Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[NH:4][CH:5]=[CH:6][CH:7]=1)=[O:2].[OH-].[K+].CS(C)=O.[Br:14][CH2:15][CH2:16]Br>O>[Br:14][CH2:15][CH2:16][N:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[CH:1]=[O:2]
Reactant: O=Cc1ccc[nH]1
Reactant: BrCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1cccn1CCBr

Procedure:
A mixture of 2-formylpyrrole (1 g), potassium hydroxide (2.3 g) and dry DMSO (20 mL) was stirred under nitrogen atmosphere. 1,2-dibromoethane (7.9 g) was added dropwise at 20-25° C. and stirred till the reaction is complete. Water (50 mL) was added and the reaction mixture was extracted with diethyl ether (3×50 mL). The combined organic layer was washed with water (30 mL), followed by brine (30 mL) and was dried over Na2SO4. The solvent was evaporated and the compound obtained was purified by column chromatography (silica gel 100-200) using ethyl acetate:hexane (2:8) as an eluent to obtain the title compound.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([N:5]1[CH2:20][CH2:19][CH2:18][C@H:6]1[C:7]([NH:9][C@H:10]([C:15]([NH2:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])=[O:4]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:1][CH2:2][C:3]([N:5]1[CH2:20][CH2:19][CH2:18][C@H:6]1[C:7]([NH:9][C@H:10]([C:15]([NH2:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])=[O:4]
Reactant: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C)C(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)[C@@H]1CCCN1C(=O)CN)C(N)=O
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Boc-Gly-Pro-Nleu-NH2 (3.5 g, 0.0089 mol.) was dissolved in a solution of 30% TFA in DCM (50 ml). The solution was stirred for 40 minutes. The DCM and TFA were removed under reduced pressure, and 3×50 ml benzene were added and distilled under reduced pressure to remove trace TFA. The resulting mixture was dissolved in 30 ml methanol and the solution was chilled to 0° C. HCl/dioxane (4N, 10 ml) was added to the solution to transfer the product from TFA salt to HCl salt. Ethyl ether (200 ml) was added to the solution and a precipitation formed. The ether was removed by filtration and a white solid product was obtained (2.9 g, 87%). Analytical RP-HPLC chromatogram, single peak, RT=15.7 min. (5-15% B in 30 min.). FAB-MS, observed (M+H)+=285. 1H-NMR (500 MHz, DMSO-d6, 25° C., assignment by TOCSY) δ8.03 (m, 3H, Gly-NH3), 7.65 (s, C-terminal NH2), 7.46 (s, C-terminal NH2), 7.34 (s, C-terminal NH2), 7.24 (d, C-terminal NH2), 7.08 (s, C-terminal NH2), 6.92 (s, C-terminal NH2), 4.94 (d, Pro-α), 4.76 (m, Pro-α), 4.59 (m, Pro-α), 4.25-3.52 (sets of bands, Nleu-α, Gly-α), 3.52-3.44 (m, Pro-δ), 3.42-2.70 (sets of bands, Gly-α, Nleu-β), 2.36-1.65 (sets of bands, Pro-β, Pro-γ, Nleu-γ), 0.90 (m, Nleu-δ), 0.79 (m, Nleu-δ).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH:9]([C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1)=[O:10]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2[CH:15]=[CH:16][C:11]([CH:9]=[O:10])=[CH:12][CH:13]=2)=[N:3][CH:4]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Brc1ccc(Br)nc1
Product: O=Cc1ccc(-c2ccc(Br)cn2)cc1
Yield: 71 %

