Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.[N:13]1C2C(=CC=CC=2)C=C(B(O)O)C=1.Br[C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[C:29]1([C:61]3[C:52](=[CH:53][C:54]4[O:59][CH2:58][CH2:57][O:56][C:55]=4[CH:60]=3)[O:51][CH2:50]1)[C:30](=[O:49])[N:31]2[CH:36]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45]C=1)C1C=CC=CC=1>>[CH3:1][N:2]([CH3:12])[C:3]1[N:4]=[CH:5][C:6]([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[C:29]2([C:61]4=[CH:60][C:55]5[O:56][CH2:57][CH2:58][O:59][C:54]=5[CH:53]=[C:52]4[O:51][CH2:50]2)[C:30](=[O:49])[N:31]3[CH2:36][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][N:13]=2)=[CH:7][CH:8]=1
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Br)c2C12COc1cc3c(cc12)OCCO3
Reactant: CN(C)c1ccc(B(O)O)cn1
Product: CN(C)c1ccc(-c2cccc3c2C2(COc4cc5c(cc42)OCCO5)C(=O)N3Cc2ccccn2)cn1

Procedure:
Following the procedure as described in EXAMPLE 2.46 and making non-critical variations using 2-(dimethylamino)pyridine-5-boronic acid to replace quinolin-3-ylboronic acid, and 4′-bromo-1-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 4′-(6-(dimethylamino)pyridin-3-yl)-1′-(pyridin-2-ylmethyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one was obtained (44%) as a colorless solid: mp 187-188° C. (methanol/dichloromethane); 1H NMR (300 MHz, CDCl3) δ 8.61-8.56 (m, 1H), 7.80-7.77 (m, 1H), 7.70-7.62 (m, 1H), 7.32-7.17 (m, 3H), 6.91-6.81 (m, 2H), 6.66 (dd, J=8.8, 2.5 Hz, 1H), 6.40 (s, 1H), 6.27 (s, 1H), 6.21 (d, J=8.8 Hz, 1H), 5.25 (d, J=15.8 Hz, 1H), 4.93 (d, J=15.8 Hz, 1H), 4.71 (d, J=9.0 Hz, 1H), 4.46 (d, J=9.0 Hz, 1H), 4.30-4.08 (m, 4H), 3.05 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 178.2, 158.5, 155.6, 155.4, 149.5, 147.4, 144.7, 142.7, 138.0, 137.6, 137.2, 137.1, 129.5, 128.8, 125.9, 122.8, 122.7, 122.0, 121.7, 111.2, 108.6, 104.3, 99.4, 64.6, 64.0, 58.4, 46.2, 38.1; MS (ES+) m/z 507.0 (M+1).
Reaction SMILES: [C:1]1([CH:7]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:26][CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29].CCOCC>CCOC(C)=O>[Br-:26].[O:29]=[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:27][N+:13]12[CH2:14][CH2:15][CH:16]([CH2:17][CH2:18]1)[C@@H:11]([O:10][C:8](=[O:9])[C@@H:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:12]2
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1)c1ccccc1
Reactant: O=C(CBr)c1ccccc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)[C@H](Nc1ccccc1)c1ccccc1)C2)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
(R)-quinuclidin-3-yl 2-phenyl-2-(phenylamino)acetate (Diasteroisomer 1 of C2) (20.3 mg, 0.06 mmol) is dissolved in EtOAc (0.60 mL) and 2-bromo-1-phenylethanone (12.0 mg, 0.06 mmol) is added. The reaction is stirred at room temperature for 2 hours (UPLC-MS: complete and clean conversion). Et2O (0.20 mL) were added and the product is triturated to obtain a white solid which is isolated by filtration and dried under vacuum overnight (31 mg, 96% yield, bromide salt, single diastereoisomer).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)[CH3:2].[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11]>C(O)C>[F:8][C:9]([F:15])([F:14])[S:10]([O-:13])(=[O:12])=[O:11].[CH2:1]([N+:3]1[CH:7]=[CH:6][NH:5][CH:4]=1)[CH3:2]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CCn1ccnc1
Solvent: CCO
Product: CC[n+]1cc[nH]c1
Product: O=S(=O)([O-])C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of 16 g of N-ethylimidazole in 20 ml of ethanol was added dropwise 25 g of trifluoromethanesulfonic acid at 0° C. After returning to room temperature, the solution was stirred overnight and dried in vacuo at 60° C. for 16 hours to give N-ethylimidazolium trifluoromethanesulfonate (hereinafter referred to as EtIm+TfS−) as a colorless transparent liquid. The melting point of the resulting salt (literature value: 7.8° C.,) was measured by DSC analysis. As a result, endothermic peaks were observed at 6.3° C. and 21.0° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl.[Br:21][C:22]1[N:27]=[CH:26][C:25]([C@@H:28]([NH2:31])[CH2:29][CH3:30])=[CH:24][CH:23]=1.C(N(CC)CC)C>S(Cl)(Cl)=O.ClCCl.[Cl-].[NH4+]>[Br:21][C:22]1[N:27]=[CH:26][C:25]([C@@H:28]([NH:31][C:17]([C:12]2[C:11]3[CH:10]=[N:9][N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:16]=3[CH:15]=[CH:14][CH:13]=2)=[O:19])[CH2:29][CH3:30])=[CH:24][CH:23]=1
Reactant: O=C(O)c1cccc2c1cnn2-c1ccc(F)cc1
