Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].[I-:2].CC(=O)CC.Cl[CH2:9][CH2:10][N:11]1[C:15]2=[N:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:14]2[CH2:13][CH2:12]1>CCOC(C)=O>[I:2][CH2:9][CH2:10][N:11]1[C:15]2=[N:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:14]2[CH2:13][CH2:12]1
Reactant: [I-]
Reactant: ClCCN1CCn2c1nc1ccccc12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: ICCN1CCn2c1nc1ccccc12
Reaction time: 5 h
Yield: 91.1 %

Procedure:
A mixture of NaI (1.73 g, 11.57 mmol) and 2-butanone (20 mL) was heated under reflux for 30 minutes 1-N-(2-Chloroethyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole (1.70 g, 7.71 mmol) and additional 2-butanone (5 mL) were added and heating was continued for 5 hours. EtOAc (50 mL) was added and the mixture was filtered. The filtrate was washed with H2O, 10% sodium bisulfite (25 mL), saturated aqueous NaHCO3, dried (MgSO4) and concentrated to give 2.2 g (92%) of a light brown solid m.p. 101°-103° C.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]1([CH3:19])[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].O>CC1C=CC(C)=CC=1.OCC(CO)O.O.CS(C)=O.[Pd](Cl)Cl>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)#[N:5]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ccccc1Cl
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: OCC(O)CO
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(-c2ccccc2C#N)cc1
Yield: 86.5 %

Procedure:
15 g of 2-chlorobenzonitrile, 14.8 g of p-tolueneboronic acid and 28.9 g of sodium carbonate in 50 ml of p-xylene, 40 ml of glycerol and 10 ml of water were heated to 120° C. At 80° C., a mixture of 38.66 mg of palladium(II) chloride and 1.1 ml of TPPTS/H2O solution (0.6 molar) in 2.5 ml of DMSO was added. After the reaction was complete, the phases were separated. The aqueous phase was washed with 50 ml of toluene. The combined organic phases were washed with 20 ml of water and subsequently dried over sodium sulfate. Crystallization from n-heptane gave 18.2 g of 2-cyano-4'-methylbiphenyl.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[N:16][C:17]([O:23][CH2:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[CH:18][CH:19]=2)[N:14]=1>O>[CH3:29][N:27]([CH3:28])[CH2:26][CH2:25][CH2:24][O:23][C:17]1[N:16]=[C:15]2[C:20]([CH:21]=[CH:22][C:13]([NH:12][C:4](=[O:6])[C:3]3[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])=[N:14]2)=[CH:19][CH:18]=1
Reactant: O=C(O)c1c(F)cccc1F
Reactant: CN(C)CCCOc1ccc2ccc(N)nc2n1
Solvent: O
Product: CN(C)CCCOc1ccc2ccc(NC(=O)c3c(F)cccc3F)nc2n1
Temperature: 4 °C
Yield: 38.9 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 2,6-difluorobenzoic acid (11.3 g), N,N'-carbonyldiimidazole (12.9 g) and 2-amino-7-(3-dimethylaminopropoxy)-1,8-naphthyridine (11.8 g). The product obtained by precipitation in water followed by drying is dissolved in boiling acetone (450 cc). After 3 hours' cooling at 4° C., the crystallized solid is separated by filtration, washed with acetone (10 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-[7-(3-Dimethylaminopropoxy)-1,8-naphthyridin-2-yl]-2,6-difluorobenzamide (7.2 g), m.p. 190° C., is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:3]=1.[Cl:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:15][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[N:3]=1
Reactant: Cc1cccc(-c2ccc(F)cc2)n1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(-c2cccc(CCl)n2)cc1

Procedure:
0.60 g (3.2 mmol) of the product of step 2 was dissolved in 50 mL of carbon tetrachloride, along with 0.54 g (3.5 mmol) of N-chloro succinimide and a catalytic amount of benzoyl peroxide. After refluxing for 20 hr, the solution was concentrated and filtered through a plug of silica gel eluting with 20% ethyl acetate:hexane. The resulting oil was contaminated with ˜10% of unreacted starting material and was used in the next step without further purification. NMR (200 MHz, CDCl3) δ 7.96 (m, 2H, ArH), 7.63 (m, 1H, ArH), 7.43 (m, 1H, ArH), 7.17 (m, 3H, ArH), 4.72 (s, 2H, CH2Cl).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[OH-].[Ca+2].[OH-].[CH2:20](O)[CH3:21]>>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:20][CH3:21])=[O:5]
Reactant: CCO
Reactant: Cc1ccc(C(=O)O)c(C)c1
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Agent: [OH-]
Product: CCOC(=O)c1ccc(C)cc1C
Yield: 95 %

