Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([CH2:9]Cl)[C:6]([CH:11]([CH3:13])[CH3:12])=[CH:5][C:4]=1[CH:14]([CH3:16])[CH3:15].[C:17]([O-:20])(=[O:19])[CH3:18].[Na+]>CN(C)C=O>[C:17]([O:20][CH2:2][C:3]1[CH:8]=[C:7]([CH2:9][O:20][C:17](=[O:19])[CH3:18])[C:6]([CH:11]([CH3:13])[CH3:12])=[CH:5][C:4]=1[CH:14]([CH3:16])[CH3:15])(=[O:19])[CH3:18]
Reactant: CC(C)c1cc(C(C)C)c(CCl)cc1CCl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc(COC(C)=O)c(C(C)C)cc1C(C)C

Procedure:
40.0 g (154 mmol) of the compound from Example 1 and 22.7 g (277 mmol) of sodium acetate are heated overnight at 80° C. in 200 ml of dimethylformamide. After distilling off the solvent, the residue is taken up with petroleum ether, washed with water and dried using sodium sulphate.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].C([O-])([O-])=O.[Na+].[Na+].[O:21]=[C:22]1[N:30]([CH2:31][CH2:32][CH3:33])[C:29]2[N:28]=[C:27]([C:34]34[CH2:41][CH2:40][C:37]([CH2:42][CH2:43][C:44]([NH2:46])=O)([CH2:38][CH2:39]3)[CH2:36][CH2:35]4)[NH:26][C:25]=2[C:24](=[O:47])[N:23]1[CH2:48][CH2:49][CH3:50]>C1COCC1>[O:21]=[C:22]1[N:30]([CH2:31][CH2:32][CH3:33])[C:29]2[N:28]=[C:27]([C:34]34[CH2:41][CH2:40][C:37]([CH2:42][CH2:43][C:44]([NH2:46])=[S:2])([CH2:38][CH2:39]3)[CH2:36][CH2:35]4)[NH:26][C:25]=2[C:24](=[O:47])[N:23]1[CH2:48][CH2:49][CH3:50]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(CCC(N)=O)(CC3)CC4)nc2n(CCC)c1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCn1c(=O)c2[nH]c(C34CCC(CCC(N)=S)(CC3)CC4)nc2n(CCC)c1=O
Reaction time: 0.33 h
Yield: 56.6 %

Procedure:
A suspension of P4S10 (23 mg, 53 μmol) and Na2CO3 (4 mg, 53 μmol) in THF (4 ml) was stirred vigorously for 20 min and 3-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo-[2.2.2]oct-1-yl]-propionamide (20 mg, 45 μmol) was added. The resulting pale yellow solution was stirred at rt for 1 h, evaporated to dryness and dried in vacuo overnight. The crude material was purified by radial chromatography (1 mm plate) using 2-5% MeOH in CH2Cl2 as eluent to afford a white solid (11 mg, 55%). MS: 432 (MH+).
Reaction SMILES: C(C1C=CC(C(O)=O)=CC=1)(=S)N.[C:13]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:23][C:24]([C:28]([O:30]CC)=[O:29])=[C:25]([CH3:27])[N:26]=2)=[CH:18][CH:17]=1)([OH:15])=[O:14]>>[C:13]([C:16]1[CH:17]=[CH:18][C:19]([C:22]2[S:23][C:24]([C:28]([OH:30])=[O:29])=[C:25]([CH3:27])[N:26]=2)=[CH:20][CH:21]=1)([OH:15])=[O:14]
Reactant: CCOC(=O)c1sc(-c2ccc(C(=O)O)cc2)nc1C
Agent: NC(=S)c1ccc(C(=O)O)cc1
Product: Cc1nc(-c2ccc(C(=O)O)cc2)sc1C(=O)O