Reactant: CC[C@H](N)c1ccc(Br)nc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC[C@H](NC(=O)c1cccc2c1cnn2-c1ccc(F)cc1)c1ccc(Br)nc1
Reaction time: 0.75 h

Procedure:
A suspension of 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid (258 mg, 1.00 mmol) was heated at reflux in thionyl chloride (5 mL) until the solid dissolved. After 45 minutes, the mixture was concentrated to dryness. The yellow residue was diluted with dichloromethane and (S)-1-(6-bromo-pyridin-3-yl)-propylamine hydrochloride (288 mg, 1.00 mmol) was added followed by triethylamine (1.0 mL, 7.2 mmol). After 30 minutes, the reaction was diluted with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (4×10 mL). The combined organic layers were washed with brine (3×10 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was diluted with dichloromethane and purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in hexanes. The material from the column was triturated with ether to afford 1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid [(S)-1-(6-bromo-pyridin-3-yl)-propyl]-amide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([O:12]C(C)(C)C)=[O:11])=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ncc(C#N)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cnc(C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a solution of tert-butyl 3-chloro-5-cyanopicolinate (1.4 g, 3.23 mmol) in DCM (10.75 ml) was added TFA (25 ml, 323 mmol). The orange solution was stirred at RT for 1 hr. It was concentrated. Then the residue was passed through a PEAX column and the acid was eluted with 2% conc. HCl in MeOH (0.3 mL in 15 mL MeOH) to yield 3-chloro-5-cyanopicolinic acid (0.55 g, 3.01 mmol, 93% yield) as yellow solid. MS m/z=183 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[C:11]3=[O:20])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Br[CH:22]([CH3:26])[C:23]([OH:25])=[O:24].CCN(CC)CC>ClCCCl>[CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH2:14][CH2:13][C:12]4([CH2:19][CH2:18][N:17]([CH:22]([CH3:26])[C:23]([OH:25])=[O:24])[CH2:16][CH2:15]4)[C:11]3=[O:20])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(Br)C(=O)O
Reactant: O=C1N(c2ccc(C3CC3)cc2)CCC12CCNCC2
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C(=O)O)N1CCC2(CCN(c3ccc(C4CC4)cc3)C2=O)CC1
Temperature: 80 °C
Yield: 19.5 %

Procedure:
A mixture of 200 mg (0.74 mmol) 2-(4-Cyclopropyl-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, 168 mg (1.11 mmol) 2-bromo-propionic acid and 224 mg (2.21 mmol) NEt3 in 5 mL DCE was heated to 80° C. for 2 h and concentrated. The residue was taken up in methanol and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated to yield 49.4 mg (19%) of the title compound. MS m/e: 343.2 [M+H]+.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].O.[NH2:18][C@@H:19]([C:30]([O:32][CH3:33])=[O:31])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1.Cl.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCl.O>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:18][C@@H:19]([C:30]([O:32][CH3:33])=[O:31])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.5 %

Procedure:
To a suspension of Boc-Leu-OH.H2O (0.997 g) and DTrp-OMe.HCl (1.021 g) in dichloromethane (10 ml) were added TEA (0.6 ml) and HOBT.H2O (0.615 g) under argon. EDCI.HCl (0.769 g) was added to the mixture at 0°-5° C. The resulting reaction mixture was stirred at room temperature for 16 h, washed successively with water, 10% aq. citric acid, sat. NaHCO3 and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was triturated with hexane to give the product (1.665 g). FAB-MS(m/e,(C23H33N3O5 +H)+):432
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:16][C:17](=[O:26])[C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:25])(=O)C.[OH-].[Na+].O>O1CCOCC1.CN(C)C=O>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:18]=1[C:17]([NH:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[N:8]=[CH:7][C:6]([CH2:5][OH:4])=[CH:15]2)=[O:26]
Reactant: CC(=O)OCc1cnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cccc2cc(CO)cnc12)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
A mixture of 3-acetoxymethyl-8-(2,6-dichlorobenzoylamino)quinoline (25.9 mg), 1N sodium hydroxide solution (0.24 ml) in dioxane and dimethylformamide (4 drops) was stirred for 2 hours at ambient temperature. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was recrystallized from ethyl acetate-n-hexane to give 8-(2,6-dichlorobenzoylamino)-3-hydroxymethylquinoline (20 mg).
