Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][CH2:16][N:17](C(C)C)C(C)C.Cl.C(N)C>CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([NH:17][CH2:16][CH3:15])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN
Agent: Cl
Solvent: CN(C)C=O
Product: CCNc1ccc(C(=O)OC)cc1[N+](=O)[O-]

Procedure:
4-Ethylamino-3-nitro-benzoic acid methyl ester (8.3 g) was prepared by following General Procedure A starting from methyl 4-chloro-3-nitrobenzoate (10.0 g), DIEA (1.6 mL) and ethylamine hydrochloride salt (4.5 g) in DMF (50.0 mL). The crude product was used in the next step without further purification.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:11](=[N:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:20](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:20][O:1][N:2]=[C:3]([C:11](=[N:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:5]
Reactant: CC(=Nc1ccccc1)C(=NO)C(=O)OC(C)(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: CON=C(C(=O)OC(C)(C)C)C(C)=Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
To a solution of tert-butyl 2-hydroxyimino-3-phenyliminobutyrate (1.0 g) in acetone (10 ml) was added potassium carbonate (0.63 g) and dimethyl sulfate (0.43 ml) under ice-cooling. The mixture was stirred at the same temperature for 30 minutes and stirred at ambient temperature for 4 hours. The resulting suspension was poured into ice-water and extracted with diisopropyl ether. The organic layer was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residual oil was subjected to column chromatography on silica gel to give tert-butyl 2-methoxyimino-3-phenyliminobutyrate (0.68 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:29])[C:5]([C:21]1[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=1)([CH3:20])[C:6](=[O:19])[NH:7]2.B(Br)(Br)Br.CCCCCC>CCOC(C)=O>[Cl:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:9]=[C:8]2[C:3]=1[C:4](=[O:29])[C:5]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([CH3:20])[C:6](=[O:19])[NH:7]2
Reactant: COc1ccc(C2(C)C(=O)Nc3cc(N4CCN(C)CC4)cc(Cl)c3C2=O)cc1
Agent: BrB(Br)Br
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CN1CCN(c2cc(Cl)c3c(c2)NC(=O)C(C)(c2ccc(O)cc2)C3=O)CC1
Yield: 67.9 %

Procedure:
The objective compound was prepared by the same procedure for the example 13, using a 5-chloro-3-(4-methoxy-phenyl)-3-methyl-7-(4-methyl-piperazine-1-yl)-1H-quinoline-2,4-dione (0.03 g, 0.07 mmol) and BBr3(0.22 mL, 1.0 M dichloromethane solution). After normal workup, the pure objective compound (19 mg, 65%) was obtained as slightly yellow solid by recrytalization (n-hexane:EtOAc=1:3): 1H NMR (200 MHz, CDCl3) δ 1.75 (s, 3H, CH3), 2.38 (s, 3H, NCH3), 2.59-2.65 (m, 4H, 2×NCH2), 2.89-2.92 (m, 4H, 2×NCH2), 3.33 (s, 3H, OCH3), 6.52-6.55 (m, 2H, ArH), 6.69-6.74 (m, 2H, ArH), 7.04-7.08 (m, 2H, ArH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:9]([Mg]Cl)([CH3:11])[CH3:10].C(N(CC)CC)C.II>COCCOC.O1CCCC1>[Cl:8][C:5]1[N:6]=[C:7]([CH:9]([CH3:11])[CH3:10])[C:2]([F:1])=[CH:3][N:4]=1
Reactant: CC(C)[Mg]Cl
Reactant: Fc1cnc(Cl)nc1
Agent: II
Solvent: CCN(CC)CC
Solvent: COCCOC
Solvent: C1CCOC1
Product: CC(C)c1nc(Cl)ncc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
A solution of 5-fluoro-2-chloropyrimidine (5.00 g, 37.7 mmol) in 1,2-dimethoxyethane (25 mL) is treated with a solution of 2 M isopropyl magnesium chloride in tetrahydrofuran (28.3 mL, 56.6 mmol) while keeping the temperature below 15° C. The resulting solution is stirred for one hour under nitrogen and then cooled to 0° C. and treated drop wise with a solution of triethylamine (5.76 mL, 37.7 mmol) in tetrahydrofuran (5 mL). A solution of iodine (9.58 g, 37.7 mmol) in tetrahydrofuran (20 mL) is added. The reaction is quenched with water and saturated sodium bicarbonate and saturated sodium bisulfate are added. The mixture is extracted three times with ethyl acetate. The combined organic layers are dried over sodium sulfate and the solvent is removed under vacuum. The crude product is purified over silica gel with a 30 minute gradient, dichloromethane/hexanes (5 to 100%) to give the title compound (2.55 g, 39%). GC/MS (m/e): 174.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[N:18][C:19](Cl)=[N:20]3)=[C:15]([O:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH2:31][C:32]1[CH:37]=[CH:36][N:35]=[C:34]2[O:38][CH2:39][O:40][C:33]=12>N.C(Cl)Cl>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[C:34]5[O:38][CH2:39][O:40][C:33]=45)=[N:18][CH:19]=[N:20]3)=[C:15]([O:24][CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Nc1ccnc2c1OCO2
Reactant: CC(=O)N1CCN(CCOc2cc(OC3CCOCC3)c3cnc(Cl)nc3c2)CC1
Agent: N
Solvent: ClCCl
Product: CC(=O)N1CCN(CCOc2cc(OC3CCOCC3)c3c(Nc4ccnc5c4OCO5)ncnc3c2)CC1
Yield: 53 %

