Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:22][C@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(OCC)(=O)C.O>[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:22][C@H:23]4[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]4)=[O:21])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a solution of 600 mg of 8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid in 10 ml of DMF were added 500 mg of tert-butyl (3S)-3-aminopiperidine-1-carboxylate, 518 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride, and 366 mg of 1-hydroxybenzotriazole, followed by stirring overnight. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 808 mg of tert-butyl (3S)-3-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)piperidine-1-carboxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1>>[N:6]1[CH:5]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:3]=[C:2]([C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)[CH:7]=1
Reactant: OB(O)c1cccnc1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: c1cncc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)c1

Procedure:
The title compound was prepared from the product of Example 65A and 3-pyridinylboronic acid according to General Method B: LC-MS Method B (ESI+) m/z 307.0 (M+H)+, retention time 1.54 minutes.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].[OH:19][C:20]1([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)(O)[O-].[Na+].CN(C)C=O>O1CCCC1>[CH3:32][C:29]1[CH:28]=[CH:27][C:26]([C:20]2([OH:19])[CH2:25][CH2:24][N:23]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:22][CH2:21]2)=[CH:31][CH:30]=1
Reactant: Cc1ccc(C2(O)CCNCC2)cc1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(C2(O)CCN(CCCN3c4cccc5cccc(c45)S3(=O)=O)CC2)cc1
Temperature: 100 °C
Yield: 23 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2,8 g), 4-hydroxy-4-(4-methylphenyl)piperidine (2.1 g) and sodium bicarbonate (0.94 g) i mixture of dimethylformamide (60 cc) and tetrahydrofuran (50 cc). The mixture is heated for 5 hours at a temperature of about 100° C. then cooled to a temperature of about 20° C. Stirring is maintained for 15 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with a mixture of dichloromethane and methanol (95-5 vol) as eluant, 2-{3-[4-(4-methylphenyl)-4-hydroxypiperidino ]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (1 g) is obtained, in the form of 1,1-dioxide (1 g) is obtained, in the form of the hydrochloride of m.p. 218° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[O:10][CH2:11][CH2:12][NH:13]CCC.C(Cl)Cl.C(N(CC)CC)C.BrCC(Br)=O>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[O:10][CH2:11][CH2:12][NH2:13]
Reactant: CCCNCCOc1c(Cl)cc(Cl)cc1Cl
Agent: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: NCCOc1c(Cl)cc(Cl)cc1Cl
Temperature: -70 °C
Reaction time: 0.08 h

Procedure:
N-(n-propyl) ethanolamine 2,4,6-trichlorophenylether, 11.3 gm, was added to 100 ml of methylene chloride. 5.6 ml of triethylamine was added to the system. The system was stirred at about -70° C for 5 minutes and then 3.5 ml of α-bromoacetyl bromide was added dropwise. The system was stirred at room temperature for an additional 18 hours. The reaction was stopped and the system poured into 100 ml of water. The product was extracted with methylene chloride. The organic solution was dried over magnesium sulfate and the methylene chloride was then removed by stripping to give the N-(α-bromoacetyl), N-(npropyl) ethanolamine 2,4,6-trichlorophenylether as a brown oil. Listed as Compound No. 3 in Table I.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH:19]3[CH2:24][C:23](=[O:25])[C:22]4[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=4[S:20]3(=[O:31])=[O:30])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.O>CO>[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH:19]3[CH2:24][CH:23]([OH:25])[C:22]4[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=4[S:20]3(=[O:30])=[O:31])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: O=C1CC(CCCN2CCN(c3ccc(F)cc3)CC2)S(=O)(=O)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=S1(=O)c2ccccc2C(O)CC1CCCN1CCN(c2ccc(F)cc2)CC1
Yield: 61.1 %

