Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[CH3:12][C:13]1[O:14][C:15]2[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=2[C:17]=1[C:18]1[CH:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=1.CCN(C(C)C)C(C)C>ClCCl.O1CCCC1.CO.[OH-].[Na+]>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:24][C:21]1[CH:20]=[CH:19][C:18]([C:17]2[C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=3[O:14][C:13]=2[CH3:12])=[CH:23][N:22]=1)=[O:5]
Reactant: Cc1oc2ccccc2c1-c1ccc(N)nc1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1oc2ccccc2c1-c1ccc(NC(=O)c2c(F)cccc2F)nc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
Under an atmosphere of argon, 2,6-difluorobenzoyl chloride (47 mg, 0.3 mmol) was added to a stirred solution of 245 (30 mg, 0.1 mmol) and Hünig's base (140 μL, 104 mg, 0.8 mmol) in dichloromethane (1.0 mL) at room temperature. The reaction was stirred for 0.5 h. The solution was diluted with tetrahydrofuran (0.8 mL), methanol (0.6 mL) and 2 M sodium hydroxide solution (0.2 mL). The mixture was stirred and heated to 60° C. for 15 min then cooled to room temperature, diluted with dichloromethane (10 mL), dried with sodium sulfate and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-20% ethyl acetate in hexane) provided 246 (35.5 mg, 73%) as a solid: LRESIMS m/z 365.1 [M+H]+, calcd. for C21H15F2N2O2 365.1.
Reaction SMILES: C([O:8][C:9]1[CH:26]=[C:12]2[CH2:13][N:14]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[O:18])[CH2:15][CH2:16][N:11]2[N:10]=1)C1C=CC=CC=1>CCOC(C)=O.CN(C=O)C.[OH-].[OH-].[Pd+2]>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C:17]([N:14]2[CH2:15][CH2:16][N:11]3[N:10]=[C:9]([OH:8])[CH:26]=[C:12]3[CH2:13]2)=[O:18])=[CH:20][CH:21]=1
Reactant: O=C(c1ccc(F)cc1)N1CCn2nc(OCc3ccccc3)cc2C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(c1ccc(F)cc1)N1CCn2nc(O)cc2C1
Yield: 98.9 %

Procedure:
A solution of 2-(benzyloxy)-5-[(4-fluorophenyl)carbonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine (0.53 g, 1.51 mmol) in a mixture of AcOEt/DMF (1.8/1.8 mL) was hydrogenated in a H-Cube reactor (1.5 ml/min, 70 mm, Pd(OH)2/C cartridge, full H2 mode, 80° C., 1 cycle). The solvents were evaporated in vacuo to yield 5-[(4-fluorophenyl)carbonyl]-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ol (0.39 g, 90% yield) as a white solid, that was used in the next step without further purification.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([C:15]#[N:16])[CH:9]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:6][CH2:7][C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([C:15]#[N:16])[CH:9]=1
Reactant: Cc1cc(C(C)(C)O[SiH2]C(C)(C)C)cc(C#N)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(CO)cc(C#N)n1
Reaction time: 1 h
Yield: 90 %

Procedure:
4-(tert-Butyl-dimethyl-silanyloxymethyl)-6-methyl-pyridine-2-carbonitrile (8 g, 30.53 mmol) was stirred with 1M tetrabutylammonium fluoride in THF (32 ml, 32 mmol) in THF (30 ml) at room temperature. After 1 hr., the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexane (4:1)) to afford 4.07 g (90%) of 4-Hydroxymethyl-6-methyl-pyridine-2-carbonitrile as a white solid. m.p. 136-138° C.; 1H NMR (200 MHz, CDCl3) δ 2.59 (3H, s), 4.78 (2H, s), 7.39 (1H, s), 7.53 (1H, s).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH3:12])=[O:10])[CH:5]([CH2:13][C:14]([CH3:22])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[CH2:4]1.I([O-])(=O)(=O)=[O:24].[Na+]>[Ru](Cl)(Cl)Cl>[CH3:12][O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([C:2]([OH:24])=[O:1])[CH2:4][CH:5]1[CH2:13][C:14]([CH3:22])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:15])=[O:10]
Reactant: COC(=O)N1CCC(CO)CC1CC(C)(C)c1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Product: COC(=O)N1CCC(C(=O)O)CC1CC(C)(C)c1ccccc1
Yield: 86.5 %

