Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15]([N:26]4[CH2:31][CH2:30][O:29][C:28]([CH3:33])([CH3:32])[CH2:27]4)=[CH:16][C:17]=3[C@@:18]32[CH2:24][O:23][C:22]([NH2:25])=[N:21]3)=[CH:9][CH:8]=1)(=O)=O.[F:36][C:37]1[C:42](B(O)O)=[CH:41][CH:40]=[CH:39][N:38]=1.CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:32][C:28]1([CH3:33])[CH2:27][N:26]([C:15]2[CH:14]=[CH:13][C:12]3[O:11][C:10]4[C:19](=[CH:20][C:7]([C:42]5[C:37]([F:36])=[N:38][CH:39]=[CH:40][CH:41]=5)=[CH:8][CH:9]=4)[C@@:18]4([CH2:24][O:23][C:22]([NH2:25])=[N:21]4)[C:17]=3[CH:16]=2)[CH2:31][CH2:30][O:29]1
Reactant: CC1(C)CN(c2ccc3c(c2)[C@]2(COC(N)=N2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2O3)CCO1
Reactant: OB(O)c1cccnc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CN(c2ccc3c(c2)[C@]2(COC(N)=N2)c2cc(-c4cccnc4F)ccc2O3)CCO1
Temperature: 85 °C
Reaction time: 2 h

Procedure:
A 25 mL RB flask was charged with (R)-2-amino-2′-(2,2-dimethylmorpholino)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (270 mg, 0.526 mmol), tetrakis(triphenylphosphine)palladium(0) (60.8 mg, 0.053 mmol), 2-fluoropyridin-3-ylboronic acid (119 mg, 0.841 mmol), DMF (2629 μL) and sodium carbonate (2M solution) (789 μL, 1.577 mmol). The mixture was stirred under argon for 2 hrs at 85° C. The mixture was diluted with water (2 ml) and extracted with 10 ml of EtOAc. The organic layer was washed with water, brine, passed through plug of Celite and concentrated. Dark residue was purified by silica gel chromatography on a 12 g RediSep column using 5-70% DCM/MeOH/NH4OH in DCM to afford (S)-2′-(2,2-dimethylmorpholino)-7′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine. Found MS: MH+=461.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:8])=[C:5]([CH3:19])[CH:4]=1)=O.Cl.[OH:21][NH2:22]>C(O)C.O>[OH:21][N:22]=[CH:1][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:8])=[C:5]([CH3:19])[CH:4]=1
Reactant: NO
Reactant: Cc1cc(C=O)ccc1C(=O)NCc1ccccn1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(C=NO)ccc1C(=O)NCc1ccccn1
Temperature: 25 °C
Yield: 85 %

Procedure:
In a solution of 0.50 g of 4-formyl-2-methyl-N-(2-pyridylmethyl) benzoic acid amide in 10 ml of ethanol and 5 ml of water, 0.18 g of hydroxyamine hydrochloride was added with stirring at room temperature, and stirred at the same temperature for 12 hours. After the completion of the reaction, solid was filtered off, ethanol was distilled off under reduced pressure, and 30 ml of saturated sodium hydrogen carbonate aqueous solution was added in the remaining aqueous solution. The precipitated crystal was filtered off, washed with water and dried to obtain 0.45 g of the aimed product as pale yellow crystal.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:10][C:4]=2[CH:3]=1.Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.C(OCC)(=O)C.[Cu]I>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:4]=2[CH:3]=1
Reactant: Brc1ccccn1
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cn1cc(-c2cc3cnc(Br)cc3n2-c2ccccn2)cn1
Temperature: 180 °C
Reaction time: 0.75 h
Yield: 48 %