Procedure:
The same procedure described for 1 was used by employing 2,5-dibromopyridine (1 equiv.) and 4-formylphenyl boronic acid (1 equiv.). Yield 71%, mp 120-121° C. 1H NMR (DMSO-d6); δ 7.97 (d, J=8.4 Hz, 2H), 8.04 (d, J=8.7 Hz, 1H), 8.16 (dd, J=2.4, 8.7 Hz, 1H), 8.26 (d, J=8.4 Hz, 2H), 8.80 (d, J=2.4 Hz, 1H), 10.08 (s, 1H). MS (ESI) m/e (rel. int.): 262 (M+, 100), 232 (30), 153 (55). Anal. Calc. for C12H8BrNO: C %, 54.99; H %, 3.08. Found C %, 54.75; H %, 3.14.
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[C:31]([CH3:43])[CH:30]=3)[C:12]3[C:13]([F:28])=[CH:14][C:15]([O:20][CH2:21][CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[C:16]([O:18][CH3:19])[C:17]=3[C:8]=2[C:7]([CH3:44])=[N:6]1)([CH3:4])[CH3:3].Cl[CH:46](Cl)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[CH3:4][C:2]([N:5]1[C:9]2[N:10]=[C:11]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[C:31]([CH3:43])[CH:30]=3)[C:12]3[C:13]([F:28])=[CH:14][C:15]([O:20][CH2:21][CH:22]4[CH2:23][CH2:24][N:25]([CH3:46])[CH2:26][CH2:27]4)=[C:16]([O:18][CH3:19])[C:17]=3[C:8]=2[C:7]([CH3:44])=[N:6]1)([CH3:1])[CH3:3]
Reactant: CC(Cl)Cl
Reactant: COc1c(OCC2CCNCC2)cc(F)c2c(-c3ccc(OCc4ccccc4)c(C)c3)nc3c(c(C)nn3C(C)(C)C)c12
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1c(OCC2CCN(C)CC2)cc(F)c2c(-c3ccc(OCc4ccccc4)c(C)c3)nc3c(c(C)nn3C(C)(C)C)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To 3-(1,1-dimethylethyl)-6-fluoro-1-methyl-9-(methyloxy)-5-{3-methyl-4-[(phenylmethyl)oxy]phenyl}-8-[(piperidin-4-ylmethyl)oxy]-3H-pyrazolo[3,4-c]iso-quinoline (159 mg, 0.26 mmol) was added dichloroethane (2 mL), 37% aqueous formaldehyde (40 μL, 0.52 mmol), and sodium triacetoxyborohydride (110 mg, 0.52 mmol). The mixture was stirred for 1 h at rt. Water and CH2Cl2 were added, and the layers were partitioned. The aqueous phase was extracted with CH2Cl2. The organic extracts were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (90% CH2Cl2, 10% methanol) to provide 83.1 mg of To 3-(1,1-dimethylethyl)-6-fluoro-1-methyl-9-(methyloxy)-5-{3-methyl-4-[(phenylmethyl)oxy]phenyl}-8-{[(1-methylpiperidin-4-yl)methyl]oxy}-3H-pyrazolo[3,4-c]isoquinoline (0.136 mmol, 52% yield) as a yellow film. 1H NMR (400 MHz, CDCl3): δ 7.49-7.32 (m, 7H), 6.96 (d, 1H), 6.81 (d, 1H), 5.15 (s, 2H), 3.98 (d, 2H), 3.89 (s, 3H), 3.10 (d, 2H), 2.87 (s, 3H), 2.40 (s, 3H), 2.36 (s, 3H), 2.17 (br t, 2H), 2.03-1.96 (m, 3H), 1.84 (s, 9H), 1.62 (m, 2H); MS (EI) for C37H43FN4O3: 611 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:23][C:24]1[O:25][CH:26]=[CH:27][CH:28]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[N:14]([CH2:23][C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: BrCc1ccco1
Reactant: CCOC(=O)N1CCC(c2c[nH]c3cc(F)ccc23)CC1
Product: CCOC(=O)N1CCC(c2cn(Cc3ccco3)c3cc(F)ccc23)CC1
Reaction time: 5 h
Yield: 100.5 %

Procedure:
This compound was obtained following procedure described in example 13 (part B) at room temperature for 5 hours, starting with 5 g (17.2 mmol) of 4-(6-fluoro-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were and 3.2 g (20 mmol) of 2-bromomethyl-furan. After standard work-up, 6.4 g (99% of yield) of 4-(6-fluoro-1-furan-2-ylmethyl-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [CH:1]([CH:4]1[CH2:6][O:5]1)([CH3:3])[CH3:2].[NH:7]1[CH:11]=[CH:10][N:9]=[CH:8]1>C(#N)C>[N:7]1([CH2:6][CH:4]([OH:5])[CH:1]([CH3:3])[CH3:2])[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: CC(C)C1CO1
Reactant: c1c[nH]cn1
Solvent: CC#N
Product: CC(C)C(O)Cn1ccnc1
Yield: 46 %