Procedure:
The compound was prepared as described in Reference Compound 4, Step 5 starting from methyl 4-(hydroxymethyl)-2-(2-methyl-2-phenylpropyl)piperidine-1-carboxylate (8.0 g, 26.2 mmol), sodium periodate (16.8 g, 78.6 mmol) and ruthenium(III) chloride (0.12 g, 0.58 mmol), which resulted in the title compound (7.24 g, 87%). MS m/z 318 (M−H)−.
Reaction SMILES: C[SH+](C)=O.[CH3:5][O:6][C:7](=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1.[SH:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>ClC(Cl)C>[CH3:5][O:6][C:7](=[O:16])[CH:8]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)[S:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1
Reactant: Sc1ccncc1
Reactant: COC(=O)Cc1cccc(Br)c1
Agent: C[SH+](C)=O
Solvent: CC(Cl)Cl
Product: COC(=O)C(Sc1ccncc1)c1cccc(Br)c1

Procedure:
To a solution of dimethylsulfoxonium ylide and 3-bromophenylacetic acid methyl ester (example 530E, 3 g) in dichloroethane (50 mL) are added 4-mercaptopyridine (2 equivalents) and [Ir(COD)Cl]2 (20 mg). The reaction mixture is refluxed overnight then concentrated to dryness under reduced pressure. The residue is purified by chromatography on silica gel (heptane/ethyl acetate 1/1) to give (3-Bromophenyl)(pyridin-4-ylsulfanyl)acetic acid methyl ester. 1H NMR: 8.50-8.35 (m, 2H), 7.68 (s, 1H), 7.55-7.45 (m, 2H), 7.35-7.20 (m, 1H), 7.20-7.05 (m, 2H), 5.08 (s, 1H), 3.77 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:12](Cl)(=[O:16])[C:13]([CH3:15])=[CH2:14]>>[CH3:15][C:13](=[CH2:14])[C:12]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]=1[CH3:1])=[O:16]
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Reactant: C=C(C)C(=O)Cl
Product: C=C(C)C(=O)Nc1cccc([N+](=O)[O-])c1C

Procedure:
2-Methyl-N-(2-methyl-3-nitrophenyl)acrylamide was prepared as described in Example 1a starting from 2-methyl-3-nitroaniline and methacryloyl chloride. 1H NMR (400 MHz, DMSO-d6): 1.97 (3H, s), 2.23 (3H, s), 5.56 (1H, s), 5.90 (1H, s), 7.40-7.46 (1H, m), 7.57-7.60 (1H, m), 7.74-7.77 (1H, m), 9.71 (1H, s).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[O:21][CH2:22][CH2:23][N:24]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1.CO.C(N(CC)CC)C>[O:21]1[CH2:22][CH2:23][N:24]=[C:20]1[C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C3=NCCO3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CO
Product: c1cc(N2CCNCC2)ccc1C1=NCCO1
Reaction time: 1 h

Procedure:
Compound 5A (826 mg; 2.49 mmol) in solution in toluene (20 ml) is treated, at room temperature, with trifluoroacetic acid (2.75 ml). After 1 h, the medium is evaporated to dryness and coevaporated 3 times with toluene. The product obtained is taken up in methanol (20 ml) and triethylamine (8 ml), stirred for 15 min at room temperature and finally evaporated to dryness. The solid obtained is purified by chromatography on a silica gel column eluted with a dichloro-methane/methanol/ammonium hydroxide mixture in the proportions 90/9/1 to give the intermediate 5B.
Reaction SMILES: [Sn].[CH:2](=[O:6])[CH2:3][CH2:4][CH3:5].[CH2:7]([C:9](=CCCC)[CH:10]=[O:11])[CH3:8].C([Sn](=O)CCCC)CCC>>[CH2:2]([O:6][C:10](=[O:11])[CH2:9][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC=O
Reactant: CCCC=C(C=O)CC
Agent: CCCC[Sn](=O)CCCC
Agent: [Sn]
Product: CCCCOC(=O)CCC
Yield: 45 %

