Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([Cl:5])(=O)=O.[CH3:6][C:7]1([CH3:23])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([S:17][CH3:18])[CH:14]=2)[N:9]([CH2:19][CH2:20]O)[C:8]1=[O:22].C(N(CC)CC)C>ClCCl>[Cl:5][CH2:20][CH2:19][N:9]1[C:10]2[C:15](=[CH:14][C:13]([S:17][CH3:18])=[CH:12][CH:11]=2)[CH2:16][C:7]([CH3:23])([CH3:6])[C:8]1=[O:22]
Reactant: CSc1ccc2c(c1)CC(C)(C)C(=O)N2CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ccc2c(c1)CC(C)(C)C(=O)N2CCCl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Methanesulfonyl chloride (1.05 ml, 1.56 g, 0.014 mol) was added to a solution of 3,4-dihydro-3,3-dimethyl-1-(2-hydroxyethyl)-6-methylthio-2(1H)-quinolinone (2.88 g, 0.011 mol) and triethylamine (2.27 ml, 1.64 g, 0.016 mol) in dichloromethane (50 ml) at 0° C. under nitrogen and the resultant mixture was stirred for 20 mins. Then the mixture was allowed to warm to room temperature and sirred for 20 hr. The reaction mixture was then washed with water (2×20 ml), dried (MgSO4), filtered and concentrated in vacuo. The residue was then dissolved in carbon tetrachloride (30 ml), filtered and the solvent was evaporated in vacuo to afford 1-(2-chloroethyl)-3,3-dimethyl-6-methylthio-2(1H)-quinolinone as an oil which solidified on standing.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20](=[O:29])[C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH3:28])[CH:22]=3)=[CH:10]2)[CH:5]=[CH:4][CH:3]=1.Cl.C(O)(=[O:33])C>>[CH3:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[CH3:27])[C:20]([C:11]1[C:12](=[O:19])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]([CH2:8][C:6]2[NH:7][C:2](=[O:33])[CH:3]=[CH:4][CH:5]=2)[CH:10]=1)=[O:29]
Reactant: CC(=O)O
Reactant: Cc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cc1C
Agent: Cl
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(=O)[nH]3)c3ccccc3c2=O)cc1C

Procedure:
182 mg (0.41 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-3-(3,4-dimethyl-benzoyl)-1H-quinolin-4-one in a solution of 3 mL acetic acid and 3 mL concentrated aqueous hydrochloric acid was heated in a sealed tube at 150° C. for 24 h. Purification on reverse-phase HPLC and free-basing gave 95 mg of a white solid: LC-MSD, m/z for C24H20N2O3 [M+H]+=385.1; HPLC retention time: 0.4 min.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH:10]1[C:22]2[CH:21]([CH2:23][O:24][C:25]([NH:27][C@@H:28]([CH2:32][C:33]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH:34]=3)[C:29]([OH:31])=[O:30])=[O:26])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+]>ClCCl>[CH:19]1[C:20]2[CH:21]([CH2:23][O:24][C:25]([NH:27][C@H:28]([C:29]([O:31][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:30])[CH2:32][C:33]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]([C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[CH:34]=3)=[O:26])[C:22]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15]=2[CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)OC(=O)n1cc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)COC(=O)[C@H](Cc1cn(C(=O)OC(C)(C)C)c2ccccc12)NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 48 h

Procedure:
tert-Butyl 2-bromoacetate (2.09 ml, 14.2 mmol) was added to a solution of (S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)propanoic acid (Fmoc-Trp(Boc)-OH) (Compound SP613) (5.0 g, 9.50 mmol) and diisopropylethylamine (DIPEA) (4.98 ml, 28.5 mmol) in dichloromethane (DCM) (9.5 ml) at room temperature under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 48 hours. An aqueous ammonium chloride solution was added to the reaction solution, the mixture was extracted with dichloromethane (DCM) twice, and the organic layer was washed with brine twice. The organic layer was dried over sodium sulfate, and then filtered and concentrated under reduced pressure. The resulting residue was purified by normal-phase silica gel chromatography (hexane/ethyl acetate) to afford (S)-tert-butyl 3-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(2-(tert-butoxy)-2-oxoethoxy)-3-oxopropyl)-1H-indole-1-carboxylate (Fmoc-Trp(Boc)-HoGly-OtBu) (Compound SP614) as a mixture (5.25 g).
Reaction SMILES: C([O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][C@H:11]2[CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])=[CH:7][C:6]=1[Br:21])C=C.O.Cl.C(OCC)(=O)C.C(N(CC)[C:33]1[CH:38]=CC=C[CH:34]=1)C>>[CH2:38]([C:13]1[C:5]([OH:4])=[C:6]([Br:21])[CH:7]=[C:8]2[C:12]=1[C@H:11]([CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH2:10][CH2:9]2)[CH:33]=[CH2:34]
Reactant: CCN(CC)c1ccccc1
Reactant: C=CCOc1cc2c(cc1Br)CC[C@H]2CCNC(=O)CC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCc1c(O)c(Br)cc2c1[C@H](CCNC(=O)CC)CC2
Temperature: 202.5 °C
Reaction time: 2.5 h
Yield: 80 %