Procedure:
A solution of 2-isopropyloxirane (2.28 g, 26 mmol) and imidazole (1.80 g, 26 mmol) in acetonitrile (25 mL) was stirred at reflux for 16 h. The mixture was concentrated, and the residue was purified by flash column chromatography (SiO2, CH2Cl2-methanol-ammonium hydroxide 80:20:1) to give 1-(1H-imidazol-1-yl)-3-methyl-2-butanol as a yellow oil, 1.88 g, 46% yield. NMR spectrum was consistent with structure. MS EI: M+• 154.1103 (M+• −154.1106). 4. 6-hydroxy-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Cl[C:17]1[O:18][CH:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:21]=1.CCN(C(C)C)C(C)C>CCO>[CH2:25]([O:24][C:22]([C:20]1[N:21]=[C:17]([N:8]2[CH2:7][CH2:6][CH:5]([O:4][C:3]3[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:2]=3[Br:1])[CH2:10][CH2:9]2)[O:18][CH:19]=1)=[O:23])[CH3:26]
Reactant: Fc1ccc(Br)c(OC2CCNCC2)c1
Reactant: CCOC(=O)c1coc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)c1coc(N2CCC(Oc3cc(F)ccc3Br)CC2)n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-(2-bromo-5-fluorophenoxy)piperidine (3.281 g, 11.97 mmol) in EtOH (28.5 mL) was added ethyl 2-chlorooxazole-4-carboxylate (1 g, 5.70 mmol) and DIPEA (1.990 mL, 11.39 mmol). The reaction mixture was stirred at rt for 5 h. The solvent was evaporated under reduced pressure. The residue was diluted with 1N HCl and extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and evaporated under reduced pressure to give the title compound.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.Cl[C:10]1[CH:16]=[C:15]([C:17]([F:26])([C:22]([F:25])([F:24])[F:23])[C:18]([Br:21])([F:20])[F:19])[CH:14]=[CH:13][C:11]=1[NH2:12]>C(#N)C>[Br:1][C:10]1[CH:16]=[C:15]([C:17]([F:26])([C:22]([F:25])([F:24])[F:23])[C:18]([Br:21])([F:20])[F:19])[CH:14]=[CH:13][C:11]=1[NH2:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)Br)cc1Cl
Solvent: CC#N
Product: Nc1ccc(C(F)(C(F)(F)F)C(F)(F)Br)cc1Br

Procedure:
22.11 g (0.12 mol) of N-bromosuccinimide were added at 60° C. to a mixture of 40.0 g (0.12 mol) of 4-(1-bromo-1,1,2,3,3,3-hexafluoro-2-propyl)aniline from Example 6 and 125 ml of acetonitrile, and the resulting mixture was heated to reflux for 3 hours. Subsequently, the solvent was for the most part distilled off, the residue was washed with 100 ml of 1N NaOH solution, the organic phase was dried over sodium sulphate and finally the remaining solvent was removed under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=O.O.[NH2:18][NH2:19]>C(O)CO>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=[N:18][NH2:19]
Reactant: COc1cccc(C(=O)c2sccc2Br)c1
Reactant: NN
Solvent: OCCO
Solvent: O
Product: COc1cccc(C(=NN)c2sccc2Br)c1
Temperature: 130 °C

Procedure:
A mixture of (3-bromothien-2-yl) (3-methoxyphenyl)methanone (10.0 g), hydrazine hydrate (10 ml, above 99% purity), and 75 ml of ethylene glycol was heated at 130° C. for three hours. The reaction mixture was then quenched with water and extracted with ether. The ether solution was washed three times with water and dried over anhydrous magnesium sulfate. The ether was then evaporated to give 5.5 g of an oil. This was then column chromatographed on a silica gel column packed in hexane using 15% ether/hexane as an eluent. The solid from the column was then recrystallized from ether/hexane.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[C:14]([CH2:16][C:17]([O:19]CC)=[O:18])#[N:15].N1CCCCC1>C(O)C>[C:14]([C:16](=[CH:1][C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1)[C:17]([OH:19])=[O:18])#[N:15]
Reactant: CCOC(=O)CC#N
Reactant: COc1cc(C=O)cc(OC)c1O
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(C=C(C#N)C(=O)O)cc(OC)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.1 %