Procedure:
340 mg (9 mmol) of sodium borohydride was added to a suspension of 375 mg (0.9 mmol) of the Compound 19 in 15 ml of methanol while stirring under cooling with ice. After stirring for two hours at room temperature, 15 ml of water was added and the mixture was stirred for one hour at room temperature and concentrated under vacuum. Ethyl acetate was added to the residue and the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by recrystallizing from ethanol to obtain 230 mg (yield: 61%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[CH:12]([Mg]Br)=[CH2:13].[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]2[C:3]=1[NH:9][CH:13]=[CH:12]2
Reactant: C=C[Mg]Br
Reactant: O=[N+]([O-])c1ccc(F)cc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Fc1cc(Br)c2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-4-fluoro-1-nitrobenzene (24 g) in anhydrous THF (200 mL) was added 1 M vinylmagnesium bromide in THF (328 mL) dropwise at −78° C. slowly, then the mixture was allowed to warm to RT and stirred for 2 hours. TLC indicated the reaction was complete. The reaction mixture was poured into saturated aqueous NH4Cl solution. The organic phase was separated by extraction with EA (3×200 mL). The crude product was purified by column chromatography to afford 7-bromo-5-fluoro-1H-indole (D131) (15 g) as a brown oil.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([NH:7][C:8]1[C:9](=[O:15])[CH:10]=[C:11]=[CH:12][CH2:13][CH:14]=1)=[O:6])C.[NH2:17][NH2:18]>C(O)C>[O:15]=[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=[C:8]1[NH:7][C:5](=[O:6])[C:4]([NH:17][NH2:18])=[O:3]
Reactant: CCOC(=O)C(=O)NC1=CCC=C=CC1=O
Reactant: NN
Solvent: CCO
Product: NNC(=O)C(=O)Nc1cccccc1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of [(2-oxo-3,4,7-cycloheptatrien-1-yl)amino]oxo-acetic acid ethyl ester (1.2 g, described in Example 1) and anhydrous hydrazine in anhydrous ethanol (25 ml) is stirred at 25° C. for 5 hr. The precipitate is collected on a filter and crystallized from methanol to give crystals of the title compound, mp 193° C.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[N+:6]([C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[NH2:16])([O-:8])=[O:7].C(=O)(O)[O-].[Na+]>O>[CH3:5][O:4][C:2]([NH:15][C:13]1[CH:12]=[CH:11][C:10]([NH2:16])=[C:9]([N+:6]([O-:8])=[O:7])[CH:14]=1)=[O:3]
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)Nc1ccc(N)c([N+](=O)[O-])c1
Temperature: 5 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
Methyl chloroformate (34 g) was added dropwise with stirring to a mixture of 2-nitro-p-phenylenediamine (50 g), sodium bicarbonate (44.5 g) and water (700 ml). The temperature was maintained at 5° C. during the addition by means of external cooling. After the addition was complete the mixture was allowed to warm to room temperature and the stirring was continued for two hours. The solid was filtered off and recrystallised from isopropanol to give 4-methoxycarbonylamino-2-nitroaniline (50 g), m.p. 171°-172° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH:12][CH:13]1[CH2:22][CH2:21][CH2:20][CH2:19][C:14]21OCCO2)=[NH:11].Cl>>[ClH:1].[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[NH:11][C:14]2[CH2:19][CH2:20][CH2:21][CH2:22][C:13]=2[N:12]=1
Reactant: N=C(Nc1c(Cl)cccc1Cl)NC1CCCCC12OCCO2
Agent: Cl
Product: Clc1cccc(Cl)c1Nc1nc2c([nH]1)CCCC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 157.7 %

Procedure:
N-(2,6-Dichlorophenyl)-N′-(1,4-dioxaspiro[4.5]dec-6-yl)guanidine (426 mg) was mixed with concentrated HCl (5 ml) and stirred at room temperature for 5 minutes. The resulting precipitate was filtered off and washed with concentrated hydrochloric acid. On dilution of the filtrate with water, a further precipitate separated out and was likewise filtered off. The combined precipitates afforded 311 mg of the desired compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8](O)[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.C1(C2C(=O)OC3C(C=2O)=C(CC2C=CC=CC=2)C=C(OC)C=3)CC1.CS(Cl)(=O)=O.[Br-:41].[Li+]>C(Cl)Cl.O.CC(C)=O.C(N(CC)CC)C>[Br:41][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH2:9][CH3:10]
Reactant: CCC(O)c1cccc(Br)c1
Reactant: [Br-]
Agent: COc1cc(Cc2ccccc2)c2c(O)c(C3CC3)c(=O)oc2c1
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: CCC(Br)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a flame-dried flask containing a solution of 1-(3-bromophenyl)propanol of Preparation 38 (3.50 g) and triethylamine (4.54 mL) in dry methylene chloride (18 mL) at 0° C. under nitrogen is added methanesulfonyl chloride (1.39 mL) over 1 min. The resulting mixture is stirred at 0° C. for 2 hrs, diluted with water (8 mL), and the layers are separated. The aqueous phase is extracted with methylene chloride (25 mL) and the combined organic phase is washed with saline (5 mL), dried over sodium sulfate, and concentrated under reduced pressure to give an oily intermediate. A mixture containing the intermediate and lithium bromide (1.42g) in acetone (50 mL) under nitrogen is refluxed for 4 hrs, cooled to RT, concentrated to remove acetone, re-diluted with methylene chloride (40 mL) and water (20 mL), and the layers are separated. The aqueous phase is extracted with methylene chloride (40 mL) and the combined organic phase is washed with saline (15 mL), dried over sodium sulfate, and concentrated to give a crude oil which is then chromatographed on silica gel (70-230 mesh, 250 g), eluting with ethyl acetate/hexane (5/95). Pooling of fractions with an Rf =0.63 by TLC (ethyl acetate/hexane, 25/75) and removal of solvent under reduced pressure gives the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5](Br)=[CH:4][C:3]=1[O:11][CH3:12].[C:13]1([C:19]#[CH:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1CCCCC1.[Cu](I)I>[C:13]1([C:19]#[C:20][C:2]2[CH:7]=[C:6]([O:8][CH3:9])[C:5]([C:20]#[C:19][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:4][C:3]=2[O:11][CH3:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C#Cc1ccccc1
Reactant: COc1cc(Br)c(OC)cc1Br
Agent: I[Cu]I
Solvent: C1CCNCC1
Product: COc1cc(C#Cc2ccccc2)c(OC)cc1C#Cc1ccccc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 75.7 %

