Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][NH2:6])=[O:4].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=O)=[CH:11][CH:10]=1>C1C=CC=CC=1.CO>[CH3:1][O:2][C:3]([NH:5][N:6]=[C:17]1[CH2:18][CH2:19][CH2:20][CH2:21][C:16]1=[CH:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:14][CH:13]=1)=[O:4]
Reactant: COC(=O)NN
Reactant: COc1ccc(C=C2CCCCC2=O)cc1
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)NN=C1CCCCC1=Cc1ccc(OC)cc1
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a solution of 22.68 g (0.252 moles) of N-methoxycarbonyl hydrazine in 100 ml of benzene a solution of 50.0 g (0.23 moles) of 2-(p-methoxyphenylmethylene)-cyclohexan-1-one in 300 ml of anhydrous methanol is added, under stirring. The reaction mixture is boiled for one hour, clarified with activated carbon, filtered and the filtrate is cooled. 63.05 g of the desired compound are obtained. Yield: 94.65%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][CH2:11][CH2:12]Br.[O:14]1[C:18]2([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[O:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][CH2:11][CH2:12][N:21]1[CH2:22][CH2:23][C:18]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:19][CH2:20]1
Reactant: BrCCCc1cc2ccccc2o1
Reactant: C1CC2(CCN1)OCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc2oc(CCCN3CCC4(CC3)OCCO4)cc2c1

Procedure:
A solution of 5 g of 3-(benzofuran-2-yl)-1-bromopropane, 3 g of 1, 4-dioxa-8-azaspiro[4.5]decane and 5.8 g of potassium carbonate in 200 ml of acetone is refluxed for 24 hours, and then evaporated to dryness. The residue is taken up in ethyl acetate, washed with water, dried and evaporated to yield the expected product.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([CH3:52])=[C:41]([N:43]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:44](=[O:46])[CH3:45])[CH:42]=1>>[C:44]([N:43]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:41]1[CH:42]=[C:37]([CH:38]=[CH:39][C:40]=1[CH3:52])[CH2:36][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1)(=[O:46])[CH3:45]
Reactant: COCCCN(C(C)=O)c1cc(CCl)ccc1C
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCN(C(C)=O)c1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C

Procedure:
Analogously to Method D, 0.238 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.147 g of N-(5-chloromethyl-2-methylphenyl)-N-(3-methoxypropyl)acetamide are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.12 (1:1 EtOAc-heptane); Rt=5.90.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:23]1[N:28]=[CH:27][C:26]2[CH:29]=[N:30][N:31]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[N:33]=3)[C:25]=2[CH:24]=1)CCC.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>CN(C)C(=O)C.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]>[F:38][C:34]1[N:33]=[C:32]([N:31]2[C:25]3[CH:24]=[C:23]([C:2]4[N:7]=[C:6]([NH:8][CH2:9][C:10]5[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=5)[CH:5]=[N:4][CH:3]=4)[N:28]=[CH:27][C:26]=3[CH:29]=[N:30]2)[CH:37]=[CH:36][CH:35]=1
Reactant: COc1ccc(CNc2cncc(Br)n2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2c(cn1)cnn2-c1cccc(F)n1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: COc1ccc(CNc2cncc(-c3cc4c(cn3)cnn4-c3cccc(F)n3)n2)cc1
Temperature: 150 °C
Yield: 74.5 %