Procedure:
To a solution of 2 g (11.0 mmol) of syringaldehyde and 1.2 ml (11.3 mmol) of ethyl cyanoacetate in 30 ml of ethanol was added 2 ml of piperidine, and the mixture was stirred at room temperature for 16 hours. The solution was evaporated under reduced pressure, subsequently the residue was acidified by adding 1N hydrochloric acid and extracted with 200 ml of ethyl acetate. The organic layer was washed with water, and concentrated under reduced pressure. A formed precipitate was washed with ethanol, and then dissolved in a mixed solvent of tetrahydrofuran and methanol (30 ml, 20 ml). To the solution was added potassium hydroxide solution (3.0 g/30 ml), and the mixture was stirred at room temperature for 1.5 hours. A 100 ml of water and 50 ml of ethyl acetate was added to the solution for separation of each layer. An aqueous layer was acidified with conc. hydrochloric acid, and a formed precipitate was filtrated to give 1.4 g (yield 51.1%) of objective α-cyano-3,5-dimethoxy-4-hydroxycinnamic acid.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[S:20][CH:19]=[C:18]([CH3:21])[N:7]2[C:8](=[O:17])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[CH3:3].Br[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][NH:27]2.C(N(CC)C(C)C)(C)C>C(O)C>[F:16][C:12]1[CH:11]=[C:10]([C:9]2[C:8](=[O:17])[N:7]3[C:18]([CH3:21])=[CH:19][S:20][C:6]3=[N:5][C:4]=2[CH:2]([NH:1][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][NH:27]3)[CH3:3])[CH:15]=[CH:14][CH:13]=1
Reactant: Brc1ncnc2[nH]cnc12
Reactant: Cc1csc2nc(C(C)N)c(-c3cccc(F)c3)c(=O)n12
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1csc2nc(C(C)Nc3ncnc4[nH]cnc34)c(-c3cccc(F)c3)c(=O)n12
Temperature: 110 °C
Yield: 43.8 %

Procedure:
A mixture of single enantiomer 7-(1-aminoethyl)-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.125 g, 0.412 mmol) made from above, 6-bromo-9H-purine (0.148 g, 0.742 mmol), and N,N-diisopropylethylamine (0.144 mL, 0.824 mmol) in ethanol (1.5 mL) was heated at 110° C. overnight. The mixture was filtered, and the filtrate was purified on preparative-LCMS (XBridge C18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to give the desired product (0.076 g, 44%). LCMS calculated for C20H17FN7OS (M+H)+: m/z=422.1. Found: 422.0. 1H NMR (DMSO-d6, 500 MHz) δ 8.05 (2H, s), 7.43 (1H, m), 7.24˜7.14 (5H, m), 6.99 (1H, s), 5.08 (1H, m), 2.59 (3H, s), 1.29 (3H, d, J=6.5 Hz) ppm. 19F NMR (DMSO-d6, 376.3 MHz) δ −114 ppm.
Reaction SMILES: [N:1]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:3][CH:2]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:19][C:18]([F:20])([F:21])[C:15]1[CH:14]=[CH:13][C:12]([NH:11][C:4]2[C:5]3[CH2:10][CH2:9][N:8]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:7][C:6]=3[N:1]=[CH:2][N:3]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccccc1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CCN(c2ccccc2)C3)cc1
Reaction time: 6 h
Yield: 6.4 %

Procedure:
The (5,6,7,8-Tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-(4-trifluoromethylphenyl)amine (100 mg, 0.34 mmol) was dissolved in anhydrous THF (2 mL). To the mixture was added phenylboronic acid (83 mg, 0.68 mmol), Cu(OAc)2 (124 mg, 0.68 mmol) and triethylamine (0.68 g, 0.095 mL). The mixture was agitated for 6 h and the solvent was removed under the vacuum. The residue was purified using a gradient of ethyl acetate: hexane (0-100%) to give the desired compound as reddish powder (8.0 mg, 6.0%).
Reaction SMILES: Br[CH:2]1[CH2:5][CH2:4][CH2:3]1.[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[OH:15])[C:10]#[N:11].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][CH:2]1[CH2:5][CH2:4][CH2:3]1)[C:10]#[N:11]
Reactant: N#Cc1ccc(O)c(Br)c1
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(OC2CCC2)c(Br)c1
Yield: 86 %

