Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:19]2[CH:20]=[C:21]3[C:27]([C:28]4[CH:29]=[CH:30][C:31]([OH:34])=[N:32][CH:33]=4)=[CH:26][NH:25][C:22]3=[N:23][CH:24]=2)[CH:6]=[CH:7][C:8]=1[O:9]CC1C=CC(OC)=CC=1.C1(S)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCl>[OH:9][C:8]1[CH:7]=[CH:6][C:5]([C:19]2[CH:20]=[C:21]3[C:27]([C:28]4[CH:29]=[CH:30][C:31]([OH:34])=[N:32][CH:33]=4)=[CH:26][NH:25][C:22]3=[N:23][CH:24]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(COc2ccc(-c3cnc4[nH]cc(-c5ccc(O)nc5)c4c3)cc2OC)cc1
Agent: Sc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2cnc3[nH]cc(-c4ccc(O)nc4)c3c2)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a suspension of 5-{5-[3-methoxy-4-(4-methoxy-benzyloxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-pyridin-2-ol (25 mg, 0.055 mmol) in 1.5 ml of dichloromethane was added 78 mg of PS-thiophenol resin (Argonaut Technologies, 1.41 mmol-g−1), followed by TFA (0.3 ml). The clear suspension was stirred at room temperature for 1 hour, then the resin was filtered off, washed with ethyl acetate, then methanol. The filtrate was evaporated and the residue was taken up in 2 ml of ethyl acetate and saturated aqueous solution of sodium bicarbonate. The resulting precipitate was filtered off, washed with water, then ethyl acetate and dried in vacuo to afford 5-(5-(4-hydroxy-3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-2-ol as a light beige solid (15 mg, 80% yield). 1H NMR (DMSO-d6): δ 11.83 (broad s, 1H), 11.67 (broad s, 1H), 9.05 (s, 1H), 8.49 (d, J=2.0 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H), 7.88 (dd, J=3.0, 9.5 Hz, 1H), 7.74 (d, J=2.5 Hz, 1H), 7.71 (d. J=2.0 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 7.12 (dd. J=2.0, 8.5 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 6.44 (d, s 9.0 Hz, 1H), 3.86 (s, 3H); HPLC/MS m/z: 334.1 [MH]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([NH:25][C@H:26]3[CH2:30][CH2:29][NH:28][CH2:27]3)=[O:24])=[C:16]2[CH:15]=1.[S:31](N)([NH2:34])(=[O:33])=[O:32]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([NH:25][C@H:26]3[CH2:30][CH2:29][N:28]([S:31](=[O:33])(=[O:32])[NH2:34])[CH2:27]3)=[O:24])=[C:16]2[CH:15]=1
Reactant: O=C(N[C@H]1CCNC1)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)cc12
Reactant: NS(N)(=O)=O
Product: NS(=O)(=O)N1CC[C@H](NC(=O)c2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)cc23)C1

Procedure:
The title compound was prepared by the method substantially similar to that mentioned in Example-98, using 5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-((S)-pyrrolidin-3-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (Example-82) and Sulfamide to afford the crude, which was purified by Preparative HPLC [Column: 21.2×250×7 um, Zorbax, XDB,C-18(#22), Mobile phase-A: 10 mmol.NH4OAc in water, B: ACN, Gradient (Time/% B): 0/30, 2/30, 8/90 and Flow rate: 20 mL/min] to afford 26 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-])=O)[CH:4]=1.[Cl-].[NH4+]>CCO.O.[Fe]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:7])=[CH:8][CH:9]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1ccc(N)c(N)c1
Reaction time: 8 h
Yield: 68.8 %