Procedure:
6-Bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22, 27 mg 0.10 mmole) and 2-bromopyridine (24 mg, 15 uL, 0.15 mmole) were dissolved in DMA (0.7 ml) and potassium carbonate (20 mg, 0.14 mmole) and copper(I) iodide (4.0 mg, 0.022 mmole) were added. The reaction was placed under argon and heated by microwave at 180° C. for 60 minutes followed by 210° C. for 45 minutes. The reaction was taken up in ethyl acetate (25 mL) and the solution washed with water (3×7 mL) and brine. The aqueous solutions were backwashed with a single portion of ethyl acetate. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified using preparative TLC eluting with ethyl acetate to afford the title compound 17 mg (48%). 1H-NMR (CDCl3, 500 MHz): 3.88 (s, 3H), 6.72 (d, J=0.95 Hz, 1H), 7.18 (d of t, J=0.95, 7.88 Hz, 1H), 7.24 (s, 1H), 7.26 (d, J=0.63 Hz, 1H), 7.44 (ddd, J=0.95, 4.73, 7.57 Hz, 1H), 7.51 (t, J=0.95 Hz, 1H), 7.86 (t of d, J=1.89, 7.57 Hz, 1H), 8.66 (d, J=0.95 Hz, 1H), 8.73 (ddd, J=0.95, 1.89, 4.73 Hz, 1H).
Reaction SMILES: [CH2:1]([N:4]1[C:8](=[O:9])[CH:7]([OH:10])[S:6][C:5]1=[N:11][N:12]=[C:13]1[N:17]([CH3:18])[C:16](=[O:19])[CH2:15][S:14]1)[CH:2]=[CH2:3].Cl[P:21]1(=[O:27])[N:25]([CH3:26])[CH2:24][CH2:23][O:22]1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:4]1[C:8](=[O:9])[CH:7]([O:10][P:21]2(=[O:27])[N:25]([CH3:26])[CH2:24][CH2:23][O:22]2)[S:6][C:5]1=[N:11][N:12]=[C:13]1[N:17]([CH3:18])[C:16](=[O:19])[CH2:15][S:14]1)[CH:2]=[CH2:3]
Reactant: C=CCN1C(=O)C(O)SC1=NN=C1SCC(=O)N1C
Reactant: CN1CCOP1(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCN1C(=O)C(OP2(=O)OCCN2C)SC1=NN=C1SCC(=O)N1C

Procedure:
In a manner analogous to that described in Example 24 starting from 7.5 g (0.025 mol) of 3-allyl-5-hydroxy-2-[[3-methyl-4-oxo-2-thiazolidinylidene]-hydrazono]-4-thiazolidinone, 7.8 g (0.05 mol) of 2-chloro-3-methyl-1,3,2-oxazaphospholidine-2-oxide and 4.53 ml (0.0325 mol) of triethylamine in 50 ml of methylene chloride there is obtained 2-[3-allyl-2-[[3-methyl-4-oxo-2-thiazolidinylidene]-hydrazono]-4-oxo-5-thiazol-idinoxy]-3-methyl-2-oxo-1,3,2-oxazaphospholidine having a melting point of 184°-185°.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[CH:9]([C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)=O.N1CCCCC1>C(O)C>[C:1](/[C:3](=[CH:9]/[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)/[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: CCOC(=O)CC#N
Reactant: N#Cc1ccc(C=O)cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)/C(C#N)=C\c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl cyanoacetate (2.59 g, 22.88 mmol) and 4-formylbenzonitrile (3.0 g, 22.88 mmol) are dissolved in ethanol (100 ml). Piperidine (100 mg, 1.14 mmol) is added, and the reaction mixture is stirred at room temperature for 2 hours. The solvent is removed in vacuo, and the residue is purified by column chromatography on silica with cyclohexane/ethyl acetate mixtures as eluent.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[S:18][CH:19]=[C:20]([C:22](OCC)=[O:23])[N:21]=4)=[C:13]([NH:27][CH:28]([CH3:30])[CH3:29])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:31]1[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32]1>CO>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[S:18][CH:19]=[C:20]([C:22]([N:31]5[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32]5)=[O:23])[N:21]=4)=[C:13]([NH:27][CH:28]([CH3:29])[CH3:30])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: OC1CCNC1
Reactant: CCOC(=O)c1csc(-c2cnc(Nc3ccc4ncsc4c3)cc2NC(C)C)n1
Solvent: CO
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nc(C(=O)N2CCC(O)C2)cs1
Temperature: 80 °C

