Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH3:10][O:11][C:12](=[O:21])/[C:13](/I)=[CH:14]\[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:41][C:42]1[CH:47]=[C:46](I)[CH:45]=[CH:44][C:43]=1[N:49]1[C:53]([CH3:54])=[N:52][N:51]=[N:50]1.[Cl-].[NH4+]>O1CCCC1.[Zn].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]>[CH3:10][O:11][C:12](=[O:21])/[C:13](/[C:46]1[CH:45]=[CH:44][C:43]([N:49]2[C:53]([CH3:54])=[N:52][N:51]=[N:50]2)=[C:42]([Cl:41])[CH:47]=1)=[CH:14]/[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)/C(I)=C\C1CCCC1
Reactant: Cc1nnnn1-c1ccc(I)cc1Cl
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COC(=O)/C(=C/C1CCCC1)c1ccc(-n2nnnc2C)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.7 %

Procedure:
A mixture of zinc dust (650 mg, 10 mmol, Aldrich, −325 mesh) and dry tetrahydrofuran (1 mL) under argon was treated with 1,2-dibromoethane (187 mg, 1 mmol). The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again. This process was repeated three times to make sure the zinc dust was activated. The activated zinc dust suspension was then treated with trimethylsilyl chloride (108 mg, 1 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-3-cyclopentyl-2-iodo-acrylic acid methyl ester (prepared in Example 7, 1.26 g, 4.5 mmol) in dry tetrahydrofuran (2 mL) over 3 min. The reaction mixture was then stirred at 40-45° C. for 1 h and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (3 mL), and the stirring was stopped to allow the excess zinc dust to settle down (˜2 h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (54 mg, 0.1 mmol) and triphenylphosphine (104 mg, 0.4 mmol) in dry tetrahydrofuran (4 mL) was stirred at 25° C. under argon for 10 min and then treated with 1-(2-chloro-4-iodo-phenyl)-5-methyl-1H-tetrazole (prepared in Example 4, 875 mg, 2.73 mmol) and the freshly prepared zinc compound in tetrahydrofuran. The resulting brick red solution was stirred at 25° C. over the weekend and then heated at 40-45° C. for 4 h. The reaction mixture was cooled to 25° C. and then poured into a saturated aqueous ammonium chloride solution (50 mL), and the organic compound was extracted into ethyl acetate (3×35 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 4/1 to 1/1 hexanes/ethyl acetate) afforded (E)-2-[3-chloro-4-(5-methyl-tetrazol-1-yl)-phenyl]-3-cyclopentyl-acrylic acid methyl ester (859 mg, 91%) as a light yellow semi-solid: EI-HRMS m/e calcd for C17H19ClN4O2 (M+) 346.1196, found 346.1190.
Reaction SMILES: [P].[F:2][C:3]([F:20])([F:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:15]3[N:16]=[CH:17][CH:18]=[C:14]3[N:13]=[CH:12][CH:11]=2)[CH:5]=1.[OH-].[Na+].CN(C)[CH:25]=[O:26]>>[F:20][C:3]([F:19])([F:2])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:15]3[N:16]=[CH:17][C:18]([CH:25]=[O:26])=[C:14]3[N:13]=[CH:12][CH:11]=2)[CH:5]=1
Reactant: FC(F)(F)c1cccc(-c2ccnc3ccnn23)c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Agent: [P]
Product: O=Cc1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Temperature: 0 °C

