Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[C:16]([O:23][C:24]1[CH:29]=[CH:28][C:27](Cl)=[CH:26][CH:25]=1)[CH:15]=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C>C(O)(C)C.[Pd]>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[C:16]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:15]=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2]
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3cccc(Oc4ccc(Cl)cc4)c3c12
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3cccc(Oc4ccccc4)c3c12

Procedure:
2 g of 5-(4-chlorophenoxy)-4-methoxymethyl-beta-carboline-3-carboxylic acid isopropyl ester in 40 ml of isopropanol is hydrogenated with 200 mg of palladium on carbon (10%) and 0.9 ml of triethylamine at room temperature under normal hydrogen pressure. After filtering off of the catalyst, concentration of the filtrate and digesting of the residue with diisopropyl ether, 1.4 g of 5-phenoxy-4-methoxymethyl-beta-carboline-3-carboxylic acid isopropyl ester with a melting point of 201°-203° C. is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14](N(C)C)=[O:15])[CH2:10]1.[C:19]1(C)C=CC=CC=1.C[Mg]Br.Cl>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14](=[O:15])[CH3:19])[CH2:10]1
Reactant: Cc1ccccc1
Reactant: CN(C)C(=O)C1=NOC(c2c(F)cccc2F)C1
Agent: C[Mg]Br
Agent: Cl
Solvent: O
Product: CC(=O)C1=NOC(c2c(F)cccc2F)C1
Temperature: -5 °C

Procedure:
To a 1 L flask equipped with a thermometer and addition funnel was added 5-(2,6-difluorophenyl)-4,5-dihydro-N,N-dimethyl-3-isoxazolecarboxamide (i.e. the product of Step A) (80.0 g, 0.31 mol) and toluene (320 mL). The reaction mixture was cooled to −5° C., and methyl magnesium bromide (3.0 M in tetrahydrofuran, 120 mL, 0.36 mmol) was added dropwise while maintaining the temperature between −10 and −5° C. When gas chromatography analysis of the reaction mixture showed about 2% of 5-(2,6-difluorophenyl)-4,5-dihydro-N,N-dimethyl-3-isoxazolecarboxamide remaining, the reaction mixture was poured into a stirred solution of concentrated hydrochloric acid (80 mL) and water (320 mL) while maintaining the temperature between 10 and 30° C. The organic layer was separated, washed with saturated aqueous sodium chloride solution (80 mL), and then concentrated under reduced pressure. The resulting oil was crystallized from hexanes (100 mL), collected by filtration, washed with hexanes, and dried in a vacuum oven overnight at 23° C. to provide the title compound as a waxy, off-white solid (65 g), melting at 47-50° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:22])[CH:3]=1>N1CCCCC1>[CH3:22][C:4]1[CH:3]=[C:2]([N:5]2[CH2:6][CH2:11][CH2:2][CH2:3][CH2:4]2)[C:11]2[C:6](=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1cc(Cl)c2ccc(COc3ccc(C#N)cc3)cc2n1
Solvent: C1CCNCC1
Product: Cc1cc(N2CCCCC2)c2ccc(COc3ccc(C#N)cc3)cc2n1
Yield: 69.9 %

Procedure:
A solution of 4-(4-chloro-2-methyl-quinolin-7-ylmethoxy)-benzonitrile (example 54a, 100 mg, 0.32 mmol) in piperidine (1 mL) was heated at 100° C. for 21 h. After cooling the reaciton mixture was partitioned between sat. aq. sodium hydrogencarbonate solution and dichloromethane, the organic layer was separated, washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, dichloromethane/methanol 19:1) yielded the title compound (40 mg, 32%). Light yellow gum, ISP-MS: m/e=358.4 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([OH:14])=O.[C-]#N.[K+].S(Cl)(Cl)=O.[CH2:22]([NH:25][CH2:26][CH2:27][CH3:28])[CH2:23][CH3:24]>>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:11][C:12]([N:25]([CH2:26][CH2:27][CH3:28])[CH2:22][CH2:23][CH3:24])=[O:14]
Reactant: Cc1c(CC(=O)O)cccc1[N+](=O)[O-]
Reactant: CCCNCCC
Agent: [C-]#N
Agent: [K+]
Solvent: O=S(Cl)Cl
Product: CCCN(CCC)C(=O)Cc1cccc([N+](=O)[O-])c1C

