Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[NH:11][C:12]([NH:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[Cl:23])=[O:13].N1C=CC=CC=1.Cl[C:32]([O:34][CH3:35])=[O:33].O>CN1CCCC1=O.C(O)(=O)C>[Cl:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[C:15]([NH:14][C:12](=[O:13])[NH:11][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[NH:1][C:32]([O:34][CH3:35])=[O:33])[C:6]([OH:8])=[O:7])=[O:24]
Reactant: Nc1ccc(C(=O)O)cc1NC(=O)NC(=O)c1ccc(F)cc1Cl
Reactant: COC(=O)Cl
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)Nc1ccc(C(=O)O)cc1NC(=O)NC(=O)c1ccc(F)cc1Cl
Yield: 55 %

Procedure:
28 mg (0.08 mmol) of 4-amino-3-[3-(2-chloro-4-fluorobenzoyl)ureido]benzoic acid were dissolved in 0.5 ml of N-methyl-2-pyrrolidinone and stirred with 0.02 ml (0.24 mmol) of pyridine and 0.007 ml of methyl chloroformate at room temperature for 4 hours. Water and acetic acid were added, and the resulting precipitate was filtered off with suction. 18 mg (55%) of the desired product were obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:33]=[CH:32][C:19]([CH:20]=[C:21]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=1>CO.O1CCCC1.[C].[Pd]>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][CH:21]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:32][CH:33]=1
Reactant: CCOC(=O)C(=Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OCC
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OCC
Yield: 54.4 %

Procedure:
Diethyl 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzylidenemalonate (9.55 g, 21.3 mmol) obtained in Example 54 was dissolved in methanol (48 ml) and tetrahydrofuran (32 ml). 5% Palladium carbon (1 g) was added and the mixture was vigorously stirred at normal temperature under a hydrogen atmosphere (3.1 kgf/cm2). One and a half hours later, the catalyst was filtered off. The solvent was evaporated to give a crude solid. Recrystallization from ethyl acetate-hexane gave the title compound (5.23 g, yield 55%) as white crystals.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd].CO.O1CCOCC1>[NH2:1][C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1cccc(/C=C/c2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cccnc1Nc1cccc(CCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 88.9 %

Procedure:
A mixture of 3-nitro-2-((E)-3-styrylphenylamino)pyridine (1.03 g) and 10% palladium on carbon (0.3 g) in methanol (20 ml) and 1,4-dioxane (20 ml) was stirred under hydrogen (3 atm) at room temperature for 1.5 hours. The catalyst was removed by filtration and the solvent was evaporated. The resulting solid was collected and washed with isopropyl ether to give 3-amino-2-(3-phenethylphenylamino)pyridine (835 mg).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([NH:14][NH2:15])=O)(=[O:4])=[O:3].[OH-].[K+].[C:18](=[S:20])=[S:19]>C(O)C.O>[SH:20][C:18]1[S:19][C:12]([CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:2]([NH2:1])(=[O:4])=[O:3])=[N:14][N:15]=1
Reactant: NNC(=O)Cc1ccccc1S(N)(=O)=O
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)c1ccccc1Cc1nnc(S)s1

Procedure:
To a suspension of 22 g of the hydrazide prepared in Example 1 in 175 ml of absolute ethanol was added a solution of 5.4 g of potassium hydroxide in 40 ml of water. After stirring several minutes, 9.2 g of carbon disulfide was added dropwise. The suspension was refluxed 4 hours then concentrated in vacuo. After water (about 200 ml) was added to the residue and the suspension stirred several minutes, the suspension was filtered, and the filtrate was acidified with concentrated hydrochloric acid (red to litmus paper). The mixture was filtered and the solid isolated was suction-dried to give 5 g of the crude subject compound; m.p. 173°-197° C.
Reaction SMILES: [CH3:1][S:2]([CH2:4][S:5][CH3:6])=[O:3].[OH-].[Na+].[O:9]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10]1>O>[O:9]1[CH:13]=[CH:12][C:11]([CH:14]=[C:4]([S:2]([CH3:1])=[O:3])[S:5][CH3:6])=[CH:10]1
Reactant: O=Cc1ccoc1
Reactant: CSCS(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSC(=Cc1ccoc1)S(C)=O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To 20 ml of methyl methylsulfinylmethyl sulfide, 1.34 g (33.5 mmol) of powdered sodium hydroxide was added, followed by stirring at 80° C. for 30 minutes. This mixture was added to 9.627 g (100.2 mmol) of 3-furaldehyde, followed by stirring at 80° C. for 3 hours. After this was cooled to room temperature, water was added, followed by 3 extractions with dichloromethane. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/2) to yield 2-(3-furyl)-1-(methylsulfinyl)-1-(methylthio)ethylene.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=2[O:16][CH3:17])=[C:5]([CH3:18])[O:4][N:3]=1.CC(O)=O>C(O)C.[Pd]>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([CH:10]=[CH:9][C:8]=2[O:16][CH3:17])[NH2:13])=[C:5]([CH3:18])[O:4][N:3]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1c(C)noc1C
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(N)cc1-c1c(C)noc1C
Reaction time: 4 h