Procedure:
A suspension of (S)-N-[2-(6-allyloxy-5-bromoindan-1-yl)ethyl]propionamide (50.75 g, 144 mmol.) in N,N-diethylaniline (150 mL) was stirred for 2.5 hours at 200-205° C. under argon atmosphere. The reaction mixture was cooled, followed by distilling off N,N-diethylaniline under reduced pressure to leave an oily residue. To the residue were added water (50 mL), 2N HCl (50 mL) and ethyl acetate (100 mL). The mixture was subjected to extraction twice to extract the organic matter. The extract solution was washed with a saturated aqueous saline solution and water, which was then dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of silica gel column chromatography (ethyl acetate:hexane=7:3) to afford the title compound (yield 40.6 g, 80%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[CH2:29]([OH:38])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1>>[CH3:37][O:36][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][CH:33]=1)[CH2:29][O:38][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1
Reactant: COc1cccc(CO)c1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Product: COc1cccc(COCc2ccc(-c3nccnc3NS(=O)(=O)c3ccccc3C(F)(F)F)cc2)c1
Yield: 64 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 3-anisyl alcohol, the title compound was isolated as a yellow solid in 64% yield (92% purity by HPLC).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[C:16]=1[OH:25].[CH3:26]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].CI>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[C:16]=1[O:25][CH3:26]
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2c([N+](=O)[O-])cnc3ccc(Cl)cc23)c(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COc1ccc(-c2c([N+](=O)[O-])cnc3ccc(Cl)cc23)c(OC)c1OC
Reaction time: 0.17 h
Yield: 89.6 %

Procedure:
A mixture of 6-chloro-4-(2-hydroxy-3,4-dimethoxyphenyl)-3-nitroquinoline (1.20 g), N,N-dimethylformamide (20 ml), potassium carbonate powder (0.92 g) and methyl iodide (0.41 ml) was stirred for 10 mins. at 0° C. and for 2 hrs. at room temperature, and then diluted with water, extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was recrystallized from methanol to give 6-chloro-4-(2,3,4-trimethoxyphenyl)-3-nitroquinoline as yellow crystals (1.12 g, 89.6%). m.p. 114°-116° C.
Reaction SMILES: CO[C:3](=[O:24])[C:4]([C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[CH:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1>C1(OC2C=CC=CC=2)C=CC=CC=1.CCCCCC>[CH3:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[CH3:21])[C:14]([C:4]1[C:3](=[O:24])[C:8]2[C:7](=[CH:12][CH:11]=[C:10]([F:13])[CH:9]=2)[NH:6][CH:5]=1)=[O:23]
Reactant: COC(=O)C(=CNc1ccc(F)cc1)C(=O)c1ccc(C)c(C)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: Cc1ccc(C(=O)c2c[nH]c3ccc(F)cc3c2=O)cc1C
Temperature: 25 °C
Yield: 66.1 %