Procedure:
To a solution of commercially available 2,4-dimethylbenzoic acid (67.8 g, 451 mmol) in 1000 mL of ethanol was added 10 mL of sulfuric acid. The mixture was refluxed over night, cooled down and was neutralized by adding calcium hydroxide in small portions (˜30 g). The suspension was filtered over celite and concentrated in vacuo. The crude product was purified by vacuum distillation yielding 76.4 g (95%) of 1 as a colorless oil: 1H-NMR (400 MHz, CDCl3): δ 1.38 (t, J=7.3 Hz, 3H), 2.34 (s, 3H), 2.57 (s, 3H), 4.33 (q, J=7.2 Hz, 2H), 7.01-7.06 (m, 2H), 7.82 (d, J=8.5 Hz, 1H); 13C-NMR (100 MHz, CDCl3): δ 14.3, 21.3, 21.7, 60.4, 126.3, 126.9, 130.7, 132.4, 140.1, 142.3, 167.6; MS (ESI) m/z=133.0 (100), 132.0 (57), 178.1 (M+, 51).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)=[C:11]3[C:28]([O:30]CC)=[O:29])=[CH:4][C:3]=2[O:2]1>CO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)[CH:11]3[C:28]([OH:30])=[O:29])=[CH:4][C:3]=2[O:2]1
Reactant: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Solvent: CO
Product: O=C(O)C1C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 8 h

Procedure:
Ethyl (RS)-1,3-di-(3,4-Methylenedioxyphenyl)indene-2-carboxylate (163 mg, 0.38 mmol) was placed in MeOH (0.05 ml), and to this was added SmI2 (10 ml of 0.1M solution in THF, 1.0 mmol). The resulting mixture was stirred under an argon atmosphere overnight, at which time thin layer chromatographic analysis indicated that the reaction was incomplete. Additional SmI2 (5ml of 0.1M solution in THF, 0.5 mmol) was added, and stirng was continued for 2 h. The reaction mixture was partitioned between Et2O and 5% aqueous Na2S2O3. The organic extract was washed with saturated aqueous NaCl and dried (MgSO4). The solvent was removed under reduced pressure, and the residue was purified by flash chromatography, eluting with 10% EtOAc/hexanes to afford the title compound as a colorless, glassy solid (120 mg, 75%).
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]([CH2:40][OH:41])([CH2:38][OH:39])[CH2:36][OH:37])=[CH:26][CH:25]=3)[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].Br[CH2:43][C:44]([NH2:46])=[O:45].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C)C=O.O>[C:44]([CH2:43][N:15]1[C:16]2[C:21](=[C:20]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]([CH2:36][OH:37])([CH2:40][OH:41])[CH2:38][OH:39])=[CH:26][CH:25]=3)[CH:19]=[CH:18][CH:17]=2)[C:13]([O:12][C@@H:1]2[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]2[OH:3])=[N:14]1)(=[O:45])[NH2:46]
Reactant: OC[C@H]1O[C@@H](Oc2n[nH]c3cccc(CCc4ccc(OCCCNC(CO)(CO)CO)cc4)c23)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)Cn1nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c2c(CCc3ccc(OCCCNC(CO)(CO)CO)cc3)cccc21
Yield: 11.2 %

Procedure:
A mixture of 3-(β-D-glucopyranosyloxy)-4-[2-(4-{3-[2-hydroxy-1,1-bis(hydroxymethyl)ethylamino]propoxy}phenyl)-ethyl]-1H-indazole (57 mg), 2-bromoacetoamide (41 mg), cesium carbonate (97 mg) and a catalytic amount of sodium iodide in N,N-dimethylformamide (1 mL) was stirred at room temperature overnight. To the reaction mixture was added water, and the resulting mixture was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol) and preparative reverse phase column chromatography (Shiseido CAPCELL PAK UG120 ODS, 5 μm, 120 Å, 20×50 mm, flow rate 30 mL/minute linear gradient, water/methanol=90/10-10/90) successively to give the title compound (7 mg).
Reaction SMILES: C([O:3][C:4](=[O:45])[CH2:5][C@@H:6]([CH2:34][CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1)[NH:7][C:8](=[O:33])[CH2:9][N:10]([C:14](=[O:32])[CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:19]=1[NH2:31])[CH:11]1[CH2:13][CH2:12]1)C.[OH-].[Na+]>CCO.CCOC(C)=O>[C:24]([C:20]1[C:19]([NH2:31])=[C:18]([CH2:17][CH2:16][CH2:15][C:14]([N:10]([CH:11]2[CH2:13][CH2:12]2)[CH2:9][C:8]([NH:7][C@H:6]([CH2:34][CH2:35][C:36]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[NH:38][CH:37]=2)[CH2:5][C:4]([OH:45])=[O:3])=[O:33])=[O:32])[CH:23]=[CH:22][N:21]=1)([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25]
Reactant: CCOC(=O)C[C@@H](CCc1c[nH]c2ccccc12)NC(=O)CN(C(=O)CCCc1ccnc(C(=O)OC(C)(C)C)c1N)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1nccc(CCCC(=O)N(CC(=O)N[C@H](CCc2c[nH]c3ccccc23)CC(=O)O)C2CC2)c1N