Procedure:
Using an analogous procedure to that described in Example 1, 7-[2-(4-acetylpiperazin-1-yl)ethoxy]chloro-5-tetrahydropyran-4-yloxyquinazoline (0.113 g) was reacted with 4-amino-2,3-methylenedioxypyridine (0.036 g). The reaction mixture was quenched with glacial acetic acid (0.031 g) and diluted with methanol. The mixture was evaporated and the residue was purified by column chromatography on a C18 reversed phase silica column (Waters Symmetry column, 5 microns silica, 20 mm diameter, 100 mm length) using a decreasingly polar mixture of water and acetonitrile (containing 1% acetic acid) as eluent. The material so obtained was diluted with a 7M methanolic ammonia solution. The mixture was evaporated and the material so obtained was dissolved in methylene chloride. The solution was dried over magnesium sulphate and evaporated to give the title compound as a foam in 53% yield; NMR Spectrum: (CDCl3) 2.02 (m, 2H), 2.1 (s, 3H), 2.22 (m, 2H), 2.6 (m, 4H), 2.9 (m, 2H), 3.51 (m, 2H), 3.6 (m, 2H), 3.66 (m, 2H), 4.1 (m, 2H), 4.25 (m, 2H), 4.73 (m, 1H), 6.13 (s, 2H), 6.59 (s, 1H), 6.9 (s, 1H), 7.7 (d, 1H), 8.36 (d, 1H), 8.66 (s, 1H); Mass Spectrum: M+H+ 537.
Reaction SMILES: [C:1]([C@H:5]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:10][C@H:9]2[N:19]([CH3:20])[C@@H:6]1[CH2:7][CH2:8]2)([O:3]C)=[O:2]>O1CCOCC1.O>[C:1]([C@H:5]1[C@@H:11]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[CH2:10][C@H:9]2[N:19]([CH3:20])[C@@H:6]1[CH2:7][CH2:8]2)([OH:3])=[O:2]
Reactant: COC(=O)[C@H]1[C@@H](c2ccc(F)cc2)C[C@@H]2CC[C@H]1N2C
Solvent: C1COCCO1
Solvent: O
Product: CN1[C@H]2CC[C@@H]1[C@@H](C(=O)O)[C@@H](c1ccc(F)cc1)C2

