Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2([C:20]([OH:22])=O)[CH2:13][CH:12]3[N:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[C:29]([NH2:33])([CH3:32])([CH3:31])[CH3:30]>C(Cl)(Cl)Cl.CN(C=O)C>[C:29]([NH:33][C:20]([C:7]1([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:13][CH:12]2[N:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]([CH2:10][CH2:11]2)[CH2:8]1)=[O:22])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)N
Reactant: CCOC(=O)N1C2CCC1CC(C(=O)O)(C1CCCCC1)C2
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1C2CCC1CC(C(=O)NC(C)(C)C)(C1CCCCC1)C2
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-cyclohexyl-8-(ethoxycarbonyl)-8-azabicyclo[3.2.1]octane-3-carboxylic acid (1-7) (1.50 g, 4.85 mmol) in CHCl3 (60.0 mL) was slowly added oxalyl chloride (2.67 mL, 5.33 mmol, 2.0 N), followed by addition of DMF (3 drops) as a catalyst. After the bubbling ceased, the mixture was stirred for 30 min and the solvents were removed under vacuum. To the mixture was added t-BuNH2 (5.32 g, 72.7 mmol) and the resulting suspension was warmed up to 80° C. overnight. The solvents were removed under vacuum; the reaction was quenched with 1 N HCl, and then extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated to give a crude residue. Purification of the crude residue by flash chromatography over silica gel (10% ethyl acetate/hexanes as eluent) afforded (1-8) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[O:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C@@H:13]([CH3:49])[CH2:14][O:15][C:16]2[CH:48]=[CH:47][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[N:23](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:22]3=[O:46])=[CH:18][CH:17]=2)[CH2:8]1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:50]=[CH:51][CH:52]=1)[O:5][CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C@@H:13]([CH3:49])[CH2:14][O:15][C:16]2[CH:48]=[CH:47][C:19]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:46])=[CH:18][CH:17]=2)[CH2:8]1
Reactant: C[C@@H](COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)N1C[C@H](COc2cccc(Cl)c2)OC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](COc1ccc(CC2SC(=O)NC2=O)cc1)N1C[C@H](COc2cccc(Cl)c2)OC1=O
Yield: 79.8 %

Procedure:
A procedure similar to that described in Example 1 was repeated, except that 0.73 g of 5-[4-{2(S)-[5(R)-(3-chlorophenoxymethyl)-2-oxooxazolidin-3-yl]-propoxy}benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 37), 4 ml of methylene chloride and 4 ml of trifluoroacetic acid were used, to give 0.39 g of the title compound having a melting point of 55° C. to 60° C. (softening) and having [α]D =-52.4° (methanol, c=0.990).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:18])[C:4](=[O:17])[C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:6][CH2:7]C.C(OC(N[C@@H](CC)C(O)=O)=O)(C)(C)C>>[CH3:1][O:2][N:3]([CH3:18])[C:4](=[O:17])[C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:6][CH3:7]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)OC
Agent: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)OC

Procedure:
was synthesised in the same way as (91d) from commercially available (2S)-2-[(tert-butoxycarbonyl)amino]butanoic acid (0.935 g, 4.60 mmol).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:13])=[C:6]([C:10]([OH:12])=O)[NH:7][C:8]=1[CH3:9])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[Cl:27][CH2:28][CH2:29][NH2:30]>CN(C=O)C>[Cl:27][CH2:28][CH2:29][NH:30][C:10]([C:6]1[NH:7][C:8]([CH3:9])=[C:4]([C:1](=[O:3])[CH3:2])[C:5]=1[CH3:13])=[O:12]
Reactant: CC(=O)c1c(C)[nH]c(C(=O)O)c1C
Reactant: NCCCl
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(=O)c1c(C)[nH]c(C(=O)NCCCl)c1C
Temperature: 0 °C
Yield: 49 %