Procedure:
0.691 g (2.11 mmol) of 2-(3,4-Dimethyl-benzoyl)-3-(4-fluoro-phenylamino)-acrylic acid methyl ester 2g was dissolved in 30 mL of diphenyl ether and the resultant solution was heated at 250° C. After 2.5 h the solution was cooled to room temperature and diluted with 50 mL of hexane. The crude product precipitated out of solution and was isolated by filtration. The crude product was further washed with hexane to yield 0.412 g of 3-(3,4-dimethyl-benzoyl)-6-fluoro-1H-quinolin-4-one 3j as a brown solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH2:8][CH2:9][NH2:10])=[N:2]1.CS[C:13](=[NH:18])[NH:14][N+:15]([O-:17])=[O:16]>>[N+:15]([NH:14][C:13]([NH:10][CH2:9][CH2:8][NH:7][CH2:6][C:3]1[CH:4]=[CH:5][NH:1][N:2]=1)=[NH:18])([O-:17])=[O:16]
Reactant: NCCNCc1cc[nH]n1
Reactant: CSC(=N)N[N+](=O)[O-]
Product: N=C(NCCNCc1cc[nH]n1)N[N+](=O)[O-]

Procedure:
Reaction of N-(3-pyrazolylmethyl)ethylenediamine with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-nitro-N'-[2-(3-pyrazolylmethylamino)-ethyl]guanidine, and in the procedure of Example 2(iii) gives N-methyl-N'-[2-(3-pyrazolylmethylamino)ethyl]-N"-nitroguanidine.
Reaction SMILES: [CH:1]([O:14][C:15]([CH2:17][O:18]/[N:19]=[C:20](/[C:52]1[N:53]=[C:54]([NH:57][C:58]([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[S:55][CH:56]=1)\[C:21]([NH:23][CH:24]1[C:50](=[O:51])[N:26]2[C:27]([C:34]([O:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])=[C:28]([CH2:32]Cl)[CH2:29][S:30](=[O:31])[C@H:25]12)=[O:22])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:77].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].C(OCC)(=O)C>CC(C)=O>[CH:1]([O:14][C:15]([CH2:17][O:18]/[N:19]=[C:20](/[C:52]1[N:53]=[C:54]([NH:57][C:58]([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[S:55][CH:56]=1)\[C:21]([NH:23][CH:24]1[C:50](=[O:51])[N:26]2[C:27]([C:34]([O:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])=[C:28]([CH2:32][I:77])[CH2:29][S:30](=[O:31])[C@H:25]12)=[O:22])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)OC(c1ccccc1)c1ccccc1
Reactant: [I-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C(CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound obtained in (A) was dissolved in 380 ml of acetone, and 7.4 g (49 mmol) of sodium iodide was added thereto. The mixture was stirred at room temperature for 30 minutes. To the reaction solution, 300 ml of a 10% sodium thiosulfate aqueous solution and 1150 ml of ethyl acetate were added for liquid separation. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flush column chromatography (ethyl acetate/n-hexane=1/1) to obtain 22.4 g (yield based on the previous step: 86.7%) of a powder of the above identified compound.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]O)=[O:7])=[CH:4][CH:3]=1.O.C(OCC)C.[BrH:24]>>[Br:24][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Br
Reactant: O=C(NCCCCCCO)c1ccc(Cl)cc1
Solvent: O
Solvent: CCOCC
Product: O=C(NCCCCCCBr)c1ccc(Cl)cc1

Procedure:
6-(4-Chlorobenzoylamino)hexan-1-ol (17.0 g) was refluxed in 48% hydrobromic acid (260 ml) for 2.5 h. The mixture was cooled and added to water (450 ml) and diethyl ether (450 ml). The organic layer was washed with saturated sodium bicarbonate (450 ml) and brine (450 ml) and was dried over magnesium sulfate. Evaporation followed by recrystallisation from diethyl ether gave 1-bromo-6-(4-chlorobenzoylamino)hexane (8.6 g). 1H-NMR (CDCl3) δ 1.3-2.0 (8H, m), 3.35-3.55 (4H, m), 6.15 (1H, bs), 7.40 (2H, m) and 7.70 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][C:7]2[S:8][C:9]3[N:10]=[C:11]([NH2:18])[N:12]=[C:13]([S:16][CH3:17])[C:14]=3[N:15]=2)=[CH:4][CH:3]=1.[OH-].[Na+].I[CH3:24].O>CS(C)=O>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH:6]([C:7]2[S:8][C:9]3[N:10]=[C:11]([NH2:18])[N:12]=[C:13]([S:16][CH3:17])[C:14]=3[N:15]=2)[CH3:24])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CSc1nc(N)nc2sc(Cc3ccc(F)cc3)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CSc1nc(N)nc2sc(C(C)c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.1 %

