Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:37]=[CH:36][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:27]([N:29]([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])=[O:28])=[C:18]([CH:26]=2)[O:19][C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])=[CH:5][CH:4]=1)#[N:2].Cl.[CH2:39](N=C=NCCCN(C)C)[CH3:40].OC1C2N=NNC=2C=CC=1.C(O)C>ClCCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:27]([N:29]([CH:30]([CH3:32])[CH3:31])[CH:33]([CH3:35])[CH3:34])=[O:28])=[C:18]([CH:26]=2)[O:19][C:20]([CH3:25])([CH3:24])[C:21]([O:23][CH2:39][CH3:40])=[O:22])=[CH:36][CH:37]=1)#[N:2]
Reactant: CC(C)N(C(=O)c1ccc(OCCCCCOc2ccc(C#N)cc2)cc1OC(C)(C)C(=O)O)C(C)C
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1cc(OCCCCCOc2ccc(C#N)cc2)ccc1C(=O)N(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A stirred solution of 2-[5-[5-(4-cyanophenoxy)pentyloxy]-2-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]-2-methylpropanoic acid (2.0 g, 4.0 mmol) in 50 mL of dichloromethane is treated with 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (770 mg, 4.0 mmol), hydroxybenztriazole (540 mg, 4.0 mmol), and ethanol (220 mg, 4.8 mmol) and stirred at room temperature over 3 days. The reaction is concentrated in vacuo and purified by chromatography on silica gel (60 g) with 40-50% ethyl acetate/hexane as the eluent to afford ethyl 2-[5-[5-(4-cyanophenoxy)pentyloxy]-2-[N,N-bis(1-methylethyl)aminocarbonyl]phenoxy]-2- methylpropanoate as a colorless foam.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[NH:11]1[CH2:14][CH:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:12]1.Cl[C:24]1[O:25][C:26]2[C:27](=[C:29]([C:41]#[N:42])[C:30]([CH3:40])=[C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:32]=2[F:33])[N:28]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:41]([C:29]1[C:27]2[N:28]=[C:24]([N:11]3[CH2:14][CH:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:12]3)[O:25][C:26]=2[C:32]([F:33])=[C:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:30]=1[CH3:40])#[N:42]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccccc2)c(F)c2oc(N3CC(NC(=O)OC(C)(C)C)C3)nc2c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Diisopropylethylamine (787 μl, 4.63 mmol) and tert-butyl azetidin-3-ylcarbamate hydrochloride (483 mg, 2.31 mmol) were added to a dichloromethane (20 ml) solution of 2-chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (553 mg, 1.93 mmol), followed by stirring at room temperature for 30 minutes. With cooling with ice, aqueous 10% citric acid solution (10 ml) was added to the reaction liquid, followed by extraction with chloroform (50 ml), then the organic layer was washed with saturated brine (50 ml). After drying over anhydrous sodium sulfate and concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate=2:1) to obtain the entitled compound (815 mg, 100%) as a colorless oily substance.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26](O)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:74][C:75]1[CH:76]=[N:77][CH:78]=[CH:79][CH:80]=1>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:74][C:75]4[CH:76]=[N:77][CH:78]=[CH:79][CH:80]=4)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Reactant: Nc1cccnc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1)Nc1cccnc1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (100 mg, 0.24 mmol), PyBOP® (125 mg, 0.24 mmol), DIEA (250 μL, 0.44 mmol) in CH2Cl2:DMF (4 mL:1 mL) stirred at RT for 10-15 minutes. To this solution of activated acid was added 3-amino pyridine (23 mg, 0.24 mmol) and the reaction mixture was stirred at 50° C. for 1.5 h. Concentrated in vacuo and the crude product was purified using prep HPLC (method 10-35—90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(pyridin-3-yl)acetamide. (11 mg, 0.023 mmol, 9%)
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O.O>[C:32]([O:31][C:29]([NH:28][CH2:27][CH2:26][CH2:25][O:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[O:17][C:13]1[CH:14]=[C:15]([CH3:16])[C:7]2[CH:6]([CH2:5][C:4]([OH:36])=[O:3])[O:10][B:9]([OH:11])[C:8]=2[CH:12]=1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cccc(OCCCNC(=O)OC(C)(C)C)c3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2cccc(OCCCNC(=O)OC(C)(C)C)c2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C