Procedure:
To a solution of 3,5-dimethyl-4-[2-(methoxy)-5-nitrophenyl]isoxazole (for a preparation see intermediate 3, 1.7 g, 6.85 mmol, 1 eq.) in ethanol (170 ml), was added Pd/C (10% on carbon, 85 mg) and the reaction was stirred under hydrogen for 4 h. AcOH (1.7 ml) was added and the reaction was hydrogenated for 20 h. After filtration, the solvent was evaporated in vacuo. The crude compound was dissolved into DCM and washed with saturated aqueous Sodium hydrogen carbonate, dried over Na2SO4, filtered and evaporated. The title compound was obtained as a red oil (1.38 g, 88%). GC/MS m/z: 218.
Reaction SMILES: [C:1]([C:3]1[C:7]([S:8][C:9]([F:12])([F:11])[F:10])=[C:6](C=O)[N:5]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[Cl:26])[N:4]=1)#[N:2].[CH3:27][O:28][CH:29](OC)[O:30][CH3:31].C(OCC)C>CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([C:3]1[C:7]([S:8][C:9]([F:10])([F:12])[F:11])=[C:6]([CH:29]([O:30][CH3:31])[O:28][CH3:27])[N:5]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:23])[F:24])=[CH:17][C:16]=2[Cl:26])[N:4]=1)#[N:2]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(C=O)c1SC(F)(F)F
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: COC(OC)c1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Yield: 76.2 %

Procedure:
The product of Example 3 (2.0 g, 0.005 mol) was combined with trimethylorthoformate (10 ml, 0.09 mol) and para-toluenesulfonic acid monohydrate (50 mg, catalytic) in anhydrous methanol. The mixture was refluxed for 72 hours, cooled to room temperature, poured into diethyl ether, washed with a 1:1 mixture of 10% aqueous sodium hydroxide solution and concentrated aqueous sodium chloride solution (100 ml), water (100 ml) and saturated aqueous sodium chloride solution (100 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to leave an oil that was purified by silica gel chromatography using a 3:1 hexane:dichloromethane solvent mixture. This provided the title compound as a white solid (1.83 g), m.p. about 93° C. Also prepared by this method: Compound 18.
Reaction SMILES: [CH:1]1([C:6]2[CH:18]=[CH:17][C:9]([C:10]([O:12]C(C)(C)C)=[O:11])=[C:8]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:7]=2)[CH2:5][CH2:4][CH:3]=[CH:2]1>[C].[Pd].CO>[CH:1]1([C:6]2[CH:18]=[CH:17][C:9]([C:10]([OH:12])=[O:11])=[C:8]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)c1ccc(C2C=CCC2)cc1Nc1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Product: O=C(O)c1ccc(C2CCCC2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63 %

Procedure:
To methanol 2.0 mL solution of tert-butyl 4-(2-cyclopenten-1-yl)-2-(4-fluoroanilino)benzoate 45 mg was added 5% palladium-carbon 9 mg, and it was stirred under hydrogen atmosphere at room temperature for 6 hours. Insoluble matter was filtrated, and the solvent was removed under reduced pressure. Trifluoroacetic acid 10 mL was added to the obtained residue, and it was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, methanol was added to the obtained residue, and solid matter was filtrated to give 4-cyclopentyl-2-(4-fluoroanilino)benzoic acid 24 mg of white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([O:11]CC)=[O:10])[CH2:4][CH2:3]1.[ClH:20]>O1CCOCC1>[ClH:20].[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH:8]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:9]([OH:11])=[O:10])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C(c1ccccc1)N1CCC(C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC1CCN(C(C(=O)O)c2ccccc2)CC1
Temperature: 100 °C
Yield: 96.1 %

