Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[NH:23]1[CH:27]=[CH:26][N:25]=[C:24]1[CH:28]=O>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:28][C:24]4[NH:23][CH:27]=[CH:26][N:25]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ncc[nH]1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Solvent: CC(=O)O
Solvent: CO
Product: Clc1cccc(Nc2ncnc3[nH]nc(N=Cc4ncc[nH]4)c23)c1

Procedure:
Analogously to Example 32, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) and 180 mg of acetic acid are dissolved in 26 ml of methanol and reacted with 144 mg (1.5 mmol) of imidazole-2-carbaldehyde to form 4-(3-chloro-phenylamino)-3-[(1H-imidazol-2-yl)-methyleneamino]-1H-pyrazolo[3,4-d]pyrimidine. Reduction of the above intermediate in 15 ml of DMEU with 8 ml (8 mmol) of DIBAL-H, analogous working-up and digestion in ethanol yield 4-(3-chlorophenylamino)-3-(1H-imidazol-2-yl)-methylamino]-1H-pyrazolo[3,4-d]pyrimidine; HPLC: tRet(grad20-100/20) 5.8; FABMS: (M+H)+=341.
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[CH:28]=[CH:27][C:9]2[N:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:11](/[CH:13]=[CH:14]/[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:12][C:8]=2[CH:7]=1)([O-])=O>C(O)C.O.[Fe]>[NH2:3][C:6]1[CH:28]=[CH:27][C:9]2[N:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:11](/[CH:13]=[CH:14]/[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:12][C:8]=2[CH:7]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Yield: 70.4 %

Procedure:
Iron powder (1.95 g, 35 mmol) and ammonium chloride (200 mg, 3.7 mmol) was added to a solution of (E)-5-nitro-1-(2-pyridyl)-2-styryl-1H-benzimidazole (2.41 g, 7.0 mmol) in ethanol (50 ml) and water (25 ml). After the reaction mixture was refluxed for 3 h, the hot reaction mixture was filtered through a pad of celite and the filtrate was evaporated under reduced pressure. The obtained residue was partitioned between ethyl acetate (200 ml) and saturated aqueous sodium bicarbonate solution (200 ml). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (200 ml). The combined extracts were washed with brine (20 ml), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 200 g; n-hexane/ethyl acetate (1/2)) and obtained solids (1.54 g, 70%) were recrystallized from ethyl acetate to afford the titled compound as brown solids. MW: 312.38; mp: 146.0-148.0° C.; 1H-NMR (CDCl3) δ: 8.75 (1H. ddd, J=4.8, 1.8, 1.1 Hz), 8.01-7.91 (1H, m), 7.95 (1H, d, J=16.0 Hz), 7.56-7.23 (8H, m), 7.13 (1H, d, J=16.0 Hz), 7.11 (1H, d, J=2.2 Hz), 6.69 (1H, dd, J=8.8, 2.2 Hz), 3.70 (2H, br.s).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([NH:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[CH:11]2)=[O:4].[C:18]([C:22]1[CH:31]=[C:30]2[C:25]([CH:26]([NH2:32])[CH2:27][CH2:28][O:29]2)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].N12CCCN=C1CCCCC2>C(#N)C>[C:18]([C:22]1[CH:31]=[C:30]2[C:25]([CH:26]([NH:32][C:3]([NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:15]=3[N:14]=[CH:13][CH:12]=[CH:11]4)=[O:4])[CH2:27][CH2:28][O:29]2)=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc2c(c1)OCCC2N
Reactant: O=C(Nc1cccc2cccnc12)C(Cl)(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)c1ccc2c(c1)OCCC2NC(=O)Nc1cccc2cccnc12
Yield: 14.4 %

