Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][NH:6][C:7](=[O:34])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH:28]2[CH2:31][C:30]([CH3:33])([CH3:32])[CH2:29]2)[NH:15][C:16]2[C:25]([CH3:26])=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:27])[CH:22]=3)[N:17]=2)=[CH:10][CH:9]=1.[OH-].[Na+]>CO.C1COCC1>[CH3:32][C:30]1([CH3:33])[CH2:31][CH:28]([CH:14]([NH:15][C:16]2[C:25]([CH3:26])=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:27])[CH:22]=3)[N:17]=2)[C:11]2[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:35])=[O:2])=[O:34])=[CH:13][CH:12]=2)[CH2:29]1
Reactant: COC(=O)CCNC(=O)c1ccc(C(Nc2nc3ccc(F)cc3cc2C)C2CC(C)(C)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2cc(F)ccc2nc1NC(c1ccc(C(=O)NCCC(=O)O)cc1)C1CC(C)(C)C1

Procedure:
The title compound was prepared by treating 3-{4-[(3,3-Dimethyl-cyclobutyl)-(6-fluoro-3-methyl-quinolin-2-ylamino)-methyl]-benzoylamino}-propionic acid methyl ester, isomer 2, (intermediate 75) with 1N NaOH (2.5 eq.) in methanol/THF in a similar manner as described in Example 19 to provide the title compound. Analytical chiral SFC: (Chiralpak IC column, 4.6 mm×25 cm, 25% methanol/carbon dioxide eluent, 2.5 mL/min flow rate, 4.81 retention time); 1H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.37 (t, J=5.5 Hz, 1H), 7.65-7.71 (m, 3H), 7.54 (d, J=8.3 Hz, 2H), 7.39-7.47 (m, 1H), 7.29-7.37 (m, 1H), 7.19-7.29 (m, 1H), 6.53 (d, J=8.1 Hz, 1H), 5.13-5.23 (m, 1H), 3.41 (dd, J=12.4, 6.8 Hz, 2H), 2.77-2.90 (m, 1H), 2.46 (t, J=7.1 Hz, 2H), 2.28 (s, 3H), 1.92-2.00 (m, 1H), 1.56-1.66 (m, 2H), 1.42-1.53 (m, 1H), 1.11 (s, 3H), 1.07 (s, 3H); MS (M+1): 464.2.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.CN(C)C=O.Br[C:17]1[N:25]2[C:20]([CH:21]=[N:22][C:23]([S:26][CH3:27])=[N:24]2)=[CH:19][CH:18]=1>CCOC(C)=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>[CH3:27][S:26][C:23]1[N:22]=[CH:21][C:20]2=[CH:19][CH:18]=[C:17]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[N:25]2[N:24]=1
Reactant: C[Sn](C)(C)c1ccccn1
Reactant: CSc1ncc2ccc(Br)n2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ncc2ccc(-c3ccccn3)n2n1
Temperature: 80 °C
Yield: 70 %

Procedure:
2-Trimethylstannanyl-pyridine (0.557 g, 2.30 mmol) in N,N-Dimethylformamide (7.6 mL, 98 mmol) was added 7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.250 g, 1.02 mmol) and Tetrakis(triphenylphosphine)palladium(0) (67 mg, 0.058 mmol) in a vial, and the mixture was heated in a block at 80° C. The reaction mixture was then diluted with EtOAc (30 mL) and washed with water (1×, 10 mL), 2.5M KF (2×, 10 mL), and brine (1×, 10 mL), followed by drying with sodium sulfate, filtering, and conc. in vacuo. The crude product was purified by ISCO column chromatography (0-25, 25-100% EtOAc/Hex) to give 2-Methylsulfanyl-7-pyridin-2-yl-pyrrolo[2,1-f][1,2,4]triazine (0.173 g, 70%). 1H-NMR (DMSO-d6): 9.09 (s, 1H), 8.71 (m, 2H), 7.98 (dt, 1H, J=7.80 Hz), 7.63 (d, 1H, J=4.74 Hz), 7.38 (dt, 1H, J=6.40), 7.12 (d, 1H, 4.98 Hz), 2.65 (s, 3H).