Procedure:
2β-Carbomethoxy-3β-(4-fluorophenyl)tropane (WIN 35,428) (1), is boiled for 24 h in a 1:1 dioxane-water solution. The solvent is removed in vacuo and the residue is almost completely dissolved in CHCl3. Remaining undissolved solid can then be filtered off, toluene can then be added, and the volume of the solution is reduced in vacuo to approximately 25%. Cooling the resulting white suspension in a freezer for 2 h will provide a precipitated solid which can then be isolated by filtration and is washed with cold 1:1 CHCl3-toluene. The solid can then be pumped dry to give the product.
Reaction SMILES: CO[C:3](=[O:39])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.[CH3:40][O:41]C(=O)OC[C:45]1[CH:50]=[C:49]([CH2:51][O:52][C:53]([O:55][CH3:56])=[O:54])[CH:48]=[C:47]([NH2:57])[CH:46]=1>>[OH:39][CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:33])[CH3:34])[C:14]2=[O:37])[CH:7]=[C:8]([CH2:40][OH:41])[CH:9]=1.[CH3:56][O:55][C:53](=[O:54])[O:52][CH2:51][C:49]1[CH:50]=[CH:45][CH:46]=[C:47]([NH:57][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:35])[CH3:33])[C:14]2=[O:37])[CH:48]=1
Reactant: COC(=O)OCc1cc(N)cc(COC(=O)OC)c1
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Product: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)Nc2cc(CO)cc(CO)c2)N=C(C2CCCCC2)c2ccccc21
Product: COC(=O)OCc1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was prepared by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that carbonic acid 3-amino-5-methoxycarbonyloxymethyl-benzyl ester methyl ester was used instead of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place carbonic acid 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzyl ester methyl ester (Example 48, step a), according to the method of Example 48, step b. 1H NMR (CDCl3) 8.37 (1H, s), 7.47 (2H, m), 7.30 (3H, m), 7.09 (1H, s), 7.02 (1H, d), 4.78-4.58 (6H, m), 4.23 (2H, m), 2.79 (1H, m), 2.04-1.44 (8H, m), 1.26 (13H, m). Found: C, 64.88; H, 7.45; N, 10.15%; C30H38N4O5.1.2H2O requires: C, 64.75; H, 7.32; N, 10.07%.
Reaction SMILES: C(=O)([O-])O.[K+].BrC[CH2:8][CH:9]1[CH2:11][CH2:10]1.[C:12]([O:16][C:17](=[O:22])[NH:18][CH2:19][CH2:20][NH2:21])([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[C:12]([O:16][C:17](=[O:22])[NH:18][CH2:19][CH2:20][NH:21][CH2:10][CH:11]1[CH2:8][CH2:9]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: BrCCC1CC1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNCC1CC1
Temperature: 66 °C
Yield: 30.3 %

Procedure:
Potassium hydrogen carbonate (220 mg, 2.2 mmol) and (bromoethyl)cyclopropane (270 mg, 2.0 mmol) were added to a solution of tert-butyl-N-(2-aminoethyl)carbamate (320 mg, 2.0 mmol) in THF (10 ml). The mixture was heated at 66° C. for 20 h and solvents were concentrated in vacuo. The residue was dissolved in chloroform, washed with water, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 1% triethylamine:4% methanol:95% chloroform) to yield the title compound (130 mg, 30%).
Reaction SMILES: [F:1][C:2]([F:24])([O:7][C:8]([F:23])([F:22])[C:9]([F:21])([F:20])[O:10][C:11]([F:19])([F:18])[CH2:12][O:13][CH2:14][CH2:15][CH2:16]Cl)[C:3]([F:6])([F:5])[F:4].FC(F)(OC(F)(F)C(F)(F)OC(F)(F)COCCCBr)C(F)(F)F.[CH2:49]([O:57][C:58]1[CH:59]=[N:60][C:61]([C:64]2[CH:69]=[CH:68][C:67]([OH:70])=[CH:66][CH:65]=2)=[N:62][CH:63]=1)[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]>>[CH2:49]([O:57][C:58]1[CH:63]=[N:62][C:61]([C:64]2[CH:65]=[CH:66][C:67]([O:70][CH2:16][CH2:15][CH2:14][O:13][CH2:12][C:11]([O:10][C:9]([F:21])([F:20])[C:8]([F:23])([F:22])[O:7][C:2]([F:24])([F:1])[C:3]([F:6])([F:5])[F:4])([F:19])[F:18])=[CH:68][CH:69]=2)=[N:60][CH:59]=1)[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56]
Reactant: FC(F)(COCCCCl)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F
Reactant: CCCCCCCCOc1cnc(-c2ccc(O)cc2)nc1
Agent: FC(F)(COCCCBr)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F
Product: CCCCCCCCOc1cnc(-c2ccc(OCCCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 1 by combining a mixture of 3-(2-(2-(pentafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)propyl chloride and 3-(2-(2-(pentafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)propyl bromide (75:25 mole ratio, total 4.18 g, 10 mmol, Example 20) with 5-octyloxy-2-(4-hydroxyphenyl)pyrimidine (3.18 g, 10.0 mmol). The resulting crude product was purified by recrystallization from ethanol followed by Kugelrohr distillation (240° C. at 0.4 torr) to provide a yield of 4.3 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH:6]2[CH2:7][CH2:8][CH:3]1[C:4](=O)[C:5]2=O.C(OP([CH:20]([CH3:28])[C:21](=O)[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=O)OCC)C.O.[NH2:30][NH2:31]>>[CH3:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:21]1[C:20]([CH3:28])=[C:5]2[C:4]([CH:3]3[C:2]([CH3:11])([CH3:1])[CH:6]2[CH2:7][CH2:8]3)=[N:31][N:30]=1
Reactant: CC1(C)C2CCC1C(=O)C2=O
Reactant: NN
Reactant: CCOP(=O)(OCC)C(C)C(=O)CC(C)(C)C
Solvent: O
Product: Cc1c(CC(C)(C)C)nnc2c1C1CCC2C1(C)C

