Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)[CH2:3][CH2:4][N:5]1C(=O)C2C(=CC=CC=2)C1=O.NN>C(O)C>[CH3:1][N:2]([CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)[CH2:3][CH2:4][NH2:5]
Reactant: CN(CCN1C(=O)c2ccccc2C1=O)Cc1ccc2ccccc2n1
Agent: NN
Solvent: CCO
Product: CN(CCN)Cc1ccc2ccccc2n1
Temperature: 65 °C

Procedure:
To 2-[2-(Methyl-quinolin-2-ylmethyl-amino)-ethyl]-isoindole-1,3-dione (1 eq) in Ethanol was added hydrazine (2 eq). A Reflux condenser was attached and the solution was heated 65° C. for 19 hours. The solution was then filtered, concentrated, and co-evaporated from toluene to yield N1-Methyl-N1-quinolin-2-ylmethyl-ethane-1,2-diamine in quantitative yield as a dark oil. MH+(216).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][CH2:17][CH:16]([C:19](O)=[O:20])[C:15]3=[O:22])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH3:25]>>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][CH2:17][CH:16]([C:19]([NH2:25])=[O:20])[C:15]3=[O:22])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: N
Reactant: O=C(O)C1CCN(c2ccc(OCc3ccc(F)cc3)cc2)C1=O
Product: NC(=O)C1CCN(c2ccc(OCc3ccc(F)cc3)cc2)C1=O

Procedure:
The title compound is prepared in analogy to Example 3d) from (RS)-1-[4-(4-fluoro-benzyloxy)-phenyl]-2-oxo-pyrrolidine-3-carboxylic acid and ammonia. Yield: 18% of a brownish solid. MS: m/e=329.3 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:34]([O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[C:48]([CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)=[O:49])[CH3:35]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:53]2[CH2:54][CH2:55][CH:50]([C:48]([C:40]3[N:39]([CH2:38][CH2:37][O:36][CH2:34][CH3:35])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)=[O:49])[CH2:51][CH2:52]2)([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(C(=O)C2CCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CCS(C)(=O)=O)(c3ccc(C)c(C)c3)C2)cc(OC)c1OC
Product: CCOCCn1c(C(=O)C2CCN(CCC3(c4ccc(C)c(C)c4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 6.6.2 using 1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-dimethyl-phenyl)-3-(2-methanesulfonyl-ethyl)-pyrrolidine and 4-[1-(2-ethoxy-ethyl)-1H-benzoimidazole-2-carbonyl]-piperidine to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH:7]=[N:8][OH:9])([O-:3])=[O:2].[Cl:13]Cl>C(Cl)(Cl)Cl>[ClH:13].[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]#[N+:8][O-:9])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(C=NO)c1
Reactant: ClCl
Solvent: ClC(Cl)Cl
Product: Cl
Product: O=[N+]([O-])c1cccc(C#[N+][O-])c1
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a solution of 79 (1.66 g, 10 mmol) in chloroform (50 mL) was introduced chlorine gas at −5° C. over 15 minutes. The color of the reaction mixture changed from colorless to light blue, green, and finally yellow. After an additional 15 minutes, the reaction mixture was concentrated under reduced pressure to give 80 (2.0 g, 100%) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:12]3[C:13](=[O:16])[NH:14][CH2:15][C:11]=3[CH:10]=[C:9]([NH:17][C@@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[N:8]=2)[CH:4]=[N:3]1.[Cl:32]N1C(=O)CCC1=O.O.C(Cl)(Cl)Cl>C(Cl)Cl>[Cl:32][C:10]1[C:11]2[CH2:15][NH:14][C:13](=[O:16])[C:12]=2[C:7]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)=[N:8][C:9]=1[NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29]
Reactant: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)cc3c2C(=O)NC3)cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: Cn1cc(-c2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)c(Cl)c3c2C(=O)NC3)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