Procedure:
Seventy-five milliliters of dried dimethylformamide is cooled in an ice bath and 25 ml. of phosphorus osychloride is added dropwise with swirling. To this ice cold mixture is added 19.5 g. of 7-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine in one portion and the reaction mixture is then heated on a steam bath for 1.5 hours. The mixture is poured onto ice and made basic (pH 10) with 10 N NaOH. The precipitated solid is removed by filtration and recrystallized from methylene chloride-hexane to give the product, m.p. 196°-198° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[C:7]([CH3:10])[CH:6]=[C:5]([CH3:11])[C:4]=1Br.C([Li])CCC.CCCCCC.[CH2:24]([N:31]1[CH2:36][CH2:35][CH:34]([C:37](=[O:47])[C:38]2[CH:43]=[CH:42][C:41]([CH:44]([CH3:46])[CH3:45])=[CH:40][CH:39]=2)[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1.O>[CH2:24]([N:31]1[CH2:32][CH2:33][CH:34]([C:37]([C:38]2[CH:39]=[CH:40][C:41]([CH:44]([CH3:46])[CH3:45])=[CH:42][CH:43]=2)([C:4]2[C:5]([CH3:11])=[CH:6][C:7]([CH3:10])=[C:8]([CH3:9])[C:3]=2[O:2][CH3:1])[OH:47])[CH2:35][CH2:36]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)c1ccc(C(=O)C2CCN(Cc3ccccc3)CC2)cc1
Reactant: COc1c(C)c(C)cc(C)c1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: COc1c(C)c(C)cc(C)c1C(O)(c1ccc(C(C)C)cc1)C1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
To a solution of 2-methoxy-3,4,6-trimethylbromobenzene (15.48 g, 67.56 mmol) in tetrahydrofuran (200 ml), which was kept at −78° C., was added dropwise under an argon atmosphere a solution of n-butyllithium in hexane (1.59 mol/l, 42 ml, 66.78 mmol) and the mixture was stirred for 30 minutes. To this mixture was added dropwise a solution of 1-benzyl-4-(4-isopropylbenzoyl)piperidine (19.81 g, 61.63 mmol) in tetrahydrofuran (50 ml) and the resulting mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture and the product was extracted with ethyl acetate. The extracts were washed with an aqueous saturated solution of sodium chloride, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain 23.01 g (79% yield) of the title compound. Melting point: 154-156° C.
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH:8]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH2:7][C:6]1=[O:17])C.Cl.[NH2:19][C:20]([NH2:22])=[NH:21].C(=O)([O-])[O-].[Na+].[Na+].NC1N=CC2C(=O)CC(C3C=CC(Cl)=CC=3)CC=2N=1>>[NH2:21][C:20]1[N:22]=[CH:4][C:5]2[C:6](=[O:17])[CH2:7][CH:8]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)[CH2:9][C:10]=2[N:19]=1
Reactant: CN(C)C=C1C(=O)CC(c2cccs2)CC1=O
Reactant: N=C(N)N
Agent: Cl
Agent: Nc1ncc2c(n1)CC(c1ccc(Cl)cc1)CC2=O
Agent: O=C([O-])[O-]
Product: Nc1ncc2c(n1)CC(c1cccs1)CC2=O

Procedure:
The title compound was prepared from 2-dimethylaminomethylene-5-thien-2-yl-cyclohexane-1,3-dione (267 mg, 1.09 mmol) from stage 1, guanidine hydrochloride (205 mg, 2.14 mmol) and sodium carbonate (342 mg, 3.21 mmol), following the procedure described for the synthesis of 2-amino-7-(4-chloro-phenyl)-7,8-dihydro-6H-quinazolin-5-one (example 2/a stage 2) except that the mixture was heated to reflux for 16 h.
Reaction SMILES: [CH2:1]([C@@H:3]1[C@@H:7](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:6][N:5]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:4]1)[CH3:2].[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C=O)C.O.C(OCC)(=O)C.O>[N:29]([C@H:7]1[C@@H:3]([CH2:1][CH3:2])[CH2:4][N:5]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:6]1)=[N+:30]=[N-:31]
Reactant: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1OS(=O)(=O)c1ccc(C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1N=[N+]=[N-]
Yield: 100.4 %

Procedure:
(3S,4R)-Benzyl 3-ethyl-4-(tosyloxy)pyrrolidine-1-carboxylate (21.25 g, 52.7 mmol) in DMF (50 mL) was added to a solution of sodium azide (8.56 g, 132 mmol) in DMF (50 mL) and water (30 mL) and heated to a bath temp. of 100° C. overnight. The reaction mixture was diluted with ethyl acetate/water and stirred. The organic layer was washed with water, dried (Na2SO4) and concentrated to give (3S,4S)-benzyl 3-azido-4-ethylpyrrolidine-1-carboxylate (14.5 g, 52.9 mmol, 100% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 7.34-7.41 (5H, m), 5.13-5.21 (2H, m), 4.08-4.11 (1H, m), LCMS: M+23=299, t=2.15 min.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:8]([Cl:9])=[C:7]([C:10](Cl)=[O:11])[S:6][N:5]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C1COCC1>[Cl:3][C:4]1[C:8]([Cl:9])=[C:7]([CH2:10][OH:11])[S:6][N:5]=1
Reactant: O=C(Cl)c1snc(Cl)c1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1snc(Cl)c1Cl
Reaction time: 0.5 h
Yield: 81 %