Procedure:
Ethyl 2-(4-methylpiperidin-1-yl)-2-phenylacetate (225 mg, 0.86 mmol) and 37% aq HCl (0.52 ml, 17.2 mmol) were dissolved in Dioxane (7 ml) and heated under microwave irradiation into a sealed vial at 100° C. for 8 hours. The solvents were evaporated, the residue was suspended in EtOAc and evaporated. The residue was suspended in EtOAc/Et2O (1/1), sonicated and filtered under suction to obtain 2-(4-methylpiperidin-1-yl)-2-phenylacetic acid hydrochloride (223 mg, 96% yield) as a white solid
Reaction SMILES: [CH3:1][S:2][CH2:3][C@@:4]12[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:22])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]1=[CH:8][C:7](=O)[CH2:6][CH2:5]2.[Cl-].[Cl:25][CH2:26][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.O>O1CCCC1.CCOCC>[Cl:25][CH:26]=[C:7]1[CH2:6][CH2:5][C@@:4]2([CH2:3][S:2][CH3:1])[C:9]([CH2:10][CH2:11][C@@H:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][C:16]2=[O:22])=[CH:8]1
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CSC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CSC[C@]12CCC(=CCl)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.7 %

Procedure:
500 mg of 19-methylthio-4-androstene-3,17-dione (European patent 100,566) is added to a suspension of 5.21 g of chloromethyl triphenylphosphonium chloride in 50 ml of tetrahydrofuran, which was stirred with 9.5 ml of (1.6 m of butyllithium in ether) 0.5 hours at 20° C., and stirred for 30 minutes at 0° C. Then it is mixed with water, extracted three times with ethyl acetate, washed neutral, dried on sodium sulfate and concentrated to dryness. 995 mg of raw product is obtained, which after chromatographic purification yields 273 mg of pure 3-chloromethylene-19-methylthio-4-androsten-17-one with a melting point of 114°-115° C., [α]D +241.5° C. (CHCl3), as pure E form.
Reaction SMILES: [F:1][C:2]([F:56])([CH2:29][CH2:30][N:31]([S:46]([C:49]1[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][CH:50]=1)(=[O:48])=[O:47])[CH2:32][CH2:33][CH2:34][N:35]1C(=O)C2=CC=CC=C2C1=O)[CH2:3][N:4]([S:19]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:5][CH2:6][CH2:7][N:8]1C(=O)C2=CC=CC=C2C1=O.O.NN>C(O)C.O.CO.Cl>[NH2:8][CH2:7][CH2:6][CH2:5][N:4]([S:19]([C:22]1[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=1)(=[O:21])=[O:20])[CH2:3][C:2]([F:56])([F:1])[CH2:29][CH2:30][N:31]([S:46]([C:49]1[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][CH:50]=1)(=[O:47])=[O:48])[CH2:32][CH2:33][CH2:34][NH2:35]
Reactant: Cc1ccc(S(=O)(=O)N(CCCN2C(=O)c3ccccc3C2=O)CCC(F)(F)CN(CCCN2C(=O)c3ccccc3C2=O)S(=O)(=O)c2ccc(C)cc2)cc1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N(CCCN)CCC(F)(F)CN(CCCN)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 90 °C

Procedure:
A mixture of 6,6-difluoro-1,12-diphthalimido-4,9-di-p-toluenesulfonyl-4,9-diaza-dodecane (3.4 g, 4.22 mM), ethanol (8.5 mL) and 8.5 mL of a 1N solution of hydrazine hydrate in ethanol is stirred and heated (bath temperature: 90° C.) overnight. Evaporation and stripping twice with methanol yields a residue which is dissolved in a mixture of water (20 mL), methanol (20 mL), and concentrated HCl (40 mL), and heated (bath temperature: 90° C.) under reflux for 3 hours. The reaction mixture is cooled, filtered and evaporated, and the residue is dissolved in hot 1N HCl. The solution is filtered, the filtrate is evaporated, and the residue is stripped with isopropanol (twice) and ethanol (twice). The residue is dissolved in ethanol, ether is added, and upon evaporation of the solvent, there is obtained 1,12-diamino-6,6-difluoro-4,9-di-p-toluenesulfonyl-4,9-diaza-dodecane as a white crystalline foam: 2.7 g (quantitative yield).
Reaction SMILES: Br[C:2]1[C:7]([C:8]2[C:9](=[O:29])[N:10]([CH:26]([CH3:28])[CH3:27])[C:11](=[O:25])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:13]=2[CH3:14])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)#[N:31].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH:26]([N:10]1[C:9](=[O:29])[C:8]([C:7]2[C:2]([C:35]3[CH:36]=[CH:37][C:32]([C:30]#[N:31])=[CH:33][CH:34]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[C:13]([CH3:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:11]1=[O:25])([CH3:28])[CH3:27]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Cc1c(-c2cccnc2Br)c(=O)n(C(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(-c2cccnc2-c2ccc(C#N)cc2)c(=O)n(C(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 85.3 %

