Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=3)[N:11](C(OC(C)(C)C)=O)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:29][C:2]([F:1])([F:30])[C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:15][CH:16]=3)[NH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc2c(-c3cccc(C(F)(F)F)c3)cn(C(=O)OC(C)(C)C)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(-c3cccc(C(F)(F)F)c3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 122.9 %

Procedure:
To a solution of compound 15c (900 mg, 2.14 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (2 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated to give compound 15d (840 mg) as a white solid. MS m/z (M+H+) 320.0.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:18][C@H:17]([S:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][C@H:15]1[C:39](O)=[O:40])(=[O:13])=[O:12].[C:42]([O:46][C:47](=[O:58])[CH2:48][NH:49][CH2:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)([CH3:45])([CH3:44])[CH3:43].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[C:42]([O:46][C:47](=[O:58])[CH2:48][N:49]([C:39]([C@@H:15]1[CH2:16][C@@H:17]([S:19][C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:18][N:14]1[S:11]([C:2]1[CH:1]=[CH:10][C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:3]=1)(=[O:12])=[O:13])=[O:40])[CH2:50][CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1)([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)CNCCc1ccccc1
Reactant: O=C(O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN(CCc1ccccc1)C(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Yield: 26.4 %

Procedure:
A solution of 800 mg (1.38 mmol) (2S,4R)-1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carboxylic acid and 390 mg (1.66 mmol) crude phenethylamino-acetic acid tert-butyl ester in 14 ml THF was cooled to 0° C. and treated with 318 mg (1.66 mmol) EDCI and 19 mg (0.14 mmol) HOBT. The reaction was warmed up to RT over night and partitioned between aqueous 10% KHSO4/ethyl acetate (3×). The organic phases were washed with aqueous saturated NaHCO3 solution and dried over Na2SO4. Purification by flash-chromatography on silicagel (Hexane/EtOAc 4:1 to 1:1) gave 290 mg (26%) (2S,4R)-{[1-(Naphthalene-2-sulfonyl)-4-tritylsulfanyl-pyrrolidine-2-carbonyl]-phenethyl-amino}-acetic acid tert-butyl ester, MS: 797 (MH+)
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([N:20]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:25][CH:26]=2)=[CH:10][C:11]=1[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])C.Cl>C(O)C.[OH-].[Na+].O>[CH2:13]([NH:12][C:11]1[CH:10]=[C:9]([N:20]([CH2:33][C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[C:21]2[CH:22]=[N:23][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:25][CH:26]=2)[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cnc(N(Cc2ccc(OC)cc2)c2ccc(N3CCOCC3)nc2)cc1NCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(CN(c2ccc(N3CCOCC3)nc2)c2cc(NCc3ccccc3)c(C(=O)O)cn2)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 119.4 %

Procedure:
3.0 mg of 4-benzylamino-6-[4-methoxybenzyl-(6-morpholinopyridin-3-yl)amino]pyridine-3-carboxylic acid ethylester was dissolved in 1 mL of ethanol, to which 1 mL of 2 mol/L sodium hydroxide in water was added, and stirred at 80° C. for 1 hour. After cooling, hydrochloric acid was added to neutralize the reaction mixture. It was extracted with chloroform, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated to obtain 3.4 mg of the title compound containing impurities as a brown oil. Without further purification, this was used in the next reaction as it was.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[CH3:18][S:19]([C:22]1[CH:23]=[C:24]([C:34](O)=[O:35])[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:26][CH:27]=1)(=[O:21])=[O:20]>>[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:24]([C:34]([N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:16])[F:17])=[CH:5][CH:6]=3)[CH2:15][CH2:14]2)=[O:35])[CH:23]=1)(=[O:20])=[O:21]
Reactant: FC(F)(F)Oc1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)N2CCN(c3ccc(OC(F)(F)F)cc3)CC2)c1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from 1-(4-Trifluoromethoxy-phenyl)-piperazine [187669-62-1] and 4-Methanesulfonyl-biphenyl-2-carboxylic acid (Example V). MS (ISP): 505.4 MH+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][O:7][B:8]([OH:9])[C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:15][CH2:16][CH3:17].Cl>CN(C=O)C>[CH2:15]([O:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][O:7][B:8]([OH:9])[C:4]=2[CH:3]=1)[CH2:16][CH3:17]
Reactant: OB1OCc2ccc(O)cc21
Reactant: CCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOc1ccc2c(c1)B(O)OC2
Temperature: 0 °C
Reaction time: 24 h
Yield: 63.5 %