Procedure:
To a solution of 2-(4-fluorobenzyl)-7-(methylthio)thiazolo[5,4-d]pyrimidin-5-amine (0.4 g, 1.31 mmol) and 2N NaOH (0.65 ml, 1.31 mmol) in DMSO (7 ml) was added iodomethane (81 μl, 1.31 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was poured into water and extracted with ethyl acetate, brine and dried over Na2SO4. After removing the solvents under reduced pressure, the residue was purified by chromatography on silica gel (hexane/EtOAc 5:1) yielding the title compound as a white solid (0.29 g, 69%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]1[O:10][C@@H:9]1[CH2:11]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:7]([CH2:11][C@@H:9]1[CH2:8][O:10]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc(OC[C@@H]2CO2)cc1
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A solution of phenol (9.4 g, 100 mmol) and (2S)-(+)glycidyl 3-nitrobenzenesulfonate (25.9 g, 100 mmol) in 500 mL of acetone was treated with 3 equivalents of potassium carbonate (41.5 g, 300 mmol) and stirred at reflux for 1 day. The suspension was cooled to ambient temperature; the solid was filtered; and the filtrate was concentrated to dryness. The residue was partitioned between methylene chloride and water. The aqueous layer was extracted with CH2Cl2. The organic layers were combined and dried over MgSO4 and concentrated to give the title compound (15.0 g, 99%) as an orange oil; 1H NMR (300 MHz, CDCl3) δ 2.76 (dd, J=4.9, 2.6 Hz, 1 H), 2.90 (dd, J=4.9, 4.9 Hz, 1 H), 3.30–3.40 (m, 1 H), 3.95 (dd, J=11.0, 5.4 Hz, 1 H), 4.18 (dd, J=11.0, 3.0 Hz, 1 H), 6.85–7.00 (m, 3 H), 7.25–7.35 (m, 2 H); MS (ES) m/z: 151.0 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:7]=[C:8]([NH:13][C:14]2[C:15]3[N:24]=[C:23]([Cl:25])[NH:22][CH2:21][C:16]=3[N:17]=[C:18]([Cl:20])[N:19]=2)[CH:9]=[CH:10][C:11]=1[F:12].C(N(C(C)C)C(C)C)C>C(OCC)(=O)C>[Cl:25][C:23]1[N:22]([C:1](=[O:3])[CH3:2])[CH2:21][C:16]2[N:17]=[C:18]([Cl:20])[N:19]=[C:14]([NH:13][C:8]3[CH:9]=[CH:10][C:11]([F:12])=[C:6]([Cl:5])[CH:7]=3)[C:15]=2[N:24]=1
Reactant: Fc1ccc(Nc2nc(Cl)nc3c2N=C(Cl)NC3)cc1Cl
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1Cc2nc(Cl)nc(Nc3ccc(F)c(Cl)c3)c2N=C1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
At 10° C., 56.4 ml (0.789 mol) of acetylchloride are added dropwise to a suspension of 210.6 g (0.608 mol) of (2) and 176 ml of N-ethyldiisopropylamine (0.95 mol) in 2.1 l of ethyl acetate. The mixture is stirred for 90 minutes at ambient temperature and then washed 3 times with 700 ml of water at 60° C. The organic phase is evaporated down and combined with 590 ml of ethanol. The mixture is briefly brought to boiling point, cooled to 0-5° C. and stirred at this temperature for 30 minutes. The product that crystallises out is filtered off and dried at 60° C. in vacuo. Yield: 180.3 g (76.3%), melting point: 177.6° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O>[N:25]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:3]=1)=[N+:26]=[N-:27]
Reactant: CS(=O)(=O)c1ccc(-c2ccc(Cl)nc2-c2ccc(F)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2ccc(N=[N+]=[N-])nc2-c2ccc(F)cc2)cc1
Yield: 37 %

Procedure:
A solution of 1.00 g (2.76 mMol) of 2-chloro-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyridine (Example 1) and 539 mg (8.29 mMol) of sodium azide in 15 ml of dimethylformamide was stirred in an oil bath at 100° C. for two days. After cooling, the mixture was partitioned between dichloromethane and water. The aqueous layer was further extracted with dichloromethane, the combined organic extracts were dried over sodium sulfate, filtered, and evaporated. Chromatography of the residue over silica gel using ethyl acetate as eluent gave the title compound (376 mg) as a pale yellow crystalline solid: m.p. 229° C. (DSC). Anal. Calc'd for C18H13 N4O2S·1/4 H2O (MW 372.89): C, 57.98; H, 3.51; N, 15.03. Found: C, 58.35; H, 3.82; N, 14.70.
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([C:34](=[O:41])[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:20][CH2:21]3)[CH2:11][CH2:10]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCNCC2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(CC2CCN(C(=O)c3ccccc3)CC2)CC1
Reaction time: 5 h