Procedure:
50 g (160 mmol) of 1,4-dibromo-2,5-dimethoxy benzene, 3.6 g (0.005 mol) of bistriphenylphosphine palladium dichloride and 0.97 g (0.005 mol) of copper iodide were put into a 1 litter 3-neck flask equipped with a stirrer, a thermometer and a reflux condenser under an argon atmosphere, and dissolved in 500 ml of piperidine. 43 g (0.422 mol) of phenylacetylene was then slowly added dropwise at room temperature. The reaction temperature was slowly raised to 80° C. and then the reaction mixture was stirred at the same temperature for 12 hours. When the reaction was completed, the reaction mixture was cooled down to room temperature, and then generated salt was filtered off. The solvent was removed under a reduced pressure, and then the residue was extracted with methylene chloride. Organic layer was washed with water several times and dried with anhydrous magnesium sulfate, and then the solvent was removed to obtain yellow solid. This solid was recrystallized from ethyl acetate to obtain yellow crystal, which was sufficiently dried in a vacuum oven at 40° C. to give 41 g (yield: 72%) of the desired product, and its melting point was 172° C.–174° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[S:16][C:15]([NH:18][C:19]([NH:21][CH2:22][CH3:23])=[O:20])=[N:14][C:13]=3[CH:12]=[C:11](OS(C(F)(F)F)(=O)=O)[CH:10]=2)=[N:7][CH:8]=1)#[N:2].[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[S:16][C:15]([NH:18][C:19]([NH:21][CH2:22][CH3:23])=[O:20])=[N:14][C:13]=3[CH:12]=[C:11]([C:34]3[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=3)[CH:10]=2)=[N:7][CH:8]=1)#[N:2]
Reactant: CCNC(=O)Nc1nc2cc(OS(=O)(=O)C(F)(F)F)cc(-c3ccc(C#N)cn3)c2s1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(-c3ccc(C#N)cn3)c2s1
Temperature: 80 °C

Procedure:
A stirred mixture of the crude trifluoro-methanesulfonic acid 7-(5-cyano-pyridin-2-yl)-2-(3-ethyl-ureido)-benzothiazol-5-yl ester (108 mg, 0.23 mmol), 3-pyridineboronic acid (56 mg, 0.46 mmol), aqueous caesium carbonate (0.155 ml, 0.57 mmol, 3.7M), dimethylformamide (2.4 ml) and water (0.4 ml) was purged with nitrogen for 15 min. treated with tetrakistriphenylphosphine palladium (0) (27 mg, 0.023 mmol), sealed and heated at 80° C. for 8 h. After cooling to ambient temperature, the mixture was filtered through celite and washed through with methanol. The filtrate was evaporated in vacuo to give the crude 1-[7-(5-Cyano-pyridin-2-yl)-5-pyridin-3-yl-benzothiazol-2-yl]-3-ethyl-urea as a brown solid.
Reaction SMILES: C(OC(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(N[C@H](C(NC[C:67]1[C:80](OC)=[CH:79][CH:78]=[C:77]2[C:68]=1[O:69][C:70]1[C:71]([CH2:87][C:88]([O:90]CC3C=CC=CC=3)=[O:89])=[C:72](OC)[CH:73]=[CH:74][C:75]=1[C:76]2(C)C)=O)C)=O)CC(C)C)=O)C)=O)CC(C)C)=O)CC1C=CC=CC=1)=O)C)=O)C)=O)C(C)C)=O)C1C=CC=CC=1.COC1C=CC2C(C)(C)C3C(OC=2C=1CC([O-])=O)=CC(OC)=CC=3>FC(F)(F)C(O)C(F)(F)F.[Pd]>[CH:74]1[C:75]2[CH2:76][C:77]3[C:68](=[CH:67][CH:80]=[CH:79][CH:78]=3)[O:69][C:70]=2[C:71]([CH2:87][C:88]([OH:90])=[O:89])=[CH:72][CH:73]=1
Reactant: COc1ccc2c(c1CNC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)Oc1c(ccc(OC)c1CC(=O)OCc1ccccc1)C2(C)C
Agent: [Pd]
Agent: COc1ccc2c(c1)Oc1c(ccc(OC)c1CC(=O)[O-])C2(C)C
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: O=C(O)Cc1cccc2c1Oc1ccccc1C2
Reaction time: 3 h