Procedure:
To a solution of 4-methoxy-2-nitroaniline (10 g, 59.4 mmol) in EtOH (200 mL) and water (80 mL) was added iron (12 g, 210 mmol) and ammonium chloride (9.63 g, 180 mmol). The mixture was then heated to reflux and stirred overnight. The mixture was filtered and the filtrate was evaporated to remove the EtOH and the residue was purified by flash chromatography on silica gel column (elution with DCM/MeOH=80:1) to give 4-methoxybenzene-1,2-diamine (intermediate 35) (5.65 g, 69%) as a yellow solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:28]1[S:32][N:31]=[CH:30][N:29]=1)[S:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[F:19])[N:15]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1I)[N:14]=[CH:13]2)(=[O:9])=[O:8].CC1(C)C(C)(C)OB([CH2:47]/[CH:48]=[CH:49]/[NH:50]C(=O)OC(C)(C)C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[NH2:50][CH2:49]/[CH:48]=[CH:47]/[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][N:15]1[C:16]2[C:12](=[CH:11][C:10]([S:7]([NH:6][C:28]3[S:32][N:31]=[CH:30][N:29]=3)(=[O:8])=[O:9])=[C:18]([F:19])[CH:17]=2)[CH:13]=[N:14]1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3cnn(Cc4ccccc4I)c3cc2F)c(OC)c1
Reactant: CC(C)(C)OC(=O)N/C=C/CB1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: NC/C=C/c1ccccc1Cn1ncc2cc(S(=O)(=O)Nc3ncns3)c(F)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(2,4-dimethoxybenzyl)-6-fluoro-1-(2-iodobenzyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indazole-5-sulfonamide (2-3, 0.068 g, 0.103 mmol, 1.0 equiv) in THF (0.94 mL) was added (E)-tert-butyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-1-yl)carbamate (0.088 g, 0.310 mmol, 3.0 equiv) and Pd(Cl)2dppf (0.008 g, 10.34 μmol, 0.1 equiv) followed by 1M cesium carbonate (0.094 mL) and the system was irradiated at 120° C. for 10 min. The reaction contents were extracted with EtOAc and water and the organic phase was dried over Na2SO4, filtered and concentrated. To this residue was added DCM (0.69 mL) followed by TFA (0.17 mL) and the system was stirred at room temperature for 1 h. The reaction contents were then concentrated in vacuo and purified by reverse phase chromatography (10%→70% 0.1% TFA in ACN: 0.1% TFA in water) to yield compound Ex-5 as a mono TFA salt. 1H NMR (400 MHz, CDCl3) δ 8.30-8.43 (m, 3H), 8.00 (br s, 2H), 7.80 (m, 1H), 7.50 (m, 1H), 7.18-7.39 (m, 3H), 6.80 (m, 1H), 6.20 (m, 1H), 5.70 (s, 2H), 2.45 (m, 3H). HRMS [M+H] C19H17FN6O2S2 calc'd 445.0911. found 445.0910.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH2:10]O)[C:4]=2[CH:3]=[CH:2]1.C1(P([N:26]=[N+:27]=[N-:28])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>O1CCCC1>[N:26]([CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2)=[N+:27]=[N-:28]
Reactant: OCc1cccc2[nH]ccc12
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: [N-]=[N+]=NCc1cccc2[nH]ccc12
Reaction time: 5 h
Yield: 1810.1 %

Procedure:
To a solution of 1H-indole-4-methanol (Example 17; 71 mg, 0.48 mmol) in tetrahydrofuran (1 mL) at 0° C. was added diphenylphosphoryl azide (156 μL, 0.72 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (87.4 μL, 0.58 mmol). The cooling bath was removed and the solution was allowed to stir for 5 h. After the solvent was evaporated, ethyl acetate was added and the solution was washed with 1N hydrochloric acid solution and brine, dried (MgSO4), filtered and concentrated. The residual material was chromatographed over silica gel (12% ethyl acetateihexanes) to give 4-(azidomethyl)-1H-indole (1.496 g, 88% yield) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:11]3[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[Br:26]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[Br:26][C:10]1[N:9]=[C:8]([C@@H:11]2[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:12]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([CH3:1])[C:3]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nccn2c([C@@H]3CCN(C(=O)OCc4ccccc4)C3)ncc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nccn2c([C@@H]3CCN(C(=O)OCc4ccccc4)C3)nc(Br)c12
Yield: 96 %