A solution of tert-butyl (1S,2R)-2-(4-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (30 mg, 0.070 mmol) and N-chlorosuccinimide (9.86 mg, 0.074 mmol) in DCM (1 mL) was stirred at RT overnight. Additional N-chlorosuccinimide (1 eq) was added and the mixture was stirred at RT for 3 h. Water and CHCl3 were added to the mixture and the organic phase was washed with brine, dried over MgSO4, and evaporated. The residue was purified by preparative HPLC to give the title compound (20 mg, 61.7%). 1H NMR (500 MHz, CDCl3) δ ppm 1.18-2.09 (m, 17H), 4.02 (s, 3H), 4.28-4.45 (m, 2H), 5.80 (br s, 1H), 8.39 (br s, 1H), 9.03 (br s, 1H). [M+H] calc'd for C22H29ClN6O3, 461. found, 461.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:3]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:18][CH:17]=1.C1COCC1.[H-].[Na+].Br[CH2:38][C:39]([O:41][CH3:42])=[O:40]>O>[C:11]([O:10][C:8]([N:4]1[CH2:5][CH2:6][N:7]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[C:2](=[O:1])[CH:3]1[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:20][CH:21]=1)=[O:9])([CH3:13])([CH3:14])[CH3:12]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1Cc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CN1CCN(C(=O)OC(C)(C)C)C(Cc2ccc(OCc3ccccc3)cc2)C1=O
Reaction time: 8 h

Procedure:
To a solution of t-boc-(4-benzyloxybenzyl)piperazinone 3a (2.66 g, 6.72×10-3 mole) and dry THF (20 ml) under argon at room temperature is added portionwise NaH (0.30 g, 7.4×10-3 mole, 59% oil dispersion). After stirring 1/2 hour at room temperature a solution of methyl α-bromoacetate (0.62 ml, 7.4×10-3 mole) is added via syringe. After stirring overnight the reaction mixture is poured into water which is subsequently extracted with Et2O (3 times). The combined ethereal extracts are washed with saturated aqueous NaCl before being dried over Na2SO4. Filtration of the drying agent and evaporation of the filtrate affords a viscous oil which after column chromatography (silica gel, 10% EtOAc/CHCl3) gives a clear, colorless oil. After standing in the refrigerator this oil crystallizes. The resulting solid is triturated with hexane and collected by filtration affording 4a as colorless matted needles: 2.3 g (74%), m.p. 84°-87° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])=[C:5]([NH2:13])[NH:4][N:3]=1.CO[CH:16](OC)[CH:17]([CH:21](OC)OC)[CH2:18][C:19]#[N:20].NC1C(C(ON2C3C=CC=CC=3N=N2)=O)=C2N=CC(CC#N)=CN2N=1.C([O-])(O)=O.[Na+]>CS(C)=O.O.CCOC(C)=O>[NH2:13][C:5]1[C:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])=[C:2]2[N:1]=[CH:16][C:17]([CH2:18][C:19]#[N:20])=[CH:21][N:3]2[N:4]=1
Reactant: C=CCOC(=O)c1c(N)n[nH]c1N
Reactant: COC(OC)C(CC#N)C(OC)OC
Agent: N#CCc1cnc2c(C(=O)On3nnc4ccccc43)c(N)nn2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)c1c(N)nn2cc(CC#N)cnc12
Temperature: 85 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To a suspension of allyl 3,5-diamino-1H-pyrazole-4-carboxylate 3 (63.49 g, 348.5 mmol) in a mixture of DMSO (340 mL) and water (340 mL), was added 3-(dimethoxymethyl)-4,4-dimethoxy-butanenitrile (Scheme 3, below) (85 g, 418.2 mmol), followed by para-toluene Sulfonic acid hydrate (1) (11.27 g, 59.24 mmol). The reaction mixture was heated to 85° C. and stirred overnight. The reaction mixture was cooled with an ice bath. The mixture was diluted with EtOAc (680 mL) and a saturated aqueous solution of NaHCO3 (1.36 L). The precipitate was filtered and rinsed with water, then with a mixture of water and EtOAc. The brown solid was dried under vacuum to give allyl 2-amino-6-(cyanomethyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylate 4c as a brown solid (55.94 g, 62% yield).