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][CH:6]1[CH2:10][NH:9][C@H:8]([C:11]([OH:13])=[O:12])[CH2:7]1.[CH2:14](O)[CH3:15]>>[ClH:3].[CH2:14]([O:12][C:11](=[O:13])[C@@H:8]1[CH2:7][CH:6]([OH:5])[CH2:10][NH:9]1)[CH3:15]
Reactant: CCO
Reactant: O=S(Cl)Cl
Reactant: O=C(O)[C@@H]1CC(O)CN1
Product: CCOC(=O)[C@@H]1CC(O)CN1
Product: Cl

Procedure:
200 mL of absolute ethanol were placed in a 500-mL one-necked round-bottomed flask equipped with an addition funnel. The flask was then cooled in a dry ice/acetone bath, then 17 mL (0.23 mmoles) of thionyl chloride were added from the addition funnel over a 10 minute period. The funnel was removed, and 26.2 g (0.20 mmoles) of 4-hydroxyproline were added in one portion while stirring. The flask was equipped with a reflux condenser and a sodium hydroxide trap, and the mixture was refluxed for two hours. The product was precipitated in ether, isolated by filtration, and washed three times with ether, then it was dried under a stream of nitrogen followed by high vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]>C(Cl)Cl.FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 107.9 %

Procedure:
1-dimethylethyl 4-[3-(methyloxy)-4-nitrophenyl]-1-piperazinecarboxylate (2.25 g, 6.67 mmol) was dissolved in methylene chloride (50 mL) and trifluoroacetic acid (10 mL). The resulting solution turns immediately dark and was stirred overnight. The solution was concentrated and partitioned between methylene chloride and 2.0N sodium hydroxide. The organic layer was collected and the aqueous layer was saturated by addition of sodium chloride and subsequently backextracted with additional methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, and taken to a residue under reduced pressure to afford analytically pure 1-[3-(methyloxy)-4-nitrophenyl]piperazine as a yellow solid (1.7 g, 7.2 mmol, quant. yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.28-2.37 (m, 1 H), 2.76 (q, J=4.64 Hz, 4 H), 3.29-3.34 (m, 4 H), 3.86 (s, 3 H), 6.46 (d, J=2.38 Hz, 1 H), 6.54 (dd, J=9.43, 2.47 Hz, 1 H), 7.84 (d, J=9.34 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([CH3:13])([CH3:12])[C:10]#N.[OH2:14].[OH:15]S(O)(=O)=O>O1CCOCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([CH3:13])([CH3:12])[C:10]([OH:15])=[O:14]
Reactant: O
Reactant: CC(C)(C#N)c1cccc(F)c1F
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(C)(C(=O)O)c1cccc(F)c1F
Temperature: 110 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(2,3-difluorophenyl)-2-methylpropanenitrile (9.5 g, 52 mmol) in 50 mL dioxane was treated with 10 mL H2O and concentrated H2SO4 (3 mL, 105 mmol). The resulting mixture was stirred at 110° C. for 16 hours, M+1=201. The reaction was then cooled to room temperature. The mixture was extracted with EtOAc and the organic layer discarded. The water layer was acidified with concentrated HCl, extracted with EtOAc, washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give 4.74 g of the title compound as a pale yellow solid. MS (m/z)=201 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[F:21][C:22]([F:31])([F:30])[C:23]1[CH:24]=[C:25]([SH:29])[CH:26]=[CH:27][CH:28]=1.C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[CH2:19]([O:18][C:16]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[S:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:30])[F:31])[CH:24]=1)=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=2)=[O:17])[CH3:20]
Reactant: CCOC(=O)c1cnc2ccc(C(F)(F)F)cc2c1Cl
Reactant: FC(F)(F)c1cccc(S)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc2ccc(C(F)(F)F)cc2c1Sc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.3 %

Procedure:
The reaction mixture of 151.8 mg (0.50 mmol) of 4-chloro-3-ethoxycarbonyl-6-trifluoromethylquinoline, 106.9 mg (0.60 mmol) of 3-trifluoromethylthiophenol and 100 μL of diisopropylethylamine in 2.0 mL of N,N-dimethylformamide was stirred at room temperature for 2 h and cooled. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulphate and concentrated. The resulting residue was purified on silica gel column eluting with ethyl acetate-hexane (1:3) to give 76.4 mg (34%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14].[NH2:25][C@H:26]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:27][OH:28]>O1CCCC1>[OH:28][CH2:27][C@H:26]([NH:25][C:13](=[O:14])[NH:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)c1sc(N)nc1C