Procedure:
A mixture of 6-bromo-N-[(4-methoxyphenyl)methyl]pyrazin-2-amine (0.9932 mmol; 768.8 mg), tributyl-[1-(6-fluoro-2-pyridyl)pyrazolo[4,3-c]pyridin-6-yl]stannane (2.173 mmol; 1093 mg), tricyclohexylphosphine (0.1192 mmol; 33.42 mg) and Tris(dibenzylideneacetone)dipalladium (0) (0.04966 mmol; 45.47 mg) in N,N-Dimethylacetamide (15 mL) was purged with Argon for 1 min. The reaction mixture was sealed and heated at 150° C. under microwave for 45 min. The mixture was partitioned between EtOAc and water. The organic layer was concentrated and the residue was purified on silica eluted with 0 to 100% EtOAc in Heptane to afford 6-[1-(6-fluoro-2-pyridyl)pyrazolo[4,3-c]pyridin-6-yl]-N-[(4-methoxyphenyl)methyl]pyrazin-2-amine (316.3 mg, 48%).
Reaction SMILES: C([O:8][NH:9][C:10](=[O:32])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:31]=[CH:30][C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]=2[CH:20]=1)C1C=CC=CC=1>O1CCCC1.[Pd]>[OH:8][NH:9][C:10](=[O:32])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:31]=[CH:30][C:29]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][C:21]=2[CH:20]=1
Reactant: O=C(CCCCCCCOc1ccc2c(c1)[nH]c1ccccc12)NOCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: O=C(CCCCCCCOc1ccc2c(c1)[nH]c1ccccc12)NO
Yield: 0 %

Procedure:
In a manner anologous to that of example 1(c), 8-(9H-carbazol-2-yloxy)-octanoic acid benzyloxyamide (90 mg, 430 mmol) in tetrahydrofuran was hydrogenated in the presence of palladium on barium sulfate to give the title compound as a crystalline solid (16 mg). MS (M−H+)=339.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH3:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[CH:2].[CH3:14][O:15][C:16](=[O:25])[CH2:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][O:12][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:21]3[CH:22]=[CH:23][C:18]([CH2:17][C:16]([O:15][CH3:14])=[O:25])=[CH:19][CH:20]=3)=[CH:4][CH:5]=2)[CH2:10][CH2:11]1
Reactant: C#Cc1ccc(C2(OC)CC2)cc1
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2ccc(C3(OC)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-methoxycyclopropyl)-benzene (Intermediate 61, 120.0 mg, 0.56 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 154.0 mg, 0.56 mmol) in triethyl amine (6 mL) was treated with copper(I)iodide (35.0 mg, 0.19 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (130 mg, 0.19 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-8% EtOAc-hexanes) afforded 140.0 mg (78%) of the title compound as an orange solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12](=[O:14])[N:11]([CH2:15][C:16]#[CH:17])[C:10](=[O:18])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:20]1[C:21]([NH:28][CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[N:22][C:23]([C:26]#[N:27])=[N:24][CH:25]=1.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:1]([N:8]1[CH2:9][C:10](=[O:18])[N:11]([CH2:15][C:16]#[C:17][C:20]2[C:21]([NH:28][CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[N:22][C:23]([C:26]#[N:27])=[N:24][CH:25]=2)[C:12](=[O:14])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C#CCN1C(=O)CN(Cc2ccccc2)CC1=O
Reactant: CC(C)(C)CNc1nc(C#N)ncc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)CNc1nc(C#N)ncc1C#CCN1C(=O)CN(Cc2ccccc2)CC1=O
Temperature: 85 °C
Yield: 93 %