Reaction SMILES: [NH2:1][C:2]1[N:21]=[C:20]([CH2:22][O:23][CH3:24])[CH:19]=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=2[CH:12]=1)=[O:5].O[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[NH2:1][C:2]1[N:21]=[C:20]([CH2:22][O:23][CH3:24])[CH:19]=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([O:17][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH:14]=[CH:13][C:11]=2[CH:12]=1)=[O:5]
Reactant: COCc1ccc(C(=O)NCc2cc3ccc(O)cc3o2)c(N)n1
Reactant: OCc1ccccn1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCc1ccc(C(=O)NCc2cc3ccc(OCc4ccccn4)cc3o2)c(N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a tetrahydrofuran (2 mL) solution of 2-amino-N-(6-hydroxy-benzofuran-2-ylmethyl)-6-methoxymethyl-nicotinamide (20 mg, 61 μmol) described in Production Example 5-1 were added 2-(hydroxymethyl)pyridine (6.5 μL, 67 μmol), triphenylphosphine (19.2 mg, 73 μmol) and diethylazodicarboxylate (33 μL, 73 μmol) at room temperature, which was stirred at room temperature for 30 minutes. After filtering the reaction solution, the filtrate was purified by reverse phase high-performance liquid chromatography (using an acetonitrile-aqueous mobile phase (containing 0.1% trifluoroacetic acid)) to obtain a mixture of the title compound and 2-amino-N-(6-hydroxy-benzofuran-2-ylmethyl)-6-methoxymethyl-nicotinamide. Then, this mixture was purified by silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (6 mg, 24%) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C:5]1[C:9]2[C:10]([CH3:25])=[CH:11][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])=[C:13]([CH3:14])[C:8]=2[O:7][CH:6]=1.CO.[OH-].[Na+]>C1COCC1>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[CH:11]=[C:10]([CH3:25])[C:9]2[C:5]([CH2:4][C:3]([OH:26])=[O:2])=[CH:6][O:7][C:8]=2[C:13]=1[CH3:14]
Reactant: COC(=O)Cc1coc2c(C)c(OCc3ccc(Cl)cc3Cl)cc(C)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(OCc2ccc(Cl)cc2Cl)cc(C)c2c(CC(=O)O)coc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
To a mixture of methyl(6-((2,4-dichlorobenzyl)oxy)-4,7-dimethyl-1-benzofuran-3-yl)acetate (147 mg), MeOH (2.0 mL) and THF (dry) (2.0 mL) was added 1N NaOH (1.12 mL) at room temperature. The mixture was stirred at room temperature for 2 h, and then concentrated in vacuo. The residue was neutralized with 1N HCl, and the mixture was extracted with EtOAc. The organic layer was washed with brine and, dried over MgSO4, and concentrated in vacuo. The precipitate was collected by filtration, and crystallized from EtOAc-hexane to give the title compound (118 mg).