Procedure:
1.9 g (50.5 mmol) of sodium borohydride was suspended in 40 ml of water. To the resulting suspension was dropwise added, at 10 to 15° C., a solution of the 3,4-dichloroisothiazole-5-carbonyl chloride dissolved in THF (4 ml). Stirring was conducted at 15° C. for 30 minutes. Then, an aqueous citric acid solution was added to make the mixture weakly acidic and extraction with ethyl acetate was conducted. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The resulting crystals were washed with hexane to obtain 3.0 g (yield: 81%) of (3,4-dichloroisothiazol-5-yl)methanol as colorless crystals (melting point: 94 to 95° C.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[CH:11]=[C:12]([CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([OH:22])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn].O>[O:22]=[C:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][C:5]=2[C:10]2[CH:11]=[C:12]([CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)[NH:1]1
Reactant: CCO
Reactant: O=C(O)Cc1cccc(-c2cccc3[nH]ccc23)c1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cc1cccc(-c2cccc3c2CC(=O)N3)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the suspension of [3-(1H-indol-4-yl)phenyl]-acetic acid (3.52 g, 14 mmol) in t-BuOH: ethanol: acetic acid (93 mL: 56 mL: 67 mL) was added pyridinium tribromide (14.14 g, 42 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added acetic acid (60 mL). Water (2 mL) and zinc dust (14 g, excess) were added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (3×), sat. NaHCO3, brine, dried over Na2SO4 and concentrated to give 2.59 g (70%) of [3-2-oxo-2,3-dihydro-1H-indol-4-yl)-phenyl]-acetic acid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N-:5]=[N+:6]=[N-:7].[Na+].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:22]=1)[C:15](=[O:21])[C:16]([C:19]#[N:20])=[CH:17][N:18]=2.Cl>O1CCCC1>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH:22]=1)[C:15](=[O:21])[C:16]([C:19]1[NH:20][N:7]=[N:6][N:5]=1)=[CH:17][N:18]=2
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cnc2ccc(Cl)cn2c1=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=c1c(-c2nnn[nH]2)cnc2ccc(Cl)cn12
Temperature: 0 °C
Yield: 49.5 %

Procedure:
Aluminum chloride (0.72 g., 5.45 mmoles) was carefully added to cold (-30°) tetrahydrofuran (29 ml.). Sodium azide (1.06 g., 16.27 mmoles) was then added and the mixture heated under reflux for 30 minutes. 7-Chloro-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbonitrile (1.0 g., 4.47 mmoles) was added and the mixture heated under reflux for 18 hours. The cooled mixture was poured onto 500 ml. of ice water and the resulting mixture acidified to pH 2 with 6N hydrochloric acid. The precipitate was collected and recrystallized from N,N-dimethylformamide to give the title compound (0.55 g., 49.5%), m.p. 300°-301° (decomp).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[N:4][C:3]=1[CH2:26][CH:27]1[C:39](=[O:40])[C:38]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][C:30]=2[CH2:29][CH2:28]1.[H-].[Na+].C1(C)C=CC(S(O[CH2:53][CH:54]2[CH2:58][CH2:57][CH2:56][CH2:55]2)(=O)=O)=CC=1>>[CH:54]1([CH2:53][N:31]2[C:30]3[CH2:29][CH2:28][CH:27]([CH2:26][C:3]4[N:4]=[CH:5][N:6]([C:7]([C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:2]=4[CH3:1])[C:39](=[O:40])[C:38]=3[C:37]3[C:32]2=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:58][CH2:57][CH2:56][CH2:55]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Reactant: Cc1c(CC2CCc3[nH]c4ccccc4c3C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: Cc1c(CC2CCc3c(c4ccccc4n3CC3CCCC3)C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 48.9 %