Procedure:
H181 (110 mg, 0.73 mmol) was dissolved in DMF (6.0 mL) and cooled to 0° C. with ice bath. To this solution under nitrogen were added in sequence NaH (60% in mineral oil, 117 mg, 2.93 mmol) and 1-bromopropane (0.26 mL, 2.93 mmol). The reaction mixture was stirred for 1 d then treated with 1.0 M HCl (10.0 mL). After extraction with ethyl acetate, the organic phase was washed with water and brine, and dried over anhydrous Na2SO4. The residue after rotary evaporation was purified by column chromatography over silica gel to give the title compound (89 mg, 64% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.10 (s, 1H), 7.29 (d, J=8.4 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 7.03 (dd, J=8.1 & 2.4 Hz, 1H), 4.91 (s, 2H), 3.92 (t, J=6.8 Hz, 2H), 1.78-1.68 (m, 2H) and 0.98 (t, J=7.2 Hz, 3H) ppm; Mp: 80-81° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[CH:11][N:10]=[C:9]([SH:13])[N:8]=1.[C:14](=O)([O-])[O-].[Na+].[Na+].IC>CC(C)=O>[CH3:14][S:13][C:9]1[N:8]=[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[N:12]=[CH:11][N:10]=1
Reactant: O=C([O-])[O-]
Reactant: Sc1ncnc(-c2ccccn2)n1
Agent: [Na+]
Solvent: CI
Solvent: CC(C)=O
Product: CSc1ncnc(-c2ccccn2)n1
Reaction time: 8 h

Procedure:
To a stirred suspension of the product of step 1 (0.707 g, 3.72 mmol) in acetone (36 mL) was added sodium carbonate (0.79 g, 7.5 mmol) followed by iodomethane (0.35 mL, 5.6 mmol). After overnight stirring, the reaction was filtered free of undissolved solid and concentrated to afford product as light brown solid: 1H NMR (DMSO-d6) δ 9.13 (s, 1H), 8.84-8.76 (m, 1H), 8.55-8.43 (m, 1H), 8.11-8.00 (m, 1H, 7.69-7.60 (m, 1H), 2.63 (s, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][N:17]=1>C1COCC1>[F:25][C:15]([F:14])([F:24])[C:16]1[N:17]=[CH:18][C:19](/[CH:20]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4])=[CH:22][CH:23]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 101.3 %

Procedure:
To a stirring solution of trimethyl phosphonoacetate (0.510 mL, 3.14 mmol) in THF (15 mL) at 0° C. was added NaH (88.0 mg, 3.3 mmol). After stirring for ca. 20 min, the slurry was allowed to warm to ambient temperature for 10 min, then cooled again to 0° C. To this was added dropwise 6-(trifluoro-methyl)nicotinaldehyde (500 mg, 2.86 mmol), which is commercially available from Oakwood Products, Inc. (1741 Old Dunbar Rd., West Columbia, S.C. 29172), in THF (5 mL) over 2 min. The bath was allowed to expire and the reaction stirred at ambient temperature for ca. 24 h. The reaction was quenched with H2O (50 mL) then diluted with EtOAc (100 mL). The phases were separated and the organics further washed with H2O (2×20 mL), brine (5 mL), dried over MgSO4, filtered and concentrated in vacuo to afford 670 mg 26A in ca. 85% purity as a white solid (86% yield). This was taken forward without further purification. m/z (ES+) M+1=232.1; HPLC tR=1.07 min. 1H NMR (500 MHz, CDCl3) δ 8.84 (dd, J=2.1, 0.6 Hz, 1H), 7.99 (dt, J=8.2, 1.2 Hz, 1H), 7.77-7.65 (m, 2H), 6.59 (d, J=16.2 Hz, 1H), 3.85 (s, 3H).
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[CH2:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[O:22])[CH3:21])[CH3:12].[OH-].[Na+]>O>[C:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:13]([CH2:11][CH3:12])[CH:8]=[O:10])(=[O:22])[CH3:21]
Reactant: CCNc1ccccc1C(C)=O
Reactant: O=CO
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCN(C=O)c1ccccc1C(C)=O
Reaction time: 4 h