Reaction SMILES: Cl.F[C:3]1[CH:8]=[C:7]([S:9]([CH3:12])(=[O:11])=[O:10])[CH:6]=[CH:5][C:4]=1[NH:13][C:14]1[C:19]2[O:20][CH2:21][CH2:22][N:23]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:18]=2[N:17]=[CH:16][N:15]=1.Cl[C:31]([O:33][CH:34]([CH3:39])[C:35]([F:38])([F:37])[F:36])=[O:32]>C(Cl)Cl>[CH3:12][S:9]([C:7]1[CH:8]=[CH:3][C:4]([NH:13][C:14]2[C:19]3[O:20][CH2:21][CH2:22][N:23]([CH:24]4[CH2:25][CH2:26][N:27]([C:31]([O:33][CH:34]([CH3:39])[C:35]([F:38])([F:37])[F:36])=[O:32])[CH2:28][CH2:29]4)[C:18]=3[N:17]=[CH:16][N:15]=2)=[CH:5][CH:6]=1)(=[O:11])=[O:10]
Reactant: CC(OC(=O)Cl)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc3c2OCCN3C2CCNCC2)c(F)c1
Agent: Cl
Solvent: ClCCl
Product: CC(OC(=O)N1CCC(N2CCOc3c(Nc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1)C(F)(F)F
Reaction time: 0.5 h
Yield: 51 %

Procedure:
To a suspension of N-(2-fluoro-4-(methylsulfonyl)phenyl)-8-(piperidin-4-yl)-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine hydrochloric acid salt from Example 8A (35.5 mg, 0.08 mmol) in CH2Cl2 (1.5 mL) was added DIEP (70 μL, 0.40 mmol, Aldrich) followed by addition of 1,1,1-trifluoropropan-2-yl chloroformate (⅓ of the material from Step A, 0.33 mmol) in CH2Cl2 (0.5 mL). The reaction mixture was stirred for 30 min and then evaporated under the reduced pressure to yield the crude product which was purified by preparative HPLC(C18 column; 10-100% acetonitrile in water containing 0.05% trifluoroacetic acid) to give the desired product (33.9 mg, off-white solid, 51%) upon lyophilization. 1H NMR (500 MHz, CDCl3, 50° C.). δ 8.42 (t, J=8.25 Hz, 1H), 8.31 (brs, 1H), 8.14 (s, 1H), 7.59-7.78 (m, 2H), 5.18-5.34 (m, 1H), 4.78-4.93 (m, 1H), 4.22-4.41 (m, 4H), 3.47-3.55 (m, 2H), 3.04 (s, 3H), 2.88-3.07 (m, 2H), 1.79 (m, 2H), 1.60-1.75 (m, 2H), 1.42 (d, J=6.60 Hz, 3H).). LRMS (ESI) 548 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:5][CH:4]=1.[BH4-].[Na+].C(O)(=O)C>CC(O)C.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][CH2:14][NH2:15])=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(CCN3C(=O)c4ccccc4C3=O)c2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2cccc(CCN)c2c1
Temperature: 25 °C

Procedure:
In a reactor, 1 g of the compound obtained in Step C and 5 eq. of NaBH4 are introduced into a 2-propanol/water 6/1 mixture, and the mixture is stirred at ambient temperature. Acetic acid (0.2 eq.) is then added and the reaction mixture is heated at 80° C. for 8 hours. After evaporating off the solvents and co-evaporation of water with toluene, the crude residue obtained is used directly in the acetylation reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([I:19])[CH:15]=[CH:14][C:13]=2[C:12]2[NH:20][N:21]=[CH:22][C:11]=2[N:10]=1.[H-].[Na+].[CH3:25][N:26]([CH3:31])[S:27](Cl)(=[O:29])=[O:28].O>C1COCC1.CN(C=O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[C:9]1[C:18]2[CH:17]=[C:16]([I:19])[CH:15]=[CH:14][C:13]=2[C:12]2[N:20]([S:27]([N:26]([CH3:31])[CH3:25])(=[O:29])=[O:28])[N:21]=[CH:22][C:11]=2[N:10]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Fc1cccc(F)c1-c1nc2cn[nH]c2c2ccc(I)cc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)n1ncc2nc(-c3c(F)cccc3F)c3cc(I)ccc3c21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A 250 ml three-necked flask equipped with a magnetic stirrer and an argon intake is charged with 4 g of 5-(2,6-difluorophenyl)-7-iodo-1H-pyrazolo[4,3-c]isoquinoline, prepared in step 6 of example 1, in 120 ml of THF and 3 ml of DMF. The mixture is cooled to 0° C. using an ice bath and then 952 mg of sodium hydride (60%) are added. After 15 min at 0° C., 1.3 ml of dimethylsulphamoyl chloride are added. After 16 h at RT, the mixture is poured into 300 ml of water and extracted with ethyl acetate. The organic phase is dried over MgSO4, filtered and concentrated under RP. The solid obtained is triturated in diisopropyl ether. The insoluble material is filtered off under RP and dried under vacuum to give 2.94 g of 5-(2,6-difluorophenyl)-7-iodo-N,N-dimethyl-1H-pyrazolo[4,3-c]isoquinoline-1-sulphonamide (beige solid). LC-MS-DAD-ELSD: 515(+)=(M+H)(+).