Procedure:
Tin metal supported on silica gel is described as a vapor phase aldol catalyst by Swift, Bozik, and Massota, in Catalysis 15 407 (1969). Swift also describes the vapor phase reaction of n-butyraldehyde with tin metal supported on silica gel in U.S. Pat. No. 3,542,878. The product of the reaction is 2-ethylhexenal in 95 percent selectivity, at 40 percent n-butyraldehyde conversion. Japanese workers have described the simple Tischenko reaction of aldehydes in Japan Kokai No. 76/39,619 using dibutyltin oxide. The products claimed were simple esters, for example, n-butyraldehyde reacted in the presence of dibutyltin oxide to form butylbutyrate in approximately 45 percent yield. The catalyst and process described by this invention produce only traces of simple esters (less than 1 percent).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([S:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[CH3:6])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:22][C:23](C)=O>>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([S:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:22][CH3:23])=[CH:12][CH:13]=1)[CH3:6])[CH3:2]
Reactant: CC(C)=O
Reactant: CCOC(=O)C(C)Sc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(C)Sc1ccc(OCC)cc1

Procedure:
To stired solution of 2-(4-hydroxy-phenylsulfanyl)-propionic acid ethyl ester (11.3 g, 50 mmol), and K2CO3 (50 g, excess) in acetone (300 ml) ethyl iodide (20 ml, excess) was added and refluxed for 8 hrs. At the end, reaction mixture was filtered and concentrated. The residue obtained was extracted with chloroform and washed well with water. It was dried and concentrated. The product, 2-(4-ethoxy-phenylsulfanyl)-propionic acid ethyl ester was isolated as colorless oil. Yield: 12.0 g, 98%; MS: 255 (M+H).
Reaction SMILES: CCOC(C)=O.[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[N+:17]([O-])=O)[C:11]([NH2:13])=O.CCN(CC)CC>C(Cl)Cl>[F:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[NH2:17])[C:11]#[N:13]
Reactant: NC(=O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N)c(F)c1
Reaction time: 2 h
Yield: 114.1 %

Procedure:
To a 0° C. EtOAc (150 mL) solution of 3-fluoro-4-nitrobenzamide (4.85 g, 26.4 mmol) and Et3N (5.34 g, 52.8 mmol) was added dropwise a CH2Cl2 (50 mL) solution of 1,1,1-trichloroacetyl chloride (5.28 g, 29.04 mmol). The reaction was complete in 2 h (TLC, 1:1 hexane:EtOAc), then it was washed with 1N HCl, dried (MgSO4) and evaporated to give 4.1 g of the corresponding nitrile.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:22]=[CH:21][C:9]([CH:10]=[C:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:20])=[CH:8][C:7]=1[O:23][CH3:24].[NH:25]1[CH:29]=[CH:28][N:27]=[CH:26]1>>[N:25]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:22]=[CH:21][C:9]([CH:10]=[C:11]3[CH2:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:20])=[CH:8][C:7]=2[O:23][CH3:24])[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: c1c[nH]cn1
Reactant: COc1cc(C=C2Cc3ccccc3C2=O)ccc1OCCCCl
Product: COc1cc(C=C2Cc3ccccc3C2=O)ccc1OCCCn1ccnc1