Procedure:
A mixture of acetic anhydride (23 ml) and formic acid (15.5 ml) was stirred at 50° for 4 hours and then cooled to 0° in an ice/salt bath. 2'-(Ethylamino)-acetophenone (20.5 g) was added in small portions over 15 minutes and the mixture allowed to stand at room temperature for 1 hour. The mixture was cooled to 0° and water (100 ml) followed by aqueous sodium hydroxide (specific gravity 1.5, 10 ml) was added dropwise whilst maintaining the temperature below 10°. The resultant mixture was extracted with dichloromethane (4×100 ml) and the combined extracts were dried over magnesium sulphate to give a solution of 2'-acetyl-N-ethylformanilide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:4]=1[CH2:5][N:6]1[CH2:11][C@@H:10]([CH3:12])[N:9](C(=O)C(F)(F)F)[C@@H:8]([CH3:19])[C:7]1=[O:20].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CO.O>[CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:4]=1[CH2:5][N:6]1[CH2:11][C@@H:10]([CH3:12])[NH:9][C@@H:8]([CH3:19])[C:7]1=[O:20]
Reactant: COc1ccc(CN2C[C@@H](C)N(C(=O)C(F)(F)F)[C@@H](C)C2=O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C[C@@H](C)N[C@@H](C)C2=O)c(OC)c1
Yield: 90.3 %

Procedure:
(3S, 5R)-1-(2,4-Dimethoxy-benzyl)-3,5-dimethyl-4-trifluoroacetyl-piperazin-2-one (575 mg, 1.54 mmol) is dissolved in 30 mL of methanol and 3 mL of H2O. Potassium carbonate (883 mg, 6.4 mmol) is added to the solution, and the reaction is refluxed for one and half hours before concentration. Ethyl acetate (3×50 mL) is used to extract the aqueous layer. Removal of Ethyl acetate afforded the crude amine (387 mg, 91% yield) as a clear oil. C15H22N2O3 MS m/z: 279.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25](Br)[N:26]=3)[N:21](COCC[Si](C)(C)C)[CH:20]=2)=[O:18])[C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].C([CH:39]1[CH2:44][CH2:43][N:42](C(=O)[C@H](NC(C2C3C(=NC=C(Br)N=3)N(COCC[Si](C)(C)C)C=2)=O)C2CC2)[CH2:41][CH2:40]1)#N.C([Sn](CCCC)(CCCC)C1C=CC=CN=1)CCC.C(C1C=CN=C([Sn](CCCC)(CCCC)CCCC)C=1)(C)(C)C>>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([C@H:11]([NH:16][C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([C:41]4[CH:40]=[CH:39][CH:44]=[CH:43][N:42]=4)[N:26]=3)[NH:21][CH:20]=2)=[O:18])[C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CCC(C#N)CC1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(Br)cnc21
Agent: CCCC[Sn](CCCC)(CCCC)c1cc(C(C)(C)C)ccn1
Agent: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Product: CC(C)(C)[C@@H](NC(=O)c1c[nH]c2ncc(-c3ccccn3)nc12)C(=O)N1CCC(C#N)CC1