Procedure:
To a solution of 4-benzyl-1-prop-2-ynyl-piperazine-2,6-dione (1.5 mmol) and 5-bromo-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile (1 mmol) in DMF (5 ml), triethylamine (3.0 mmol), dichlorobis(triphenylphosphine)palladium (II) (0.1 mmol) and copper (I) iodide (0.2 mmol) are added. The reaction mixture is heated at 85° C. ca. for 1 day. Saturated aqueous solution of ammonium chloride is added to the reaction mixture and then aqueous layer is extracted with two 50 ml portions of AcOEt. The combined extracts are washed with brine, dried over magnesium sulfate and concentrated under vacuum to give crude product, which is purified by silica gel column chromatography. Yield: 93%. Rf=0.3 (AcOEt only)
Reaction SMILES: [CH3:1][S:2][C:3](=O)[NH:4][CH2:5][C:6]1[C:11]([Cl:12])=[N:10][CH:9]=[CH:8][N:7]=1.CN(C=O)C.O=P(Cl)(Cl)Cl>CC#N>[Cl:12][C:11]1[C:6]2[N:7]([C:3]([S:2][CH3:1])=[N:4][CH:5]=2)[CH:8]=[CH:9][N:10]=1
Reactant: CSC(=O)NCc1nccnc1Cl
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CSc1ncc2c(Cl)nccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of (3-chloro-pyrazin-2-ylmethyl)-thiocarbamic acid S-methyl ester (3.05 g, 0.0140 mol) in MeCN (70 mL) were added DMF (4.3 mL, 0.056 mol) and POCl3 (5.2 mL, 0.056 mol) at 0° C. under nitrogen. The reaction mixture was slowly warmed to rt and stirred at rt overnight. LC-MS showed the SM was completely consumed. The solvent was evaporated under reduced pressure and the residue was cooled at 0° C. and diluted with EtOAc (250 mL), then quenched with sat. aq. NaHCO3 (100 mL). The mixture was washed brine (50 mL), and dried over anhydrous sodium sulfate. The crude material was purified by silica gel chromatography (Hexane EtOAc=80:20→70:30) to give the title compound as a light-yellow solid, 1.75 g, 63% yield. LC-MS (ES+): 200/202 (3/1) [MH+], and 1H NMR (CDCl3, 400 MHz): δ 2.71 (s, 3H), 7.40 (d, J=5.1 Hz, 1H), 7.74 (dd, J=5.1, 1.0 Hz, 1H), 7.90 (s, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=3[Cl:20])[C:6]=2[CH:5]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH:3]=1.O.[CH3:28][N:29](C=O)C>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].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.[Fe+2].[C-]#N.[C-]#N.[Zn+2].[Zn]>[Cl:20][C:14]1[C:15]([Cl:19])=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][N:7]1[C:6]2[CH:5]=[C:4]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH:3]=[C:2]([C:28]#[N:29])[C:10]=2[N:9]=[C:8]1[CH3:11]
Reactant: CN(C)C=O
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: Cc1nc2c(C#N)cc(N3CCOCC3)cc2n1Cc1cccc(Cl)c1Cl
Temperature: 100 °C
Reaction time: 20 h
Yield: 45 %

Procedure:
A mixture of 4-bromo-1-[(2,3-dichlorophenyl)methyl]-2-methyl-6-(4-morpholinyl)-1H-benzimidazole (1 g, 2.2 mmol), Pd(dba)2 (161 mg, 0.22 mmol), dppf (244 mg, 0.44 mmol), Zn(CN)2 (1030 mg, 8.8 mmol), water (1 mL), Fe(OAc)2 (191 mg, 1.1 mmol) and Zn powder (429 mg, 6.6 mmol) in DMF (50 mL) was stirred at 100° C. under N2 for 20 h. When TLC showed no starting material remaining, the reaction mixture was quenched with water and extracted with EtOAc (100 mL×3). The organic layer was washed with brine, dried over MgSO4, concentrated. The resulting residue was purified by silica gel chromatography eluted with EtOAc to give the product (400 mg, 45%), as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.43 (s, 3H), 3.11 (t, 4H, J=4.8 Hz), 3.72 (t, 4H, J=4.8 Hz), 5.60 (s, 2H), 6.30 (dd, 1H, J=1.2, 8.1 Hz), 7.25 (t, 1H, J=8.1 Hz), 7.35 (d, 1H, J=2.1 Hz), 7.42 (d, 1H, J=2.1 Hz), 7.60 (dd, 1H, J=1.2, 8.1 Hz); LC-MS: m/e=401 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[N:9][NH:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][CH:13]=1)=O.C1(P)C=CC=CC=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(=O)([O-])[O-].[Na+].[Na+].N>C(Cl)Cl.O>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[C:4]1[C:13]2[CH:14]=[C:15]([I:18])[CH:16]=[CH:17][C:12]=2[C:11]2[NH:10][N:9]=[CH:8][C:7]=2[N:6]=1
Reactant: O=C(Nc1cn[nH]c1-c1ccc(I)cc1)c1c(F)cccc1F
Agent: N
Agent: O=C([O-])[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Solvent: O
Product: Fc1cccc(F)c1-c1nc2cn[nH]c2c2ccc(I)cc12
Temperature: 25 °C
Reaction time: 23 h
Yield: 84 %