Reactant: N[C@@H](CO)Cc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(NC(=O)N[C@@H](CO)Cc2ccccc2)nc1C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of ethyl 2-amino-4-methylthiazole-5-carboxylate (1.86 g, 10.0 mmol) in tetrahydrofuran (50 mL) was added 1,1′-carbonyldiimidazole (1.95 g, 12.0 mmol) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 17 hours, followed by the addition of (R)-(+)-2-amino-3-phenyl-1-propanol (2.00 g, 13.2 mmol). The reaction mixture was kept stirring at ambient temperature for 50 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (200 mL) and washed with water and brine. The organic solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford the title compound in 88% (3.20 g): MS (ES+) m/z 364.4 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11].O([CH2:28][C:29]([F:32])([F:31])[F:30])S(C(F)(F)F)(=O)=O>CN(C)C=O.ClCCl>[CH3:17][O:16][C:15]1[C:8]([O:7][CH2:28][C:29]([F:32])([F:31])[F:30])=[C:9]([CH:12]=[CH:13][C:14]=1[O:18][CH3:19])[C:10]#[N:11]
Reactant: COc1ccc(C#N)c(O)c1OC
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C#N)c(OCC(F)(F)F)c1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
Potassium carbonate (6.91 g, 0.05 mol) was added to a stirred solution of 2-hydroxy-3,4-dimethoxybenzonitrile (from Example 10(c), 5.61 g, 0.031 mol) in dimethylformamide (30 ml). This was followed by the addition of a solution of 2,2,2-trifluoroethyl triflate (23.2 g, 0.10 mol) in dichloromethane (100 ml) and the reaction was stirred at room temperature for 18 hours. The reaction was partitioned between 2N hydrochloric acid and ethyl acetate, the organic layer separated, washed sequentially with saturated aqueous brine and water, dried (MgSO4) and evaporated under reduced pressure. Trituration with diethyl ether followed by filtration afforded the subtitle compound as a colourless solid (7.67 g, 94%). Rf 0.76 (dichloromethane:methanol 95:5, v/v). MS m/z 279 (MNH4)+
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]([F:23])([CH:16](OS(C)(=O)=O)[CH3:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C)C=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]([CH:16]([N:24]=[N+:25]=[N-:26])[CH3:17])([F:23])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(OS(C)(=O)=O)C1(F)CCN(C(=O)OCc2ccccc2)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(N=[N+]=[N-])C1(F)CCN(C(=O)OCc2ccccc2)C1
Temperature: 120 °C
Yield: 76 %

Procedure:
To a solution of 3-fluoro-3-(1-methanesulfonyloxyethyl)pyrrolidine-1-carboxylic acid benzyl ester (Example A15, 0.25 g, 0.72 mmol) in N,N-dimethylformamide (5 mL) is added sodium azide (0.13 g, 2 mmol). The reaction mixture is heated at 120° C. overnight. The mixture is diluted with water and extracted with ethyl acetate. The extracts are washed with brine, dried over Na2SO4 and concentrated to afford the title compound (0.160 g). 1H NMR (200 MHz, CDCl3): δ 7.28 (s, 5H), 5.08 (s, 2H), 3.80-3.25 (m, 5H), 2.13-1.75 (m, 2H), 1.40 (d, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6](Cl)[CH3:7])=[CH:2]1.[N-:9]=[N+:10]=[N-:11].[Na+].O>CN(C=O)C>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]([N:9]=[N+:10]=[N-:11])[CH3:7])=[CH:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(Cl)c1ccsc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(N=[N+]=[N-])c1ccsc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.4 %

Procedure:
A mixture of 1-(thien-3-yl)chloroethane (5.0 g, 34 mmol) and sodium azide (2.65 g, 41 mmol) in DMF was stirred at room temperature for three days. The reaction mixture was poured into H2O (500 ml) and extracted with CH2Cl2 (3×200 ml). The organic extracts were washed with H2O (5×100 ml), dried over MgSO4 and concentrated in vacuo to give the product (5.02 g, 96% yield) as a brown oil; IR (neat) 2110 cm-1 ; 1H NMR (CDCl3) δ1.55 (d, J=7 Hz, 3H, CHCH3), 4.67 (q, J=7 Hz, 1H, CHCH3), 6.98-7.43 (m, 3H, thiophene-H).