Procedure:
To a solution of {6-[3-(3-tert-butoxycarbonylamino-propoxy)-phenoxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid ethyl ester (0.6 g, 1.2 mmol) in THF:H2O (1:1, 10 mL) at 0° C. was added a solution of LiOH (0.086 g, 3.6 mmol) in water (1 mL). The solution was allowed to warm to room temperature over 3 hours then acidified to pH 2 with 1N HCl at 0° C. and extracted with EtOAc (2×10 mL). The organic extracts were dried and concentrated in vacuo to give crude 6-[3-(3-tert-butoxycarbonylamino-propoxy)-phenoxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid (0.5 g) which was used without further purification MS (ESI) m/z=470 [M−H]−.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([CH:12]1[CH:16]([C:17](OCC)=[O:18])[O:15][CH2:14][O:13]1)=O)C.O.[OH-].[Na+]>O1CCCC1>[OH:9][CH2:10][CH:12]1[CH:16]([CH2:17][OH:18])[O:15][CH2:14][O:13]1
Reactant: CCOC(=O)C1OCOC1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCC1OCOC1CO

Procedure:
100 ml of tetrahydrofuran was added to 11.4 g of lithium aluminum hydride, and the mixture was heated while refluxing. To this was added dropwise a solution of 21.8 g of (4RS,5SR)-4,5-bis(ethoxycarbonyl)-1,3-dioxolane prepared in Example 18 in 30 ml of tetrahydrofuran. After the addition, the mixture was reacted for one hour while refluxing. After allowing to cool, 30 ml of water was slowly added while cooling with ice to hydrolyze excessive lithium aluminum hydride. Then, 30 ml of 4N aqueous solution of sodium hydroxide and 90 ml of water was added dropwise. The mixture was filtered with suction, following which the precipitate was extracted with 1000 ml of ethanol-dioxane mixture at 60° C. and filtered with suction. This procedure was repeated three times. All filtrates were concentrated by evaporator to obtain a crude title compound.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[F:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[C:1]([C:4]([CH:17]1[CH2:21][CH2:20][N:19]([CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][C:23]([F:22])=[CH:24][CH:25]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: Fc1ccc(CCBr)cc1
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCN(CCc2ccc(F)cc2)C1
Temperature: 25 °C

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.5 g--see Preparation 8), 4-fluorophenethyl bromide (0.36 g--see J.A.C.S., 63, 602 (1941)), anhydrous potassium carbonate (0.5 g) and acetonitrile (15 ml) was heated under reflux for 2 hours. On cooling to room temperature, water (70 ml) was added and the mixture was extracted with dichloromethane (3×50 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a glass which was purified by column chromatography on silica eluting with dichloromethane containing methanol (2% up to 4%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless glass, yield, 0.056 g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:26]1[CH:31]=[C:30]([CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:29]=[CH:28][C:27]=1B(O)O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:27]4[CH:28]=[CH:29][C:30]([CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:31][CH:26]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cc1ccc(B(O)O)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C2(C)Cc3cc(Cl)ncc3O2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C2(C)Cc3cc(-c4ccc(CS(C)(=O)=O)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 2-fluoro-4-(methylsulfonylmethyl)phenylboronic acid following a procedure analogous to that described in Example 28. LC (method 6): tR=1.14 min; Mass spectrum (ESI+): m/z=505 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([O:18]C)=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([OH:18])=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1N1CCN(Cc2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1N1CCN(Cc2ccccc2)CC1
Temperature: 60 °C
Yield: 93.5 %

Procedure:
To a 150 mL round-bottomed flask equipped with magnetic stirring was added methyl 2-[4-benzylpiperazinyl]benzoate (Preparation XIII) (2.3 g, 7.4 mmol) in THF (60 mL). A soln of LiOH (Aldrich) (940 mg, 22 mmol) in H2O (20 mL), was added and the reaction mixture was heated at 60° C. for 12 h. After cooling to RT, the reaction mixture was concentrated in vacuo and diluted with EtOAc (100 mL). A 10% soln of citric acid (25 mL) was added, the organic layer was separated and the aqueous layer was extracted with EtOAc (2×25 mL). The organic layers were combined, washed with H2O, satd NaCl, dried over Na2SO4, filtered and concentrated in vacuo to afford 2-[4-benzylpiperazinyl]benzoic acid as a white solid (2.05 g). MS (ESI, pos. ion) m/z: 297 (M+H). Calc'd for C18H20N2O2: 296.15: 296.15.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][N:15]=[C:16]([N:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)[C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[C:24]([O:28][C:29](=[O:40])[NH:30][CH2:31][CH:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([CH3:27])([CH3:26])[CH3:25].CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:24]([O:28][C:29](=[O:40])[NH:30][CH2:31][CH:32]([NH:39][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][N:15]=[C:16]([N:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)[C:11]3=[N:10][CH:9]=2)[N:7]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CN1CCN(c2nccn3c(-c4cccc(Br)n4)cnc23)CC1
Reactant: CC(C)(C)OC(=O)NCC(N)c1ccccc1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1CCN(c2nccn3c(-c4cccc(NC(CNC(=O)OC(C)(C)C)c5ccccc5)n4)cnc23)CC1
Temperature: 130 °C