Procedure:
To (R)-benzyl 3-(8-methylimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (1.332 mmol, 448 mg) in N,N-dimethylformamide (5 ml) was added N-bromosuccinimide (1.332 mmol, 237 mg). After stirring at room temperature for five minutes saturated aqueous sodium hydrogencarbonate solution was added, the organic layer was separated and the aqueous layer extracted three times with ethyl acetate. The combined organic layers were washed with water, brine, dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; dichloromethane/methanol (gradient 0 to 10% methanol)) to give (R)-benzyl 3-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (531 mg).
Reaction SMILES: O[CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH2:4][CH2:3]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[N:26]1C=CC=C[CH:27]=1>>[C:27]([CH:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=2[CH2:4][CH2:3]1)#[N:26]
Reactant: c1ccncc1
Reactant: COC(=O)c1cccc2c1CCC2O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Product: COC(=O)c1cccc2c1CCC2C#N
Reaction time: 6 h

Procedure:
To 40 ml. of pyridine is added 19.2 g. of methyl 1-hydroxyindan-4-carboxylate and, while the mixture is stirred at a temperature of not more than 10°C, 21 g. of p-toluenesulfonyl chloride is added in small installments. After the addition has been completed, the reaction mixture is allowed to stand at a temperature not exceeding 10°C for 6 hours. Then, following the addition of ice, the reaction mixture is extracted with ether. The extract is washed with water and dried. The solvent is then distilled off under reduced pressure and the resultant 4-carbomethoxy-1-indanyl p-toluenesulfonate is dissolved in 100 ml. of dimethylsulfoxide, followed by stirring. Then, 5.5 g. of sodium cyanide is added and the mixture is stirred at room temperature for 11 hours. Following the addition of 850 ml. of water, the reaction mixture is extracted with ether. The extract is washed with a saturated aqueous solution of sodium chloride and, then, dried. The solvent is distilled off under reduced pressure and the residue is purified by column chromatography on silica gel (600 g. silica gel; eluant: chloroform). The described procedure gives methyl 1-cyanoindan-4-carboxylate as crystals melting at 76°-77°C.
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8](=O)[NH:7][N:6]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:20])=O>>[CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([Cl:20])=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(=O)c2cc(OC)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCc1nnc(Cl)c2cc(OC)ccc12

Procedure:
This compound is obtained according to the procedure described in 1.3. by reacting 4-butyl-7-methoxy-2H-phthalazin-1-one with phosphoryl chloride.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](Cl)=[O:18])=[CH:13][C:12]=1[C:20](Cl)=[O:21]>>[CH2:1]([NH:8][C:17](=[O:18])[C:14]1[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[C:12]([C:20]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:21])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(C(=O)Cl)cc1C(=O)Cl
Product: COc1ccc(C(=O)NCc2ccccc2)cc1C(=O)NCc1ccccc1

Procedure:
By following the general method of Example 1, benzyl amine was reacted with 4-methoxy-1,3-benzenedicarbonyl dichloride to give the titled compound. MS: M+1=375.2.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11]2[C:16](=[O:20])[O:17][CH2:18][CH2:19][C:10]3=2)[CH:5]=[N:4][CH:3]=[N:2]1.Cl.CS(O)(=O)=O.[CH3:27][OH:28]>>[CH3:27][O:28][C:16]([C:11]1[NH:12][C:13]2[C:9]([C:10]=1[CH2:19][CH2:18][OH:17])=[CH:8][C:7]([CH2:6][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)=[CH:15][CH:14]=2)=[O:20]
Reactant: O=C1OCCc2c1[nH]c1ccc(Cn3cncn3)cc21
Reactant: CO
Agent: CS(=O)(=O)O
Agent: Cl
Product: COC(=O)c1[nH]c2ccc(Cn3cncn3)cc2c1CCO
Reaction time: 4 h
Yield: 94 %