Reaction SMILES: C[Si](C)(C)C#CCP(=O)(OCC)OCC.[N+:16]([C:19]1[C:20]([N:25]2[CH2:30][CH2:29][C:28](=[CH:31][C:32]#[CH:33])[CH2:27][CH2:26]2)=[N:21][CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17].I[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1>>[N+:16]([C:19]1[C:20]([N:25]2[CH2:30][CH2:29][C:28](=[CH:31][C:32]#[C:33][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[CH2:27][CH2:26]2)=[N:21][CH:22]=[CH:23][CH:24]=1)([O-:18])=[O:17]
Reactant: C#CC=C1CCN(c2ncccc2[N+](=O)[O-])CC1
Reactant: Ic1ccccn1
Agent: CCOP(=O)(CC#C[Si](C)(C)C)OCC
Product: O=[N+]([O-])c1cccnc1N1CCC(=CC#Cc2ccccn2)CC1

Procedure:
The title compound was obtained as described for the Compound of Example 1, reacting Compound 1c with 2-iodopyridine instead of 2-bromo-6-methylpyridine. The crude was purified by flash chromatography (EtOAc—Petroleum Ether 1:1) affording the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[CH2:7][C@H:8]([NH:16][C:17]([C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25](=[O:41])[CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]2)[CH2:20]1)=[O:18])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([OH:15])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F:49][CH2:50][CH2:51]OS(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[C:1]([O:5][C:6](=[O:42])[CH2:7][C@H:8]([NH:16][C:17]([C@@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25](=[O:41])[CH2:26][CH2:27][CH:28]2[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]2)[CH2:20]1)=[O:18])[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([O:15][CH2:51][CH2:50][F:49])[CH:14]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(OCCF)c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 77.6 %

Procedure:
Tert-butyl 4-{3-[(3R)-3-{[(1S)-3-tert-butoxy-1-(5-hydroxypyridin-3-yl)-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 25e, 800 mg, 1.36 mmol) was dissolved in N,N-dimethylformamide (52 mL). Cesium carbonate (1.1 g, 3.4 mmol) and 2-fluoroethyltosylat (445 mg, 2.04 mmol) were added. The mixture was stirred at room temperature for 3.5 hours, additional cesium carbonate (70 mg, 0.21 mmol) and 2-fluoroethyltosylate (28 mg, 0.13 mmol) were added and stirring was continued for 2.5 hours at room temperature and 17 hours at 5° C. The mixture was quenched by addition of saturated aqueous ammonium chloride solution and extracted with diethyl ether and ethyl acetate. The combined extracts were washed with brine and dried over sodium sulfate. The solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (ethyl acetate in hexane 20 to 100% followed by dioxane in ethyl acetate 0 to 50%) to yield 670 mg of tert-butyl 4-{3-[(3R)-3-({(1S)-3-tert-butoxy-1-[5-(2-fluoroethoxy)pyridin-3-yl]-3-oxopropyl}carbamoyl)piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylat.