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:30]=3)[C:25]([OH:27])=O)=[CH:17][CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:39][C:40]1[CH:45]=[N:44][C:43]([CH3:46])=[CH:42][N:41]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[N:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:30]=3)[C:25]([NH:39][C:40]3[CH:45]=[N:44][C:43]([CH3:46])=[CH:42][N:41]=3)=[O:27])=[CH:17][CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1
Reactant: Cc1cnc(N)cn1
Reactant: O=C(O)c1cc(OCc2ccccc2)cc(Oc2ccc(C(=O)N3CCC3)nc2)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(Oc3ccc(C(=O)N4CCC4)nc3)c2)cn1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 52.9 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (2.67 mL, 20 mmol) was added to a solution of 3-{[6-(azetidin-1-ylcarbonyl)pyridin-3-yl]oxy}-5-[(phenylmethyl)oxy]benzoic acid (6.18 g, 15.3 mmol) in DCM (100 mL) and the reaction stirred at RT for 50 mins. 2-Amino-5-methylpyrazine (3.34 g, 30.6 mmol) and pyridine (2.5 mL, 30.6 mmol) were added and the reaction stirred overnight. The solvent was removed in vacuo, and the residue taken up in ethyl acetate (350 mL). The organic phase was washed with water (2×100 mL), brine (100 mL), dried (MgSO4), filtered, and evaporated in vacuo. The residue was chromatographed on silica, eluting with a gradient of 50-75% ethyl acetate in isohexane, to give the desired material (4.01 g). 1H NMR δ (CDCl3): 2.28 (quin, 2H), 2.49 (s, 3H), 4.18 (t, 2H), 4.63 (t, 2H), 5.05 (s, 2H), 6.78 (s, 1H), 7.10 (s, 1H), 7.25-7.37 (m, 7H), 8.04 (d, 1H), 8.07 (s, 1H), 8.25 (s, 2H), 9.46 (s, 1H); m/z 496 (M+H)+
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].[CH:42]([NH:45][C:46](=[O:49])[CH2:47]Cl)([CH3:44])[CH3:43]>C1COCC1>[CH:42]([NH:45][C:46](=[O:49])[CH2:47][N:33]1[CH2:34][CH2:35][CH:30]([C:28]2[CH:27]=[CH:26][C:23]3[C:24]4[N:18]([CH:17]=[C:16]([C:15]5[N:11]([CH:8]([CH3:10])[CH3:9])[N:12]=[CH:13][N:14]=5)[N:25]=4)[CH2:19][CH2:20][O:21][C:22]=3[CH:29]=2)[CH2:31][CH2:32]1)([CH3:44])[CH3:43]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Reactant: CC(C)NC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)NC(=O)CN1CCC(c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.1 %

Procedure:
To a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetic acid salt (350 mg, 0.71 mmol) in THF was added potassium carbonate (245 mg, 1.78 mmol) followed by N-isopropyl-2-chloroacetamide (106 mg, 0.78 mmol) and the reaction mixture stirred for 18 h at RT then heated at 50° C. for 2 h. The resultant mixture was concentrated in vacuo and the residue subjected to flash chromatography (SiO2, gradient 0 to 5% MeOH in DCM to give 247 as a white solid (180 mg, 53%). 1H NMR δ (ppm) (DMSO-d6): 8.28 (1 H, d, J=8.28 Hz), 7.86 (1 H, d, J=0.63 Hz), 7.85 (1 H, s), 7.40 (1 H, d, J=8.18 Hz), 7.03 (1 H, dd, J=8.36, 1.77 Hz), 6.89 (1 H, d, J=1.72 Hz), 5.88-5.79 (1 H, m), 4.48-4.41 (4 H, m), 3.89-3.83 (1 H, m), 2.89-2.79 (4 H, m), 2.13 (2 H, td, J=10.70, 4.11 Hz), 1.74-1.64 (4 H, m), 1.43 (6 H, d, J=6.60 Hz), 1.04 (6 H, d, J=6.59 Hz). 1 Proton obscured by solvent peak. LCMS: RT=2.94 min, M+H+=478