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2.[N+:15]([O-])([O-:17])=[O:16].[K+]>OS(O)(=O)=O>[N+:15]([C:11]1[C:2]([Cl:1])=[C:3]2[C:8](=[CH:9][C:10]=1[Cl:12])[NH:7][C:6](=[O:13])[C:5](=[O:14])[NH:4]2)([O-:17])=[O:16]
Reactant: O=c1[nH]c2cc(Cl)cc(Cl)c2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])c(Cl)c2[nH]c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
The method of Cheeseman, supra. was adapted. 5,7-Dichloro-1,4-dihydroquinoxaline-2,3-dione (239 mg, 1.03 mMol) was dissolved in concentrated H2SO4 (3 mL) at 0° C. for 30 min, and KNO3 (125.3 mg, 1.24 mMol, Baker) was added to this solution. The mixture was stirred at 0° C. for 3 h and then was stirred at room temperature for 30 h. It was then poured into ice water (15 g). A precipitate came out and was collected by filtration, was dissolved in 1N KOH (10 mL) and the red precipitate was removed by filtration. The solution then was acidified to pH=2 with 4N HCl to give a cream precipitate, which was collected by filtration, then was dried in the air at 50° C. for 4 h to afford the pure 6-nitro-5,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (231 mg, 80%), as yellow microcrystals. mp: 320°-25° C. (dec. from 290° C.). IR (KBr, cm-1): 3467, 3140, 3055, 2946, 1717, 1693, 1541. NMR (1H, DMSO-d6): δ7.221 (s, 1H), 11.932 (s, 1H), 12.312 (s, 1H). HRMS: calcd. for C8H3N3O4Cl2 (M+) m/z: 274.9499, found: 274.9509.
Reaction SMILES: [CH:1]1([C:5]2[N:6]=[C:7]([CH2:10][CH2:11][C:12]3[CH:40]=[CH:39][N:15]4[C:16](=[O:38])[C:17](/[CH:29]=[CH:30]/[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[C:18]([N:20]5[CH2:25][CH2:24][CH2:23][CH:22]([O:26]C=O)[CH2:21]5)[N:19]=[C:14]4[CH:13]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C[O-].[Na+].C(Cl)(Cl)Cl>CO.[Cl-].[Na+].O>[CH:1]1([C:5]2[N:6]=[C:7]([CH2:10][CH2:11][C:12]3[CH:40]=[CH:39][N:15]4[C:16](=[O:38])[C:17](/[CH:29]=[CH:30]/[C:31]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:32])=[C:18]([N:20]5[CH2:25][CH2:24][CH2:23][CH:22]([OH:26])[CH2:21]5)[N:19]=[C:14]4[CH:13]=3)[S:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)/C=C/c1c(N2CCCC(OC=O)C2)nc2cc(CCc3nc(C4CCC4)cs3)ccn2c1=O
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)/C=C/c1c(N2CCCC(O)C2)nc2cc(CCc3nc(C4CCC4)cs3)ccn2c1=O
Reaction time: 0.75 h
Yield: 84.3 %

Procedure:
tert-Butyl (E)-3-[8-[2-(4-cyclobutyl-1,3-thiazol-2-yl)ethyl]-2-(3-formyloxy-piperidino)-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl]-2-propenoate (95 mg, 0.168 mmol) dissolved in methanol (4 ml) was added with sodium methoxide (4 mg, 0.074 mmol) under ice cooling and stirred for 45 minutes under ice cooling. Then the reaction solution was further added with sodium methoxide (4 mg), and after 5 minutes, further added with sodium methoxide (10 mg). After the reaction solution was stirred for 15 minutes, the reaction was stopped with saturated brine and added with chloroform for extraction. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was purified by thin layer silica gel chromatography (chloroform:methanol=20:1) to obtain 76 mg (84%) of the title compound as yellow crystals in a mixture with triphenylphosphine oxide.