Procedure:
2-[4-(3-IMIDAZOL-1YL PROPOXY)-3-METHOXYBENZYLIDENE)INDAN-1-ONE (8) (RG-DPJ-195) was prepared by fusing compound 7 with imidazole following the method described for 2
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][C:18]3[CH:19]=[N:20][NH:21][CH:22]=3)[C:6](=[O:23])[N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:4]=2[N:3]=1.CC(C)([O-])C.[K+].[Cl:35][C:36]1[S:37][C:38]([CH2:41]Cl)=[CH:39][CH:40]=1>C1COCC1>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH2:17][C:18]3[CH:22]=[N:21][N:20]([CH2:41][C:38]4[S:37][C:36]([Cl:35])=[CH:40][CH:39]=4)[CH:19]=3)[C:6](=[O:23])[N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:4]=2[N:3]=1
Reactant: ClCc1ccc(Cl)s1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCc1cn[nH]c1)c(=O)n2CCCCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCn1c(=O)n(CCCc2cnn(Cc3ccc(Cl)s3)c2)c(=O)c2[nH]c(Cl)nc21
Reaction time: 0.25 h
Yield: 6.9 %

Procedure:
To 8-chloro-3-pentyl-7-(2-propen-1-yl)-1-[3-(1H-pyrazol-4-yl)propyl]-3,7-dihydro-1H-purine-2,6-dione (61 mg, 0.15 mmol) in dry THF (1 ml) at −78° C., under nitrogen, was added potassium t-butoxide (1M in THF, 0.15 ml), followed by 2-chloro-5-(chloromethyl)thiophene (25 mg, 0.15 mmol). Stirring was continued at −78° C. for 15 min, then at room temperature for 1 h and finally at 60° C. for 18 h. The solution was degassed and morpholine (0.13 ml) and tetrakis(triphenylphosphine)palladium(0) (35 mg) added and stirring continued for 6 h. Further quantities (0.2 ml morpholine, 50 mg Pd(PPh3)4) were added and stirring continued overnight. Worked up by partition between EtOAc and 2M HCl, the organic phase evaporated and purified by the standard aminopropyl SPE procedure followed by MDAP yielding title compound as a white solid (5.1 mg).
Reaction SMILES: [CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6]2.N1C=CC=CC=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH3:1][C:2]1([C:17]2[CH:18]=[C:19]([NH:23][S:31]([CH3:30])(=[O:33])=[O:32])[CH:20]=[CH:21][CH:22]=2)[CH:3]2[CH:7]1[CH2:6][N:5]([CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4]2
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2cccc(N)c2)C2CN(CCCc3ccccc3)CC21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(CCCc3ccccc3)CC21
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of 3-[6-methyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine (Preparation 8, 28 mg, 0.09 mmol) in dichloromethane (2 ml), at 0° C. under nitrogen was added pyridine (20 μl, 0.24 mmol) and then methanesulfonylchloride (25 μl, 37 mg , 0.32 mmol) over 5 minutes. The mixture was allowed to warm to room temperature and was then stirred for 2 hours. The mixture was concentrated in vacuo and the residue was purified by silica (5 g) column chromatography eluting with 80:20:1 ethyl acetate:hexane:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless oil (18 mg, 52%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH:10](=[O:12])[CH3:11]>CCO>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:11][CH:10]=[O:12])=[CH:4][CH:3]=1
Reactant: CC=O
Reactant: O=Cc1ccc(F)cc1
Solvent: CCO
Product: O=CC=Cc1ccc(F)cc1

Procedure:
This compound was prepared following the procedure of Preparation 17 starting from p-fluorobenzaldehyde and acetaldehyde. Yield, 47%. b.p. 80°-95°/2 mm., λmax. (EtOH) 220, 285 nm., ε 10500, 23400.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.S[C:8]1[O:9][C:10]2[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:11]=2[N:12]=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:8]2[O:9][C:10]3[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:11]=3[N:12]=2)[CH2:22][CH2:21]1
Reactant: Sc1nc2cc(Cl)cc(Cl)c2o1
Reactant: CN1CCNCC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CN1CCN(c2nc3cc(Cl)cc(Cl)c3o2)CC1
Temperature: 100 °C