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[N:23][C:24]=3[NH2:26])[N:19]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:18]=2)[CH:6]=[CH:7][C:8]=1[NH:9][CH2:10][C:11]1[O:12][C:13]([CH3:16])=[CH:14][CH:15]=1.[CH3:33][N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[CH:39]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[N:23][C:24]=3[NH2:26])[N:19]([CH:27]3[CH2:32][CH2:31][N:30]([CH2:39][C:35]4[N:34]([CH3:33])[CH:38]=[CH:37][N:36]=4)[CH2:29][CH2:28]3)[N:18]=2)[CH:6]=[CH:7][C:8]=1[NH:9][CH2:10][C:11]1[O:12][C:13]([CH3:16])=[CH:14][CH:15]=1
Reactant: Cn1ccnc1C=O
Reactant: COc1cc(-c2nn(C3CCNCC3)c3ncnc(N)c23)ccc1NCc1ccc(C)o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COc1cc(-c2nn(C3CCN(Cc4nccn4C)CC3)c3ncnc(N)c23)ccc1NCc1ccc(C)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
A mixture 3-(3-methoxy-4-{[(5-methyl-2-furyl)methyl]amino}phenyl)-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.045 g, 0.0001 mol), 1-methyl-2-imidazole carboxaldehyde (0.011 g, 0.00011 mol), and acetic acid (0.018 g, 0.0003 mol) in dichloroethane (4 mL) was stirred at room temperature under an atmosphere of nitrogen for 1.5 hrs. Sodium triacetoxyborohydride (0.064 g, 0.0003 mol) was added into the mixture and the mixture was stirred at ambient temperature under an atmosphere of nitrogen for 18 hours. The reaction was quenched with an aqueous 5 N solution of sodium hydroxide. The solvents were removed under reduced pressure, and the residue was partitioned between water and dichloromethane. The organic layer was washed with water and brine. The solvents were removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield 3-(3-methoxy-4-{[(5-methyl-2-furyl)methyl]amino}phenyl)-1-{1-[(1-methyl-1H-2-imidazolyl)methyl]-4-piperidyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.03 g, 0.00006 mol).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[C:9](Cl)(=[O:11])[CH3:10]>[OH-].[Na+].O.O1CCCC1.C(Cl)(Cl)Cl>[C:5]([OH:11])(=[O:6])[CH3:7].[C:9]([OH:11])(=[O:2])[CH3:10].[C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2]
Reactant: CC(=O)Cl
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Hydroquinone (110 g) was dissolved in a solution of sodium hydroxide (80 g) in water (400 ml) and to the resulting solution was added dropwise a solution of acetyl chloride (157 g) in tetrahydrofuran (157 g) with ice-cooling (0° C.). The reaction mixture was allowed to stand overnight at room temperature. The reaction mixture was poured into water (1 liter) and the crystals formed was filered and dissolved in chloroform. The solution was washed with dil. sodium hydroxide solution to remove unreacted hydroquinone. After removal of the solvent, the residue was recrystallized from water/ethanol to give hydroquinone diacetate (175 g). m.p. 121°-122.5° C.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[Br:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][CH:17]([NH:16][C:2]2[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=3)[N:3]=2)[C:18]([OH:20])=[O:19])=[CH:27][CH:26]=1
Reactant: NC(Cc1ccc(Br)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1ccc(Br)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-(4-bromo-phenyl)-propionic acid in DMSO to provide the title compound in good yield.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:21]([O:23]C)=[O:22])[C:6](=[O:20])[NH:7][C:8]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[CH2:14][CH2:13][CH2:12]2)[CH3:2].O[Li].O>C1COCC1.O>[CH2:1]([C:3]1[CH:4]=[C:5]([C:21]([OH:23])=[O:22])[C:6](=[O:20])[NH:7][C:8]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[CH2:14][CH2:13][CH2:12]2)[CH3:2]