Procedure:
Alternative process for the preparation of Ropinirole is described in J. Med. Chem. 1985, 28, 1533-1536 as shown in Scheme-2. The process comprises, the reduction 2-Methyl-3-nitro-benzoic acid (VIII) with diborane to carbinol of formula (IX). The carbinol compound (IX) is chlorinated with thionyl chloride in pyridine to give highly lachrymatory compound of formula (X), which is further converted to compound of formula (XII) by reaction with Potassium cyanide and followed by hydrolysis. 2-methyl-3-nitrophenyl acetic acid (XII) is converted to its acid chloride with thionyl chloride and treated with Di-n-propylamine to give 2-Methyl-3-nitrophenyl-N,N-di-n-propyl acetamide of formula (IV). The compound of formula (IV) is further reduced with borane in THF under reflux to give 2-Methyl-3-nitrophenylethyl-N,N-di-n-propyl amine (V). The amine of formula (V) is reacted with potassium metal in Ethanol and diethyl oxalate resulting in compound (VI) (where R=H), which is treated with hydrogen peroxide, NaOH and HCl to give the intermediate 2-Nitro-6-(2-di-n-propylaminoethyl)-phenyl acetic acid hydrochloride of formula (VII). This intermediate is hydrogenated on palladium/carbon in ethanol to give desired compound Ropinirole hydrochloride of formula (Ia)
Reaction SMILES: [SH2:1].[Na].[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][C:9](Cl)=[C:8]([Cl:13])[CH:7]=1)=[O:5]>CN1CCCC1=O>[Cl:13][C:8]1[CH:7]=[C:6]([C:4](=[O:5])[CH3:3])[CH:11]=[CH:10][C:9]=1[SH:1]
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: S
Agent: [Na]
Solvent: CN1CCCC1=O
Product: CC(=O)c1ccc(S)c(Cl)c1
Temperature: 140 °C
Yield: 90.6 %

Procedure:
110 g (1.48 mol) of sodium hydrogen sulphide (NaSH·H2O) are initially introduced together with 1 l of N-methylpyrrolidone and the water is removed at 160° C. with nitrogen. The mixture is cooled to 140° C. and 112 g (0.59 mol) of 3,4-dichloroacetophenone are added, and the mixture is reacted further at 160° C. for 3 hours, and N-methylpyrrolidone is distilled off. The residue is taken up in 1 l of water and filtered, and the filtrate is acidified at 0°-10° C. with half-concentrated hydrochloric acid. The precipitate is filtered off with suction, washed neutral and dried. Distillation under reduced pressure gives 99.8 g (90.7% of theory) of 2-chloro-4-acetylthiophenol of boiling point: 125°-130° C./0.1 mbar.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][C:15]([C:18]2[NH:22][N:21]=[N:20][N:19]=2)=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])C1C=CC=CC=1.[OH-].[NH4+]>CO.[Pd]>[OH:8][C:9]1[CH:17]=[CH:16][C:15]([C:18]2[NH:22][N:21]=[N:20][N:19]=2)=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12]
Reactant: NC(=O)c1cc(-c2nnn[nH]2)ccc1OCc1ccccc1
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1cc(-c2nnn[nH]2)ccc1O
Reaction time: 24 h
Yield: 98.1 %

Procedure:
A suspension of 400 mg (1.04 mmol) of 2-benzyloxy-5-(1H-tetrazol-5-yl)benzamide and 500 mg of 10% Pd/C (50% water) in 2 mL of methanol containing 1 mL of 28% aqueous ammonium hydroxide is stirred under hydrogen at 48 psi for 24 hr. The reaction mixture is filtered and the filtrate concentrated to give 210 mg (1.02 mmol, 98% yield) of 2-hydroxy-5-(1H-tetrazol-5-yl)benzamide.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH2:17].C(N(CC)C(C)C)(C)C>C(#N)C>[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][NH:17][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: NCc1cccc(Br)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(F)cc1NCc1cccc(Br)c1
Yield: 81.6 %

Procedure:
2,4-Difluoronitrobenzene (2.9 g, 18.1 mmol), 3-Bromobenzylamine (2.6 g, 18.1 mmol) and N,N-diisopropylethylamine (2.4 g, 18.1 mmol) were stirred in acetonitrile (25 mL) at room temperature for 2 hours. The solvent was evaporated and the crude mixture was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated in vacuo to collect the title compound (4.8 g, 95% yield). 1H NMR (400 MHz, CDCl3): δ 8.55 (s, 1H), 8.25 (dd, 1H), 7.32-7.21 (m, 4H), 6.41 (m, 2H), 4.50 (d, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][CH2:24][NH:25][CH3:26])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][CH2:24][N:25]([CH3:26])[C:10](=[O:12])[CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CNCCc1ccc(OC)c(OC)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CCN(C)C(=O)CCc2ccc(O)cc2)cc1OC
Reaction time: 8 h
Yield: 97 %

