M+H)+ (calculated for C11H14ClNO 211.7); 1H NMR data (DMSO-d6): 9.96 (br.s, 1H, OH); 7.08 (t, 1H, J=7.8 Hz, Ar—H); 6.91 (dd, 1H, J1=1.7 Hz, J2=7.3 Hz, Ar—H); 6.86 (dd, 1H, J1=1.7 Hz, J2=8.0 Hz, Ar—H); 3.64 (s, 2H, CH2Ar); 2.43-2.52 (m, 4H+DMSO); 1.65-1.74 (m, 4H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.Cl.[CH2:28]([OH:30])[CH3:29]>>[CH2:28]([O:30][C:19](=[NH:20])[C:18]1[CH:17]=[CH:16][C:15]([CH:14]=[C:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9][CH2:10]2)=[CH:22][CH:21]=1)[CH3:29]
Reactant: N#Cc1ccc(C=C2CCN(Cc3ccccc3)CC2)cc1
Reactant: CCO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=N)c1ccc(C=C2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.4 %

Procedure:
A mixture of 4-(1-benzyl-piperidin-4-ylidenemethyl)-benzonitrile (14 g, 48.6 mmol), chloroform (10 mL) and 6 M hydrogen chloride in ethanol (300 mL) was stirred at room temperature for 48 hours. The solution was concentrated in vacuo, the remaining solid was repeatedly dissolved in ethanol (400 mL) and concentrated in vacuo to yield 16.4 g (92.4%) of the title compound, which was used in the next steps without further purification.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(OC(N(C)C)=[N+](C)C)[C:12]2N=CC=C[C:11]=2N=N1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[C:41]2[C:36](=[N:37][CH:38]=[C:39]([C:42]3[CH:43]=[C:44]([C:51]([N:53]([CH3:55])[CH3:54])=[O:52])[CH:45]=[C:46]([CH:50]=3)[C:47](O)=[O:48])[CH:40]=2)[N:35](COCC[Si](C)(C)C)[N:34]=1.C(N)C.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:12]([NH:8][C:47](=[O:48])[C:46]1[CH:50]=[C:42]([C:39]2[CH:40]=[C:41]3[C:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[O:26][CH3:25])=[N:34][NH:35][C:36]3=[N:37][CH:38]=2)[CH:43]=[C:44]([C:51]([N:53]([CH3:55])[CH3:54])=[O:52])[CH:45]=1)[CH3:11]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cc(C(=O)O)cc(C(=O)N(C)C)c3)cc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCNC(=O)c1cc(C(=O)N(C)C)cc(-c2cnc3[nH]nc(-c4ccccc4OC)c3c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 13.3 %

Procedure:
In a microwave vial O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexa-fluorophosphate (34.8 mg, 0.9 mmol) was added to a solution of 5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-iso-phthalamic acid (50 mg, 0.09 mmol), ethyl amine (69 μL, 0.14 mmol), and di-iso-propyl ethyl amine (47.8 μL, 0.27 mmol) in tetrahydrofuran (1 mL). The vial was sealed and the solution irradiated to 100° C. for 10 min in a microwave reactor. The solvent was then removed on under reduced pressure. Trifluoroacetic acid (1 mL) was then added to the residue and the mixture stirred at room temperature for 16 hours. The solvent was then removed under reduced pressure and the residue purified by preparative high pressure liquid chromatography to give N-ethyl-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N′,N′-dimethyl-isophthalamide (5.30 mg, 13% yield). 1H-NMR (500 MHz, Dimethyl sulfoxide-d6) δ 1.15 (t, J=14 Hz, 3H) 2.97 (s, 3H); 3.03 (s, 3H)); 3.29 (dq, J=5.5 Hz, J=7 Hz, 2H); 3.84 (s, 3H); 7.11 (t, J=7.5 Hz 1H); 7.23 (d, J=8 Hz 1H) 7.48 (t, J=7.5 Hz, 1H); 7.67 (d, J=8 Hz 1H); 7.86 (s, 1H); 7.94 (s, 1H); 8.25 (s, 1H); 8.45 (s, 1H); 8.69 (t, J=5.5 Hz, 1H); 8.94 (s, 1H); 13.88 (s, br, 1H) MS: m/z 444.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][C:11]2[C:16]3[S:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:15]=3[CH:14]=[CH:13][CH:12]=2)=[O:9])=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:37][C:38]1[C:39]([O:53][CH3:54])=[C:40]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH:41]=[C:42]([C:44]([CH3:47])([CH3:46])[CH3:45])[CH:43]=1>CN(C=O)C>[C:44]([C:42]1[CH:41]=[C:40]([NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[C:39]([O:53][CH3:54])=[C:38]([NH:37][C:20]([C:18]2[S:17][C:16]3[C:11]([NH:10][C:8](=[O:9])[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][CH:6]=4)=[CH:12][CH:13]=[CH:14][C:15]=3[CH:19]=2)=[O:22])[CH:43]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(Nc1cccc2cc(C(=O)O)sc12)c1ccc(Cl)nc1
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1c(NC(=O)c2cc3cccc(NC(=O)c4ccc(Cl)nc4)c3s2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
To a solution of the above carboxylic acid (50 mg) in DMF (1.5 mL) was added EDC (1.5 eq) and HOBT (1.5 eq). The reaction was stirred at room temperature for 15 min, then N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (1.2 eq) was added. The reaction was stirred 12 h, then the DMF was removed in vacuo, the residue was taken up in EtOAc and washed with water, followed by brine. The organics were dried over MgSO4, filtered, and concentrated and the residue was purified by flash chromatography on silica gel (20%-60% EtOAc/hexane) to give the title compound as a white solid (36 mg, 41% yield for two steps).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[Li]CCCC.[O:15]1[C:19]2([CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]2)[O:18][CH2:17][CH2:16]1>C1COCC1.CCOCC>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([C:22]2([OH:25])[CH2:23][CH2:24][C:19]3([O:18][CH2:17][CH2:16][O:15]3)[CH2:20][CH2:21]2)=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cn1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCC3(CC2)OCCO3)cn1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A solution of 5-bromo-2-methoxy-pyridine (Aldrich, 5.0 g, 26.6 mmol) in THF or ether (30 mL) at −78° C. was treated with n-BuLi (2.5 M in hexanes, 12 mL, 30 mmol) dropped slowly over 10 min. The reaction was stirred for an additional 20 min. at −78° C. A solution of 1,4-dioxa-spiro[4.5]decan-8-one (Aldrich, 4.37 g, 28 mmol) in THF (10 mL) was slowly dropped into the reaction. After addition, the reaction was stirred for an additional 2 hours at −78° C. The reaction was then quenched with water and warmed to room temperature. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow solid, which was then purified by silica gel column on a CombiFlash® system (Teledyne Isco, Inc, Lincoln, Nebr.) using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a yellow solid.