Procedure:
yellow solid. MS (ESI): 259.3 (MH+). Prepared from 7,7-dimethyl-bicyclo[2.2.l]heptane-2,3-dione, (1,4,4-trimethyl-2-oxo-pentyl)-phosphonic acid diethyl ester, hydrazine monohydrate.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH2:2][CH2:3]CCCCC.[C:11]([OH:24])(=O)[CH2:12][CH2:13]CCCCCCCCC.[C:25](O)(=O)CCCCCCCCCCCCC.C(O)(=O)CCCCCCCCCCCCCCC.C(O)(=O)CCCCCCCCCCCCCCCCC>>[C:1]([O:10][CH2:13][CH:12]1[O:24][CH2:11]1)(=[O:9])[C:2]([CH3:3])=[CH2:25]
Reactant: CCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCCCC(=O)O
Product: C=C(C)C(=O)OCC1CO1

Procedure:
16% of saturated fatty acids (C8 - C18 -fatty acids: (caprylic acid, lauric acid, myristic acid, palmitic acid and stearic acid)
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH:16]1[C:25]2[C:20](=[C:21]3[CH:33]=[CH:32][CH:31]=[CH:30][C:22]3=[C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]3=2)[CH:19]=[C:18](O)[N:17]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:18]1[N:17]=[CH:16][C:25]2[C:20]([CH:19]=1)=[C:21]1[CH:33]=[CH:32][CH:31]=[CH:30][C:22]1=[C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=21)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1cc2c3ccccc3c3ccccc3c2cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Oc1cc2c3ccccc3c3ccccc3c2cn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoromethanesulfonic anhydride (5.2 g, 19 mmol) was added to a mixture of dibenzo[f,h]isoquinolin-3-ol (0.91 g, 3.7 mmol), pyridine (1.2 g, 15 mmol) and dichloromethane 100 mL under nitrogen at 0° C. and stirred overnight at room temperature. The reaction was quenched with saturated NaHCO3. The organic layer was washed with water and dried on Na2SO4. The residue was purified by flash chromatography on silica (hexane:ethyl acetate) to give (1.1 g, 79%).
Reaction SMILES: Cl.Cl.Cl[C:4]1[CH:9]=[CH:8][NH:7][C:6](=[O:10])[C:5]=1[C:11]1[NH:12][C:13]2[C:21]([N:22]=1)=[CH:20][C:19]1[C:18](=[O:23])[N:17]([CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:16][C:15]=1[CH:14]=2.Cl.[CH3:33][C@H:34]([NH2:41])[CH2:35][C:36]1[S:37][CH:38]=[CH:39][CH:40]=1.CCN(CC)CC>CCO>[CH3:33][C@H:34]([NH:41][C:4]1[CH:9]=[CH:8][NH:7][C:6](=[O:10])[C:5]=1[C:11]1[NH:12][C:13]2[C:21]([N:22]=1)=[CH:20][C:19]1[C:18](=[O:23])[N:17]([CH2:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:16][C:15]=1[CH:14]=2)[CH2:35][C:36]1[S:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=C1c2cc3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3cc2CN1CCCN1CCCC1
Reactant: C[C@H](N)Cc1cccs1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@@H](Cc1cccs1)Nc1cc[nH]c(=O)c1-c1nc2cc3c(cc2[nH]1)CN(CCCN1CCCC1)C3=O
Temperature: 100 °C
Yield: 47.4 %