Procedure:
3-(4-Hydroxyphenyl)propionic acid (166.2 mg, 1 mmol) was dissolved in DMF (4 ml). 2-(3,4-Dimethoxyphenyl)-N-methylethylamine (211 mg, 1.05 mmol) was added. The mixture was cooled in an ice-bath. TBTU (337 mg, 1.05 mmol) was added, followed by DIPEA (0.37 ml, 2.1 mmol). The mixture was stirred overnight and the temperature was allowed up to room temperature. Ethyl acetate and sodium hydrogencarbonate aqueous solution (sat.) were added and then the two phases were separated. The water phase was extracted with ethyl acetate. The organic phases were combined and dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 5 g/15 ml) using DCM and then MeOH/DCM (1:99) as eluant gave 333 mg the desired product, yield 97%.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[CH2:20]([O:1][C:2]1[C:3]([N+:11]([O-:13])=[O:12])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:5][C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1)=[O:6])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(OCc1ccccc1)c1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Reaction time: 8 h
Yield: 136.3 %

Procedure:
To a suspension of 3-hydroxy-2-nitrobenzoic acid (500 mg) and potassium carbonate (1.13 g) in dimethylformamide (5 ml) was added benzyl bromide (1.12 g) at ambient temperature, and the mixture was stirred overnight. To the reaction mixture-was added water, and extracted with ethyl acetate twice. The organic layers were combined, wished with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel flash chromatography (hexane—ethyl acetate) and crystallized with diisopropyl ether to give benzyl 3-benzyloxy-2-nitrobenzoate (676 mg).
Reaction SMILES: Cl.[CH:2]([C:4]1[C:9]([OH:10])=[C:8]([CH2:11]O)[C:7]([CH2:13][OH:14])=[CH:6][N:5]=1)=[CH2:3].[OH-].[Na+].C(=S)=[S:18]>>[CH:2]([C:4]1[C:9]([OH:10])=[C:8]([CH2:11][SH:18])[C:7]([CH2:13][OH:14])=[CH:6][N:5]=1)=[CH2:3]
Reactant: S=C=S
Reactant: C=Cc1ncc(CO)c(CO)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C=Cc1ncc(CO)c(CS)c1O

Procedure:
The product from Step F is treated with sodium hydroxide and carbon disulfide as described in Example 1, Step C, to produce 2-vinyl-3-hydroxy-4-mercaptomethyl-5-hydroxymethylpyridine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH:12]2[CH2:17][CH2:16][Si:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:6][CH:5]=1)[CH3:2].[H][H]>C(OCC)(=O)C.[C].[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH:12]2[CH2:13][CH2:14][Si:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:16][CH2:17]2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCCCC[Si]1(c2ccccc2)CCC(C=Cc2ccc(OCC)cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCC[Si]1(c2ccccc2)CCC(CCc2ccc(OCC)cc2)CC1

Procedure:
36.0 g of the thus obtained 4-(2-(4-ethoxyphenyl)ethenyl)-1-n-pentyl-1-phenyl- 1-silacyclohexane was dissolved in 100 ml of ethyl acetate, followed by hydrogenation at a pressure of 5 kg/cm2 of hydrogen at room temperature in the presence of 200 mg of palladium-carbon used as a catalyst. After the hydrogen had been consumed theoretically, the catalyst was removed by filtration and the resultant flitrate was concentrated to obtain 36.2 g (quantitative yield) of 4-(2-(4-ethoxyphenyl)ethyl)-1-n-pentyl-1-phenyl-1-silacyclohexane.
Reaction SMILES: [CH2:1]([NH:13][CH2:14][CH2:15][NH2:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:17](OCC)(=[O:22])[CH2:18][C:19]([CH3:21])=O>>[CH2:1]([N:13]1[C:17](=[O:22])[CH2:18][C:19]([CH3:21])=[N:16][CH2:15][CH2:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCNCCN
Reactant: CCOC(=O)CC(C)=O
Product: CCCCCCCCCCCCN1CCN=C(C)CC1=O