Procedure:
4-Acetyl-3,5-dimethylpyrrole carboxylic acid (15.731 g, 86.82 mmol), was taken up in anhydrous DMF (40 mL) and cooled to 0° C. Carbonyldiimidazole (14.512 g, 86.82 mmol) was added to this slurry and stirred until the evolution of gas ceased and a clear solution formed. 2-Chloroethyl amine hydrochloride (10.574 g, 91.16 mmol) was added in one portion. The reaction mixture was left to stir overnight at room temperature. The reaction mixture was extracted in water (50 mL) from DCM (4×20 mL). The aqueous layer (containing precipitate) was filtered off and washed with cold water. The white solid was found to be the target compound. (10.316 g, 42.51 mmol, 49% yield).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C1([O:18][C:19](=O)[NH:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([OH:31])[CH:29]=3)[CH:24]=[CH:23][CH:22]=2)C=CC=CC=1>CS(C)=O>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([NH:11][C:19]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([OH:31])[CH:29]=3)[CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1CCC(N)CC1
Reactant: O=C(Nc1cccc2ccc(O)cc12)Oc1ccccc1
Solvent: CS(C)=O
Product: CC(C)(C)C1CCC(NC(=O)Nc2cccc3ccc(O)cc23)CC1

Procedure:
4-tert-Butyl-cyclohexylamine (69 mg, 0.44 mmol) and (7-hydroxy-naphthalen-1-yl)-carbamic acid phenyl ester (125 mg, 0.44 mmol) were combined and stirred at ambient temperature in DMSO (3 mL) overnight. The product was purified by directly injecting the crude reaction onto a reverse phase prep-HPLC (90–10% water:acetonitrile gradient). The appropriate fractions were lyophilized to yield 1-(4-tert-Butyl-cyclohexyl)-3-(7-hydroxy-naphthalen-1-yl)-urea
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:22])=[O:21]
Reactant: CCOC(=O)CCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCCS(C)(=O)=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of ethyl 6-hydroxyhexanoate (5 g, 31.2 mmol) in anhydrous dichloromethane (115 mL) under nitrogen at −10° C. was added triethylamine (8.7 mL, 62.5 mmol) followed by methanesulfonyl chloride (4.8 mL, 62.5 mmol) dropwise over 1 hour. The resulting solution was stirred at room temperature for 6 hours and then diluted to 300 mL using dichloromethane. The solution was washed with twice saturated NaHCO3, and the aqueous layers backextracted with dichloromethane. The combined organics were dried over MgSO4, filtered, and concentrated. The resulting dark orange oil was purified by column chromatography (column 5″L×2″W; eluted with a gradient of 100% hexanes→10%→20% ethyl acetate in hexanes) to afford the product as a pale yellow oil.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:36])/[CH:23]=[C:24](\[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=2)/[CH:25]([CH3:27])[CH3:26])=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C.C(OCC)(=O)C.C([O-])(=O)C.[NH4+:47]>CO>[CH3:27][CH:25](/[C:24](/[C:28]1[CH:29]=[C:30]([C:34]([NH2:35])=[NH:47])[CH:31]=[CH:32][CH:33]=1)=[CH:23]/[C:22](=[O:36])[NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6](=[O:8])(=[O:7])[NH2:5])=[CH:20][CH:19]=1)[CH3:26]
Reactant: [NH4+]
Reactant: CC(C)/C(=C/C(=O)Nc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1)c1cccc(C#N)c1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)/C(=C/C(=O)Nc1ccc(-c2ccccc2S(N)(=O)=O)cc1)c1cccc(C(=N)N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.8 %