Procedure:
Using the procedures described above for Intermediate 10, 1,2,3,9-tetrahydro-3-[[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]methyl]-4H-carbazol-4-one (500 mg) was treated with sodium hydride (73% dispersion in oil; 38 mg) and was then stirred with cyclopentanemethanol (p-toluenesulphonate) (292 mg) for 24 h. Work up and FCC was described above gave the title compound (283 mg), p.p. 177°-179°.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:11]([CH3:27])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)(=[O:18])=[O:17])[CH:11]([CH3:27])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N2c3ccc(Br)cc3-c3ccccc3C2C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CC1c2ccccc2-c2cc(Br)ccc2N1S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
A stirred suspension of 2-bromo-5-[(4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (333 mg, 0.75 mmol) and cyclohexene (1.64 g, 20 mmol) was treated at room temperature under nitrogen with a solution of 1.0 M boron tribromide in dichloromethane (5 mL, 5 mmol). After stirring for approximately four hours at room temperature, the reaction was quenched with methanol (20 mL) and diluted with dichloromethane. The mixture was washed sequentially with an aqueous potassium carbonate solution, a saturated, aqueous sodium chloride solution, and water. The organic phase was dried over anhydrous sodium sulfate, filtered through a short column of silica gel, and eluted with ethyl acetate. The ethyl acetate phase was evaporated in vacuo to a crude orange residue (0.5 g). The crude residue was purified by preparative chromatography on a Biotage® 40 Mi column of pre-packed silica gel (90 g) with gradient elution of between 10% to 30% methyl tert-butyl ether in hexane at a flow rate of 50 mL/min; and afforded, after evaporation of the solvent, a colorless oil. Crystallization of the colorless oil from a mixture of diethyl ether-hexane yielded the title compound (0.220 g, 0.51 mmol, 68%) as a homogeneous, off-white, crystalline solid, m.p. 201-203° C.;
Reaction SMILES: CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.[C:22]([P:28](=[O:33])([OH:32])[O:29][CH2:30][CH3:31])#[C:23][CH2:24][CH2:25][CH2:26][CH3:27].[CH2:34]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:35][C:36]#[CH:37]>[Au].ClC(Cl)C>[CH2:30]([O:29][P:28]1(=[O:32])[CH:22]=[C:23]([CH2:24][CH2:25][CH2:26][CH3:27])[CH:37]=[C:36]([CH2:35][CH2:34][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:33]1)[CH3:31]
Reactant: CCCCC#CP(=O)(O)OCC
Reactant: C#CCCc1ccccc1
Agent: [Au]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: CC(Cl)Cl
Product: CCCCC1=CP(=O)(OCC)OC(CCc2ccccc2)=C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67 %

Procedure:
A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tert-butylphosphine] (11.3 mg, 0.015 mmol) was put into a reaction container, and dichloroethane (0.4 mL) was put thereinto. After stirring at room temperature for 5 minutes, ethyl hydrogen hex-1-ynylphosphonate (57.0 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto, and finally, but-3-ynylbenzene (78 mg, 0.6 mmol) was put thereinto. Then, when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain 2-ethoxy-4-n-butyl-6-phenethyl-1,2-oxaphosphorin 2-oxide (64.4 mg, 67%) which is a title compound.
Reaction SMILES: C(OC([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21](=[O:39])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][CH2:29][C:30]3[C:38]4[C:33](=[N:34][CH:35]=[CH:36][CH:37]=4)[NH:32][CH:31]=3)=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH3:18][C:16]1([CH3:19])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21](=[O:39])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[NH:28][CH2:29][C:30]3[C:38]4[C:33](=[N:34][CH:35]=[CH:36][CH:37]=4)[NH:32][CH:31]=3)=[CH:13][CH:14]=2)[CH2:9][NH:8][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3ccccc3NCc3c[nH]c4ncccc34)ccc2C(C)(C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CNCc2cc(NC(=O)c3ccccc3NCc3c[nH]c4ncccc34)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4,4-Dimethyl-7-{2-[(1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amino]-benzoylamino}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (Step B, 0.45 g, 0.86 mmol) was treated with 10 mL of 1/1 TFA/CH2Cl2 solution and stirred at RT for 1 h. The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography to obtain the titled compound as a white solid. MS (ES+): 426.1 (M+H)+. Calc'd for C26H27N5O-425.22.
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.[C:23]([NH:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])(=[O:27])[CH:24]([CH3:26])[CH3:25].N12CCCN=C1CCCCC2>CN(C)C=O>[C:23]([NH:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1)=[O:33])(=[O:27])[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)C(=O)NCCCC(=O)O
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)C(=O)NCCCC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 39.3 %

Procedure:
The procedure is as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (9.9 g) in anhydrous dimethylformamide (100 cc), 4-isobutyrylaminobutyric acid (5.2 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.6 g). The residue obtained is recrystallized in acetonitrile and then purified by chromatography on silica (0.063-0.2 mm; 130 g) contained in a column 3 cm in diameter [eluant: methylene chloride/methanol (98:2 by volume) mixture] collecting 25-cc fractions. Fractions 79 to 85 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is crystallized by stirring in isopropyl ether. 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 4-isobutyrylaminobutyrate (5.5 g), m.p. 208° C., is thereby obtained.
Reaction SMILES: C[CH:2](C)[C@@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)=[O:25])=[CH:19][CH:18]=3)[CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5].BrC1C=C2C(=CC=1)[C:45](=[O:49])N([C@@H](COC)C(OC)=O)C2.CC1(C)C(C)(C)OB(C2C=CC(NC(NC3C=CC=C(C(F)(F)F)C=3)=O)=CC=2)O1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:45][O:49][CH2:2][C@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:36])[F:35])[CH:28]=4)=[O:25])=[CH:19][CH:18]=3)[CH:14]=2)[C:9]1=[O:37])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Reactant: COC[C@@H](C(=O)OC)N1Cc2cc(Br)ccc2C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)OB(c2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)OC1(C)C
Solvent: ClCCl
Product: COC[C@@H](C(=O)OC)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O