Procedure:
A mixture of the product of Example 3A (145mg, 0.5 mmol), the product of Example 1C (103mg, 0.5 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 190 mg, 1.25 mmol) in acetonitrile (15 mL) was heated at reflux for 3.5 hours, cooled, and the acetonitrile removed under reduced pressure. The residue was taken up in ethyl acetate and washed with water. The isolated organic layer was dried with magnesium sulfate, filtered and the solvent removed under reduced pressure. The resulting residue was purified by reverse-phase HPLC (acetonitrile/water) to give 27 mg of the title compound (14% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 9.37 (s, 1H), 8.83 (dd, J=4.1 and 1.7 Hz, 1H), 8.54 (dd, J=7.3 and 1.9 Hz, 1H), 8.34 (dd, J=8.5 and 1.7 Hz, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.55-7.60 (m, 1H), 7.46-7.53 (m, 2H), 7.22 (d, J=8.1 Hz, 1H), 6.94 (dd, J=8.1 and 2.0 Hz, 1H), 6.77 (d, J=2.0 Hz, 1H), 4.87-4.93 (m, 1H), 4.22-4.29 (m, 1H), 4.12-4.20 (m, 1H), 2.07-2.16 (m, 1H), 1.91-2.00 (m, 1H), 1.24 (s, 9H). MS (ESI) m/e 376 (M+H)+. Calcd. For C23H25N3O2.0.35CF3CO2H: C, 68.53; H, 6.15; N, 10.12. Found C, 68.33; H, 6.00; N, 10.00.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4](Cl)=[O:5].[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:9]1([NH:8][C:4](=[O:5])[CH:3]=[C:2]([CH3:7])[CH3:1])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccccc1
Reactant: CC(C)=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)=CC(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3,3-dimethylacryloyl chloride (4.8 mL, 43.2 mmol) in dry DCM (100 mL), was added aniline (4.02 g, 43.2 mmol) followed by diisopropylethylamine (14.28 mL, 86.4 mmol). The mixture was stirred at ambient temperature for 2 hrs. Saturated sodium bicarbonate was added to quench the reaction. The organic layer was separated and washed with sat NaHCO3 (50 mL) and water (50 mL×2). The resulting solution was dried over MgSO4 and the filtrate evaporated to afford 3-methyl-but-2-enoic acid phenylamide as a brown solid in quantitative yield (7.6 g). MS: 176.0 (M+H)+; tR=2.40 min (method 1).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[N:24][CH:25]=3)[NH:18][CH:19]=2)=[CH:11][CH:10]=1.N1C=CC=CC=1>C1COCC1>[CH3:1][N:2]([CH3:7])[S:3]([N:29]1[CH2:28][CH2:27][N:26]([C:23]2[CH:22]=[CH:21][C:20]([C:17]3[NH:18][CH:19]=[C:15]([C:12]4[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=4)[N:16]=3)=[CH:25][N:24]=2)[CH2:31][CH2:30]1)(=[O:5])=[O:4]
Reactant: Fc1ccc(-c2c[nH]c(-c3ccc(N4CCNCC4)nc3)n2)cc1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)N1CCN(c2ccc(-c3nc(-c4ccc(F)cc4)c[nH]3)cn2)CC1
Reaction time: 8 h
Yield: 41.3 %