Procedure:
To a solution of 4-amino-5-chloro-2-methoxy-N-[1-(4-piperidinylmethyl)-4-piperidinyl]benzamide (610 mg) and triethylamine (0.22 ml) in methylene chloride (30 ml) is added benzoyl chloride (0.19 ml) at room temperature, and the mixture is stirred for 5 hours. The reaction mixture is washed with water, and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform: methanol=20:1) to give the desired compound (610 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Cl.Cl[CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[CH2:12][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCc2ccc3ccccc3n2)c1
Yield: 87.3 %

Procedure:
With stirring, a mixture of 3-hydroxybenzaldehyde (8.5 g), 2-chloromethylquinoline hydrochloride (17 g), and anhydrous potassium carbonate (100 g) in dimethylformamide (200 ml) was heated for 6 hours. After filtration, the solvent was removed with reduced pressure and the residue was partitioned between chloroform and water. The organic layer was dried and concentrated to an oil which upon cooling and treatment withhexane, gave the product as an off-white colored solid (16 g), m.p. 48°-53° C.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][N:7]1[C:11]([OH:12])=[CH:10][C:9]([C:13]2[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:15][N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=23)=[N:8]1)=[O:4].[OH-].[Na+]>C(O)C>[C:3]([CH2:5][CH2:6][N:7]1[C:11]([OH:12])=[CH:10][C:9]([C:13]2[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:15][N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=23)=[N:8]1)([OH:4])=[O:2]
Reactant: COC(=O)CCn1nc(-c2c(-c3ccccc3)nn3ccccc23)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCn1nc(-c2c(-c3ccccc3)nn3ccccc23)cc1O
Yield: 29.3 %

Procedure:
A mixture of 3-[1-(2-methoxycarbonylethyl)-5-hydroxypyrazol-3-yl]-2-phenylpyrazolo[1,5-a]pyridine (0.50 g), 1N sodium hydroxide aqueous solution (3 ml) and ethanol (5 ml) was heated under reflux for 2.5 hours. Ethanol was evaporated in vacuo. The residue was acidified with 5% hydrochloric acid and extracted with chloroform (25 ml×2). Combined extract was washed with a saturated aqueous solution of sodium chloride (25 ml), dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of chloroform and methanol (30:1) as an eluent and recrystallized from ethanol to give crystal of 3-[1-(2-carboxyethyl)-5-hydroxypyrazol-3-yl]-2-phenylpyrazolo[1,5-a]pyridine (141 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:40][C:41]([NH:43][CH:44]1[CH2:46][CH2:45]1)=[O:42].O>CN(C)C=O>[CH:44]1([NH:43][C:41](=[O:42])[CH2:40][O:22][C:18]2[CH:17]=[C:16]([S:13]([N:12]3[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[CH:9][C:10]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[CH:11]3)(=[O:14])=[O:15])[CH:21]=[CH:20][CH:19]=2)[CH2:46][CH2:45]1
Reactant: O=C(CBr)NC1CC1
Reactant: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(O)c2)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(OCC(=O)NC3CC3)c2)c1)C(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
tert-Butyl ((5-(2-fluorophenyl)-1-((3-hydroxyphenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 1h (100 mg, 0.22 mmol) was dissolved in 20 mL of N,N-dimethylformamide, followed by addition of cesium carbonate (215 mg, 0.66 mmol) and 2-bromo-N-cyclopropyl-acetamide (61 mg, 0.34 mmol, prepared by a known method disclosed in “Journal of Medicinal Chemistry, 1987, 30(1), 20-24”) and then the reaction solution was stirred for 16 h. 50 mL of water were added, and the reaction solution was extracted with dichloromethane (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product tert-butyl ((1-((3-(2-(cyclopropylamino)-2-oxoethoxy)phenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 3a (100 mg, a yellow oil), which was used directly in the next step.