Procedure:
A mixture of 3-(6-bromo-pyridin-2-yl)-8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazine (from Example 39 supra) (0.56 g, 1.5 mmol), (2-amino-2-phenyl-ethyl)-carbamic acid tert-butyl ester (from Example 51 supra) (0.425 g, 1.8 mmol), Pd2(dba)3 (90 mg), Davephos (120 mg), K2CO3 (0.25 g, 1.8 mmol) in dioxane (40 mL) in a sealed tube was bubbled with N2 for several minutes and then heated under N2 at 130° C. overnight. The mixture was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was first purified by chromatography (CH2Cl2:CH3OH, 100:1), then by preparative-HPLC to give (2-{6-[8-(4-methyl-piperazin-1-yl)-imidazo[1,2-a]pyrazin-3-yl]-pyridin-2-ylamino}-2-phenyl-ethyl)-carbamic acid tert-butyl ester. (Yield 30 mg, 3.8%). LC-MS: [M+H]+ 529.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[C:6]([C:11]3([OH:17])[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:24](Br)[CH3:25]>CN(C)C=O.O>[CH2:24]([N:13]1[CH2:14][CH2:15][CH2:16][C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][NH:2]3)([OH:17])[CH2:12]1)[CH3:25]
Reactant: CCBr
Reactant: OC1(c2cccc3[nH]ccc23)CCCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCCC(O)(c2cccc3[nH]ccc23)C1

Procedure:
A mixture of 10 g of 3-(1H-indol-4-yl)-3-piperidinol hydrochloride in 200 ml of dimethylformamide was agitated for 4 hours under an inert atmosphere with 13.44 g of sodium carbonate and 4.2 ml of ethyl bromide. The mixture was taken up in water and was extracted with ethyl acetate. The organic phase was washed with water, dried, filtered and evaporated to dryness under reduced pressure at 50° C. The residue was purified by chromatography over silica and eluted with a 6-3-1 mixture of cyclohexane-chloroform-triethylamine to obtain 6.6 g of 1-ethyl-3-(1H-indol-4-yl)-3-piperidinol which was used as is for the following step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:4]=1[CH2:5][N:6]1[C:14](=O)[C:13]2[C:8](=[CH:9][C:10]([N+:28]([O-:30])=[O:29])=[C:11]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=3[O:26][CH3:27])[CH:12]=2)[C:7]1=O.CO.C(N(CC)CC)C.II>O1CCCC1.C(O)(=O)C>[CH3:27][O:26][C:19]1[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=1[CH2:17][NH:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][C:10]=1[N+:28]([O-:30])=[O:29])[CH2:7][N:6]([CH2:5][C:4]1[CH:32]=[CH:33][C:34]([O:36][CH3:37])=[CH:35][C:3]=1[O:2][CH3:1])[CH2:14]2
Reactant: COc1ccc(CNc2cc3c(cc2[N+](=O)[O-])C(=O)N(Cc2ccc(OC)cc2OC)C3=O)c(OC)c1
Agent: II
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(CNc2cc3c(cc2[N+](=O)[O-])CN(Cc2ccc(OC)cc2OC)C3)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2,4-dimethoxybenzyl)-5-(2,4-dimethoxybenzylamino)-6-nitroisoindoline-1,3-dione T-02 (6.1 g, 12 mmol) in anhydrous tetrahydrofuran (50 mL) cooled in an ice bath was added borane dimethyl sulfide complex (10 M, 36 mL, 360 mmol) in a dropwise manner. The reaction mixture was heated under reflux for 4 hours. The reaction mixture was cooled in an ice bath and methanol (75 mL) was added in a dropwise manner. To the reaction mixture were added triethylamine (6 mL), acetic acid (9 mL) and a solution of iodine (1 g) in anhydrous tetrahydrofuran (5 mL). The reaction mixture was stirred at room temperature overnight. Solvent was removed under reduced pressure. The crude product was diluted with ethyl acetate. The organic layer was washed with 1 N sodium hydroxide solution, water and saturated brine. The organic layer was dried over sodium sulfate. Solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography to afford the desired N,2-bis(2,4-dimethoxybenzyl)-6-nitroisoindolin-5-amine T-03 (2.7 g, 5.6 mmol).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][C@@H:12]([CH3:17])[C:13]([O:15]C)=O)[CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][C@H:20]([OH:32])[CH2:21][N:22]1[CH2:31][CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1>CCO>[CH2:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:30][CH2:31][N:22]1[CH2:21][C@@H:20]([OH:32])[CH2:19][NH:18][C:13](=[O:15])[C@@H:12]([O:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:1]=[CH:2][CH:3]=[CH:4]2)[CH3:17]
Reactant: NC[C@H](O)CN1CCc2ccccc2C1
Reactant: COC(=O)[C@H](C)Oc1cccc2cccnc12
Solvent: CCO
Product: C[C@H](Oc1cccc2cccnc12)C(=O)NC[C@H](O)CN1CCc2ccccc2C1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 27.9 %