Procedure:
A 500 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 9.2 g of 2,6-difluoro-N-[5-(4-iodophenyl)-1H-pyrazol-4-yl]benzamide, 168 ml of phenylphosphine acid dichloride and 46.3 g of phosphorus pentoxide. After 23 h at 165° C., the mixture is cooled to RT and then poured into a mixture of 260 ml of water and 400 g of ice. The temperature rises to 40° C. Neutralization is carried out by slow addition of 930 ml of 3M sodium carbonate solution and then 110 ml of 28% aqueous ammonia. Extraction is carried out with once 1150 ml and 2 times 550 ml of AcOEt. The organic extracts are combined, washed with saturated NaCl solution and dried over MgSO4, and then concentrated under RP. The solid obtained is stirred in 220 ml of DCM at reflux for 15 min, cooled using an ice bath, and then filtered and washed with 2 times 28 ml of ice-cold DCM. Drying under vacuum at 40° C. gives 7.4 g of 5-(2,6-difluorophenyl)-7-iodo-1H-pyrazolo[4,3-c]isoquinoline (cream solid). MS (E/I): m/z=407 (M+); 1H NMR: 7.39 (t, J=8.0H, 2H); 7.71 (m, 1H); 7.99 (broad s, 1H); 8.33 (m, 2H); 8.45 (broad s, 1H); 14.35 (broad s, 1H); m.p. (Kofler bench)=260° C.
Reaction SMILES: [CH:1](=[O:5])[CH:2]([CH3:4])[CH3:3].[C:6](#[N:9])[CH:7]=[CH2:8].[OH-].[Na+]>O1CCOCC1.O.C1(C=CC(O)=CC=1)O>[CH3:3][C:2]([CH3:4])([CH:1]=[O:5])[CH2:8][CH2:7][C:6]#[N:9]
Reactant: C=CC#N
Reactant: CC(C)C=O
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C=O)CCC#N
Temperature: 65 °C
Yield: 48042.2 %

Procedure:
To a solution of 64.8 g (0.898 mmol, 51.45 mL) of isobutyraldehyde in 300 mL of dry dioxane was added 300 mg of hydroquinone (0.0027 mmol) and 60.0 g (1.13 mmol; 1.26 eq; 48.4 mL) of acrylonitrile. To this stirred solution was added all at once a freshly prepared solution of 3 g of NaOH dissolved in 60 mL of water and the whole was heated at 65° C. during 150 min. After cooling to 20° C., removal of the solvents under aspirator vacuum gave a residue which was partitioned between water and CH2Cl2. After separation, the aqueous layer was extracted 3 times with CH2Cl2 and the combined organic layers dried over Na2SO4 and concentrated under vacuum (aspirator). The crude residue was distilled under vacuum (81° C./1 mm Hg) to yield 54 g (49%) of 4,4-dimethyl-5-oxovaleronitrile.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([C:31]([CH:28]2[CH2:30][CH2:29]2)=[O:32])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: O=C(Cl)C1CC1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)C(=O)C1CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: C(O)(=O)C.[C:5]([NH2:9])(=[NH:8])[CH2:6][CH3:7].[C:10](OC)(=[O:16])[CH2:11][C:12](OC)=[O:13]>C[O-].[Na+]>[OH:13][C:12]1[CH:11]=[C:10]([OH:16])[N:9]=[C:5]([CH2:6][CH3:7])[N:8]=1
Reactant: COC(=O)CC(=O)OC
Reactant: CCC(=N)N
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1nc(O)cc(O)n1
Yield: 84.1 %