Procedure:
100 mg of benzyl 5-[(N-benzyloxycarbonyl-L-valyl-L-alanyl-L-alanyl-L-phenylalanyl-L-leucyl-L-alanyl-L-leucyl-L-alanyl)aminomethyl]-3,6-dimethoxy-9,9-dimethylxanthene-4-acetate (benzyl 5-[(N-benzyloxycarbonyl-SEQ ID NO:9)aminomethyl]-3,6-dimethoxy-9,9-dimethylxanthene-4-acetate) were dissolved in 200 ml of hexafluoroisopropanol, treated with 60 mg of palladium on calcium carbonate (10%) and stirred under hydrogen for 3 hours. After filtering the catalyst the filtrate was concentrated. The residue remaining was washed several times with methanol and thereafter chromatographed over silica gel in chloroform/methanol/hexafluoroisopropanol, whereby 65 mg of 3,6-dimethoxy-9,9-dimethyl-5-[(L-valyl-L-alanyl-L-alanyl-L-phenylalanyl-L-leucyl-L-alanyl-L-leucyl-L-alanyl)aminomethyl]xanthene-4-acetic acid (3,6-dimethoxy-9,9-dimethyl-5-[(SEQ ID NO:9)aminomethyl]xanthene-4-acetic acid) were obtained; IR 3393, 3288, 2963, 1685, 1636, 1531 cm-1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.Br[C:13]1[CH:26]=[CH:25][C:16]([O:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>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].O1CCOCC1>[N:20]1([CH2:19][CH2:18][O:17][C:16]2[CH:25]=[CH:26][C:13]([NH:1][C:2]3[N:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:7]=3)=[CH:14][CH:15]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1cnc(N)nc1
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cnc(Nc2ccc(OCCN3CCCC3)cc2)nc1
Temperature: 25 °C
Yield: 47 %

Procedure:
100 mL round-bottom flask was charged with methyl 2-aminopyrimidine-5-carboxylate (1.53 g, 10.0 mmol), 1-[2-(4-bromo-phenoxy)-ethyl]-pyrrolidine (4.05 g, 15.0 mmol), Pd2(dba)3 (366 mg, 0.4 mmol), XantPhos (694 mg, 1.2 mmol), Cs2CO3 (6.51 g, 20.0 mmol) and anhydrous dioxane (70 mL). The mixture was purged with argon gas for 15 min, and then refluxed under argon atmosphere for 2 days. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (3×100 mL). Combined EtOAc solutions were washed with H2O (2×100 mL), brine (2×100 mL) and dried over anhydrous Na2SO4. The resulting solution was concentrated in vacuo with ca. 15 g of silica gel. The loaded silica gel was taken to the ISCO system for further purification (80 g column, solid method, 0% to 20% MeOH gradient in DCM, 40 min method). Fractions, containing the product, were combined and concentrated in vacuo to give a yellow solid. The solid was re-crystallized from 20 mL of CH3CN to give the title compound as a beige powder (1.61 g, 47% yield).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[C:10](Cl)[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4].[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[CH2:25][SH:26]>>[CH2:1]([N:5]1[C:9]2=[C:10]([S:26][CH2:25][C:19]3[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:18]=3[F:17])[N:11]=[N:12][CH:13]=[C:8]2[C:7]([CH3:15])=[C:6]1[CH3:16])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CCn1c(C)c(C)c2cnnc(Cl)c21
Reactant: Fc1ccc(CS)c(F)c1
Product: CC=CCn1c(C)c(C)c2cnnc(SCc3ccc(F)cc3F)c21
Yield: 39 %