Reaction SMILES: [Na].[C:2]([O:5][C:6](=[O:8])[CH3:7])(=[O:4])[CH3:3].[C:9]([NH:12][C:13]1[CH:23]=[C:22]([Cl:24])[C:21]2[C:25]3C=1CC[C:17]=3[CH:18]=[CH:19][C:20]=2[Cl:26])(=[O:11])[CH3:10].[OH2:27]>C(O)(=O)C>[C:9]([NH:12][C:13]1[CH:23]=[C:22]([Cl:24])[C:21]2[C:25](=[CH:17][CH:18]=[CH:19][C:20]=2[Cl:26])[C:3]=1[C:2]([O:5][C:6]([C:7]1[C:25]2[C:21](=[C:20]([Cl:26])[CH:19]=[CH:18][CH:17]=2)[C:22]([Cl:24])=[CH:23][C:13]=1[NH:12][C:9](=[O:11])[CH3:10])=[O:8])=[O:4])(=[O:27])[CH3:10]
Reactant: O
Reactant: CC(=O)Nc1cc(Cl)c2c(Cl)ccc3c2c1CC3
Reactant: CC(=O)OC(C)=O
Agent: [Na]
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(Cl)c2c(Cl)cccc2c1C(=O)OC(=O)c1c(NC(C)=O)cc(Cl)c2c(Cl)cccc12
Temperature: 25 °C

Procedure:
A suspension of sodium dichloromate dihydrate (7.5 g, 25 mmol) in 50 mL of acetic acid was heated to reflux and treated with acetic anhydride (6.6 g, 65 mmol). The reaction was stirred at reflux and treated portionwise with 3-acetylamino-5,6-dichloroacenapthene (1.4 g, 5.0 mmol, from Example E4). The reaction was refluxed for 5 hours, cooled to room temperature and poured into a mixture of ice and water. The resulting precipitate was removed by filtration, washed with water and dried in vacuo to give 1.2 g of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15](OCC)=[O:16])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)#[N:2].[NH2:22][NH2:23]>CCO>[C:1]([C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]([NH:22][NH2:23])=[O:16])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)CN1CCN(Cc2ccc(C#N)cc2)CC1
Reactant: NN
Solvent: CCO
Product: N#Cc1ccc(CN2CCN(CC(=O)NN)CC2)cc1
Yield: 67.1 %

Procedure:
Synthesized according to General Procedure C: 51d (2.71 g, 9.43 mmol, 1.0 equiv.), anhydrous hydrazine (1.18 mL, 37.7 mmol, 4.0 equiv.), EtOH (19 mL, 0.5 M). 46d (1.73 g, 67.1%) was obtained as an off-white solid after extraction without further purification. 1H-NMR (500 MHz, CDCl3) δ 8.10 (br s, 1H), 7.60 (d, 2H, J=8.0 Hz), 7.43 (d, 2H, J=8.5 Hz), 3.84 (br d, 2H, J=5.0 Hz), 3.55 (s, 2H), 3.08 (s, 2H), 2.55 (br s, 4H), 2.46 (br s, 4H). 13C-NMR (125 MHz, CDCl3) δ 170.6, 144.1, 132.4, 129.6, 119.1, 111.2, 62.5, 60.8, 53.8, 53.3. HRMS (ESI): 274.1673 (M+1); calcd. for C14H20N5O: 274.1668.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([N:19]([CH3:21])[CH3:20])[CH:15]([F:22])[CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH2:29]([C:31]1[NH:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH3:30]>>[CH2:29]([C:31]1[N:32]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:18][CH2:17][C@@H:16]([N:19]([CH3:20])[CH3:21])[C@@H:15]([F:22])[CH2:14]4)[N:8]3[CH3:11])=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:3]=2)[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1)[CH3:30]
Reactant: CN(C)C1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)CC1F
Reactant: CCc1nc2ccccc2[nH]1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC[C@@H](N(C)C)[C@@H](F)C3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, racemic 1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)-3-fluoro-N,N-dimethylpiperidin-4-amine and 2-ethylbenzimidazole were reacted. The enantiomers were separated by SFC to give 227. LCMS m/z: 522.3 (MH+)