Reaction SMILES: [CH2:1]([SH:16])[CH2:2][CH:3]=[CH:4][CH2:5][CH:6]=[CH:7][CH2:8][CH:9]=[CH:10][CH2:11][CH:12]=[CH:13][CH2:14][CH3:15].[H-].[Na+].Br[CH:20]([CH2:26][CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C)C=O>[CH2:1]([S:16][CH:20]([CH2:26][CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:2]/[CH:3]=[CH:4]\[CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH3:15]
Reactant: CCOC(=O)C(Br)CC
Reactant: CCC=CCC=CCC=CCC=CCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\CCSC(CC)C(=O)OCC
Yield: 96.9 %

Procedure:
A solution of 3Z,6Z,9Z,12Z)-pentadeca-3,6,9,12-tetraene-1-thiol (9.80 g, 41.5 mmol) in dry dimethylformamide (DMF) (70 mL) at 0° C. under inert atmosphere was added NaH (60% in mineral oil, 1.82 g, 45.6 mmol) and stirred at this temperature for ten minutes. Ethyl bromobutyrate (6.39 mL, 43.5 mmol) was added and the mixture was stirred at ambient temperature for 30 minutes. The mixture was partitioned between saturated NH4Cl (150 mL) and heptane (150 mL). The aqueous layer was extracted twice with heptane (100 mL each) and the combined organic extract were washed with water (100 mL) and brine (100 mL). The organic layer was dried (Na2SO4), filtrated and concentrated. The residue was purification by flash chromatography on silica gel (heptane:EtOAc 99:1 then 95:5). Concentration of the appropriate fractions afforded 14.1 g (97% yield) of the title compound as oil.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:13]=[N:14][C:15]2[C:20]([CH:21]=1)=[N:19][CH:18]=[C:17](Br)[CH:16]=2>CN(C=O)C>[CH2:1]([O:8][C:17]1[CH:18]=[N:19][C:20]2[C:15]([CH:16]=1)=[N:14][CH:13]=[C:12]([Br:11])[CH:21]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cnc2cc(Br)cnc2c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1cnc2cc(OCc3ccccc3)cnc2c1
Temperature: 60 °C
Yield: 36.5 %

Procedure:
To a solution of benzyl alcohol (2.25 g, 20.8 mmol) in DMF (25 mL) was added NaH (60% in mineral oil, 0.83 g, 20.8 mmol). The resulting mixture was heated to 60° C. for 10 minutes and was added to 3,7-dibromo-1,5-naphthyridine (Intermediate 3, 5.0 g, 17.4 mmol) in DMF (25.0 mL) at 100° C. The resulting mixture was stirred over night at 100° C., cooled, and concentrated under reduced pressure. Water (50 mL) was added and the aqueous layer was washed with DCM (3×50 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification (FCC, SiO2, DCM/petroleum ether, 1:1) afforded the title compound as a white solid (2.0 g, 36.7%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:32][O:33][CH2:34]Cl>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([O:25][CH2:32][O:33][CH3:34])[CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCl
Reactant: COC(=O)c1ccc(O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCOc1ccc(C(=O)OC)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.4 %

Procedure:
Methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-hydroxybenzoate (9.13 g, 26.0 mmol) was dissolved in DMF. Potassium carbonate (7.19 g, 52.0 mmol) was added, followed by methoxymethyl chloride (2.51 g, 31.2 mmol), and the reaction was stirred at room temperature under a drying tube for 24 h. An additional 1.2 eq of methoxymethyl chloride was added and the reaction stirred an additional 48 h. The DMF was removed in vacuo. The residue was dissolved in ethyl acetate, washed with water, dried, and the solvent was removed in vacuo to give 9.91 g (96.2%) of a viscous oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([C:21](=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[N:14][CH:13]=[C:12]2[CH:31]=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.P([O-])(O)(O)=[O:35].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[C:15]([C:21](=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)=[N:14][CH:13]=[C:12]2[C:31]([OH:35])=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P([O-])(O)O
Reactant: COc1cccc(C(=O)c2ncc(C=O)c3cc(OCc4ccccc4)c(OC)cc23)c1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1cccc(C(=O)c2ncc(C(=O)O)c3cc(OCc4ccccc4)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 60.7 %

Procedure:
To a stirred solution of 6-benzyloxy-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carbaldehyde (55 mg, 0.13 mmol) in t-butanol (2 mL) and water (2 mL) solution was added sodium dihydrogenphosphate monohydrate (71.1 mg, 0.52 mmol), 2-methyl-2-butene (0.087 mL, 0.77 mmol) and sodium chlorite (69.9 mg, 0.77 mmol) at room temperature. The reaction suspension was then stirred at room temperature for 14 hrs. The resulting two-phase mixture was partitioned between dichloromethane and water and acidified to pH=3 by addition of acetic acid. The aqueous phase was then extracted with dichloromethane (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a brown semi-solid oil. The crude product was recrystallized in methanol to afford 6-Benzyloxy-7-methoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid (35 mg, 62% yield) as a light yellow solid. HR-MS m/e calcd for C26H21N1O6 (M−H+) 444.1442, found 444.1442; 1H NMR (300 MHz) compatible.