Procedure:
Prepared according to the procedure outlined in Example 111, steps 4-5 substituting 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(4-cyano-piperidine-1-carbonyl)-2,2-dimethyl-propyl]-amide for 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide and 2-(tributylstannanyl)pyridine for 4-tert-butyl-2-(tributylstannyl)pyridine. MS: (M+H)+=446.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[C:14]([CH2:23][C:24]([OH:26])=[O:25])=[C:13]3[CH3:27])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.B(F)(F)F.[CH3:32]COCC.C([O-])(=O)C.[Na+]>CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=4)[C:14]([CH2:23][C:24]([O:26][CH3:32])=[O:25])=[C:13]3[CH3:27])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2-c1ncnc2cc(Cl)ccc12
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1c(C)n(-c2ncnc3cc(Cl)ccc23)c2ccc(OC)cc12

Procedure:
To a solution of 1-(7-chloroquinazolin-4-yl)-5-methoxy-2-methylindol-3-ylacetic acid (1.0g.) in dry methanol (50ml.) was added freshly distilled boron trifluoride etherate (0.5ml.), and the dark red solution was heated under reflux for 30 mins. To the solution was added saturated sodium acetate solution (5ml.), and the mixture was concentrated in vacuo. The residual mixture was shaken with a mixture of water (50ml.) and chloroform (30ml.). The aqueous layer was separated and extracted with further chloroform (2 × 20 ml.), and the combined extracts were washed successively with saturated sodium hydrogen carbonate solution (2 × 20ml.), water (10ml.) and saturated sodium chloride solution (15ml.). After drying, the extracts were evaporated to give methyl 1(7-chloroquinazolin-4-yl)-5-methoxy-2-methylindol-3-ylacetate, m.p. 111°-113° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4](Cl)[N:3]=1.CCN(C(C)C)C(C)C.[CH:22]([O:25][C:26]1[NH:30][N:29]=[C:28]([NH2:31])[CH:27]=1)([CH3:24])[CH3:23]>C1COCC1>[Cl:8][C:7]1[CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]([NH:31][C:28]2[CH:27]=[C:26]([O:25][CH:22]([CH3:24])[CH3:23])[NH:30][N:29]=2)=[N:3][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)nc1Cl
Reactant: CC(C)Oc1cc(N)n[nH]1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(Cl)c(Cl)cc2[N+](=O)[O-])n[nH]1
Temperature: 25 °C
Reaction time: 120 h
Yield: 27.3 %