Procedure:
Phosphorus pentachloride (454 mg) was dissolved in anhydrous toluene (6 ml), the resulting solution was mixed with 2-mercapto-5,7-dichlorobenzoxazole (400 mg) which has been obtained in the same manner as described in Reference Example 1, and the mixture was then stirred with heating at 100° C. for 2 hours. With cooling in an ice bath, to this was added dropwise N-methylpiperazine (2.0 ml). After 20 minutes of stirring, the thus obtained mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine in that order. After drying with magnesium sulfate, the solvent was evaporated under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography (methylene chloride:methanol=10:1) to obtain the title compound 2-(4-methyl-1-piperazinyl)-5,7-dichlorobenzoxazole (89.9 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[S:10][C:3]=12.[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[OH:29].C(=O)([O-])[O-].[K+].[K+]>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl>[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[O:29][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[S:10][C:3]=12
Reactant: COc1ccc(-c2cc3nccc(Cl)c3s2)cn1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cn1
Temperature: 170 °C
Yield: 43 %

Procedure:
A suspension of 418 (0.638 g, 2.31 mmol), 2-fluoro-4-nitrophenol (0.725 g, 4.61 mmol) and potassium carbonate (0.638 g, 4.61 mmol) in diphenyl ether (6 mL) was heated to 170° C. for 8 h in a pressure tube. The resulting dark solution was cooled to room temperature, diluted with CH2Cl2 and then filtered. The filtrate was concentrated and the residue was purified by flash chromatography (eluent 100% hexanes to 50/50 ethyl acetate/hexanes) to produce title compound 419 as a yellow solid (0.395 g, 43% yield). MS (m/z): 398.0 (M+H).
Reaction SMILES: CN(C[C:5]1[CH:6]=[C:7]([NH:11][C:12]2[S:13][C:14]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)=[CH:15][N:16]=2)[CH:8]=[CH:9][CH:10]=1)C.[CH3:22][N:23]1[CH2:28][CH2:27][N:26](C2C=CC(NC(N)=S)=CC=2)[CH2:25][CH2:24]1>>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:10]2[CH:5]=[CH:6][C:7]([NH:11][C:12]3[S:13][C:14]([C:17]4[CH:21]=[CH:20][S:19][CH:18]=4)=[CH:15][N:16]=3)=[CH:8][CH:9]=2)[CH2:25][CH2:24]1
Reactant: CN(C)Cc1cccc(Nc2ncc(-c3ccsc3)s2)c1
Reactant: CN1CCN(c2ccc(NC(N)=S)cc2)CC1
Product: CN1CCN(c2ccc(Nc3ncc(-c4ccsc4)s3)cc2)CC1

Procedure:
The title compound is prepared as described in Example 19 for (3-dimethylaminomethyl-phenyl)-(5-thiophen-3-yl-thiazol-2-yl)-amine but starting from [4-(4-methyl-piperazin-1-yl)-phenyl]-thiourea (Example 5). MPLC (CH3CN/H2O/TFA) purification affords the title compound: ES-MS: 357.1 [M+H]+; single peak at tR=2.82 min (System 2); Rf=0.59 (CH2Cl2/MeOH, 90/10).
Reaction SMILES: C(N(CC)CCC[N:7]1[C:15]2[C:10](=[C:11]([Cl:16])[CH:12]=[CH:13][CH:14]=2)[C:9](NCCCN(CC)CC)=[N:8]1)C.[ClH:28].C(OCC)C>C(O)C>[ClH:16].[ClH:28].[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[CH:9]=[N:8][NH:7]2
Reactant: CCN(CC)CCCNc1nn(CCCN(CC)CC)c2cccc(Cl)c12
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: Clc1cccc2[nH]ncc12