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:20][CH:19]=[C:18]([CH3:21])[N:9]2[C:10](=[O:17])[C:11]=1[C:12]1[S:13][CH:14]=[CH:15][N:16]=1)[CH3:5])=[N+]=[N-].CP(C)C.C(OCC)(=O)C>O1CCCC1.O>[NH2:1][CH:4]([C:6]1[N:7]=[C:8]2[S:20][CH:19]=[C:18]([CH3:21])[N:9]2[C:10](=[O:17])[C:11]=1[C:12]1[S:13][CH:14]=[CH:15][N:16]=1)[CH3:5]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3nccs3)c(=O)n12
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1csc2nc(C(C)N)c(-c3nccs3)c(=O)n12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 7-(1-azidoethyl)-3-methyl-6-(1,3-thiazol-2-yl)-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.030 g, 0.094 mmol) in tetrahydrofuran (0.3 mL) and water (0.068 mL) was added 1.00 M of trimethylphosphine in tetrahydrofuran (0.11 mL, 0.11 mmol) at room temperature and the mixture was stirred at room temperature for 1 hour. To the mixture was added ethyl acetate and the mixture was extracted with 1 N HCl two times. The combined extracts were neutralized with solid sodium bicarbonate, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was used directly in next step. LCMS calculated for C12H13N4OS2(M+H)+: m/z=293.1. Found: 293.0.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:28](=[O:35])[N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:10][C:11]1[CH:12]=[C:13]([C:17](=[CH2:27])[CH2:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])[CH:14]=[CH:15][CH:16]=1)=O)(C)(C)C.C(O)(=O)C.[CH:40]1[C:52]2[CH:51]([CH2:53][O:54][C:55]([O:57]N3C(=O)CCC3=O)=O)[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44]=2[CH:43]=[CH:42][CH:41]=1>O.O1CCOCC1>[CH:45]1[C:50]2[CH:51]([CH2:53][O:54][C:55]([NH:8][C@H:9]([C:28](=[O:35])[N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:10][C:11]3[CH:12]=[C:13]([C:17](=[CH2:27])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH:14]=[CH:15][CH:16]=3)=[O:57])[C:52]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:49]=2[CH:48]=[CH:47][CH:46]=1
Reactant: C=C(CCC(=O)OC(C)(C)C)c1cccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N2CCCCC2)c1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Solvent: C1COCCO1
Solvent: O
Solvent: CC(=O)O
Product: C=C(CCC(=O)O)c1cccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)N2CCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl (S)-4-(3-(2-((tert-butoxycarbonyl)amino)-3-oxo-3-(piperidin-1-yl)propyl)phenyl)pent-4-enoate (Compound SP420) (0.50 g, 1.03 mmol) was suspended in acetic acid (7.0 ml, 122.28 mmol) and water (7.0 ml), and the suspension was stirred with heating at reflux for 8 hours. The same reaction was additionally carried out four times. The reaction solutions were combined and concentrated under reduced pressure, and the resulting residue was suspended in a 10% aqueous sodium carbonate solution (38 ml). A solution of N-(9-fluorenylmethoxycarbonyloxy)-succinimide (1.65 g, 4.89 mmol) in 1,4-dioxane (19.0 ml) was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with diethyl ether, made acidic by adding acetic acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was purified by column chromatography (hexane:ethyl acetate=100:0-50:50) to afford the title compound SP421 (0.78 g, 27.5%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[C:13]([O:30][CH3:31])[CH:12]=3)[CH:9]=2)[N:4]([S:32]([C:35]2[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH:3]=1.