Procedure:
N,N-Dimethylsulfamoyl chloride (0.09 g) was added to a solution of 1-{5-[4-(4-Fluoro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-piperazine (0.2 g) and pyridine (0.05 g) in THF. The reaction mixture was held at room temperature overnight and then concentrated in vacuo. The residue was diluted with 1N NaOH and the resultant mixture extracted with dichloromethane. The organics were extracted with 6N HCl, and the acidic extracts basified with 1N NaOH. The basic aqueous layer was then extracted with dichloromethane. The organics were dried over magnesium sulfate and were concentrated. The residue was purified by flash column chromatography on silica (20% ethyl acetate in hexanes grading to ethyl acetate grading to dichloromethane) to provide 4-{5-[4-(4-Fluoro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-piperazine-1-sulfonic acid dimethylamide (0.11 g). MS m/z 431 (M++1).
Reaction SMILES: OCCCCCCCCN[C:11]([C:13]1[CH:14]=[C:15]([S:19]([C:22]2[CH:23]=[C:24]3[C:29](=[C:30]([CH3:32])[CH:31]=2)[N:28]=[CH:27][C:26]([C:33]([NH2:35])=[O:34])=[C:25]3[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=2)(=[O:21])=[O:20])[CH:16]=[CH:17][CH:18]=1)=[O:12].[NH2:45][C:46]1[CH:47]=[C:48]([C:52]2[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][CH2:60][C:61]([O:63][CH3:64])=[O:62])=[CH:54][CH:53]=2)[CH:49]=[CH:50][CH:51]=1>>[C:33]([C:26]1[CH:27]=[N:28][C:29]2[C:24]([C:25]=1[NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH3:44])[CH:38]=1)=[CH:23][C:22]([S:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:11]([NH:45][C:46]1[CH:47]=[C:48]([C:52]3[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][CH2:60][C:61]([O:63][CH3:64])=[O:62])=[CH:54][CH:53]=3)[CH:49]=[CH:50][CH:51]=1)=[O:12])(=[O:21])=[O:20])=[CH:31][C:30]=2[CH3:32])(=[O:34])[NH2:35]
Reactant: COC(=O)CCCc1ccc(-c2cccc(N)c2)cc1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCO)c4)cc23)c1
Product: COC(=O)CCCc1ccc(-c2cccc(NC(=O)c3cccc(S(=O)(=O)c4cc(C)c5ncc(C(N)=O)c(Nc6cccc(OC)c6)c5c4)c3)c2)cc1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 70, using Intermediate 30 in place of 8-aminooctanol. ES/MS calcd. for C42H39N4O7S+ 743.3. Found m/z=743.4 (M+H)+.
Reaction SMILES: [C]=O.[F:3][CH2:4][C:5]1([CH2:27][F:28])[CH:10]=[C:9](OS(C(F)(F)F)(=O)=O)[C:8]2[CH:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[CH:21]=[CH:22][C:7]=2[O:6]1.[C:29]([O-:32])(=[O:31])C.[K+]>CN(C)C(=O)C>[F:3][CH2:4][C:5]1([CH2:27][F:28])[CH:10]=[C:9]([C:29]([OH:32])=[O:31])[C:8]2[CH:19]=[C:20]([C:23]([F:24])([F:25])[F:26])[CH:21]=[CH:22][C:7]=2[O:6]1
Reactant: CC(=O)[O-]
Reactant: O=S(=O)(OC1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21)C(F)(F)F
Agent: [C]=O
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C(O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21

Procedure:
A three-necked 50-ml flask (equipped with a reflux condenser, a thermometer, and a CO introducing pipe connected with a balloon charged with carbon monoxide gas) was charged with 1.0 g (2.4 mmol) of trifluoromethanesulfonic acid 2,2-bis(fluoromethyl)-6-(trifluoromethyl) -2 H- 1-benzopyran-4-yl ester, 0.95 g (9.7 mmol) of potassium acetate, and 10 ml of N,N-dimethylacetamide. Under stirring of the mixture, predetermined amounts of reagents were added, as shown in Table. Then, the reaction was conducted under conditions shown in Table. After that, the reaction mixture was subjected to the same post-treatments as those of Example 5. As a result, 2,2-bis(fluoromethyl)-6-(trifluoromethyl)-2 H- 1-benzopyran-4-carboxylic acid was obtained, as shown by yield in Table.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH2:13][C:12]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)=[N:11]1.CN(C)C=O.[Br:33]Br>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([Br:33])[C:12]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=2)=[N:11]1
Reactant: O=C(NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1)c1cccc([N+](=O)[O-])c1
Reactant: BrBr
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1Br)c1cccc([N+](=O)[O-])c1
Yield: 96.6 %