Procedure:
To a suspension of 2.5 g (8.2 mmoles) of the 6-(1,2,4-triazol-1-ylmethyl)-4,9-dihydro-3H-pyrano[3,4-b]indol-1-on a hydrochloride in 50 ml of methanol were added 0.66 ml (10.2 mmoles) of methanesulphonic acid. The mixture was left under stirring at the reflux temperature for 4 hours. The solvent was evaporated to dryness under reduced pressure, the residue dissolved with 10 ml of a saturated bicarbonate solution and extracted 3 times with ethyl acetate. The combined organic phases were dried and evaporated to dryness and the evaporated solid recrystallised from isopropyl alcohol/heptane to give 2.3 g (94%) of the title ester as a yellow crystalline solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:2].C([O:16][C:17]([C:19]1[C:20](Cl)=[N:21][C:22]([S:25][CH3:26])=[N:23][CH:24]=1)=O)C.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:5]1[CH2:6][N:7]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:20]2[N:21]=[C:22]([S:25][CH3:26])[N:23]=[CH:24][C:19]=2[C:17]1=[O:16])=[O:13])[CH3:2]
Reactant: CCOC(=O)CCNC1CCCC1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CN(C2CCCC2)c2nc(SC)ncc2C1=O
Reaction time: 16 h

Procedure:
3-Cyclopentylamino-propionic acid ethyl ester (1.0 g, 5.4 mmol) and 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (1.25 g, 5.4 mmol) were combined in DCM (10 mL) and diisopropylethylamine (0.83 g, 6.5 mmol) was added. After 16 h, the solution was partitioned between water and DCM and the organic layer was dried (MgSO4) and concentrated. Chromatography (0-20% EtOAc/hexanes gradient) provided the title compound that was directly carried on to the next step. Sodium (25 wt % dispersion in paraffin wax, 0.25 g, 6.0 mmol) was added to t-butanol (5.0 mL) at rt. After 10 minutes, a solution of 4-[cyclopentyl-(2-ethoxycarbonyl-ethyl)-amino]-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (2.0 g, 5.4 mmol) in 10 mL of toluene was added to the sodium t-butoxide solution and the resulting mixture was heated at 90° C. for 30 minutes. The reaction mixture was then cooled and the solution was adjusted to pH 7 using a 1N HCl solution. The solution was then extracted with EtOAc (2×20 mL) and the organic layer was dried (MgSO4) and concentrated to provide 0.26 g (14%). 1H-NMR (400 MHz, CDCl3:) 5 ppm 12.0 (br s, 1H), 8.20 (s, 1H), 5.10-5.18 (m, 1H), 4.26-4.31 (m, 3H), 3.72 (q, 2H, J=7.0 Hz), 2.50 (s, 3H), 1.63-1.86 (m, 5H), 1.20-1.35 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[C:18]2[C:13](=[N:14][C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][CH:17]=2)[N:12]([CH2:26][CH2:27][CH:28]=O)[N:11]=1.[CH3:30][NH:31][CH3:32].Cl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(CC)CC)C>ClCCCl>[CH3:30][N:31]([CH3:32])[CH2:28][CH2:27][CH2:26][N:12]1[C:13]2=[N:14][C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][CH:17]=[C:18]2[C:10]([NH:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[N:11]1
Reactant: CNC
Reactant: Cc1cccc(C)c1Nc1nn(CCC=O)c2nc(Nc3ccccc3)ncc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1cccc(C)c1Nc1nn(CCCN(C)C)c2nc(Nc3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 66 mg (0.2 mmol) of crude 3-(3-(2,6-dimethylphenylamino)-6-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propanal 36 (Example 4, Step A) and 28 mg (0.3 mmol) of dimethylamine•HCl in 7 mL of 1,2-dichloroethane was treated sequentially with 60 mg (95%, 0.3 mmol) of NaBH(OAc)3 and 75 μl (0.5 mmol) of triethylamine. The resulting brown slurry was stirred at room temperature for 17 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (15 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was purified by chromatography on silica gel (CH2Cl2:MeOH, 44:6 grading to CH2Cl2:MeOH, 4:1) to give the title compound 38. 1H-NMR (CD3OD) δ 2.06-2.14 (m, 2H), 2.28 (s, 6H), 2.49 (s, 6H), 2.72 (t, J=7.3 Hz, 2H), 4.19 (t, J=6.3 Hz, 2H), 7.01 (t, J=7.4 Hz, 1H), 7.12-7.19 (m, 3H), 7.31 (t, J=8.0 Hz, 2H), 7.75 (dd, J=8.6 Hz, 0.9 Hz, 2H), 8.27 (s, 1H). Mass Spectrum (ESI) m/e=416.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11](O)=[O:12])[C:5]([Cl:18])=[CH:4][N:3]=1.Cl.CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.Cl.[O:42]([NH2:44])[CH3:43].C(N(C(C)C)CC)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH:44][O:42][CH3:43])=[O:12])[C:5]([Cl:18])=[CH:4][N:3]=1
Reactant: CON
Reactant: O=C(O)c1ccccc1Nc1cc(Cl)ncc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CONC(=O)c1ccccc1Nc1cc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.1 %