Procedure:
The compound of example 384 was prepared analogous to compound of example 360 by reaction of the compound of example 383, compound of example 357 and Pd(dppf)Cl2: CH2Cl2. The compound of example 384 was directly used for the preparation of compound of example 385 without purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:19][C:20]1([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:23]2[CH2:22][CH2:21][C:20]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:19])[CH2:25][CH2:24]2)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CC1(NC(=O)OC(C)(C)C)CCNCC1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Solvent: CO
Product: CC1(NC(=O)OC(C)(C)C)CCN(c2nc(Cl)nc3c2CCC3c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 168 h
Yield: 24.4 %

Procedure:
To a solution of 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) (400 mg, 1.413 mmol) in MeOH (14.100 mL) was added tert-butyl 4-methylpiperidin-4-ylcarbamate (303 mg, 1.413 mmol). The resulting mixture was stirred at RT for 7 days. At that time, the reaction mixture was concentrated in vacuo. Purification by flash chromatography (Silica, EtOAc/Hexanes) gave tert-butyl 1-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-4-methylpiperidin-4-ylcarbamate (159 mg, 0.345 mmol, 24.41% yield) as a yellow foam. LC-MS (M+H)+=461.2. 1H NMR (500 MHz, MeOD) δ ppm 7.12-7.22 (2 H, m), 6.98-7.09 (2 H, m), 4.19 (3 H, d, J=2.14 Hz), 3.38-3.56 (2 H, m), 3.13-3.25 (1 H, m), 3.02-3.13 (1 H, m), 2.53-2.67 (1 H, m), 2.11-2.24 (2 H, m), 1.96-2.08 (1 H, m), 1.53-1.65 (2 H, m), 1.47 (9 H, s), 1.37 (3 H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[Si:11]([C:15]#[CH:16])([CH3:14])([CH3:13])[CH3:12]>[Cu]I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:16]#[C:15][Si:11]([CH3:14])([CH3:13])[CH3:12])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C#C[Si](C)(C)C
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Product: C[Si](C)(C)C#Cc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Alternatively, 2-bromo-5-nitro-pyridine (1.22 g, 6.0 mmoles), TMS-acetylene (0.9 mL, 6.4 mmoles), CuI (11 mg, 0.06 mmoles) and dichlorobis(triphenylphosphine)palladium (II) (210 mg, 0.3 mmoles) were combined and flushed with dry nitrogen for 10 min. After this period the mix was solubilized with 24 mL of anhydrous triethylamine (degassed), and the mix was stirred at ambient temperature for 4 hours. After this period the reaction mix was evaporated in vacuo and purified directly using flash silica chromatography (0-10% EtOAc/Hexane) to yield 5-nitro-2-trimethylsilanylethynyl-pyridine as a brown solid. This material was dissolved into THF (10 mL) and to this solution was added 100 mg of TFAB (on silica gel, 1.0-1.5 mmole F/g resin). The solution was stirred at ambient temperature for 15 min. After this period the reaction mix was evaporated in vacuo purified directly using flash silica chromatography (0-20% EtOAc/Hexane) to yield 2-ethynyl-5-nitro-pyridine as a clear liquid. This product was combined with 10% Pd/C (90 mg) and ethanol (20 ml) and was flushed with dry nitrogen. After oxygen exclusion the stirring mix was flushed with H2 and stirred under H2 pressure (balloon) for 16 hours. After this period the reaction mixture was flushed with nitrogen and then filtered through Celite. The filtrate was evaporated in vacuo and purified using flash silica chromatography (0-10% MeOH/DCM w/0.1% diethylamine) to yield 6-ethyl-pyridin-3-ylamine (442 mg, 60%—3 steps) as a brownish residue. 1H-NMR (CDCl3): δ 8.05-8.02 (m, 1H), 6.96-6.93 (m, 2H), 3.55 (br s, 2H), 2.71 (q, J=7.3 Hz, 2H), 1.25 (t, J=7.3 Hz, 3H).