Procedure:
428 g (1.0 mol) of 1-(2,4,6-trichlorophenyl)-3-(3-nitrobenzamido)-5-oxo-2-pyrazoline was added to 2.2 liters of dimethylformamide. To the solution, there was added dropwise 160 g (1.0 mol) of bromine with stirring while cooling with ice, and after stirring for about 1 hour, the reaction solution was poured into 9 liters of water. The crystals thus-separated were collected by filtration to obtain 489.5 g (96.6% yield) of 1-(2,4,6-trichlorophenyl)-3-(3-nitrobenzamido)-4-bromo-5-oxo-2-pyrazoline.
Reaction SMILES: C1(CCO[C:7]2[CH:19]=[CH:18][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=2)CC1.OC1C=CC(C(OC)=O)=CC=1.[F:31][C:32]([F:37])([F:36])[CH2:33][CH2:34][OH:35]>>[F:31][C:32]([F:37])([F:36])[CH2:33][CH2:34][O:35][C:7]1[CH:19]=[CH:18][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(O)CNC(=O)c1ccc(OCCC2CC2)cc1
Reactant: OCCC(F)(F)F
Agent: COC(=O)c1ccc(O)cc1
Product: O=C(O)CNC(=O)c1ccc(OCCC(F)(F)F)cc1
Yield: 14 %

Procedure:
Reactions similar to those described in Example 1 (1a) and (1b) were conducted using methyl 4-hydroxybenzoate (1.52 g, 10.0 mmol) and 3,3,3-trifluoropropan-1-ol (1.14 g, 10.0 mmol) to give 385 mg of the title compound (white powder, yield: 14%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([NH:24][CH2:25][CH3:26])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([N:24]([CH2:25][CH3:26])[C:12]1[C:13]([CH:21]2[CH2:23][CH2:22]2)=[CH:14][C:15]2[C:10]([CH:11]=1)=[N:9][N:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[C:16]=2[C:17]([NH:19][CH3:20])=[O:18])(=[O:38])[CH3:37]
Reactant: CCNc1cc2nn(-c3ccc(Br)cc3)c(C(=O)NC)c2cc1C1CC1
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(C(C)=O)c1cc2nn(-c3ccc(Br)cc3)c(C(=O)NC)c2cc1C1CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.6 %

Procedure:
To a solution of compound (ii) (6 mg, 0.015 mmol) in DCM was added DIPEA (7 μL, 0.040 mmol), followed by acetyl chloride (7 μL, 0.098 mmol) and the reaction was stirred at RT for 20 min. After concentrating to dryness, the residue was purified by flash column chromatography eluting with MeOH/DCM (0-20%) to give Compound (48) as a white solid (4 mg, 61%). ESI-MS m/z calculated for [M+H]+: 455.1/457.1; found: 455.4/457.4; 1H NMR (400 MHz, CDCl3) δ 7.71-7.63 (m, 2H), 7.56 (brs, 1H), 7.52-7.46 (m, 2H), 7.43 (s, 1H), 5.77 (brs, 1H), 4.32 (dq, J=14.3, 7.2 Hz, 1H), 3.25 (dq, J=14.2, 7.1 Hz, 1H), 3.01 (d, J=4.9 Hz, 3H), 1.96-1.74 (m, 4H), 1.21 (t, J=7.2 Hz, 3H), 1.10-0.97 (m, 2H), 0.86-0.70 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=O)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:25]=1[CH:26]=[N:27][NH:28][C:29]2=[O:34]>CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C.[Ti+4]>[F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=[N:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH:26]=[N:27][NH:28][C:29]3=[O:34])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1ccc(F)c(F)c1OC
Reactant: Nc1cccc2c(=O)[nH]ncc12
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Product: CC[C@H](C[C@@](O)(C=Nc1cccc2c(=O)[nH]ncc12)C(F)(F)F)c1ccc(F)c(F)c1OC