Procedure:
To a mixture of 2,3,6-trichloro-5-nitropyridine (2.61 g, 11.4 mmol) and DIEA (1.90 ml, 11.4 mmol) in THF (50 ml) was added the 5-isopropoxy-1H-pyrazol-3-amine (1.20 g, 8.50 mmol) at 0° C. After addition, the reaction mixture was stirred at 25° C. for 5 days. The solvent was removed under reduced pressure and the resulting residue was purified by column chromatography (hexane-EtOAc=2.5:1) to give the title compound as a yellow solid (0.77 g, 27%). 1H NMR (400 MHz) δ 12.26 & 11.64 (s, 1H), 10.42 & 10.04 (s, 1H), 8.81 & 8.77 (s, 1H), 6.02 & 5.94 (s, 1H), 4.70 & 4.48 (m, 1H), 1.32 (d, J=6.0 Hz, 3H), 1.27 (d, J=6.0 Hz, 1H). MS: Calcd.: 331. Found: [M+H]+ 332.
Reaction SMILES: [CH2:1]([C:3]1([CH2:14][CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:4]1=[O:13])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[CH2:14]([C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:16]([O-:18])=[O:17])[CH:10]=2)[N:5]([CH3:12])[C:4]1=[O:13])[CH3:15]
Reactant: O=[N+]([O-])O
Reactant: CCC1(CC)C(=O)N(C)c2ccccc21
Agent: O=S(=O)(O)O
Product: CCC1(CC)C(=O)N(C)c2ccc([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3,3-diethyl-1-methyl-1,3-dihydro-indol-2-one (J. Chem. Soc., 1971, 1375) (7.6 g) in concentrated sulfuric acid (12 ml) is added a mixture of nitric acid (65%, 2.7 ml) and concentrated sulfuric acid (4.4 ml) at 0° C. over a period of 30 min. The reaction mixture is stirred at this temperature for 30 min and then poured into ice water. The precipitate is collected by filtration and washed with water to give the respective compound (9.3 g).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]2[C:8]([CH:9]=[CH:10][CH:11]=1)=[N:7][N:6]([C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)[CH:5]=2.CC(=CC)C.[O-:25]Cl=O.[Na+]>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([N:6]2[CH:5]=[C:4]3[C:8]([CH:9]=[CH:10][CH:11]=[C:3]3[C:2]([OH:25])=[O:1])=[N:7]2)=[CH:19][CH:18]=1)#[N:17]
Reactant: N#Cc1ccc(-n2cc3c(CO)cccc3n2)cc1
Reactant: [O-][Cl+][O-]
Agent: [Mn+4]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc(-n2cc3c(C(=O)O)cccc3n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (C5) in dry DCM (0.07 M) was added manganese (IV) oxide. The reaction mixture was stirred at RT for 2 h. Then, the suspension was filtered and the precipitated washed several times with DCM. The combined organic extracts were concentrated to dryness. The resulting crude was dissolved in a mixture of water/tert-butanol (1:1, 0.04 M). Afterwards, 2-methyl-2-butene (20 eq., 2 M in THF), NaH2PO4 (8 eq.) and NaClO2 (8 eq.) were added. The reaction mixture was stirred at RT for 30 min. Then, the mixture was extracted with DCM (3×) and the organic extracts washed with brine (2×) and dried (Na2SO4). Evaporation of the solvent gave the title compound as a yellow powder that was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6, 300K) δ 13.23 (1H, bs), 9.38 (1H, s), 8.45 (2H, d, J=7.3 Hz), 8.12-8.09 (3H, m), 7.91 (1H, d, J=6.8 Hz), 7.52 (1H, t, J=7.0 Hz). MS (ES+) C15H9N3O2 required: 263, found: 264 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:3]([C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([CH3:11])[CH:7]=[CH:6]2.BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[H-].[Na+].[CH3:45][C:46]1[CH:51]=[CH:50][N:49]=[C:48]2[N:52]=[C:53]([CH2:55][CH2:56][CH3:57])[NH:54][C:47]=12>CN(C=O)C.C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[N:3]([C:12]2[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:4]=[C:5]2[C:10]=1[CH:9]=[C:8]([CH2:11][N:52]1[C:48]3=[N:49][CH:50]=[CH:51][C:46]([CH3:45])=[C:47]3[N:54]=[C:53]1[CH2:55][CH2:56][CH3:57])[CH:7]=[CH:6]2
Reactant: CCCc1nc2nccc(C)c2[nH]1
Reactant: CCOC(=O)c1ccccc1-n1nc2ccc(C)cc2c1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Agent: [H-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc2nn(-c3ccccc3C(=O)OCC)c(Br)c2c1
Yield: 19.7 %