Procedure:
Into a four-necked flask provided with a stirrer, thermometer, gas inlet tube, and water measuring tube connected with a reflux condenser, were charged 228.1 g (1 mole) of N-dodecylethylenediamine and 130.1 g (1 mole) of ethyl acetoacetate. While bubbling nitrogen gas, the flask was heated at 150° to 160° C. to distill off 18 g of water and 46 g of ethanol, and then 4-dodecyl-7-methyl-3,6-dihydro-2H-1,4-diazepin-5-one in slight yellow liquid was obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH3:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>>[CH3:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:31])[NH:1][CH2:2][C:3]([N:5]([CH2:12][C:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])=[O:14])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:4])[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CCCN(CCC)C(=O)CN(C(=O)CN)c1ccccc1
Product: CCCN(CCC)C(=O)CN(C(=O)CNC(=O)Nc1cccc(C)c1)c1ccccc1
Yield: 44.8 %

Procedure:
Working in a manner similar to that described in Example 1, but starting with 2-(2-amino-N-phenylacetamido)-N,N-dipropylacetamide (1.7 g) and 3-methylphenyl isocyanate (0.77 g), and after recrystallization in acetonitrile, 2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}-N,N-dipropylacetamide (1.1 g), m.p. 182° C., is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.Cl.[NH:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:18]2[CH2:22][CH2:21][CH2:20][CH:19]2[CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[O:15])=[CH:6][CH:7]=1
Reactant: c1cncc(CC2CCCN2)c1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Agent: Cl
Product: Cc1ccc(-c2oncc2C(=O)N2CCCC2Cc2cccnc2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-pyrrolidin-2-ylmethylpyridine dihydrochloride (14.1 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (4.7 mg). Calcd for C21H21N3O2: 347.1634, found 347.1635.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][N:51]([C:54](=[O:63])[CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58](Br)[CH:57]=2)[CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:43])[CH3:42]>>[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][N:51]([C:54](=[O:63])[CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[C:60]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:20]=[C:15]([C:12]5[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]6[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=6)[CH2:30][C:31]6[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=6)=[N:14][CH:13]=5)[C:16]=4[CH2:29][CH2:28]3)[CH:61]=2)[CH2:50][CH2:49]1)=[O:47])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2cccc(Br)c2)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(CC(=O)N4CCN(C(=O)OC(C)(C)C)CC4)c3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (150 mg) and 4-[2-(3-bromo-phenyl)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester (128 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 4-{2-[3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-acetyl}-piperazine-1-carboxylic acid tert-butyl ester was obtained, and further PMB group and BOC group were removed according to the above Deprotection method 2, to obtain the desired compound (D-171) as a colorless powder (4 mg, 3%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N+:17]([O-:19])=[O:18])=[CH:14][CH:15]=2)[C:10](I)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:26]1[N:31]=[C:30]([N:32]2[CH2:37][CH2:36][CH:35]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:34][CH2:33]2)[CH:29]=[N:28][CH:27]=1)CCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:41]([O:40][C:39]([NH:38][CH:35]1[CH2:36][CH2:37][N:32]([C:30]2[N:31]=[C:26]([C:10]3[C:11]4[C:16](=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=4)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:9]=3)[CH:27]=[N:28][CH:29]=2)[CH2:33][CH2:34]1)=[O:45])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)OC(=O)n1cc(I)c2cc([N+](=O)[O-])ccc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(N2CCC(NC(=O)OC(C)(C)C)CC2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3cn(C(=O)OC(C)(C)C)c4ccc([N+](=O)[O-])cc34)n2)CC1
Reaction time: 1 h
Yield: 30.2 %

Procedure:
To a mixture of 3-Iodo-5-nitro-indole-1-carboxylic acid tert-butyl ester (480 mg, 1.23 mmol) and tert-butyl 1-(6-(tributylstannyl)pyrazin-2-yl)piperidin-4-ylcarbamate 1d (700 mg, 1.23 mmol) in DMF (4.8 mL) was purged with argon gas for 5 min and added Cut (352 mg, 1.84 mmol) and palladium tetrakis (171 mg, 0.15 mmol). The resulting mixture was purged with argon gas for 5 min and stiffed under nitrogen atmosphere at 90° C. for 1 h. The reaction mixture was then poured into water. The resulting precipitate was collected by filtration. The filtrate was extracted with diethyl ether. The organic layer was concentrated and combined with the above precipitate to give the crude product. Purification was carried out by column chromatography to obtain the title compound as a white solid (200 mg, 30%). MS (ESI, pos. ion) m/z: 539.3 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=1>C(#N)C>[O:14]1[C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:12]([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[O:5][CH2:4][CH2:3][CH2:2][NH:33][CH2:32][C:31]2[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:36])[F:37])=[CH:35][CH:34]=2)=[N:13]1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NCc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)c1ccc(CNCCCOc2cccc(-c3noc4ccsc34)c2)cc1