Procedure:
The ethyl 2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazole-4-carboxylate (Example 20) (100 mg, 0.228 mmol) was dissolved in methanol (10 mL) and to it pyrrolidin-3-ol (0.455 mmol, 2 equiv) was added and heated at 80° C. for 2 h. The reaction mixture was concentrated, the crude obtained was purified on preparative TLC to obtain (2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(3-hydroxypyrrolidin-1-yl)methanone. 1H NMR: 400 MHz, DMSO-d6: δ 1.24 (d, J=4.00 Hz, 6H), 1.85-1.86 (m, 3H), 3.46-3.50 (m, 1H), 3.56-3.57 (m, 1H), 3.72-3.73 (m, 1H), 3.90-3.91 (m, 1H), 4.35 (bs, 1H), 5.00-5.01 (m, 1H), 6.18 (s, 1H), 7.58 (dd, J=2.00, 9.00 Hz, 1H), 7.95-7.97 (m, 1H), 8.13-8.13 (m, 1H), 8.14-8.18 (m, 1H), 8.52-8.52 (m, 1H), 8.72-8.72 (m, 1H), 9.16 (s, 1H), 9.37 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm-2.7 μm; Solvent A=2% ACN: 98% H2O: 10 mM NH4COOH; Solvent B=98% ACN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 3 min; retention time: 1.883 min; LCMS (ES-API), m/z 481.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 5.062 min; Purity: 92.2%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([N+:24]([O-])=O)=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[H][H]>CO.C(Cl)Cl.[Ni]>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3[N+](=O)[O-])CC2)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3N)CC2)cc1
Reaction time: 4 h
Yield: 88.1 %

Procedure:
4-[1-(3-Nitro-2-pyridyl)piperazin-4-yl-carbonyl]benzoic acid methyl ester (5 g) was dissolved in a co-solvent of methanol (80 ml) and methylene chloride (60 ml) in a pressurized reactor. With the addition of about 1 g of Raney-nickel (50% slurry in water), the reaction mixture was filled with hydrogen gas and stirred at 50~60 psi for 4 hours. After completion of the reaction, reaction mixture was filtered through celite and filtrate was concentrated under reduced pressure. The concentrated residue was treated with hexane and ether for crystallization, filtered, washed and dried to give 4.05 g (yield: 88%) of the desired compound.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[CH2:24]([O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1)[CH2:25][CH2:26][CH3:27].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:24]([O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([N:21]2[CH2:22][CH2:23][CH:18]([N:4]([CH:1]3[CH2:3][CH2:2]3)[S:5]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=3)(=[O:6])=[O:7])[CH2:19][CH2:20]2)(=[O:37])=[O:36])=[CH:31][CH:30]=1)[CH2:25][CH2:26][CH3:27]
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCOc1ccc(S(=O)(=O)N2CCC(N(C3CC3)S(=O)(=O)c3cccc(C(F)(F)F)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
150 mg (0.434 mmol) of N-cyclopropyl-N-piperidin-4-yl-3-trifluoromethylbenzenesulfonamide (available from Lancaster) and 108 mg (0.434 mmol) of 4-butoxyphenylsulfonyl chloride (available from Matrix Scientific) were each dissolved in 10 mL of DCM and then combined. 1.5 eq. of DIEA (0.113 mL) was added to the mixture by syringe. The mixture was stirred overnight at room temperature and then concentrated under vacuum. The resultant product 29 was purified through a column of silica gel with a gradient of 0% to 20% EtOAc in hexanes and the pure material was concentrated (yield 25%, white solid). 1H NMR (CDCl3): δ 8.058 (s, 1H), 8.003-7.983 (d, 1H), 7.851-7.831 (d, 1H), 7.688-7.641 (m, 3H), 7.017-6.980 (m, 2H), 4.055-4.022 (t, 2H), 3.843-3.746 (m, 3H), 2.286-2.226 (t, 2H), 2.068-1.901 (m, 3H), 1.843-1.773 (m, 2H), 1.6151-1.470 (m, 4H), 1.014-0.976 (t, 3H), 0.944-0.903 (m, 2H), 0.793-0.744 (m, 2H). LC: 100%. MS (e/z): 562 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]#[N:12])=[CH:2]1.CO.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[O-].[Na+]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11]#[N:12])=[CH:2]1
Reactant: O=Cc1ccccc1
Reactant: N#CCc1c[nH]c2ccccc12
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: N#CC(=Cc1ccccc1)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.4 %