Procedure:
A vessel was charged with 2-[(2,5-dichloro-4-pyridinyl)amino]benzoic acid (1.0 g, 3.53 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (677 mg, 3.53 mmol) and hydroxybenzotriazole (HOBT) (541 mg, 3.53 mmol) in N,N-dimethylformamide (DMF, 7.0 mL) and was stirred at room temperature for 30 min. To this solution methoxylamine hydrochloride (0.3 g, 3.53 mmol) was added and reaction mixture was stirred for another 10 min. The reaction mixture was cooled to 0° C. by using an ice bath. To this reaction mixture diisopropylethylamine (1.2 mL, 7.06 mmol) was added and the mixture was stirred at room temperature overnight. After concentrating under vacuum, the residue was worked up by using a saturated aqueous solution of NaHCO3 and CH2Cl2. The organic phase was washed with brine then dried over MgSO4 and filtered. The CH2Cl2 was removed by rotary evaporation. The crude material was loaded on silica gel column and eluted by MeOH in CH2Cl2 with NH4OH 0.1%, which gave the desired product 2-[(2, 5-dichloro-4-pyridinyl) amino]-N-(methyloxy)benzamide (850 mg, 2.72 mmol, 77% yield) MS: M(C13H11C12N3O2)=312.15, (M+H)+=312, 314; 1H NMR (400 MHz, CHLOROFORM-d)δ ppm 9.57 (br. s., 1 H) 8.72 (s, 1 H) 8.22 (s, 1 H) 7.51 - 7.67 (m, 3H) 7.25 (s, 1 H) 7.07 - 7.21 (m, 1 H) 3.92 (s, 3 H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:33][CH3:34].[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:34][O:33][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:7]=1[O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:39]1[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=1[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26]
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCCl
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCN1CCN(C)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
(2-{[7-(4-Chlorobutoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (60 mg), 4-methylpiperazine (39 mg), and potassium carbonate (90 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (41 mg, yield 60%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=2)[CH2:12][CH2:11]1
Reactant: CN1CCNCC1
Reactant: Nc1ccc(Cl)nn1
Product: CN1CCN(c2ccc(N)nn2)CC1
Temperature: 165 °C
Yield: 24.5 %

Procedure:
6-Chloro-pyridazin-3-ylamine (2.0 g, 15.4 mmol, Eq: 1.00) was dissolved in 1-methylpiperazine (15.5 g, 154 mmol, Eq: 10.0) and heated in a sand bath at 165° C. for 4 hours. The reaction mixture was then heated at 200° C. for 2 hours in a microwave reactor. The crude product was purified by chromatography using 10% methanol (with approximately 2% ammonium hydroxide) in DCM. To the still impure product was added aqueous sodium bicarbonate and DCM and the layers were separated. The aqueous layer was back extracted twice with DCM. The combined organic layers were concentrated, triturated with isopropyl acetate, filtered and dried to give 730 mg (24.5%) of a yellow solid.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=O)=[CH:8]2.[N:23]1(O)C2C=CC=CC=2N=N1.N.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.CN(C)C=O>[CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:23])=[O:14])=[CH:8]2
Reactant: On1nnc2ccccc21
Reactant: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Agent: N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cccc2cc(C(N)=O)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 66.9 %