Reactant: CCc1cc(C(=O)OC)c(=O)[nH]c1-c1ccc2c(c1)CCCN2C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CCc1cc(C(=O)O)c(=O)[nH]c1-c1ccc2c(c1)CCCN2C
Temperature: 65 °C
Reaction time: 1 h
Yield: 63.9 %

Procedure:
To a suspension of methyl 5-ethyl-6-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (200 mg, 0.61 mmol) in THF (1 mL) and H2O (1 mL) was added LiOH—H2O (85 mg, 2.03 mmol, 3.3 eq) at room temperature. The reaction mixture was heated to 65° C. and stirred for 1 h. The reaction was monitored by LC-MS. Upon complete consumption of starting material, the reaction was quenched with 1N HCl (2 mL). The precipitate was collected by filtration then washed with Et2O to afford the title compound as a yellow solid (121 mg, 0.39 mmol, 14% over three steps).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([OH:8])[C@@H:6]([C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[O:5][C:3]1=[O:4].[H][H].CCCCCC.C(OC(C)C)(C)C>C(O)C>[OH:1][C@H:2]1[C@H:7]([OH:8])[C@H:6](/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[O:5][C:3]1=[O:4]
Reactant: [H][H]
Reactant: CCCCCCCCC#C[C@H]1OC(=O)[C@@H](O)[C@@H]1O
Solvent: CCO
Solvent: CCCCCC
Solvent: CC(C)OC(C)C
Product: CCCCCCCC/C=C\[C@@H]1OC(=O)[C@@H](O)[C@@H]1O
Yield: 74.6 %

Procedure:
1.924 g (7.58 mmol) of the compound (15) obtained in step e were dissolved in 20 ml of ethanol, 40 mg of 5 wt % Pd--CaCO3 /Pb (Lindlar catalyst) were added thereto, and the resultant solution was strongly stirred in a hydrogen flow. The solid product in the reaction solution was filtered, and the solvent was distilled at a reduced pressure, thereby obtaining a colorless solid product. This solid product was recrystallized using 50 ml of a hexane/isopropyl ether solution mixture obtained by mixing hexane with isopropyl ether at a mixing ratio of 20:30 to obtain 1.45 g of a colorless fibrous compound (16) (yield:74.6%). The physical data of the resultant compound (16) were as follows.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH3:7].CCCCCC.C([Li])CCC.[CH3:19][C:20]1[CH:21]=[C:22]([O:25][C:26]=1[CH3:27])[CH:23]=[O:24]>O1CCCC1.O>[CH3:19][C:20]1[CH:21]=[C:22]([CH:23]([C:4]2[S:5][C:6]([CH3:7])=[C:2]([CH3:1])[N:3]=2)[OH:24])[O:25][C:26]=1[CH3:27]
Reactant: Cc1ncsc1C
Reactant: Cc1cc(C=O)oc1C
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(C(O)c2nc(C)c(C)s2)oc1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
4,5-Dimethylthiazole (1.0 g) was dissolved in tetrahydrofuran (40 ml) under an argon atmosphere to prepare a solution. A 1.6M hexane solution (5.6 ml) of n-butyllithium was added dropwise at −78° C., and the mixture was then stirred at −78° C. for 30 min. A solution of 4,5-dimethylfurfural (1 g) in tetrahydrofuran (20 ml) was added dropwise thereto, and the temperature of the mixture was raised to room temperature with stirring. Water was added to the reaction solution to stop the reaction. The solvent was removed by distillation under the reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-acetone to give (4,5-dimethylfuran-2-yl)-(4,5-dimethylthiazol-2-yl)methanol (945 mg, yield 50%).