Procedure:
Ester 8-1 (223 mg, 0.36 mmol) was dissolved in 4 mL EtOH, then 1 N NaOH (0.90 mL, 0.90 mmol) was added. After a few hours the reaction was diluted with EtOAc, extracted with water and the pH of the aq. phase was adjusted to 1 with 10% KHSO4. The aqueous layer was extracted with EtOAc (2x), the combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated, providing 8-2 as an oil.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:28][O:29][C:30]1[N:35]=[C:34]([O:36][CH3:37])[C:33](B(O)O)=[CH:32][N:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:33]3[C:34]([O:36][CH3:37])=[N:35][C:30]([O:29][CH3:28])=[N:31][CH:32]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1ncc(-c2cc(C(=O)Nc3ccc(OC(F)(F)Cl)cc3)cnc2N2CC[C@@H](O)C2)c(OC)n1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
(R)-5-Bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 171.1, 150 mg, 0.324 mmol), 2,4-dimethoxypyrimidin-5-ylboronic acid (71.6 mg, 0.389 mmol), PdCl2(dppf)-(CH2Cl2) (39.7 mg, 0.049 mmol) and K3PO4 (206 mg, 0.973 mmol) were added to a vial and flushed with argon. Dioxane (1.5 mL) was added and the mixture was stirred at 120° C. overnight. The solvent was evaporated off under reduced pressure, the residue was treated with Si-Thiol (Biotage, load: 1.3 mmol/g) in MeOH and purified by preparative SFC (Column DEAP, from 18% to 23% in 6 min) to afford the title compound as an off-white powder after lyophilization from water/MeCN. UPLC-MS (Condition 11), tR=1.05 min, m/z=522.3/524.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.92 (m, 2H) 2.89-3.43 (m, 4H) 3.91 (br. s, 3H) 3.95 (s, 3H) 4.21 (br. s, 1H) 4.74-5.00 (m, 1H) 7.33 (d, J=8.91 Hz, 2H) 7.83-7.90 (m, 3H) 8.32 (br. s, 1H) 8.74 (d, J=2.26 Hz, 1H) 10.11 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([O:14]C)=[O:13])[CH:8]=2)[N:3]1C(OCC)=O.[OH-].[K+]>C(O)C>[CH3:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=2)[NH:3]1
Reactant: CCOC(=O)n1c2ccc(C(=O)OC)cc2c(=O)n1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cn1[nH]c2ccc(C(=O)O)cc2c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.1 %

Procedure:
1-Ethyl 5-methyl 2-methyl-3-oxo-2,3-dihydro-1H-indazole-1,5-dicarboxylate (300 mg, 1.08 mmol) was dissolved in ethanol (4 mL). Potassium hydroxide (485 mg, 8.62 mmol) was added and the reaction was stirred at room temperature for 1.5 hours. LCMS showed the reaction to be incomplete. An aqueous solution of potassium hydroxide (10 mL, 10 mmol, 1.0 M) was then added and the reaction was heated to 65° C. for 2 hours. The reaction was cooled to room temperature and concentrated. The resulting orange solid was dissolved in water and acidified with 1 N aqueous hydrochloric acid. The precipitate was collected by filtration and dried under vacuum to give the title compound (158 mg, 76%) as a white solid. +ESI (M+H) 193.1; 1H NMR (400 MHz, DMSO-d6, δ): 12.75 (br. s., 1H), 11.06 (s, 1H), 8.15 (s, 1H), 7.99 (dd, J=8.7, 1.5 Hz, 1H), 7.28 (d, J=8.6 Hz, 1H), 3.37 (s, 3H).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([C:8]2[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=2)[NH2:11])=[C:6]([CH3:15])[O:5][N:4]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:31])[CH2:25][O:26][CH2:27][C:28](O)=[O:29])=[C:19]([C:32]([O:34]C)=[O:33])[CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:31])[CH2:25][O:26][CH2:27][C:28]([NH:11][C:10]2[CH:12]=[CH:13][CH:14]=[C:8]([C:7]3[C:3]([CH3:2])=[N:4][O:5][C:6]=3[CH3:15])[CH:9]=2)=[O:29])=[C:19]([CH:18]=1)[C:32]([OH:34])=[O:33]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: Cc1noc(C)c1-c1cccc(N)c1
Agent: Cl
Product: Cc1noc(C)c1-c1cccc(NC(=O)COCC(=O)Nc2ccc(Cl)cc2C(=O)O)c1