Procedure:
5-(2-Bromopyridin-3-yl)-3-isopropyl-6-methyl-1-(3-(trifluoromethyl)phenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 189) (132 mg) and 4-cyanophenylboronic acid (166 mg) were dissolved in 1,4-dioxane (10 ml). Thereto were added under nitrogen atmosphere water (1 ml), sodium carbonate (239 mg) and tetrakis(triphenylphosphine)palladium (33 mg) and the resulting mixture was stirred with heating under reflux for one and a half hours. The reaction mixture was cooled to room temperature, and thereto was then water and the resulting mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with saturated saline (50 ml), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: firstly hexane/ethyl acetate, secondly chloroform/methanol) to afford 4-(3-(3-isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)pyridin-2-yl)benzonitrile (118 mg).
Reaction SMILES: C(OC1C=C(OC2CC3C(C(=O)N(C)CCCCC=CC4C(C(O)=O)(NC3=O)C4)C2)C2C(=CC(OC)=CC=2)N=1)C.[CH2:41]([O:43][C:44]1[CH:53]=[C:52]([O:54][CH:55]2[CH2:72][CH:71]3[CH:57]([C:58](=[O:84])[N:59]([CH3:83])[CH2:60][CH2:61][CH2:62][CH2:63][CH:64]=[CH:65][CH:66]4[C:68]([C:74]([NH:76][S:77]([CH:80]5[CH2:82][CH2:81]5)(=[O:79])=[O:78])=[O:75])([NH:69][C:70]3=[O:73])[CH2:67]4)[CH2:56]2)[C:51]2[C:46](=[C:47](C)[C:48]([O:85][CH3:86])=[CH:49][CH:50]=2)[N:45]=1)[CH3:42]>>[CH2:41]([O:43][C:44]1[CH:53]=[C:52]([O:54][CH:55]2[CH2:72][CH:71]3[CH:57]([C:58](=[O:84])[N:59]([CH3:83])[CH2:60][CH2:61][CH2:62][CH2:63][CH:64]=[CH:65][CH:66]4[C:68]([C:74]([NH:76][S:77]([CH:80]5[CH2:82][CH2:81]5)(=[O:78])=[O:79])=[O:75])([NH:69][C:70]3=[O:73])[CH2:67]4)[CH2:56]2)[C:51]2[C:46](=[CH:47][C:48]([O:85][CH3:86])=[CH:49][CH:50]=2)[N:45]=1)[CH3:42]
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Agent: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)cc2n1
Product: CCOc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)cc2n1

Procedure:
The title compound (5) was prepared from 17-[2-ethoxy-7-methoxyquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (4) following the procedure reported for synthesis of N-[17-[2-ethoxy-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (3): m/z=555 (M+H)+. 1H NMR (CDCl3): 0.80-0.90 (m, 1H), 0.92-1.0 (m, 4H), 1.00-1.3 (m, 3H), 1.41 (t, J=7.1 Hz, 3H), 1.45-1.71 (m, 2H), 1.8-1.95 (m, 4H), 2.21-2.62 (m, 4H), 2.73-2.81 (m, 1H), 2.9-2.94 (m, 1H), 3.0 (s, 3H), 3.31-3.41 (m, 1H), 3.90 (s, 3H), 4.44 (q, J=7.1 Hz, 2H), 5.0-5.08 (m, 2H), 5.6-5.65 (m, 1H), 5.98 (s, 1H), 6.8 (br s, 1H), 7.10 (dd, J=9.1 Hz and J=2.5 Hz, 1H), 7.12 (d, J=2.5 Hz, 1H), 7.28 (s, 1H), 7.9 (d, J=9.1 Hz, 1H), 11.02 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]1[OH:13].[C:20]1([C:26](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@H:12]([OH:13])[C@H:14]([OH:15])[C@@H:16]([CH2:18][O:19][C:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:17]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O[C@H]1n1cnc2c(Cl)ncnc21
Temperature: 40 °C
Yield: 65.1 %