Procedure:
Carbon tetrachloride (4 ml) was added to ethyl 2-(3-bromo-5-methyl-2H-indazol-2-yl)benzoate (0.300 g, 0.835 mmol) as obtained in Reference Example 4, and the mixture was stirred. Thereto were added N-bromosuccinimide (0.149 g, 0.835 mmol) and azobisisobutyronitrile (14 mg, 0.0835 mmol), and the mixture was refluxed under heating for 3.5 hours. After cooling, it was filtered, and the cake was washed twice with dichloromethane (2.5 ml) and the filtrate was concentrated. The residue was then dissolved in DMF (1 ml) and added to a solution obtained by adding sodium hydride (27 mg, 0.668 mmol) to 7-methyl-2-propyl-1H-imidazo[4,5-b]pyridine (0.117 g, 0.668 mmol) in DMF (2 ml) and stirring the solution for 30 minutes. The mixture was stirred at room temperature for 30 minutes, concentrated, and partitioned by ethyl acetate (5 ml) and water (5 ml). The organic layer was washed twice with water (5 ml), dried over magnesium sulfate, and then filtered. The filtrate was concentrated and subjected to flash chromatography on silica gel using a mixed solvent of hexane/ethyl acetate (2:3), whereby 70 mg of 3-[3-bromo-2-(2-ethoxycarbonylphenyl)-2H-indazol-5-yl]methyl-7-methyl-2-propyl-3H-imidazo[4,5-b]pyridine was obtained.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:12]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10]2[C:5](=[CH:6][C:7]([NH2:23])=[C:8]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:9]=2)[N:4]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>C(O)(=O)C>[ClH:1].[CH3:2][C:3]1[CH:12]=[C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10]2[C:5](=[CH:6][C:7]([NH:23][C:24](=[O:26])[CH3:25])=[C:8]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:9]=2)[N:4]=1
Reactant: Cc1cc(N2CCCC2)c2cc(N3CCCC3)c(N)cc2n1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)Nc1cc2nc(C)cc(N3CCCC3)c2cc1N1CCCC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 58 %

Procedure:
A solution 0.1 g (0.27 mmol of 2-methyl-4,6-di-pyrrolidin-1-yl-quinolin-7-ylamine hydrochloride (×1.58 HCl), product of example 70 in acetic acid (0.22 ml) was treated with 0.1 ml (1.08 mmol) of acetic anhydride and then stirred at RT for 19 h. The reaction mixture was concentrated in vacuo, brought to pH 9 with conc. ammonia and then twice extacted with CH2CL2. The organic phase was washed with water saturated with brine and dried over magnesium sulfate. The solvent was removed in vacuo, the residue triturated with ether (10 ml) and treated tropwise with 0.3 ml of 3 N HCL in MeOH. The brown crystalline solid obtained was filtered off by suction and dried in a high vacuum to give 58.7 mg (89%) of N-(2-methyl-4,6-di-pyrrolidin-1-yl-quinolin-7-yl)-acetamide hydrochloride as a brown solid. ISP mass spectrum, m/e: 339.3 (M+1 calculated for C20H27N4O: 339).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[C:19]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=3)(=[O:24])=[O:23])[C:18]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])=[C:17]([O:41][CH3:42])[N:16]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.C(O)C.C1CCC=CC=1>O1CCOCC1.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[C:19]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=3)(=[O:24])=[O:23])[C:18]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])=[C:17]([O:41][CH3:42])[N:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2cccc(OCc3ccccc3)c2)nc1OC
Agent: [Pd]
Solvent: C1=CCCC=C1
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2cccc(O)c2)nc1OC

Procedure:
1.46 g of 5-methyl-pyridine-2-sulfonic acid [2-(3-benzyloxy-phenyl)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide were dissolved in dioxane (25 ml) by gentle warming than ethanol (50 ml) was added followed by cyclohexadiene (6 g) and palladium on charcoal, 10%, (1.46 g). The solution was refluxed for 20 h, the catalyst removed by filtration and the solution concentrated on a rotary evaporator. The yellow crystalline solid that precipitated was collected, washed with ether and dried in a vacuum to give the desired 5-methyl-pyridine-2-sulfonic acid [2-(3-hydroxy-phenyl)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide as off-white crystals. ISP mass spectrum, m/e 495.2 (M+1 calculated for C24H22N4O6S1: 495). Melting point 211°-216° C.