Procedure:
Bromocyclobutane (2.7 g, 20.2 mmol), 3-bromo-4-hydroxybenzonitrile (2.0 g, 10.1 mmol), and K2CO3 (2.8 g, 20.2 mmol) were mixed in 5 mL of dimethylformamide and reacted at 60° C. for 72 hours. The mixture was diluted with ethyl acetate, washed with water, brine, dried with MgSO4, filtered, and the solvent removed under reduced pressure. The residue was chromatographed (SiO2) using a gradient from hexane to 30% ethyl acetate in hexane over 500 mL to afford the title compound. (2.2 g, 8.7 mmol, 86% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.69-1.82 (m, 1H), 1.87-2.00 (m, 1H), 2.21-2.35 (m, 2H), 2.45-2.57 (m, 2H), 4.69-4.79 (m, 1H), 6.76 (d, J=8.48 Hz, 1H), 7.53 (dd, J=8.48, 2.03 Hz, 1H), 7.82 (d, J=2.03 Hz, 1H). MS (DCI/NH3) m/z 251.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]([NH2:17])=[O:16])[CH:10]=2)=[CH:4][CH:3]=1.[CH3:18][N:19]1[C:23]([CH3:24])=[C:22]([C:25](O)=[O:26])[C:21](=[O:28])[N:20]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl.O>[CH3:18][N:19]1[C:23]([CH3:24])=[C:22]([C:25]([NH:1][C:2]2[N:7]=[CH:6][C:5]([O:8][C:9]3[CH:14]=[CH:13][N:12]=[C:11]([C:15]([NH2:17])=[O:16])[CH:10]=3)=[CH:4][CH:3]=2)=[O:26])[C:21](=[O:28])[N:20]1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: NC(=O)c1cc(Oc2ccc(N)nc2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)cn2)c(=O)n(-c2ccccc2)n1C
Temperature: 45 °C
Reaction time: 28 h
Yield: 25 %

Procedure:
To a suspension of 4-((6-aminopyridin-3-yl)oxy)picolinamide (230 mg, 1 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (237 mg, 1.02 mmol) in DCM (5 mL) was added EDCI (230 mg, 1.2 mmol) and HOAT (27 mg, 0.2 mmol). The reaction was stirred at 45° C. for 28 hours, then cooled to rt and diluted with water (10 mL) and DCM (20 mL). The organic phase was concentrated in vacuo and the residue was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=40/1) to give the title compound as a light grey solid (111 mg, 25%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[CH:8]=[N:9][N:10]([C:12](=[NH:14])[NH2:13])[CH:11]=1)=[O:6])[CH3:3].Cl[C:16]1[C:25](Cl)=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CN(C=O)C.O>[CH2:2]([O:4][C:5]([C:7]1[CH:8]=[N:9][N:10]([C:12]2[NH:13][C:16]3=[N:17][C:18]4[C:23]([N:24]=[C:25]3[N:14]=2)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:11]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cnn(C(=N)N)c1
Reactant: Clc1nc2ccccc2nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn(-c2nc3nc4ccccc4nc3[nH]2)c1
Yield: 42.2 %

Procedure:
A solution of 1-carbamimidoyl-1H-pyrazole-4-carboxylic acid ethyl ester hydrochloride (0.220 g, 1.00 mmol), 2,3-dichloro-quinoxaline (200 mg, 1.00 mmol), and Cs2CO3 (1.63 g, 5.00 mmol) in DMF (2 mL) was stirred for 4 h. H2O (3 mL) was added and the mixture was acidified to pH 2 with aqueous 1M HCl to form a white precipitate. The precipitate was filtered, triturated with anhydrous EtOH (2 mL), and filtered to yield the titled compound (0.130 g, 43%). MS (CI): mass calcd. for C15H12N6O2, 308.1; m/z found, 309.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 9.08 (s, 1H), 8.23 (s, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.75 (t, J=7.1 Hz, 1H), 7.59 (t, J=7.5 Hz, 1H), 4.31 (q, J=7.1 Hz, 2H), 1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[CH:10][NH:11][C:5]=2[CH:4]=[N:3]1.[H-].[Na+].[F:14][C:15]1[CH:30]=[CH:29][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=2)=[O:20])=[CH:17][CH:16]=1.O>CN(C=O)C>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][N:11]3[C:5]4[CH:4]=[N:3][N:2]([CH3:1])[C:7](=[O:8])[C:6]=4[CH:9]=[CH:10]3)=[CH:23][CH:22]=2)=[O:20])=[CH:29][CH:30]=1
Reactant: Cn1ncc2[nH]ccc2c1=O
Reactant: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2c(ccn2Cc2ccc(C(=O)c3ccc(F)cc3)cc2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
A solution of 5-methyl-1H-pyrrolo[2,3-d]pyridazin-4(5H)-one (373 mg) in DMF (10 ml) was dripped into a suspension of 60% sodium hydride-oil (120 mg) in DMF (10 ml) on an ice-water bath. The mixture was stirred at room temperature for 1 hour, after which a solution of 4-(4-fluorobenzoyl)benzyl bromide (806 mg) in DMF (20 ml) was added and the mixture was further stirred at room temperature for 13 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; dichloromethane: methanol=99:1) to provide the title compound as white powder (615 mg, yield 68%).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1>>[OH:26][C:20]1([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[CH2:25][CH2:24][CH2:23][N:22]([C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[O:8])[CH2:21]1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3ccc(C#N)cc3)C2)c1