Procedure:
To a solution of 6-chloro-9-β-D-ribofuranosylpurine (5.00 g, 17.4 mmol) and triphenylmethyl chloride (9.72 g, 34.8 mmol) in DMF (60 mL) was added DIPEA (2.7 mL, 19.1 mmol) dropwise. The reaction was heated to 40° C. overnight, cooled to r.t. and filtered. The yellow filtrate was diluted with chloroform and washed with water, 0.5 N HCl, and water. The organic layer was dried (Na2SO4), filtered and concentrated. The yellow foam was purified by flash chromatography (0 to 4% MeOH/CHCl3) to yield the product as a pale yellow foam (5.99 g, 65%).
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[CH:14][C:15](O)=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.[CH3:48][O:49][C:50](=[O:57])[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][NH2:56]>[Cl-].[Na+].O.CN(C=O)C>[CH3:48][O:49][C:50](=[O:57])[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][NH:56][C:15](=[O:16])[CH:14]=[C:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=C(O)C=C1c2ccccc2-c2ccccc21
Reactant: COC(=O)CCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCCCNC(=O)C=C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 90.7 %

Procedure:
2-(9H-fluoren-9-ylidene)acetic acid (222 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (394 mg, 2 mmol), hydroxybenzo-triazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and 6-aminocaproic acid methyl ester hydrochloride (219 mg, 1.2 mmol) were added. The mixture was stirred for 24 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (317 mg, 91% yield) as a white solid. LC-MS (m/z) 350 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][OH:21])[CH2:14][CH2:13]3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:34]=[C:35]=[O:36])[CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31]>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH:34][C:35]([O:21][CH2:20][CH2:19][CH2:18][N:15]2[CH2:16][CH2:17][CH:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[CH2:13][CH2:14]2)=[O:36])[CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31]
Reactant: Cn1nc(C2CCN(CCCO)CC2)c2ccc(F)cc21
Reactant: COc1cc(N=C=O)cc(OC)c1OC
Product: COc1cc(NC(=O)OCCCN2CCC(c3nn(C)c4cc(F)ccc34)CC2)cc(OC)c1OC
Yield: 67.9 %

Procedure:
Starting from 4-(6-fluoro-1-methyl-1H-indazol-3-yl)-1-(3-hydroxyprop-1-yl)piperidine (300 mg, 1.03 mmol) and 3,4,5-trimethoxyphenylisocyanate (300 mg, 1.44 mmol) using the procedure described in example 1B was prepared 350 mg (68%) of the title compound. M.p. 85°-88° C.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[Cl:10][C:4]1[CH:3]=[C:2]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[C:18]([O:19][CH3:20])[CH:17]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Nc1c(F)cc(Br)cc1Cl
Product: COc1ccc(-c2cc(F)c(N)c(Cl)c2)cc1OC
Yield: 31.3 %

Procedure:
The title compound (39 mg) was prepared from 4-bromo-2-chloro-6-fluoroaniline (100 mg, 0.442 mmol) and 3,4-dimethoxyphenylboronic acid (80 mg, 0.62 mmol) as a pale-yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:11])[C:5]([CH2:8][C:9]#[N:10])=[N:6][CH:7]=1.[F:12][C:13]([F:20])([F:19])[C:14]1[CH:18]=[CH:17][NH:16][N:15]=1.C(=O)([O-])[O-].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>O1CCOCC1.[Cu]I>[Cl:11][C:4]1[C:5]([CH2:8][C:9]#[N:10])=[N:6][CH:7]=[C:2]([N:16]2[CH:17]=[CH:18][C:14]([C:13]([F:20])([F:19])[F:12])=[N:15]2)[CH:3]=1
Reactant: FC(F)(F)c1cc[nH]n1
Reactant: N#CCc1ncc(Br)cc1Cl
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: N#CCc1ncc(-n2ccc(C(F)(F)F)n2)cc1Cl
Temperature: 100 °C

Procedure:
To a solution of 5-bromo-3-chloro-2-pyridineacetonitrile (i.e. the product of Step A; 6.0 g, 0.025 mol) in 1,4-dioxane (50 mL) was added 3-(trifluoromethyl)-1H-pyrazole (3.74 g, 0.027 mol), copper(I) iodide (0.49 g, 0.0025 mol), potassium carbonate (13.8 g, 0.1 mol) and trans-N,N′-dimethyl-1,2-cyclohexanediamine (1.42 g, 0.01 mol) under argon atmosphere at room temperature, and the resulting mixture was heated at 100° C. for 16 h. The cooled reaction mixture was diluted with ice water and extracted with dichloromethane (2×50 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (4:6) to afford the title compound (5.0 g) as a light yellow solid.