Procedure:
2-(4-Carboxyphenyl)-4-methyl-5-thiazolecarboxylic acid was prepared from 4-thiocarbamoylbenzoic acid through an ethyl 2-(4-carboxyphenyl)-4-methyl-5-thiazolecarboxylate in the same manner as that of Example 13 (yield: 49%).
Reaction SMILES: [N:1]1[CH:2]=[C:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16](S(C)=O)[S:17][C:13]=3[CH:12]=2)[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2.Cl.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[OH:31].CCN(C(C)C)C(C)C.CN1C(=O)CCC1>O>[N:1]1[CH:2]=[C:3]([CH2:10][C:11]2[CH:22]=[CH:21][C:14]3[N:15]=[C:16]([NH:24][C@@H:25]4[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]4[OH:31])[S:17][C:13]=3[CH:12]=2)[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cc3cnc4cccnn34)cc2s1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cc3cnc4cccnn34)cc2s1
Temperature: 140 °C
Yield: 26.7 %

Procedure:
A stirred mixture of 6-(imidazo[1,2-b]pyridazin-3-ylmethyl)-2-(methylsulfinyl)benzo[d]thiazole (260 mg, 0.79 mmol) from the previous step, (1R,2R)-2-aminocyclohexanol hydrochloride (360 mg, 2.38 mmol), DIEA (408 mg, 3.16 mmol) and NMP (10 mL), was heated at 140° C. for 48 h. The mixture was cooled to rt and water (50 mL) was added. The mixture was extracted with EtOAc (30 mL×3) and the combined organic layers were washed with brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 2 to 10% MeOH in DCM to afford a solid. The solid was further purified by recrystallization from a 10:1 mixture of DCM: MeOH to afford (1R,2R)-2-((6-(imidazo[1,2-b]pyridazin-3-ylmethyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (80 mg, 27%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.53 (dd, J=4.5, 1.5 Hz, 1H), 8.10 (dd, J=9.3, 1.5 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.60 (s, 1H), 7.53 (s, 1H), 7.25 (d, J=8.7 Hz, 1H), 7.19 (m, 1H), 7.12 (dd, J=8.4, 1.8 Hz, 1H), 4.71 (d, J=4.8 Hz, 1H), 4.32 (s, 2H), 3.51 (m, 1H), 3.38 (m, 1H), 2.04 (m, 1H), 1.88 (m, 1H), 1.59-1.65 (m, 2H), 1.16-1.30 (m, 4H); LCMS (ESI) m/z 380 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=3)[C:10]([C:18]([OH:20])=[O:19])=[N:9]2)[CH:5]=[C:4]([Cl:21])[N:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[N:24][C:23]=1[C:28]([OH:32])([C:30]#[CH:31])[CH3:29]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:31]#[C:30][C:28]([OH:32])([C:23]4[N:24]=[CH:25][CH:26]=[CH:27][N:22]=4)[CH3:29])[CH:15]=3)[C:10]([C:18]([OH:20])=[O:19])=[N:9]2)[CH:5]=[C:4]([Cl:21])[N:3]=1
Reactant: C#CC(C)(O)c1ncccn1
Reactant: Nc1nc(Cl)cc(-n2nc(C(=O)O)c3ccc(I)cc32)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(O)(C#Cc1ccc2c(C(=O)O)nn(-c3cc(Cl)nc(N)n3)c2c1)c1ncccn1
Temperature: 55 °C