Procedure:
To a stirred mixture of (S)-methyl 2-(quinolin-8-yloxy)propanoate (100 mg, 0.433 mmol) in EtOH (1 mL) was added (S)-1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (89.2 mg, 0.433 mmol). The mixture was stirred in a sealed tube in a microwave apparatus at 120° C. for 0.5 hour. After cooling to room temperature the solvent was evaporated, and the residue was first purified by prep-TLC and then prep-HPLC to afford the title compound (49 mg, yield: 28%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.86-8.97 (m, 1H), 8.38 (d, J=7.03 Hz, 1H), 7.51-7.67 (m, 3H), 7.30 (d, J=7.28 Hz, 1H), 7.06-7.13 (m, 3H), 6.98 (d, J=6.53 Hz, 1H), 5.07 (q, J=6.53 Hz, 1H), 4.10-3.88 (m, 1H), 3.65-3.76 (m, 2H), 3.43-3.51 (m, 1H), 3.35 (br. s., 1H), 2.86 (dd, J=16.06, 3.76 Hz, 4H), 2.62 (d, J=6.02 Hz, 2H), 1.71 (d, J=6.53 Hz, 3H). LCMS (m/z): 406.2 [M+H]+
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]([Cl:8])([Cl:7])[Cl:6])=[O:2].[NH2:10][C:11]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].N1C=CC=CC=1>ClCCl>[CH3:21][O:20][C:18]1[C:17]([O:22][CH3:23])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([NH:10][C:1]([O:3][CH2:4][C:5]([Cl:8])([Cl:7])[Cl:6])=[O:2])[CH:19]=1
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(NC(=O)OCC(Cl)(Cl)Cl)c(C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of Troc-Cl (0.76 ml, 5.56 mmol) in dry dichloromethane (10 mL) was added dropwise to 2-amino-4,5-dimethoxybenzoic acid 102 (1 g, 5.1 mmol) and pyridine (0.82 ml, 10.1 mmol) in dry dichloromethane (20 ml) at 0° C. The reaction mixture was allowed to stir overnight at room temperature and then washed with dilute HCl (1N, 2×25 ml), water (2×25 ml) and brine (20 ml). The organic phase was dried over MgSO4 and evaporated to yield of crude product (1.6 g), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-])=O)=[C:7]([O:12][CH3:13])[C:6]([N+:14]([O-])=O)=[CH:5][C:4]=1[Cl:17]>[Fe].C(O)(=O)C>[CH3:1][O:2][C:3]1[C:8]([NH2:9])=[C:7]([O:12][CH3:13])[C:6]([NH2:14])=[CH:5][C:4]=1[Cl:17]
Reactant: COc1c(Cl)cc([N+](=O)[O-])c(OC)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1c(N)cc(Cl)c(OC)c1N