Procedure:
A mixture of 2-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(3-pyrrolidin-1-yl-propyl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one dihydrochloride (17) (2.2 g, 4.9 mmol), (1S)-1-methyl-2-thien-2-ylethylamine hydrochloride (13b) (870 mg, 4.9 mmol) and Et3N (3.44 mL, 24.5 mmol) in EtOH (20 mL) was heated at 100° C. for 12 h. The mixture was concentrated, diluted with water (20 mL) and extracted with CHCl3 (5×20 mL) the combined organic layer was dried, concentrated to a residue that was purified on silica gel column using 10% NH4OH/methanol in CH2Cl2 to get pure 2-[4-((S)-1-methyl-2-thiophen-2-yl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-6-(3-pyrrolidin-1-yl-propyl)-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one (18a) (1.2 g, 51%). 1H NMR (DMSO-d6) δ 1.33 (d, 3H, J=3.0 Hz), 1.55-1.85 (m, 6H), 2.3-2.45 9 m, 6H), 3.15-3.25− (m, 2H), 3.56 (t, 2H, J=6.0 Hz), 3.95-4.15 (m, 1H), 4.51 (s, 2H), 6.15 (d, 1H, J=9.0 Hz), 6.91-6.96 (m, 1H), 7.05 (t, 1H, J=3.0 Hz), 7.31-7.36 (m, 2H), 7.66 (s, 0.5H), 7.79 (d, 1H, J=3.0 Hz), 7.93 (s, 0.5H), 11.14 (d, 1H, J=9.0 Hz), 11.24 (bs, 1H). ESI-MS m/z 517.67 (M++1).
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)C.C([Li])[CH2:9][CH2:10][CH3:11].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=[O:17].O>O1CCCC1>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]([OH:17])[C:10]([CH3:9])([CH3:11])[C:1]#[N:4]
Reactant: CC(C)NC(C)C
Reactant: O=Cc1ccccc1F
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C#N)C(O)c1ccccc1F
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 99.7 %

Procedure:
To a stirring solution of diisopropylamine (2.27 mL, 16.1 mmol) in tetrahydrofuran (60 mL) at −20° C. under nitrogen was added a solution of n-butyllithium (7.1 mL, 17.7 mmol, 2.5 M in hexane). After the addition was complete, the mixture was cooled to −70° C., isobutyryl nitrile (1.46 mL, 16.1 mmol) was added and the reaction mixture was then warmed to −10° C. After 10 minutes, 2-fluoro-benzaldehyde (1.70 mL, 16.1 mmol) was added and the resulting solution was allowed to warm to ambient temperature. After one hour at ambient temperature, water (5 mL) was added to the reaction mixture and it was concentrated at reduced pressure. The resulting crude product was diluted with ethyl acetate (125 mL), washed with water (75 mL) followed by saturated aqueous sodium chloride (50 mL) and the organic layer was concentrated at reduced pressure to give the product as a colorless oil (3.1 g, ˜100%). 1H NMR (CDCl3) δ 7.70 (m, 1H), 7.35 (m, 1H), 7.22 (m, 1H), 7.04 (m, 1H), 4.99 (br s, 1H), 2.42 (br s, 1H), 1.24 (s, 6H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C@@H:11]3[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH:18]1([N:23]2[C:32]3[N:31]=[C:30]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([C:43](O)=[O:44])=[C:38]5[C:42]=4[O:41][CH2:40][CH2:39]5)[N:29]=[CH:28][C:27]=3[N:26]([CH3:46])[C:25](=[O:47])[C@H:24]2[CH2:48][CH3:49])[CH2:22][CH2:21][CH2:20][CH2:19]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.N>ClCCl.O>[CH:18]1([N:23]2[C:32]3[N:31]=[C:30]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([C:43]([NH:17][C@H:14]5[CH2:15][CH2:16][C@@H:11]([N:8]6[CH2:9][CH2:10][N:5]([CH2:4][CH:1]7[CH2:2][CH2:3]7)[CH2:6][CH2:7]6)[CH2:12][CH2:13]5)=[O:44])=[C:38]5[C:42]=4[O:41][CH2:40][CH2:39]5)[N:29]=[CH:28][C:27]=3[N:26]([CH3:46])[C:25](=[O:47])[C@H:24]2[CH2:48][CH3:49])[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C1CCCC1
Reactant: N[C@H]1CC[C@@H](N2CCN(CC3CC3)CC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)N[C@H]4CC[C@@H](N5CCN(CC6CC6)CC5)CC4)c4c3OCC4)nc2N1C1CCCC1
Reaction time: 2 h
Yield: 60.9 %