Procedure:
To a mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (17.20 g), 1H-1,2,3-benzotriazol-1-ol (8.29 g) and N,N-dimethylformamide (150 ml) was added N-[3-(dimethylamino)propyl]-N,N-ethylcarbodiimide hydrochloride (11.8 g) at room temperature, and the mixture was stirred at 50° C. for 20 min. The mixture was allowed to cool to room temperature, and 28% aqueous ammonia (3.4 ml) was added. The reaction mixture was stirred at room temperature for 2 hr, and water was added. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water, washed with cooled ethyl acetate, and dried to give the title compound (11.47 g, yield 67%) as colorless crystals. melting point 244-245° C.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[C:29]([Cl:31])[C:28]([O:32][CH2:33][CH2:34][C:35]([F:41])([F:40])[C:36]([F:39])([F:38])[F:37])=[C:27]([Cl:42])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[Cl:42][C:27]1[CH:26]=[C:25]([C:23]2[N:24]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][N:10]3[C:6]4[C:5](=[O:12])[N:4]([CH3:13])[C:3](=[O:14])[N:2]([CH3:1])[C:7]=4[CH:8]=[CH:9]3)[S:21][CH:22]=2)[CH:30]=[C:29]([Cl:31])[C:28]=1[O:32][CH2:33][CH2:34][C:35]([F:41])([F:40])[C:36]([F:38])([F:39])[F:37]
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Reactant: O=C(CBr)Nc1nc(-c2cc(Cl)c(OCCC(F)(F)C(F)(F)F)c(Cl)c2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3cc(Cl)c(OCCC(F)(F)C(F)(F)F)c(Cl)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (50 mg, 0.279 mmol) with 2-bromo-N-{4-[3,5-dichloro-4-(3,3,4,4,4-pentafluorobutoxy)phenyl]-1,3-thiazol-2-yl}acetamide (176 mg, 0.332 mmol) in the presence of NaH (16 mg, 0.666 mmol) in dry DMF (5.0 mL) to give 58 mg of the product as an off-white solid; 1H NMR (δ ppm, DMSO-d6, 300 MHz) 2.80-2.86 (m, 2H), 3.17 (s, 3H), 3.39 (s, 3H), 4.25-4.32 (m, 2H), 5.32 (s, 2H), 6.23 (s, 1H), 7.35 (s, 1H), 7.88 (s, 1H), 8.03 (s, 2H), 12.70 (br s, 1H); ESI-MS (m/z) 626.18 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8](=O)[CH2:7][CH2:6][O:5][CH2:4]1.C([O-])=O.[NH4+:13]>[Pd].O.CO>[CH3:1][O:2][C@H:3]1[C@@H:8]([NH2:13])[CH2:7][CH2:6][O:5][CH2:4]1
Reactant: COC1COCCC1=O
Reactant: [NH4+]
Agent: [Pd]
Agent: O=C[O-]
Solvent: CO
Solvent: O
Product: CO[C@@H]1COCC[C@@H]1N
Yield: 50.8 %

Procedure:
A slurry of 3-methoxy-tetrahydro-pyran-4-one (0.4 g, 3 mmol—described in WO03/093266(A1)), ammonium formate (1.9 g, 30 mmol), 10% palladium on charcoal (1 g) in water:MeOH (1:5, 6 ml) was stirred overnight after which time it was filtered through Hyflo, the mixture concentrated to remove the MeOH, the residue taken up in Et2O, dried (Na2SO4) and concentrated to afford the title product (0.2 g, 49%) as a yellow oil (contaminated by 10-20% of the trans isomer). 1H NMR (300 MHz, CDCl3) (cis isomer) δ 1.60-1.80 (2H, m), 2.95-3.00 (1H, m), 3.22-3.43 (5H, m). 3.82-3.95 (1H, m), 4.01-4.13 (1H, m).