Procedure:
2,4-Dimethoxy-3,5-dinitrochlorobenzene is reduced with iron in the presence of acetic acid, at a temperature of between 50° and 100° C. 2,4-Dimethoxy-3,5-diaminochlorobenzene is thereby obtained, and this is then subjected to a dehalogenation reaction. This reaction is performed in water, in a lower alcohol or in an aqueous-alcoholic mixture, in the presence of palladium on charcoal, ammonium acetate and triethylamine formate, at a temperature between 50° C. and the refluxing temperature of the solvent.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH:10]=O)[CH:7]=[CH:6][C:5]=12.[N+:12]([CH2:15][CH3:16])([O-:14])=[O:13].C(N)C>C(O)C.C(N)CCC>[N+:12]([C:15]([CH3:16])=[CH:10][C:8]1[CH:7]=[CH:6][C:5]2[N:4]([CH:3]=[CH:2][N:1]=2)[CH:9]=1)([O-:14])=[O:13]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccc2nccn2c1
Agent: CCN
Solvent: CCCCN
Solvent: CCO
Product: CC(=Cc1ccc2nccn2c1)[N+](=O)[O-]
Yield: 11.9 %

Procedure:
In 40 ml of ethanol, 6.9 g of 6-imidazo[1,2-a]pyridinecarbaldehyde was stirred under reflux for 14 hours, together with 10.6 g of nitroethane and 30 drops of n-butyl amine. Then, a small quantity of ethyl amine was added thereto and the mixture was stirred under reflux for further 18 hours. After insoluble matter was removed by filtration upon heating, 50 ml of ethanol and 150 ml of ether were further added to remove insoluble matter by filtration. The solvent was removed by distillation under reduced pressure and the residue was recrystallized twice from ethanol to obtain 1.14 g of 6-(2-nitro-1-propenyl)imidazo[1,2-a]pyridine.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:10]=2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:10]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)Cn1nc(Cc2ccc([N+](=O)[O-])cc2)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)Cn1nc(Cc2ccc(N)cc2)c2ccccc21
Yield: 53.2 %

Procedure:
1.3 g (3.83 mmol) ethyl 2-[3-(4-nitrobenzyl)-1H-indazol-1-yl]acetate was dissolved in 40 mL methanol. 200 mg palladium on carbon was added, and reacted under an atmosphere of H2 at room temperature overnight. It was filtered to remove solid, rotate evaporated to dryness to remove the solvent, and separated by a preparative chromatography to obtain a white solid 630 mg, at a yield of 53.3%.
Reaction SMILES: C(OC1C(=O)C(Br)=CN2CCN(CC3C=CC=C(Cl)C=3)C(=O)C=12)C1C=CC=CC=1.C([O:37][C:38]1[C:39](=[O:61])[C:40]([C:57]([O:59][CH3:60])=[O:58])=[CH:41][N:42]2[CH2:47][CH2:46][N:45]([CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([Cl:55])[CH:50]=3)[C:44](=[O:56])[C:43]=12)C1C=CC=CC=1>>[Cl:55][C:51]1[CH:50]=[C:49]([CH:54]=[CH:53][CH:52]=1)[CH2:48][N:45]1[CH2:46][CH2:47][N:42]2[CH:41]=[C:40]([C:57]([O:59][CH3:60])=[O:58])[C:39](=[O:61])[C:38]([OH:37])=[C:43]2[C:44]1=[O:56]
Reactant: COC(=O)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N(Cc1cccc(Cl)c1)CC2
Agent: O=C1c2c(OCc3ccccc3)c(=O)c(Br)cn2CCN1Cc1cccc(Cl)c1
Product: COC(=O)c1cn2c(c(O)c1=O)C(=O)N(Cc1cccc(Cl)c1)CC2

Procedure:
By subjecting 9-benzyloxy-7-bromo-2-(3-chlorobenzyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,8-dione (600 mg) produced by the same method as in Example 249, Step 1 to a reaction operation similar to that in Example 161, Step 3, a mixture of methyl 9-benzyloxy-2-(3-chlorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylate and methyl 2-(3-chlorobenzyl)-1,8-dioxo-9-hydroxy-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylate was obtained (13 mg). This mixture was dissolved in dimethylformamide (17 ml) and treated with benzyl bromide (1.36 g) and potassium carbonate (1.75 g) and purified by silica gel column chromatography (ethyl acetate-chloroform:methanol=10:1) to give methyl 9-benzyloxy-2-(3-chlorobenzyl)-1,8-dioxo-1,3,4,8-tetrahydro-2H-pyrido[1,2-a]pyrazine-7-carboxylate (480 mg).