[F:42][C:43]1[CH:44]=[C:45]([CH:63]=[CH:64][CH:65]=1)[CH2:46][N:47]1[C:51]([CH3:52])=[C:50](B2OC(C)(C)C(C)(C)O2)[C:49]([CH3:62])=[N:48]1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1.C(O)C.O>[F:42][C:43]1[CH:44]=[C:45]([CH:63]=[CH:64][CH:65]=1)[CH2:46][N:47]1[C:51]([CH3:52])=[C:50]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]5)=[C:13]([O:30][CH3:31])[CH:12]=4)[CH:9]=3)[N:4]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:3]=2)[C:49]([CH3:62])=[N:48]1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: COc1cc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)cn3S(=O)(=O)c2ccc(C)cc2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 150.8 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, tert-butyl 4-(4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxyphenyl)piperazine-1-carboxylate (intermediate 58) (200 mg, 0.3 mmol) was coupled with 1-(3-fluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (intermediate 16) (130 mg, 0.13 mmol) in sodium carbonate (95 mg, 0.9 mmol), Pd(PPh3)2Cl2 (15 mg, 0.015 mmol), Toluene/ethanol/water (10/2/2.5 ml) to give 150 mg (64.65% yield) of titled compound. MS: m/z=765.3 (M+1).
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[CH:10][C:11]([F:23])=[C:12]([C:14]3[C:15]([C:21]#[N:22])=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[CH:13]=2)OC1.Br[C:26]1[N:30]2[N:31]=[CH:32][C:33]([C:35]([F:38])([CH3:37])[CH3:36])=[N:34][C:29]2=[N:28][CH:27]=1.CCOC(C)=O.CCCC(C)C>>[F:20][C:17]1[CH:16]=[C:15]([C:21]#[N:22])[C:14]([C:12]2[CH:13]=[C:8]([C:26]3[N:30]4[N:31]=[CH:32][C:33]([C:35]([F:38])([CH3:36])[CH3:37])=[N:34][C:29]4=[N:28][CH:27]=3)[CH:9]=[CH:10][C:11]=2[F:23])=[CH:19][CH:18]=1
Reactant: CC1(C)COB(c2ccc(F)c(-c3ccc(F)cc3C#N)c2)OC1
Reactant: CC(C)(F)c1cnn2c(Br)cnc2n1
Solvent: CCCC(C)C
Solvent: CCOC(C)=O
Product: CC(C)(F)c1cnn2c(-c3ccc(F)c(-c4ccc(F)cc4C#N)c3)cnc2n1

Procedure:
5′-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-4,2′-difluorobiphenyl-2-carbonitrile was coupled to 7-bromo-3-(1-fluoro-1-methylethyl)imidazo[1,2-b][1,2,4]triazine in 77% yield using a similar procedure to that described in Example C, step f, to give a yellow solid: mp 156-159° C. (EtOAc-isohexane); 1H NMR (400 MHz, CDCl3) δ 1.84 (6H, d, J 22.0 Hz), 7.36-7.46 (2H, m), 7.54 (1H, dd, J7.8, 2.7 Hz), 7.57-7.60 (1H, m), 8.10-8.16 (2H, m), 8.30 (1H, s), 8.79 (1H, d, J 1.2 Hz); MS (ES+) m/z 394 [M+H]+. Anal. Found: C, 64.07; H, 3.66; N, 17.60%. Required for C21H14F3N5: C, 64.12; H, 3.59; N, 17.80%.