Procedure:
Using the procedure of Example 1, Part B1, 18.5 g (0.14 mole) of propionamidine acetate and 90 ml of 25% sodium methoxide were reacted with dimethyl malonate (0.14 mole) to provide 16.5 g (89.5%) of 4,6-dihydroxy-2-ethylpyrimidine according to Step (1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:2]1.CO[C:16](=[O:33])[C:17]([C:19]1[C:29]2=[C:30]3[C:25](=[CH:26][CH:27]=[CH:28]2)[CH2:24][C:23]([CH3:32])([CH3:31])[CH2:22][N:21]3[CH:20]=1)=O>>[CH3:32][C:23]1([CH3:31])[CH2:24][C:25]2[C:30]3=[C:29]([C:19]([C:17]4[C:16](=[O:33])[NH:13][C:11](=[O:12])[C:10]=4[C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][CH:2]=4)=[CH:20][N:21]3[CH2:22]1)[CH:28]=[CH:27][CH:26]=2
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CC(C)(C)C2
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Product: CC1(C)Cc2cccc3c(C4=C(c5c[nH]c6ccccc56)C(=O)NC4=O)cn(c23)C1

Procedure:
Beginning with (indol-3-yl)acetamide and (5,5-dimethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxo-acetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]3[CH2:23][CH2:22][CH2:21][C:10]=3[N:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[N:12]=2)[N:5]=[C:4]([NH:24][C:25](=[O:29])[CH2:26][O:27][CH3:28])[C:3]=1[O:30][CH3:31].Cl.Br[C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.O.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][N:11]1[C:10]2[CH2:21][CH2:22][CH2:23][C:9]=2[C:8]([C:6]2[N:5]=[C:4]([NH:24][C:25](=[O:29])[CH2:26][O:27][CH3:28])[C:3]([O:30][CH3:31])=[C:2]([NH:1][C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)[N:7]=2)=[N:12]1
Reactant: Brc1ccncc1
Reactant: COCC(=O)Nc1nc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc(N)c1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CN(C)C=O
Solvent: O
Product: COCC(=O)Nc1nc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc(Nc2ccncc2)c1OC
Temperature: 105 °C
Reaction time: 2 h

Procedure:
50 mg of N-{6-amino-2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]-pyrazol-3-yl]-5-methoxypyrimidin-4-yl}-2-methoxyacetamide 1-7-1 (0.12 mmol, 1.00 eq.), 25 mg of 4-bromopyridine hydrochloride (1:1) (0.13 mmol, 1.10 eq.), mg of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.02 mmol, 0.15 eq.), 115 mg of caesium carbonate (0.36 mmol, 3.00 eq.) and 2.6 mg of palladium diacetate (0.012 mmol, 0.1 eq.) were suspended in 0.5 mL of dry DMF and stirred under nitrogen atmosphere at 105° C. bath temperature for two h. The reaction mixture was diluted with water, the pH was adjusted to 7.5 using 4N aqueous hydrochloric acid and the crude product was extracted with DCM. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography yielding 29 mg (0.06 mmol, 49%) of analytically pure target compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N+:9]2[O-])=[CH:4][CH:3]=1.C[Si]([C:17]#[N:18])(C)C.CN(C)C(Cl)=O>ClCCCl>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:17]#[N:18])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#N
Reactant: Cc1ccc2ccc[n+]([O-])c2c1
Agent: CN(C)C(=O)Cl
Solvent: ClCCCl
Product: Cc1ccc2ccc(C#N)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-methylquinoline-1-oxide (18.3 g, 115 mmol) in 1,2-dichloroethane (750 mL) was added trimethylsilyl cyanide (30.8 mL, 230 mmol) followed by dimethylcarbamoyl chloride (21.2 mL, 230 mmol) and stirred at room temperature overnight. The solution was quenched slowly with a sat. solution of sodium bicarbonate, diluted with water and extracted two times with dichloromethane. The combined organic extracts were dried (MgSO4) and concentrated to give the crude compound. Flash chromatography of the residue on silica gel (eluting with 3% acetone in dichloromethane) provided the title compound. 1H NMR (400 MHz, acetone-d6): δ 8.56 (d, 1H), 8.03 (d, 1H), 7.95 (s, 1H), 7.88 (d, 1H), 7.67 (d, 1H), 2.62 (s, 3H).
Reaction SMILES: C(OC([O:8][NH:9][C:10]([C:12]1[S:16][C:15]2[CH:17]=[C:18]([CH:21]=O)[CH:19]=[CH:20][C:14]=2[CH:13]=1)=[O:11])C)C(C)C.[CH:23]1([O:28][C:29](=[O:50])[C@@H:30]([NH:42]C(OC(C)(C)C)=O)[CH2:31][CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37]([CH2:40][NH2:41])=[CH:36][CH:35]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:23]1([O:28][C:29](=[O:50])[C@@H:30]([NH2:42])[CH2:31][CH2:32][O:33][C:34]2[CH:35]=[CH:36][C:37]([CH2:40][NH:41][CH2:21][C:18]3[CH:19]=[CH:20][C:14]4[CH:13]=[C:12]([C:10](=[O:11])[NH:9][OH:8])[S:16][C:15]=4[CH:17]=3)=[CH:38][CH:39]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC(C)COC(C)ONC(=O)c1cc2ccc(C=O)cc2s1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOc1ccc(CN)cc1)C(=O)OC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: ClCCCl
Product: N[C@@H](CCOc1ccc(CNCc2ccc3cc(C(=O)NO)sc3c2)cc1)C(=O)OC1CCCC1
Reaction time: 18 h
Yield: 15.1 %