Procedure:
The compound of Example 12 was prepared according to the general preparation protocol A from 4-cyanobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [CH2:1]1[C:9]2[C:5]([S:6][C:7]3[C:8]=2[C:10]2[C:15]([C:16]=3[OH:17])=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=[CH:2]1.C[O:19][C:20](=[O:42])[C@H:21]([CH2:40]O)[NH:22]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O.OS(O)(=O)=O>FC(F)(F)C(O)=O>[CH:1]1[C:9]2[C:8]3[C:10]4[C:15]([CH:16]([O:17][CH2:40][C@@H:21]([C:20]([OH:42])=[O:19])[NH2:22])[C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:14][CH:13]=[CH:12][CH:11]=4
Reactant: OC1=c2sc3c(c2-c2ccccc21)CC=CC=3
Reactant: COC(=O)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](COC1c2ccccc2-c2c1sc1ccccc21)C(=O)O

Procedure:
from benzo[b]indeno[1,2-d]thiophen-6-ol (prepared by NaBH4 reduction of benzo[b]indeno[1,2-d]thiophen-9-one (Example i, Starting Fluorenones)) and Nα -(9-fluorenylmethoxycarbonyl)-L-serine methyl ester following method A, using trifluoroacetic acid as catalyst in place of H2SO4.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][C:9](=[O:11])[N:8]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)[CH2:7]1)=O)C.[BH4-].[Na+]>C(O)C>[OH:3][CH2:4][CH:6]1[CH2:7][N:8]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:19])[CH3:20])=[CH:14][CH:13]=2)[C:9](=[O:11])[CH2:10]1
Reactant: CCOC(=O)C1CC(=O)N(c2ccc(C(C)C)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)c1ccc(N2CC(CO)CC2=O)cc1
Temperature: 12.5 °C
Reaction time: 3.5 h

Procedure:
A mixture of 1-(4-isopropyl-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid ethyl ester obtained in step 2 (0.7 g, 2.65 mmol) and ethanol were cooled to 10-15° C. Sodium borohydride (0.25 g, 6.6 mmol) was added portion wise over a period of 20 min and the reaction mixture was stirred for 3.5 hrs at 20-25° C. The organic volatiles were evaporated and the residue was taken into brine solution (15 ml). The aqueous layer was extracted with ethyl acetate, dried over Na2SO4 and evaporated to obtain 4-hydroxymethyl-1-(4-isopropyl-phenyl)-pyrrolidin-2-one as an off white solid (0.5 g, 81%).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)(=O)=O.[CH2:26]([NH:29][CH2:30][CH2:31][CH3:32])[CH2:27][CH3:28]>ClCCl>[CH2:26]([N:29]([CH2:30][CH2:31][CH3:32])[C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)[CH2:27][CH3:28]
Reactant: CCCOc1ccccc1-c1nc2nc(S(C)(=O)=O)ncc2c(=O)[nH]1
Reactant: CCCNCCC
Solvent: ClCCl
Product: CCCOc1ccccc1-c1nc2nc(N(CCC)CCC)ncc2c(=O)[nH]1

Procedure:
In a similar manner to Example 56 reaction of 7-methylsulphonyl-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.40 g) and dipropylamine (0.74 g) in dichloromethane (10 ml) yielded the title compound, 83 mg, m.p. 123-4° C. (recrystallized from cyclohexane).