Procedure:
To a solution of crude (2Z)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3-cyanophenyl)-4-methylpent-2-enamide (190 mg, 0.379 mmol) in 10 ml 1:1 ethyl acetate:anhydrous methanol cooled to −78° C. was bubbled HCl gas until saturation was achieved. Reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated in vacuo and dried under hi vacuum. The dried methyl imidate residue was dissolved in 5 ml anhydrous methanol to which ammonium acetate (115 mg, 1.5 mmol) was added and the reaction heated to reflux for 2 hours. The reaction was concentrated and purified on a 2×25 cm Vydac C18 HPLC column to give 3-((1Z)-1-(methylethyl)-2-{N-[4-(2-sulfamoylphenyl)phenyl]carbamoyl}vinyl)benzene carboxamidine (75 mg, 43%) as a fluffy white powder after lyophilization. ES-MS (M+H+): 463.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=2[C:24](=[O:27])[NH:25][CH3:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[C:24](=[O:27])[NH:25][CH3:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC(=O)c1cc([N+](=O)[O-])ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1cc(N)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-3-(N-methylcarbamoyl)nitrobenzene (3.5 g) in methanol (50 ml) was added palladium on carbon (0.4 g) and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. The reaction mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane/methanol=19/1 as an eluant to give the desired compound (2.9 g, yield 92%) as a yellow amorphous solid.
Reaction SMILES: C([Mg]Br)C.[CH2:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]#[CH:15])=[CH:10][CH:9]=1)[CH2:6][CH3:7].[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][N:20]=1)[CH3:17]>CCOCC>[CH2:5]([C:8]1[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:16][CH3:17])=[N:20][CH:21]=2)=[CH:12][CH:13]=1)[CH2:6][CH3:7]
Reactant: CCOc1ccc(Br)cn1
Reactant: C#Cc1ccc(CCC)cc1
Agent: CC[Mg]Br
Solvent: CCOCC
Product: CCCc1ccc(C#Cc2ccc(OCC)nc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.05 m of ethylmagnesium bromide in ether are added to a mixture of 0.05 m of 4-propylphenylacetylene at 0°-10°. The mixture is stirred for 4 hours at room temperature and then a solution of 0.05 m of 2-ethoxy-5-bromopyridine and 0.5 g of NiCl2 (Ph3P)2 in ether is added. After stirring for 6 hours at room temperature and customary work-up 1-(4-propylphenyl)-2-(2-ethoxy-pyridine-5-yl)-acetylene is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[OH:27])([CH3:20])[CH3:19])[C:12]2=[O:28])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:37][CH2:38][N:39]([CH3:50])[C:40](=[O:49])[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]([CH3:20])([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH2:37][CH2:38][N:39]([CH3:50])[C:40]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:49])[CH3:19])[C:12]2=[O:28])[CH:5]=1
Reactant: COC(=O)c1ccc(C)c(-n2ccnc(NC(C)(C)c3ccccc3O)c2=O)c1
Reactant: CN(CCCl)C(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(C)c(-n2ccnc(NC(C)(C)c3ccccc3OCCN(C)C(=O)OCc3ccccc3)c2=O)c1
Temperature: 85 °C
Reaction time: 48 h
Yield: 53.1 %

Procedure:
To 3-[3-[[1-(2-Hydroxyphenyl)-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-4-methyl-benzoic acid methyl ester (Example 220b, 2.495 g) in acetonitrile (150 mL) was added potassium carbonate (1.753 g) followed by benzyl 2-chloroethyl(methyl)carbamate (J. Med. Chem., 1992, 35 (17), 3246, 1.660 g) and the reaction heated at 85° C. for 72 h under nitrogen. Further benzyl 2-chloroethyl(methyl)carbamate (0.58 g) and potassium carbonate (0.35 g) were added and the reaction stirred for 2 days. The reaction mixture was cooled, evaporated to dryness and the residue partitioned between water and dichloromethane and the organic layer separated. The aqueous was further extracted with dichloromethane (2×) and the combined organics dried (Na2SO4) and evaporated. Purification (SiO2 chromatography eluting with 40-100% ethyl acetate) gave the subtitle product (1.97 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][CH2:13][OH:14])[CH:4]=[CH:3]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:12][CH2:13][O:14][C:15](=[O:17])[CH3:16])[CH:4]=[CH:3]1
Reactant: Cn1ccc2cccc(OCCO)c21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCOc1cccc2ccn(C)c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2-(1-methyl-1H-indol-7-yloxy)-ethanol (0.78 g, 4 mmol) in pyridine (10 mL) was treated with acetic anhydride (5 mL). The reaction mixture was stirred at rt for 4 h and concentrated. The residue was quenched with ice/water and extracted with ethyl acetate. The organics were washed with 2N sulfuric acid, sat. sodium bicarbonate and brine, dried and concentrated. The residue was chromatographed on silica gel using heptanelethyl acetate as eluent to produce the desired compound (0.90 g) as an off-white solid. MS (ISP): m/e 234.1 (M+H)+
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[C:10]([OH:19])([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[CH2:9][CH2:8][C:7](=[O:20])[CH2:6]1)[CH3:3].[BH4-].[Na+].[ClH:23].[OH-].[Na+]>C(O)(C)C.O>[ClH:23].[CH3:3][N:2]([CH2:4][CH:5]1[CH2:6][CH:7]([OH:20])[CH2:8][CH2:9][C:10]1([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)[OH:19])[CH3:1]
Reactant: COc1cccc(C2(O)CCC(=O)CC2CN(C)C)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COc1cccc(C2(O)CCC(O)CC2CN(C)C)c1
Temperature: 10 °C