Procedure:
In the same way as in Example 29, 372 mg (1.14 mmol) of (2R*,4R*)-4-(3,4-difluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 200 mg (1.14 mmol) of 5-aminophthalazin-1-one and 0.36 ml of titanium tetra-tert-butoxide are reacted to give 5-{[(2R*,4R*)-4-(3,4-difluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexylidene]amino}phthalazin-1-one. 560 mg of crude imine are cyclized in the same way as in Example 29 at −30° C. with 11.8 ml (11.8 mmol) of 1 M boron tribromide solution to give the desired product. Preparative thin-layer chromatography on silica gel (hexane/2-propanol 17%) yields 249 mg of the desired product
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=O.S(C)C>C1COCC1>[Br:1][C:2]1[C:3]([F:11])=[C:4]([CH2:5][NH2:7])[CH:8]=[CH:9][CH:10]=1
Reactant: NC(=O)c1cccc(Br)c1F
Solvent: CSC
Solvent: C1CCOC1
Product: NCc1cccc(Br)c1F
Reaction time: 2 h
Yield: 46.3 %

Procedure:
To a solution of 3-bromo-2-fluorobenzamide (3.0 g, 13.76 mmol) in THF (50 mL) was added BH3.Me2S (1.57 mL, 20.6 mmol) and the mixture was stirred at 50° C. for 2 h (monitored by TLC). The reaction was quenched by adding HCl (20 mL, 3 N) after which the result mixture was stirred for 2 h and then THF was removed under vacuum. The aqueous layer was extracted with AcOEt (30 mL), and then was adjusted to pH=9.0 with NaOH (1 N). Then the aqueous layer was extracted with AcOEt (50 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 1.30 g of the title compound as a colorless oil (yield: 46%). 1H NMR (400 MHz, D2O) δ 4.30 (S, 2H), 7.19-7.22 (m, 1H), 7.47 (t, J=8.8 Hz, 1 H), 7.73-7.77 (m, 1H); 13C NMR (100 MHz, D2O) δ 37.4, 108.9, 121.2, 126.2, 130.7, 135.1, 156.2, 158.6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([O:16]C)=[O:15].[CH3:18][O:19][C:20]1[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=[CH:24][C:21]=1[CH:22]=O.C[O-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[CH:22][C:21]1[CH:24]=[CH:25][C:26]([O:30][CH3:31])=[C:27]([O:28][CH3:29])[C:20]=1[O:19][CH3:18])[C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([OH:16])=[O:15]
Reactant: COC(=O)CC1=C(C)Cc2ccc(OC)cc21
Reactant: COc1ccc(C=O)c(OC)c1OC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(c1)C(CC(=O)O)=C(C)C2=Cc1ccc(OC)c(OC)c1OC
Reaction time: 0.5 h

Procedure:
To a solution of methyl 5-methoxy-2-methyl-3-indenylacetate 8.7 g (0.037 mol) and 2,3,4-trimethoxybenzaldehyde, 7.99 g (1.1 equivalent) is added 16+ ml (2.0+ equivalents) of 25% methanolic sodium methoxide. The mixture is stirred at reflux under nitrogen for 2 hours. An equal volume of water is added dropwise and refluxing continues for 30 min. The solution is cooled, diluted with water and extracted with ether (3×). Residual ether is blown off with nitrogen, and then the aqueous solution is acidified with 50% glacial acetic acid. The precipitated product is collected and washed thoroughly with water. The crude product is crystallized to give 5-methoxy-2-methyl-1-(2,3,4-trimethoxybenzylidene)-3-indenyl acetic acid. (R and R1 =H, R2 =OCH3, R3 and R4 =H, R5, R6 and R7 =OCH3, R8 =CH3, R9 =H, R10 and R11 =double bond, m=0, n=0, M=OH)
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:5]=2[N:4]([CH3:25])[CH:3]=1.[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28].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>[CH3:25][N:4]1[C:5]2[C:10]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[N:9][CH:8]=[N:7][C:6]=2[C:2]([C:33]2[CH:34]=[CH:35][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:31][CH:32]=2)=[CH:3]1
Reactant: Cn1cc(Br)c2ncnc(NC3CCN(C(=O)OC(C)(C)C)CC3)c21
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
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
Product: Cn1cc(-c2ccc(S(C)(=O)=O)cc2)c2ncnc(NC3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 100 °C
Reaction time: 12 h