Procedure:
To a solution of 1-(2-amino-6-chloropyrimidin-4-yl)-6-iodo-1H-indazole-3-carboxylic acid (750 mg, 1.81 mmol) in 1:1 triethylamine/dry THF (12 mL) was introduced bis(triphenylphosphine)palladium(II) chloride (127 mg, 0.18 mmol), copper(I) iodide (34 mg, 0.18 mmol) and 2-(pyrimidin-2-yl)but-3-yn-2-ol (535 mg, 3.61 mmol). The reaction mixture was warmed to 55° C. for 1 hr. After cooling to RT, the reaction mixture was concentrated in vacuo to furnish the crude title compound: 1H NMR (500 MHz, DMSO) delta 1.92 (3H, s), 6.26 (1H, s), 7.09 (1H, s), 7.39 (1H, d, J=8.2 Hz), 7.51 (1H, t, J=4.9 Hz), 8.23 (1H, d, J=8.6 Hz), 8.82 (1H, s), 8.90 (2H, d, J=4.9 Hz); LC-MS: m/z=+436.05/437.70 (M+H)+. This compound, with LC-MS purity=91% UV, was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]([C:9]1[CH:14]=[C:13]([C:15]([C:21]([F:24])([F:23])[F:22])([OH:20])[C:16]([F:19])([F:18])[F:17])[CH:12]=[CH:11][C:10]=1[CH3:25])([OH:8])[C:4]([F:7])([F:6])[F:5].C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[F:1][C:2]([F:26])([F:27])[C:3]([C:9]1[CH:14]=[C:13]([C:15]([C:16]([F:17])([F:18])[F:19])([O:20][S:36]([CH3:35])(=[O:38])=[O:37])[C:21]([F:23])([F:22])[F:24])[CH:12]=[CH:11][C:10]=1[CH3:25])([O:8][S:36]([CH3:35])(=[O:38])=[O:37])[C:4]([F:7])([F:6])[F:5]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1C(O)(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(OS(C)(=O)=O)(C(F)(F)F)C(F)(F)F)cc1C(OS(C)(=O)=O)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
4.25 g (10 mmol) of 2,4-bis-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethylethyl)-toluene were dissolved in 50 ml of methylene chloride, and 2.5 g (25 mmol) of triethylamine were added. 2.86 g (25 mmol) of methanesulfonyl chloride were added dropwise at 5° to 10° C. The mixture was stirred for 16 hours at room temperature, separated off from the precipitated salt, washed with water, dried and evaporated down. The residue was chromatographed over a silica gel column with methylene chloride/n-hexane (1:1). After the eluate had been evaporated down, 2.9 g of 2,4- bis-(2,2,2-trifluoro-1-methanesulfonyloxy-1-trifluoromethylethyl)-toluene were obtained (colorless crystals, m.p.: 107° C.).
Reaction SMILES: C([CH:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9])(=O)C.[OH-].[Na+].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH:12]2[C:8](=[CH2:4])[CH2:7][O:6][C:5]2=[O:9])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)C1CCOC1=O
Agent: [Na+]
Agent: [OH-]
Product: C=C1COC(=O)C1c1ccccc1

Procedure:
The reaction was repeated using 3-acetyl-dihydro-2(3H)-furanone, sodium hydroxide and benzaldehyde to produce 3-phenyl methylene-dihydro-2(3H)-furanone. The crude yellow solid obtained from the reaction was recrystallized from chloroform to recover 3-phenylmethylene-dihydro-2(3H)-furanone, a yellow crystalline solid melting at 116° C. Proton and carbon nuclear magnetic resonance spectra for the product were as follows:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[NH:6]1)[CH3:2].[CH2:12](I)[CH3:13].[H-].[Na+].[Cl-].[NH4+]>O1CCCC1>[CH2:12]([N:6]1[C:7](=[O:10])[CH2:8][CH2:9][C@H:5]1[C:4]([O:3][CH2:1][CH3:2])=[O:11])[CH3:13]
Reactant: CCI
Reactant: CCOC(=O)[C@H]1CCC(=O)N1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CCC(=O)N1CC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 27.1 %

Procedure:
D-pyroglutamic acid ethyl ester (4.17 g, 26.53 mmol) was dissolved in tetrahydrofuran (30 ml) and ethyl iodide (2.23 ml, 27.86 mmol) was added to give a pale yellow solution. This was cooled to 0° C. and sodium hydride (60% in oil, 1.11 g, 27.86 mmol) was added portionwise. After addition of all the sodium hydride the mixture was stirred at 0° C. for a further 20 minutes until most of the bubbling had stopped. The mixture was then warmed to room temperature and stirred overnight under argon. The mixture was then treated with saturated aqueous ammonium chloride solution (˜5 ml). The organic layer was separated and the aqueous layer was extracted with more dichloromethane (3×20 ml). The combined organic layers were dried by passing through a phase separator and then concentrated to a green/brown oil (3.2 g). This was purified by automated flash silica column chromatography (Biotage SP4), eluting with a 0-100% gradient of ethyl acetate in hexane, to give ethyl 1-ethyl-5-oxoprolinate as a yellow oil (1.33 g) which was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:10]=[C:11]([Cl:15])[CH:12]=[N:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.Cl[Sn]Cl>CCO>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:10]=[C:11]([Cl:15])[CH:12]=[N:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Oc2cncc(Cl)c2)cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccc(Oc2cncc(Cl)c2)cc1
Yield: 97.4 %