Procedure:
2-(1H-Indol-3-yl)-3-phenylacrylonitrile was prepared by the addition of 3-indolylacetonitrile (2.02 g, 12.9 mmol), MeOH (18 mL), benzaldehyde (1.60 mL, 15.5 mmol), and a 25% wt solution of sodium methoxide in MeOH (3.2 mL, 14.2 mmol) to a 50 mL flask. The solution was allowed to stir at ambient temperature under N2 for 16 h. The reaction solution was diluted with DCM (20 mL), molecular sieves (250 mg) were added, and the solution was allowed to reflux for 1 hour. The reaction was quenched with the addition of sat. NH4Cl (20 mL). The organic phase was partitioned, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was chromatographed (SiO2, 100% hexane to 5% EtOAc) to yield 1.4 g (44% yield) of 2-1H-indol-3-yl-3-phenyl-acrylonitrile; 1H NMR (CDCl3) δ 8.42 (1H, br s), 7.97 (1H, d), 7.87 (2H, m), 7.63 (1H, s), 7.60 (1H, d), 7.37-7.48 (4H, m), 7.25-7.33 (2H, m); TLC (SiO2 plate, 5:1 hexane/EtOAc) Rf=0.35; MS (ESI): 245 (MH+).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.[OH:13][C:14]1[CH:18]=[C:17]([N:19]2[C:27]3[CH:26]=[CH:25][N:24]=[CH:23][C:22]=3[N:21]=[CH:20]2)[S:16][C:15]=1[C:28]([O:30][CH3:31])=[O:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:19]1([C:17]2[S:16][C:15]([C:28]([O:30][CH3:31])=[O:29])=[C:14]([O:13][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=3)[CH:18]=2)[C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[N:21]=[CH:20]1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccc(C(F)(F)F)cc1

Procedure:
In a similar manner as described for example B14, 102.8 mg of 4-(trifluoromethyl)benzyl bromide, 100 mg of methyl 3-hydroxy-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate, 59.7 mg of potassium carbonate in 3 ml anhydrous DMF yield the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([O:20]C)=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[OH-].[Li+]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(-c2ccc(OCCCCl)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccc(OCCCCl)cc2)cc1
Yield: 82.3 %

Procedure:
The product from Example 10B (3.4 g, 11.2 mmol) and lithium hydroxide (1.2 g, 28.6 mmol) in THF:water (3:1, 52 mL) were stirred vigorously at ambient temperature for 24 hours. The volume of the mixture was reduced under reduced pressure and then extracted with hexanes (2×25 mL). The remaining aqueous phase was acidified to pH 2 and then extracted with ethyl acetate (3×50 mL). The ethyl acetate extract was evaporated under reduced pressure to provide the title compound as a solid (2.68 g).
Reaction SMILES: [C:1]([C:3]1[C:11]2[O:10][CH2:9][CH2:8][C:7]=2[C:6]([NH:12][C:13](=[O:15])[CH3:14])=[CH:5][CH:4]=1)#[N:2].Cl.NC1C2CCCCC=2C(C#N)=CC=1.[OH:30][C@H:31]1[C@@H]2[N:34]([C:35](=[O:52])N(C3C4CCCCC=4C(C#N)=CC=3)C2=O)[CH2:33][CH2:32]1>>[OH:30][C@H:31]1[C@@H:14]2[N:34]([C:35](=[O:52])[N:12]([C:6]3[C:7]4[CH2:8][CH2:9][O:10][C:11]=4[C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[C:13]2=[O:15])[CH2:33][CH2:32]1
Reactant: CC(=O)Nc1ccc(C#N)c2c1CCO2
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Agent: Cl
Agent: N#Cc1ccc(N)c2c1CCCC2
Product: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1OCC2