Procedure:
The title compound (cis/trans=16:84) was prepared as pale brown crystals in 39.0% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=22/78) and 2,4-difluorophenylmethanethiol.
Reaction SMILES: [F-].[K+].[CH3:3][O:4][C:5]([C:7]1[C:12]([N:13]2[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]2[CH3:19])=[CH:11][C:10]([C:20]([F:23])([F:22])[F:21])=[C:9](Br)[N:8]=1)=[O:6].[Si]([C:29]([F:32])([F:31])[F:30])(C)(C)C.N>[Cu]I.CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1[C:12]([N:13]2[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]2[CH3:19])=[CH:11][C:10]([C:20]([F:23])([F:22])[F:21])=[C:9]([C:29]([F:32])([F:31])[F:30])[N:8]=1)=[O:6]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COC(=O)c1nc(Br)c(C(F)(F)F)cc1-n1c(C)ccc1C
Agent: [Cu]I
Agent: N
Agent: [F-]
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C(F)(F)F)c(C(F)(F)F)cc1-n1c(C)ccc1C
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A stirred mixture of KF (2.12 g, 5.62 mmol) and CuI (0.490 g, 8.43 mmol) was heated in a sealed 10.0-20.0 ml microwave vial under vacuum until a slight greenish colour began to appear. The vial was then placed under nitrogen to cool. A solution 6-bromo-3-(2,5-dimethyl-pyrrol-1-yl)-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate D) (2.64 ml, 16.86 mmol) in 1:1 dry DMF/dry NMP (14 ml) was then added, followed by TMS-CF3 (2.64 ml, 16.86 mmol). A new septum was then used to seal the vial and the reaction mixture was heated using microwave radiation with stirring at 100° C. for 3 h and allowed to cool. The mixture was added to 5M NH3 solution (50 ml) and then extracted with diethyl ether (4×50 ml). The combined organic extracts were washed with 5M NH3 solution (3×20 ml), 1M HCl (50 ml), sat. sodium bicarbonate solution (2×50 ml), brine (50 ml), dried (MgSO4) and concentrated in vacuo to give a brown oil. The crude material was purified by chromatography on silica eluting with Iso-hexane/EtOAc, 0-10% to afford the title compound as an orange solid; LC-MS Rt 1.37 min; MS m/z 367.1 [M+H]+; Method 2 minLC_v003.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.Br[CH2:14]CC1C=CC(C(O)=O)=CC=1>>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1cccc(CBr)c1
Reactant: O=C(O)c1ccc(CCBr)cc1
Product: COC(=O)Cc1cccc(CBr)c1

Procedure:
According to the procedures described in the synthesis method of Intermediate ia-01, 2-[3-(bromomethyl)phenyl]acetic acid (500 mg) synthesized according to the procedures described in International Patent Publication WO00/03980 was used instead of 4-(2-bromoethyl)benzoic acid, and the material was reacted and treated to obtain the title compound (Intermediate il-01, 471 mg).
Reaction SMILES: [CH2:1]([N:7]=[C:8]=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:10][C:11]1[N:16]=[N:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>>[CH2:1]([NH:7][C:8]([NH:10][C:11]1[N:16]=[N:15][C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:23](=[O:24])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[CH2:21][CH2:22]2)=[CH:13][CH:12]=1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: CCCCCCN=C=O
Product: CCCCCCNC(=O)Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 5, making variations only as required to use hexylisocyanate in place of (2-isocyanatocyclopropyl)benzene to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white powder (50% yield). 1H NMR (300 MHz, CD3OD) δ 7.83, 7.76, 7.69, 7.52, 7.44, 7.39, 3.87-4.00, 3.66, 3.50, 3.25-3.43, 1.53-1.67, 1.28-1.48, 0.84-0.98. MS (ES+) m/z 479 (M+1).
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22](O)=[O:23])[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](=[N:35]O)[NH2:34])=[CH:28][CH:27]=1>>[CH:1]1([C:6]([N:8]2[CH2:9][CH:10]([C:22]3[O:23][N:35]=[C:33]([CH2:32][C:29]4[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=4)[N:34]=3)[CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=3)[CH2:13]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(Cc1ccc(F)cc1)=NO
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)C3CCCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(Cc4ccc(F)cc4)no3)CN(C(=O)C3CCCC3)C2)cc1

Procedure:
66 mg (0.20 mmol) of 1-(cyclopentylcarbonyl)-5-(4-ethylphenyl)piperidine-3-carboxylic acid (Example 7A) and 37 mg (0.22 mmol, 1.1 eq.) of 2-(4-fluorophenyl)-N′-hydroxyethanimidamide were reacted according to the General Method 1. Yield: 22 mg (24% of theory)