Procedure:
Using the same method as in Example 1-(ii), 3-(3,5-dimethylisoxazol-4-yl)aniline.hydrochloride was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-([3-(3,5-dimethylisoxazol-4-yl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 82%). Note that 3-(3,5-dimethylisoxazol-4-yl) aniline.hydrochloride was neutralized in DMA by adding an equivalent amount of triethylamine, and then used in the reaction.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][N:16]([CH2:17][C:18]4[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=4)[O:21][CH2:22][C:23]([O:25]CC)=[O:24])[C:10]3=[N:9][C:8]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CCO>[C:1]1([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][N:16]([CH2:17][C:18]4[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=4)[O:21][CH2:22][C:23]([OH:25])=[O:24])[C:10]3=[N:9][C:8]=2[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)COc1cccc(CN2CCCc3nc(-c4ccccc4)c(-c4ccccc4)nc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1cccc(CN2CCCc3nc(-c4ccccc4)c(-c4ccccc4)nc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl 2-(34(2,3-diphenyl-7,8-dihydropyrido[3,2-b]pyrazin-5(6H)-yl)methyl)phenoxy)acetate (step 2) (163 mg, 0.340 mmol) in EtOH (2 ml) was treated dropwise with 2M NaOH (0.340 ml, 0.680 mmol). The solution was stirred at room temperature for 1 h. The resulting white suspension was collected by filtration, washed with water and dried in a vacuum oven at 40° C. to afford the title compound;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[N:9][N:8](C3CCCCO3)[C:5]2=[N:6][CH:7]=1.[CH3:17][C:18]1([CH3:42])[CH2:27][CH2:26][C:25]2[N:24]=[CH:23][N:22]=[C:21]([N:28]3[CH2:34][C:33]4[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][C:32]=4[O:31][CH2:30][CH2:29]3)[C:20]=2[CH2:19]1>>[CH3:17][C:18]1([CH3:42])[CH2:27][CH2:26][C:25]2[N:24]=[CH:23][N:22]=[C:21]([N:28]3[CH2:34][C:33]4[CH:35]=[C:36]([C:2]5[CH:3]=[C:4]6[CH:10]=[N:9][NH:8][C:5]6=[N:6][CH:7]=5)[CH:37]=[CH:38][C:32]=4[O:31][CH2:30][CH2:29]3)[C:20]=2[CH2:19]1
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(B(O)O)cc4C3)c2C1
Reactant: Brc1cnc2c(cnn2C2CCCCO2)c1
Product: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc6[nH]ncc6c5)cc4C3)c2C1

Procedure:
Prepared according to the method of example 5 by using 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (reagent preparation 32) and [4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]boronic acid (reagent preparation 23) in step 1. 1H NMR (400 MHz, d6-DMSO): 13.71 (s, 1H), 8.82 (d, 1H), 8.43 (d, 1H), 8.38 (s, 1H), 8.18 (d, 1H), 7.74 (d, 1H), 7.58 (dd, 1H), 7.07 (d, 1H), 4.66 (s, 2H), 4.34 (m, 2H), 3.85 (m, 2H), 2.71 (m, 2H), 2.45 (s, 2H), 1.59 (m, 2H), 0.84 (s, 6H); MS (EI) for C25H26N6O: 427 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:20](=[O:21])[C:19]3[C:18]([OH:22])=[C:17]4[CH:23]=[CH:24][CH:25]=[CH:26][C:16]4=[C:15]([OH:27])[C:14]=3[C:13]2=[O:28])=[C:8]([Cl:29])[CH:7]=1)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S(O[CH2:43][C:44]([F:47])([F:46])[F:45])(=O)=O.O>CN(C=O)C>[Cl:29][C:8]1[CH:7]=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:30])[CH:11]=[CH:10][C:9]=1[N:12]1[C:20](=[O:21])[C:19]2[C:18]([O:22][CH2:43][C:44]([F:47])([F:46])[F:45])=[C:17]3[CH:23]=[CH:24][CH:25]=[CH:26][C:16]3=[C:15]([O:27][CH2:43][C:44]([F:45])([F:46])[F:47])[C:14]=2[C:13]1=[O:28]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(O)c4ccccc4c3O)C2=O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC(F)(F)F)c4ccccc4c3OCC(F)(F)F)C2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 21 h
Yield: 90.1 %