Procedure:
The title compound as a white solid was prepared from compound 4B by procedures analogous to those described in Example 2 (from 2D to 2F). HPLC: 100% at 3.43 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient (A=90% H2O-10% MeOH-0.1% H3PO4 and B=10% H2O-90% MeOH-0.1% H3PO4). Flow rate at 2.5 mL/min. UV detection at 220 nm.). Chiral HPLC: retention time=13.69 min (100%); Conditions: OD (4.6×250 mm); Eluted with 25% isopropanol in hexane for 30 min at 1 mL/min. MS (ES) m/z 300 [M+1]+.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[CH3:31][NH:32][CH3:33].[ClH:34]>O1CCCC1.ClCCl>[ClH:34].[CH3:31][N:32]([CH3:33])[CH2:3][C@@H:2]([OH:1])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([N:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][CH:21]=4)=[CH:16][C:15]3=[O:30])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: CNC
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)ccn1-c1ccc2c(cnn2C[C@H]2CO2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C)C[C@@H](O)Cn1ncc2cc(-n3ccc(-c4ccc(C(F)(F)F)cc4)cc3=O)ccc21
Temperature: 45 °C
Yield: 80 %

Procedure:
To (S)-1-(1-(oxiran-2-ylmethyl)-1H-indazol-5-yl)-4-(4-(trifluoromethyl)phenyl)-pyridin-2(1H)-one (200 mg, 0.48 mmol) in tetrahydrofuran (5 mL) was added LiClO4 (775 mg, 7.3 mmol) followed by dimethylamine (2.4 ml of a 2 M solution in tetrahydrofuran, 4.9 mmol). The reaction mixture was heated in a 45° C. oil bath for 4.5 h. The reaction mixture was cooled to ambient temperature, diluted with dichloromethane (50 ml), washed with water (25 mL) and brine (25 mL), dried (Na2SO4), and concentrated under reduced pressure. The material was purified by column chromatography (silica gel, 9:1 CH2Cl2/MeOH to 90:9:1 CH2Cl2/MeOH/conc. NH4OH). The dried residue (160 mg, 0.35 mmol) was dissolved in dichloromethane (10 mL) and HCl (1.25 M solution in methanol, 0.31 mL, 0.43 mmol) was added. The mixture was concentrated under reduced pressure and dried to afford the title compound (190 mg, 80%) as a yellow solid: mp 210-213° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.50 (br s, 1H), 8.22 (s, 1H), 8.02-8.00 (m, 2H), 7.89-7.84 (m, 5H), 7.48 (dd, J=9.0, 2.0 Hz, 1H), 6.89 (d, J=2.0 Hz, 1H), 6.74 (dd, J=7.0 Hz, 2.0 Hz, 1H), 6.01 (br s, 1H), 4.58-4.49 (m, 2H), 4.40 (br s, 1H), 3.28-3.24 (m, 1H), 3.15-3.10 (m, 1H), 2.81 (d, J=4.5 Hz, 3H), 2.78 (d, J=4.5 Hz, 3H); ESI MS m/z 457 [M+H]+; HPLC (Method B) 96.5% (AUC), tR=14.4 min; [α]23D +10.4° (c 0.11, Methanol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:23]=[C:11]3[NH:12][C:13]([CH:16]4[CH2:21][CH2:20][NH:19][CH:18]([CH3:22])[CH2:17]4)=[N:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:4][C:3]=1[O:24]C.B(Br)(Br)Br.CCN(CC)CC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:23]=[C:11]3[NH:12][C:13]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=4)=[N:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:4][C:3]=1[OH:24]
Reactant: COc1ccc(-c2cc3[nH]c(C4CCNC(C)C4)ncc-3n2)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ncc3nc(-c4ccc(O)c(F)c4)cc-3[nH]2)ccn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.2 %