Procedure:
To a stirred solution of 6-formyl-benzo[b]thiophene-2-carboxylic acid (1-isobutoxy-ethoxy) amide (Scheme 13) (0.128 g, 0.40 mmol) in DCE (5 ml) was added (S)-4-(4-aminomethyl-phenoxy)-2-tert-butoxycarbonylamino-butyric acid cyclopentyl ester (0.156 g, 0.40 mmol) followed by sodium triacetoxyborohydride (0.253 g, 1.1 g mmol) and glacial acetic acid (0.023 ml, 0.40 mmol). After stirring for 18 hours the mixture was quenched using saturated aqueous NaHCO3 solution (5 ml). The organic layer was separated, washed further with saturated aqueous NaHCO3 solution (2×5 ml), dried (MgSO4) and the solvent removed in vacuo to give a yellow residue. The residue was redissolved in a TFA/DCM solution (1:1, 5 ml). After stirring the solution for 45 minutes the solvent was removed in vacuo. Purification by preparative HPLC gave the product as a white solid (0.030 g, 15% yield). LCMS purity 96.1%, m/z 498 [M++H]+, 1H NMR (300 MHz, DMSO), δ: 1.50-1.90 (9H, m, CH2×4, CH), 2.25 (2H, m, CH2), 4.10-4.40 (7H, m, CH2×3, CH), 5.20 (1H, m, CH), 6.95 (2H, d, ArH×2, J=8.6 Hz), 7.45 (2H, d, ArH×2, J=8.6 Hz), 7.55 (1H, d, ArH, J=7.8 Hz), 8.00 (2H, m, ArH×2), 8.15 (1H, s, ArH), 8.40 (2H, br s, ArH×2), 9.20 (2H, m ArH×2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][C@H:7]1[C@@H:16]([OH:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=2)[O:9][CH2:8]1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28]Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][C@H:7]1[C@@H:16]([OH:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:28][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)[CH:14]=2)[O:9][CH2:8]1
Reactant: ClCc1ccccn1
Reactant: COc1cccc(O[C@@H]2COc3ccc(O)cc3[C@@H]2O)c1
Solvent: ClCCl
Product: COc1cccc(O[C@@H]2COc3ccc(OCc4ccccn4)cc3[C@@H]2O)c1

Procedure:
By the method of Example 13, using flash chromatography with 40:9:1 CH2Cl2 :hexane:isopropanol as eluant and recrystallization from 1:1 toluene:hexane, the title product of Example 25 (0.37 g, 0.00128 mol) and 2-picolyl chloride were converted to present title product, 0.15 g (30%), m.p. 105°-107° C. MS (m/e) calculated: 379.1424, found: 379.1394.