Procedure:
In 50 ml of absolute ethyl alcohol was dissolved 3.2 g of the 1-(3-diethylaminopropyl)-3-(3-diethylaminopropylamino)-4 -chloroindazole, and into the solution was introduced dried hydrogen chloride gas under cooling with ice. Then to the solution was added anhydrous diethyl ether to separate crystals. The crystals were obtained by filtration and dried to give 1-(3-diethylaminopropyl)-3-diethylaminopropylamino)-4-chloroindazole dihydrochloride having the following analytical value.
Reaction SMILES: C([O:8][C:9]1[N:24]=[C:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([CH3:34])[CH:29]=[CH:28]3)[C:22]([O:35][CH3:36])=[C:21]([O:37]CC2C=CC=CC=2)[C:10]=1[C:11]([O:13]CC1C=CC=CC=1)=[O:12])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[OH:37][C:21]1[C:22]([O:35][CH3:36])=[C:23]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][CH:33]=2)[N:30]([CH3:34])[CH:29]=[CH:28]3)[NH:24][C:9](=[O:8])[C:10]=1[C:11]([OH:13])=[O:12]
Reactant: COc1c(-c2ccc3c(ccn3C)c2)nc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1c(-c2ccc3c(ccn3C)c2)[nH]c(=O)c(C(=O)O)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
A mixture of benzyl 2,4-bis(benzyloxy)-5-methoxy-6-(1-methyl-1H-indol-5-yl)nicotinate (73 mg, 0.12 mmol) and 10% Pd/C (18 mg) in ethyl acetate (3.0 mL) was stirred for 2 h at room temperature under a hydrogen balloon. The mixture was then filtered. The filtrate was evaporated and the residue was triturated with ether to give 4-hydroxy-5-methoxy-6-(1-methyl-1H-indol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (27 mg, 69%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:57]=[CH:58][CH:59]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:32][CH2:33][CH2:34][CH2:35][O:36]CC5C=CC(OC)=CC=5)=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=4)[CH:19]=3)[N:14]([S:46]([C:49]3[CH:55]=[CH:54][C:52]([CH3:53])=[CH:51][CH:50]=3)(=[O:48])=[O:47])[CH:13]=2)[C:8]([CH3:56])=[N:7]1.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:57]=[CH:58][CH:59]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([O:32][CH2:33][CH2:34][CH2:35][OH:36])=[C:25]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])[CH:26]=4)[CH:19]=3)[N:14]([S:46]([C:49]3[CH:50]=[CH:51][C:52]([CH3:53])=[CH:54][CH:55]=3)(=[O:47])=[O:48])[CH:13]=2)[C:8]([CH3:56])=[N:7]1
Reactant: COc1ccc(COCCCOc2ccc(-c3cnc4c(c3)c(-c3c(C)nn(Cc5cccc(F)c5)c3C)cn4S(=O)(=O)c3ccc(C)cc3)cc2NS(C)(=O)=O)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(OCCCO)c(NS(C)(=O)=O)c4)cnc32)cc1
Temperature: 25 °C

Procedure:
A stirred solution of N-(5-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(3-((4-methoxybenzyl)oxy)prop oxy)phenyl)methanesulfonamide (120 mg, 0.1 mmol), TFA/toluene (169 mg/3 mL) was heated to 80° C. for overnight. TLC showed reaction completion. Reaction mass was cooled to RT and solvents evaporated under reduced pressure. This afforded 60 mg of the crude titled compound. MS: m/z=718.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([S:10]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:22]Br.O>CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:22][C:21]2[CH:24]=[CH:25][C:26]([F:27])=[C:19]([F:18])[CH:20]=2)[CH:7]=[C:8]([S:10]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:12])[CH:9]=1)=[O:4]
Reactant: Fc1ccc(CBr)cc1F
Reactant: COC(=O)c1cc(S(=O)(=O)c2cccs2)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(S(=O)(=O)c2cccs2)cn1Cc1ccc(F)c(F)c1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(thiophene-2-sulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester (D1-I) in dry dimethylformamide, cesium carbonate was added at 40-50° C. To this was added 3,4-difluro benzyl bromide and stirred overnight at 40-50° C. Reaction mixture was taken in to water and extracted with ethyl acetate, organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford 1-(3,4-difluoro-benzyl)-4-(thiophene-2-sulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester (D1-II).