Procedure:
To a −78° C. solution of 2-fluoro-1-methoxy-4-[2-methyl-4-piperidylpyrrolo[4,5-d]pyrimidin-6-yl]benzene (Example 119) (0.80 g, 2.35 mmol) in CH2Cl2 (40 mL) under a N2 atmosphere was added 1 M BBr3 (4.7 mL, 4.70 mmol). The reaction mixture was allowed to warm to room temperature. The mixture was stirred at room temperature for an additional 20 h. The reaction mixture was then poured onto ice-water (200 mL) and the pH of the aqueous solution was adjusted to pH 9 with the addition of NEt3 (4 mL). The resulting mixture was stirred at room temperature for 2 h. The solid which formed was removed by filtration and dicarded. The remaining solution was transferred to a separatory funnel. The organic solution was separated, washed with H2O (100 mL), saturated NaCl (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure to afford 483 mg (62%) of 2-fluoro-4-(2-methyl-4-pyridylpyrrolo[4,5-d]pyrimidin-6-yl)phenol as a pale yellow colored solid. This compound (481 mg, 1.50 mmol) was dissolved in 4:2:1 EtOAc/MeOH/CH2Cl2 (50 mL) and heated to boiling. To the hot solution was added 1 M ethereal HCl (1.50 mL, 1.50 mmol). The solution was allowed to cool to room temperature. The resulting solid was collected by filtration, washed with EtOAc (2×10 mL), Et2O (3×15 mL) and dried under vacuum at 60° C. to give 315 mg (37%) of the title compound as a pale yellow colored solid. Mp: >280° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.63 (br s, 6), 2.49 (s, 3), 3.96 (br s, 4), 6.76 (s, 1), 7.06 (dt, 1, J=1.9, 8.7), 7.58 (d, 1, J=8.5), 7.83 (dd, 1, J=1.9, 12.5), 10.47 (s, 1), 11.79 (s, 1), 14.12 (s, 1). MS m/z: 327 (M+1 for free base). Anal. Calcd for C18H19FN4O.HCl.1.5H2O: C, 55.45; H, 5.95; N, 14.37; Cl, 9.09. Found: C, 55.49; H, 5.87; N, 14.07; Cl, 9.03.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:24]#[N:25].[K+].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][C:24]#[N:25])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccc(Cc2ccccc2OCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 84.3 %

Procedure:
To a solution of 4-(2-benzyloxybenzyl)benzyl chloride (0.66 g) in N,N-dimethylformamide (20 mL) was added potassium cyanide (0.40 g), and the mixture was stirred at 60° C. for 18 hours. The reaction mixture was cooled to room temperature, and to the mixture was added water. The mixture was extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=5/1-3/1) to give [4-(2-Benzyloxybenzyl)phenyl]-acetonitrile (0.54 g).
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+].Cl>CO.O>[CH2:22]([O:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]#[C:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][C:4]([OH:24])=[O:3])=[CH:12][CH:11]=2)=[CH:20][CH:19]=1)[CH3:23]
Reactant: CCOC(=O)CCc1ccc(C#Cc2ccc(OCC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOc1ccc(C#Cc2ccc(CCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 750 mg (2.33 mmol) 3-[4-(4-ethoxy-phenylethynyl)-phenyl]-propionic acid ethyl ester (XIII.1) in 15 mL MeOH are added 3.49 mL (6.98 mmol) 2N NaOH solution and the mixture is stirred at rt for 12 h. After that time, 7.0 mL 2N HCl are added and the mixture is diluted with water. The precipitate is filtered off, washed with water and dried at 45° C. to yield the desired product.