Procedure:
To a stirred solution of 5-(4-nitrophenoxy)-3-chloropyridine (219 mg, 0.873 mmol) in EtOH (4 mL) was added SnCl2 (730 mg, 3.24 mmol). The solution was refluxed for 1.25 hr and the solvent was removed by evaporation. The resulting crude solid was purified by chromatography (97.5:2.5 CH2Cl2:MeOH) to provide 187.7 mg (78% yield) of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1>>[OH:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[NH:16][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1cccc(O)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Product: COc1cc2ncnc(Nc3cccc(O)c3)c2cc1OC
Yield: 92 %

Procedure:
Using an analogous procedure to that described in Example 68, 4-chloro-6,7-dimethoxyquinazoline was reacted with 3-aminophenol to give 4-(3'-hydroxyanilino)-6,7-dimethoxyquinazoline in 92% yield, m.p. 256°-257° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:28])[N:15]([C:18]3[CH:27]=[N:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[C:16](=[O:17])[C:10]=2[CH2:9]1)=O)(C)(C)C.[ClH:29]>CO>[ClH:29].[CH3:28][N:14]1[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]=2[C:16](=[O:17])[N:15]1[C:18]1[CH:27]=[N:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1
Reactant: Cn1c2c(c(=O)n1-c1cnc3ccccc3n1)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Product: Cn1c2c(c(=O)n1-c1cnc3ccccc3n1)CNCC2
Temperature: 60 °C
Yield: 100 %

Procedure:
To a solution of 1-methyl-3-oxo-2-quinoxalin-2-yl-1,2,3,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (prepared according to the method of Example 75, Step B, 279 mg, 0.73 mmol) in methanol (6 mL) was added hydrogen chloride (5.85 M in methanol, 1.25 mL, 7.3 mmol). This mixture was heated at 60° C. for 30 min, cooled to room temperature, and concentrated to give 249 mg (>100%) of the title compound of Example 75, Step C as a dark red solid. 1H NMR (CD3OD, 250 MHz) δ 9.45 (s, 1H), 8.13 (dd, 1H), 8.05 (m, 1H), 7.91-7.83 (c, 2H), 4.05 (s, 2H), 3.64 (t, 2H), 3.56 (s, 3H), 3.12 (t, 2H); MS (APCI) 282 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][CH:10]=O)=[N:4][CH:5]=[CH:6][CH:7]=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]2[N:4]([CH:10]=[N:9][CH:8]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=CNCc1ncccc1Cl
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1cccn2cncc12
Temperature: 25 °C
Yield: 89 %