Procedure:
10 g (36 mmole) of compound (66) were dissolved in 80 ml isopropanol and cooled to 10° C. 0.56 g (15 mmole) sodium borohydride were added with stirring. The mixture was then stirred for two hours at room temperature. Whilst cooling the mixture in an ice bath, 20 ml dilute hydrochloric acid were added (1:4 conc. HCl:H2O) followed by 10 ml of 20% aqueous sodium hydroxide solution. The product was extracted twice with dichloromethane. After drying and removal of the solvent by distillation, the crude product obtained (10.3 g) was dissolved in 2-butanone and was converted with trimethylchlorosilane/water into the hydrochloride for the separation of the diastereoisomers. 10.2 g (90% theoretical) of compound (68) crystallised out.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH2:36][O:37][CH2:38][CH2:39]O)[CH:33]=[CH:34][CH:35]=1>C(Cl)Cl.[Al]>[Br:1][CH2:39][CH2:38][O:37][CH2:36][C:32]1[CH:33]=[CH:34][CH:35]=[C:30]([O:29][CH3:28])[CH:31]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(COCCO)c1
Agent: [Al]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cccc(COCCBr)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 104.3 %

Procedure:
A solution of N-bromosuccinimide (272 mg, 1.53 mmol) in DCM (2.5 mL) was added resin-bound triphenylphosphine (510 mg, 1.53 mEquiv, Fluka) in DCM (2.5 mL). The reaction was stirred at room temperature for 10 min. A solution of 2-({[3-(methyloxy)phenyl]methyl}oxy)ethanol (114 mg, 0.626 mmol) in DCM (1.5 mL) was added to the reaction, and the residual alcohol was transferred with additional DCM (1.5 mL). The reaction vessel was wrapped in aluminum foil and stirred at rt for 20 h. The reaction was filtered through a SPE cartridge (5 g silica) eluting with the following 10 mL fractions: DCM (fraction 1), 30% EtOAc/hexanes (fraction 2), and 50% EtOAc/hexanes (fraction 3) to give the title compound (160 mg). The product was characterized by 1H NMR (400 MHz) in CDCl3.
Reaction SMILES: [S:1]([N:11]=[N+:12]=[N-:13])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]#[CH:22].N1C(C)=CC=CC=1C>C(Cl)(Cl)Cl.[Cu]I>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[N:13]=[N:12][N:11]([S:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=2)(=[O:2])=[O:3])[CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: C#Cc1ccccc1Cl
Agent: [Cu]I
Solvent: ClC(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ccccc3Cl)nn2)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A solution of tosyl azide (16) (1.0 equiv) in CHCl3 (0.5M) cooled to 0° C. was treated with 2-chlorophenyl acetylene (15) (1.2 equiv), 2,6-lutidine (1.2 equiv) and CuI (0.1 equiv). The resulting mixture was stirred at 0° C. for 24 h, quenched with 10% HCl, the layers separated and the aqueous one washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (Hexane/AcOEt 5:1, 3:1 and 1:1) to provide 4-(2-chlorophenyl)-1-tosyl-1H-1,2,3-triazole (17) as a pale yellow crystalline solid.
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].[C:28]([O:32][C:33](=[O:62])[C:34]([S:37][C:38]1[S:39][CH:40]=[C:41]([CH2:43][CH2:44][N:45]([CH2:54][C:55]2[CH:60]=[CH:59][C:58](Br)=[CH:57][CH:56]=2)[C:46]2[N:51]=[CH:50][C:49]([CH2:52][CH3:53])=[CH:48][N:47]=2)[N:42]=1)([CH3:36])[CH3:35])([CH3:31])([CH3:30])[CH3:29].[NH:63]1[CH2:68][CH2:67][O:66][CH2:65][CH2:64]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:28]([O:32][C:33](=[O:62])[C:34]([S:37][C:38]1[S:39][CH:40]=[C:41]([CH2:43][CH2:44][N:45]([C:46]2[N:51]=[CH:50][C:49]([CH2:52][CH3:53])=[CH:48][N:47]=2)[CH2:54][C:55]2[CH:60]=[CH:59][C:58]([N:63]3[CH2:68][CH2:67][O:66][CH2:65][CH2:64]3)=[CH:57][CH:56]=2)[N:42]=1)([CH3:36])[CH3:35])([CH3:31])([CH3:30])[CH3:29]
Reactant: C1COCCN1
Reactant: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(Br)cc2)nc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(N3CCOCC3)cc2)nc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
tris(Dibenzylideneacetone)dipalladium (32 mg), 2-(di-tert-butylphosphino)biphenyl (21 mg) and sodium tert-butoxide (73 mg) were added to a 20 mL screw cap test tube substituted with nitrogen, and a solution of 2-[(4-{2-[(4-bromobenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (400 mg) synthesized in Example 402-1 and morpholine (91 mg) in toluene (1.4 mL) was added thereto. The test tube was capped, and stirred at 110° C. for 8 hr. After cooling to room temperature, the solution was directly purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=3:1 to 2:1) to give the title compound (200 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][C:44]=1[F:45])[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[N:32]=1>CN(C)C=O.CN1CCCC1=O>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:42]=[CH:43][C:44]([F:45])=[C:23]([NH:22][C:8]([C:7]5[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][CH:6]=5)=[O:10])[CH:24]=4)=[N:32][N:31]3[CH:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: CCn1nccc1C(=O)O
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: CCn1nccc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 53 %