Procedure:
tert-butyl 4-(7-bromo-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl amino)piperidin-1-carboxylate, 73 mg of 4-methanesulfonyl-phenylboronic acid, 17 mg of Pd(PPh3)4 and 0.73 ml of 2N Na2CO3 were added in 3 ml of 1,4-dioxane and stirred in a closed reactor at 100° C. for 12 hr. The resulting mixture was cooled to room temperature, extracted with ethylacetate and distilled water. The organic layer was washed with water and saline solution, dried over anhydrous sodium sulfate and concentrated under a reduced pressure to obtain 15 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:28])[C:24]([F:27])([F:26])[F:25])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:32]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:28][CH3:32])[C:24]([F:25])([F:26])[F:27])=[CH:4][CH:3]=1
Reactant: CI
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.7 %

Procedure:
To a stirred solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanol (67.6 mg, 0.150 mmol) in tetrahydrofuran (1.0 mL) was added sodium hydride (60% in oil, 7.2 mg, 0.18 mmol) at 0° C. After 15 min, iodomethane (46.7 μL, 0.75 mmol) was added. After being stirred for 1.5 h at room temperature, the reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (67.2 mg, 0.145 mmol, 96%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH2:9][CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1>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>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:8]1[C:6]2=[N:7][C:2]([C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([N:25]4[CH2:24][CH2:23][O:22][CH2:27][CH2:26]4)[CH:33]=3)=[CH:3][N:4]=[C:5]2[NH:11][CH2:10][CH2:9]1
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(Br)nc32)c1Cl
Reactant: CC1(C)OB(c2cccc(N3CCOCC3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Fc1ccc(F)c(CN2CCNc3ncc(-c4cccc(N5CCOCC5)c4)nc32)c1Cl
Temperature: 90 °C
Yield: 61 %

Procedure:
A mixture of 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine (0.14 mmol, 51 mg), 3-morpholinophenylboronic acid pinacol ester (0.16 mmol, 46 mg), and Pd(PPh3)4 (0.015 mmol, 17 mg) was placed in a Schlenk tube. This tube was degassed via 3 cycles of vacuum—refill with N2. THF (3 mL, from sureseal bottle) and aqueous K2CO3 (2.0 M, 1 mL, degassed by bubbling with N2 for 10 min) was then added to the solid mixture in the Schlenk tube. The reaction was stopped after heating at 90° C. for 16 hrs. Extraction and concentration of combined organic layers gave a residue, which was purified on a silica gel column by using 6:1 ratio of CH2Cl2/MeOH (pre-saturated with ammonia gas) as eluents, furnishing 1-(2-chloro-3,6-difluorobenzyl)-7-[3-(morpholin-4-yl)phenyl]-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine in 61% yield (38 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH:48]1([NH:51][CH2:52][C@H:53]2[NH:57][CH2:56][C@H:55]([OH:58])[CH2:54]2)[CH2:50][CH2:49]1>CN(C=O)C>[CH:48]1([NH:51][CH2:52][C@@H:53]2[CH2:54][C@@H:55]([OH:58])[CH2:56][N:57]2[C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:32])[CH2:50][CH2:49]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: O[C@H]1CN[C@H](CNC2CC2)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1C[C@H](O)C[C@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (250 mg, 0.5 mmol), HOBt (81 mg, 1.2 eq.), EDC (115 mg, 1.2 eq.), TEA (0.17 mL, 2.5 eq.) and (3R, 5S)-5-cyclopropylaminomethyl-pyrrolidin-3-ol (312 mg, 4 eq.) in DMF (10 mL) was stirred at rt for overnight, followed by heating at 45° C. for 5 hours. The reaction was concentrated, washed with water, sodium bicarbonate and brine, dried and concentrated. The residue was purified on a silica gel column to give the titled compound.