Procedure:
To a solution of ethyl[3-chloro-4-(4,9-dihydroxy-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetate (0.30 g, 0.71 mmol) in DMF (3 ml), was added sodium carbonate (0.299 g, 2.82 mmol) followed by 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.490 g, 2.12 mmol). This was stirred at room temperature for 21 hours. Further sodium carbonate (0.11 g, 1.06 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.246 g, 1.06 mmol) was added to the reaction to drive it to completion. This was then heated to 50° C. for 2.5 hours. Water was added to the reaction mixture with rapid stirring. The resulting tan coloured solid was collected by filtration, washed with water and dried in the vacuum oven to give the title compound (0.377 g, 0.64 mmol). LC/MS: Rt=3.98, [MH]+ 590.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:13])[N:11]=2)[CH:8]=1.Br[C:24]1[N:29]=[C:28]([NH2:30])[CH:27]=[CH:26][CH:25]=1>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.CN(C)C=O>[NH2:30][C:28]1[N:29]=[C:24]([C:3]2[CH:4]=[CH:5][C:6]3[N:7]([CH:9]=[C:10]([C:12]([NH:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[O:13])[N:11]=3)[CH:8]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(Br)n1
Reactant: C[Sn](C)(C)c1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Nc1cccc(-c2ccc3nc(C(=O)Nc4ccccc4)cn3c2)n1
Yield: 75.7 %

Procedure:
236 mg of 6-trimethylstannyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide (Intermediate 4), 413 mg of 6-bromopyrid-2-ylamine, 95 mg of tetrakis(triphenylphosphine)palladium and 4 mL of N,N-dimethylformamide are placed in a microwave tube. The reaction mixture is heated for 45 minutes in a microwave machine set at 150° C. and concentrated to dryness. The residue is chromatographed on a silica cartridge, eluting with a mixture of dichloromethane and ethyl acetate. The fractions containing the expected product are combined and evaporated to dryness under reduced pressure to give 147 mg of 6-(6-aminopyrid-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide in the form of a yellow solid, which product is taken up in a mixture of dioxane and methanol and treated with 112 μL of a 4 M solution of hydrogen chloride in dioxane. After stirring for 1 hour at room temperature, the precipitate is filtered off by suction, washed with dioxane and dried to give 156 mg of 6-(6-aminopyrid-2-yl)-N-phenylimidazo[1,2-a]pyridine-2-carboxamide hydrochloride (1:1) in the form of a pale yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[Li]CCCC.[S:17](Cl)([Cl:20])(=[O:19])=[O:18].C(Cl)Cl>C1COCC1>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:2]2[S:1][C:5]([S:17]([Cl:20])(=[O:19])=[O:18])=[CH:4][CH:3]=2)[CH:7]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: c1cncc(-c2cccs2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(-c2cccnc2)s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.1 %

Procedure:
To a solution of 3-thiophen-2-yl-pyridine (0.355 g, 2.20 mmol) in 15 mL of THF at -78° C. is added n-BuLi (1.44 mL of a 1.6M solution in hexanes, 2.31 mmol). After stirring for 15 min, SO2 gas is bubbled through the solution for 30 min. The solution is then allowed to warm to room temperature and stirred overnight. The solution is concentrated to dryness and the resulting solid is suspended in 20 mL of hexane. Sulfuryl chloride (0.185 mL, 2.31 mmol) is added and the reaction mixture is stirred for 30 min then a small amount of methylene chloride is added and the mixture is stirred for another 30 min. The mixture is then concentrated to dryness and diluted with ethyl acetate and washed with saturated NaHCO3 (aq), water and brine. The organic layer is dried over MgSO4, filtered and concentrated to give a brown solid as the title product (0.452 g, 1.74 mmol) which is used in the subsequent step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:6]=2[CH:22]=1>CN(C)C=O.CN(CN(C)C)C.C(Cl)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:10][N:11]([CH3:12])[CH3:5])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:6]=2[CH:22]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2
Agent: CN(C)CN(C)C
Solvent: CC(=O)Cl
Solvent: CN(C)C=O
Product: CN(C)CCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 1, a solution of 8-bromo-1-methyl-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dimethylformamide, N,N,N',N'-tetramethyldiaminomethane and acetyl chloride (in 0.1 molar excess compared to the N,N,N',N'-tetramethyldiaminomethane), are reacted together to give 8-bromo-1-[2-(dimethylamino)ethyl]- 6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.