Procedure:
Using 1-ethyl-1H-pyrazole-5-carboxylic acid (140 mg, 1.0 mmol), N,N-dimethylformamide (2 drops), tetrahydrofuran (10 mL), oxalyl chloride (0.172 mL, 2.0 mmol), N-methylpyrrolidone (5 mL) and N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (164 mg, 0.50 mmol), and in the same manner as in Example 173, the title compound (119 mg, yield 53%) was obtained. melting point 209° C.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[CH:30][C:31]([C:33]3[N:34]=[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]4[CH:41]=3)=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[CH:30][C:31]([C:33]3[N:34]=[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]4[CH:41]=3)=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2cc(-c3cn4ccccc4n3)ccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(-c3cn4ccccc4n3)ccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.butyl 4'-[[2-n-propyl-5-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:34]4[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: CN1CCNCC1
Reactant: ClCCOc1n[nH]c2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CN1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(OCc5ccccn5)c(Cl)c4)c23)CC1
Yield: 30 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine and N-methylpiperazine to give the title compound in 30% yield; NMR Spectrum: 2.10 (s, 3H), 2.27 (br s, 4H), 2.50 (hidden under DMSO, 4H), 2.78 (t, 2H), 4.41 (t, 2H), 5.28 (s, 2H), 7.24 (d, 1H), 7.36 (t, 1H), 7.56 (s, 1H), 7.58 (s, 1H), 7.86-7.91 (m, 2H), 8.29 (s, 1H), 8.42 (s, 1H), 8.59 (d, 1H); Mass Spectrum: 495 (MH+).
Reaction SMILES: [CH:1]([C:3]1[CH:21]=[C:6]2[C:7]([C:13]3[CH:14]([CH3:20])[CH2:15][C:16](=[O:19])[NH:17][N:18]=3)=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[N:5]2[N:4]=1)=O.[CH2:22]1COCC1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][O:11][C:10]1[N:5]2[N:4]=[C:3]([CH:1]=[CH2:22])[CH:21]=[C:6]2[C:7]([C:13]2[CH:14]([CH3:20])[CH2:15][C:16](=[O:19])[NH:17][N:18]=2)=[CH:8][CH:9]=1
Reactant: C1CCOC1
Reactant: COc1ccc(C2=NNC(=O)CC2C)c2cc(C=O)nn12
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: C=Cc1cc2c(C3=NNC(=O)CC3C)ccc(OC)n2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 2.71 mol/L n-butyl lithium-hexane solution (0.52 mL) was added dropwise to a solution of methyltriphenylphosphonium bromide (499 mg) in THE (5 mL) at 0° C. The mixture was stirred at room temperature for 30 min. The compound of Example 237 (80.0 mg) in THF (5 mL) was then added dropwise at 0° C. and the mixture was further stirred at room temperature for 2 hours. Subsequently, the reaction was quenched by adding a saturated aqueous solution of ammonium chloride and the reaction mixture was extracted with ethyl acetate (50 mL). The extract was washed with water and saturated brine and dried over anhydrous sodium sulfate. The dried extract was concentrated and purification by silica gel column chromatography (hexane:ethyl acetate=1:2) and recrystallization (ethyl acetate-hexane) afforded the title compound as a pale yellow powder (7.1 mg).