Procedure:
The title compound is prepared from 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 4-(trifluoromethyl)benzylamine, and acetonitrile essentially as described above in example 56. Purity by LC/MS (APCI)=98%, [M+H]+=433.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[C@H:13]1[CH2:18][C@H:17]([C:19]2[O:23][NH:22][C:21](=[O:24])[CH:20]=2)[CH2:16][CH2:15][N:14]1C(OC)=O.Br>>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:10])([F:11])[F:12])[CH:5]=[CH:4][C:3]=1[C@H:13]1[CH2:18][C@H:17]([C:19]2[O:23][NH:22][C:21](=[O:24])[CH:20]=2)[CH2:16][CH2:15][NH:14]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1ccc(OC(F)(F)F)cc1F
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](c3ccc(OC(F)(F)F)cc3F)C2)o[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.4 %

Procedure:
Trans-methyl 2-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (365 mg, 0.90 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 7.115 mL, 40.62 mmol) and stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-(trans-2-(2-fluoro-4-(trifluoromethoxy)phenyl)-piperidin-4-yl)isoxazol-3(2H)-one (185 mg, 59%). 1H NMR (600 MHz, dmso) δ 1.64-1.72 (m, 1H), 1.77-1.85 (m, 1H), 1.91-1.97 (m, 1H), 2.02-2.08 (m, 1H), 2.69 (dt, 1H), 2.86-2.92 (m, 1H), 3.17-3.22 (m, 1H), 3.95 (dd, 1H), 5.87 (d, 1H), 7.19-7.23 (m, 1H), 7.28-7.32 (m, 1H), 7.66 (t, 1H); HRMS Calculated for [C15H14F4N2O3+H]+: 347.1019. Found: 347.1002
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](O)=[CH:5][C:6](=O)[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]([NH:25][NH2:26])[CH:21]=[CH:22][C:23]=1[Cl:24]>CCO>[ClH:17].[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:25]([C:20]2[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=2)[N:26]=1)=[O:15]
Reactant: NNc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)C(O)=CC(=O)c1cccnc1
Agent: Cl
Solvent: CCO
Product: COC(=O)c1cc(-c2cccnc2)n(-c2ccc(Cl)c(Cl)c2)n1
Temperature: 0 °C
Yield: 128 %

Procedure:
To a solution of 1 (2.90 g, 14.0 mmol) in EtOH (60 mL, anhydrous) was added 3,4-dichlorophenyl hydrazine hydrochloride (3.29 g, 15.4 mmol). The solution was heated to reflux for 30 min and then cooled to 0° C. The precipitate was collected by filtration and washed with H2O and MeOH to yield 2 (3.79 g, 70%) as an off-white powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[N:11]([CH3:17])[C:12](=[O:16])[O:13][CH2:14][CH3:15].[OH:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>>[NH2:23][C:22]1[CH:24]=[CH:25][C:19]([O:18][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=2[N:11]([CH3:17])[C:12](=[O:16])[O:13][CH2:14][CH3:15])=[CH:20][CH:21]=1
Reactant: CCOC(=O)N(C)c1c(Cl)ccnc1[N+](=O)[O-]
Reactant: Nc1ccc(O)cc1
Product: CCOC(=O)N(C)c1c(Oc2ccc(N)cc2)ccnc1[N+](=O)[O-]
Yield: 11.2 %

Procedure:
Method A was used with ethyl 4-chloro-2-nitropyridin-3-yl-methyl-carbamate (400 mg, 1.5 mmol) and 4-hydroxyaniline (196 mg, 1.8 mmol) to afford the title compound (56 mg, 12%) after purification by column chromatography, eluent gradient DCM to DCM:AcOEt 1:1. 1H-NMR (δ, ppm, DMSO-d6): 1.06+1.23 (t+t, rotamers, 3H, CH3,Et), 3.18+3.23 (s+s, rotamers, 3H, NCH3), 4.04+4.12 (q+q, rotamers, 2H, CH2,Et), 5.44 (s, 2H, NH2,Ph), 5.97 (s, 2H, NH2,Py2), 6.92 (d, 2H, Harom,Ph,3+5, J=8.79 Hz), 6.92 (d, 2H, Harom,Ph,2+6, J=8.82 Hz), 7.04 (d, 1H, HPy,5, J=5.60 Hz), 8.33 (d, 1H, HPy,6, J=5.59 Hz). LC-MS (m/z): 332 (M+, 100).