Procedure:
A mixture of Example 797A (0.09 g, 0.53 mmol) and POCl3 (0.244 g, 1.6 mmol) in toluene (5 mL) was heated under reflux for 3 hours. After reaction mixture cooled to room temperature, it was poured onto water and separated. The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography eluting with 100% EtOAc to give 0.072 g of the title compound (90%). MS (APCI) m/e 153 (M+H)+, 1H NMR (500 MHz, DMSO-d6): □ 8.51 (s, 1H), 8.36 (d, J=7.06 Hz, 1H), 7.45 (s, 1H), 6.97 (d, J=7.06 Hz, 1H), 6.67 (m, 1H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:21]=1[CH2:22][NH:23][C@H:24]1[CH2:28][CH2:27][N:26]([C:29]2[N:34]=[CH:33][C:32]([C:35]#[C:36][Si](C)(C)C)=[CH:31][N:30]=2)[CH2:25]1>O1CCCC1.O.ClCCl>[Cl:19][C:20]1[CH:44]=[C:43]([Cl:45])[CH:42]=[CH:41][C:21]=1[CH2:22][NH:23][C@H:24]1[CH2:28][CH2:27][N:26]([C:29]2[N:30]=[CH:31][C:32]([C:35]#[CH:36])=[CH:33][N:34]=2)[CH2:25]1
Reactant: C[Si](C)(C)C#Cc1cnc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cnc(N2CC[C@H](NCc3ccc(Cl)cc3Cl)C2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
Add tetrabutylammonium fluoride (1.0 mL, 1.0 mmol, 1.0 M solution in tetrahydrofuran) to a stirred solution of (S)-(2,4-dichlorobenzyl)-[1-(5-trimethylsilanylethynylpyrimidin-2-yl)-pyrrolidin-3-yl]-amine (327 mg, 0.78 mmol) in tetrahydrofuran (10 mL) at 0° C. Warm to room temperature and stir for 1 hour and concentrate to give a residue. Dilute the residue with water (10 mL), extract with ethyl acetate (3×25 mL). Extract the combined organic layers with saturated aqueous sodium chloride (10 mL), concentrate to give a residue. Dissolve the residue in dichloromethane, filter, concentrate to give a residue, and chromatograph the residue on silica gel followed by chromatography on SCX-2 to give the title compound as a yellow gum (194 mg, 72%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:26]([O:28][CH3:29])=[O:27])=[N:11][N:12]2[CH:17]([CH2:18]OS(C)(=O)=O)[CH2:16][N:15]([CH3:24])[C:14](=[O:25])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([C:26]([O:28][CH3:29])=[O:27])=[N:11][N:12]2[CH:17]([CH2:18][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:16][N:15]([CH3:24])[C:14](=[O:25])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2COS(C)(=O)=O
Solvent: CN(C)C=O
Product: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)CC2CN1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 3-benzyloxy-5-methyl-7-methylsulfonyloxymethyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (57 mg, 0.14 mmol) in anhydrous DMF under an atmosphere of nitrogen was added piperidine (133 μL, 1.35 mmol). The reaction was stirred at room temperature for 2 hours, heated to 50° C. for 2 hours, and stirred at room temperature overnight. Purification by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA) and collection and concentration of the appropriate fractions afforded the title product as a yellow residue. ES MS (M+H)=413.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=4)[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Reactant: Fc1cccc(CBr)c1
Product: Cc1nc(-c2ccn(Cc3cccc(F)c3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and 1-bromomethyl-3-fluoro-benzene as described in Example 49 and isolated as white solid (0.068 mg, 49% yield). 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 8.56 (d, J=4 Hz, 1H), 7.71 (d, J=8 Hz, 1H), 7.42 (d, J=2 Hz, 1H), 7.26-7.35 (m, 2H), 6.99-7.06 (m, 2H), 6.93 (d, J=8 Hz, 1H), 6.86 (d, J=2 Hz, 1H), 6.05-6.13 (m, 1H), 5.35 (s, 2H), 4.63 (d, J=8 Hz, 2H), 2.75 (s, 3H); MS (M+H)+=408.2; Rt=1.25 min; HRMS (M+H)+=408.13.
Reaction SMILES: [Br:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]([CH2:15][CH2:16][NH:17][C:18](=[O:21])[CH2:19][CH3:20])[CH2:13][CH2:14][C:4]=2[CH:3]=1>C(O)C.[Pd]>[Br:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2[CH:12]([CH2:15][CH2:16][NH:17][C:18](=[O:21])[CH2:19][CH3:20])[CH2:13][CH2:14][C:4]=2[CH:3]=1
Reactant: CCC(=O)NCCC1CCc2cc(Br)c3c(c21)C=CCO3
Agent: [Pd]
Solvent: CCO
Product: CCC(=O)NCCC1CCc2cc(Br)c3c(c21)CCCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
To a solution of N-[2-(5-bromo-3,7,8,9-tetrahydrocyclopenta[f][1]benzopyran-9-yl)ethyl]propionamide (1.2 g, 3.4 mmol.) in ethanol (10 mL) was added 5% Pd-C (120 mg, 50% hydrous). The mixture was stirred for one hour at room temperature under hydrogen atmosphere. The reaction mixture was subjected to filtration. The filtrate was concentrated under reduced pressure. The concentrate was purified by means of silica gel column chromatography (ethyl acetate) to afford the title compound (yield 327 mg, 27%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C([Li])CCC.[F:14][C:15]1[CH:29]=[CH:28][C:18]([CH:19]=[N:20][C@@H:21]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:22][OH:23])=[CH:17][CH:16]=1.O>CCOCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C@H:19]([NH:20][C@@H:21]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:22][OH:23])[C:18]2[CH:17]=[CH:16][C:15]([F:14])=[CH:29][CH:28]=2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CC(C)C[C@@H](CO)N=Cc1ccc(F)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC(C)C[C@@H](CO)N[C@H](c1ccc(F)cc1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1,4-dibromobenzene (11.4 g, 48.35 mmol) in ether (120 mL) at −30° C. was added n-butyllithium (24.2 mL, 2.0M cyclohexane solution) over 10 minutes. The reaction mixture was stirred for 45 minutes, whereupon a solution of (S)2-[(4-fluorobenzylidene)-amino]-4-methylpentan-1-ol (maximum 2.16 g, 9.67 mmol from the previous step) in ether (30 mL) was added dropwise. After 2 hours, during which the reaction mixture was allowed to warm to 0° C., water (200 mL) was added. The product was extracted with ethyl acetate (150 mL), washed with brine (100 mL), dried over MgSO4, filtered, concentrated in vacuo, and purified on a short plug of silica gel (20% ethyl acetate/hexane elution) to give (2S)-2-{(R)-[(4-bromophenyl)-(4-fluorophenyl)-methyl]-amino}-4-methylpentan-1-ol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:17][N:18]([C:20]3[N:21]=[N:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[CH:19]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O([CH2:42][C:43]([F:46])([F:45])[F:44])S(C(F)(F)F)(=O)=O>>[C:1]([O:5][C:6]([N:8]([CH2:42][C:43]([F:46])([F:45])[F:44])[C:9]1[CH:14]=[C:13]([C:15]2[C:16]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)=[N:17][N:18]([C:20]3[N:21]=[N:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[CH:19]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2cn(-c3ccc(Cl)nn3)nc2-c2ccc(F)cc2)ccn1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)N(CC(F)(F)F)c1cc(-c2cn(-c3ccc(Cl)nn3)nc2-c2ccc(F)cc2)ccn1
Yield: 52.4 %

Procedure:
The reaction was carried out in the same manner as in Example 3-1) except for using 5.60 g (12.0 mmol) of 4-(2-t-butoxycarbonylaminopyridin-4-yl)-1-(6-chloropyridazin-3-yl)-3-(4-fluorophenyl)-1H-pyrazole obtained by the same reaction as in Example 2-3), and using 4.18 g (18.0 mmol) of 2,2,2-trifluoroethyl triflate in place of methyl iodide to obtain 3.45 g of the title compound as a pale grayish white powder. (Yield: 52%)
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]2=[N:6][S:7][N:8]=[C:4]2[C:3]=1[N+:12]([O-])=O.C(O)C.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:12][C:3]1[C:4]2[C:5](=[N:6][S:7][N:8]=2)[C:9]([CH3:11])=[CH:10][C:2]=1[CH3:1]
Reactant: Cc1cc(C)c2nsnc2c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c2nsnc2c1N

Procedure:
5,7-Dimethyl-4-nitro-2,1,3-benzothiadiazole (20 g) is warmed to ebullition in water (2.2 l) and ethanol (2.2 l) and sodium dithionite is added portionwise (strongly exothermic reaction). The reaction mixture is immediately cooled in an ice bath and extracted with ethyl acetate. The organic phase is concentrated by evaporation and the residue recrystallised in water to give 4-amino-5,7-dimethyl-2,1,3-benzothiadiazole. Mp=113-114°.
Reaction SMILES: O=[C:2]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]2[C:15]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:14][CH:13]=[C:12]([O:22][CH3:23])[C:10]=2[N:11]=1)=O.FC(F)(F)C([O-])=O.[NH4+:36]>O>[CH3:23][O:22][C:12]1[C:10]2[N:11]=[C:7]([C:5]3[NH:4][CH:3]=[C:2]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)[N:36]=3)[S:8][C:9]=2[C:15]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:14][CH:13]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)NCC(=O)c3cccs3)nc12
Reactant: [NH4+]
Agent: O=C([O-])C(F)(F)F
Solvent: O
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc(-c4cccs4)c[nH]3)nc12
Temperature: 25 °C
Yield: 21 %

Procedure:
A mixture of 0.10 g 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid (2-oxo-2-thiophen-2-yl-ethyl)-amide and 0.32 g ammonium triflouroacetate was melted at 165° C. for 60 minutes and, after cooling to room temperature, suspended in water. Extraction with dichloromethane and chromatography on silicagel with ethylacetate/hexane 1:1 gave 0.02 g (25%) 4-methoxy-7-morpholin-4-yl-2-(4-thiophen-2-yl-1H-imidazol-2-yl)-benzothiazole as yellow solid; MS (ISP): m/e=399 (M+H+).