Procedure:
(cis)-4-[4-(Cyclopropylmethyl)piperazin-1-yl]cyclohexanamine 12e (139 mg, 0.40 mmol), 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 1q (175 mg, 0.40 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (128 mg, 0.40 mmol) and diisopropylethylamine (258 mg, 2.08 mmol) were dissolved in 50 mL of dichloromethane. The reaction solution was stirred for 2 hours followed by the addition of 50 mL of water and 10 mL of aqueous ammonia successively, and stirred for another 0.5 hours. The resulting solution was extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL×3), dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-N-[(cis)-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl]-2,3-dihydrobenzofuran-4-carboxamide 12 (160 mg, yield: 61.0%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1/[CH:29]=[CH:30]/[C:31](O)=[O:32]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:31](=[O:32])/[CH:30]=[CH:29]/[C:22]3[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:21]=3[O:20][CH3:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: COc1cccc(/C=C/C(=O)O)c1OC
Product: COc1cccc(/C=C/C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)c2)c1OC

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2,3-dimethoxy-phenyl)-acrylic acid.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]([S:11]([O-:13])=[O:12])[S:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[Li+].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:24]([F:27])([F:26])[F:25])=[C:20]([CH:23]=1)[CH2:21]Br.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C(#N)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:24]([F:27])([F:26])[F:25])=[C:20]([CH:23]=1)[CH2:21][S:11]([C:9]1[S:10][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:38]3[CH2:37][CH2:36][N:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:40][CH2:39]3)[C:7]=2[CH:8]=1)(=[O:13])=[O:12]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: FC(F)(F)c1ccc(Cl)cc1CBr
Reactant: O=S([O-])c1cc2c(Cl)nccc2s1
Agent: [Li+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2nccc3sc(S(=O)(=O)Cc4cc(Cl)ccc4C(F)(F)F)cc23)CC1

Procedure:
Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.44 mmol) was treated with 5-chloro-2-(trifluoromethyl)benzylbromide (0.59 mmol) as described in Method P above and then reacted further with tert-butyl-piperazine-1-carboxylate as described in Method Q. Yield 0.019 g (7.5% over two steps). Beige solid. 1H NMR (300 MHz, CDCl3) δ 8.12-8.14 (m, 1H), 7.80-7.88 (m, 2H), 7.47-7.66 (m, 2H), 4.71 (s, 2H), 3.74-3.83 (m, 4H), 3.63-3.72 (m, 4H), 1.49 (s, 9H); MS (ESI+) for C24H25ClF3 N3O4S2 m/z 576 (M+H)+. HPLC 74%, RT 2.30 min (YMC ODS AQ, 33×3 mm, 10-90% acetonitrile in 3 min).
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:13][CH2:12][NH:11][C:10]([CH3:25])([CH2:14][C:15]3[CH:20]=[CH:19][C:18]4[O:21][CH2:22][CH2:23][O:24][C:17]=4[CH:16]=3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:39]([O:41][C:42](Cl)=[O:43])[CH3:40]>C1C=CC=CC=1>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:13][CH2:12][N:11]([C:42]([O:41][CH2:39][CH3:40])=[O:43])[C:10]([CH3:25])([CH2:14][C:15]3[CH:20]=[CH:19][C:18]4[O:21][CH2:22][CH2:23][O:24][C:17]=4[CH:16]=3)[CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC1(Cc2ccc3c(c2)OCCO3)CN(C(c2ccccc2)c2ccccc2)CCN1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1(C)Cc1ccc2c(c1)OCCO2
Temperature: 25 °C
Yield: 90 %

Procedure:
12.4 g of 1-diphenylmethyl-3-methyl-3-(3,4-ethylenedioxybenzyl)-piperazine (3a) are dissolved in 100 ml of dry benzene and combined with 3.3 g of triethylamine. 3.6 g of chloroformic acid ethyl ester in 20 ml of benzene are added dropwise with stirring at room temperature. After 12 hours the solution is washed free of halogen with water and evaporated to dryness in vacuum. 13.1 g (90%) of 1-diphenylmethyl-3-methyl-3-(3,4-ethylenedioxybenzyl)-4-carbethoxypiperazine are obtained (m.p. = 153° - 155° C., diisopropylether), which are dissolved in 100 ml of dry tetrahydrofuran and added dropwise with stirring over 30 minutes to a boiling suspension of 3.8 g of lithium aluminum hydride in 200 ml of tetrahydrofuran. After three hours, the mixture is combined with water and filtered. The filtrate is evaporated to dryness in vacuum. 10.7 g (93%) of 1-diphenylmethyl-3-methyl-3-(3,4-ethylenedioxybenzyl)-4-methylpiperazine are obtained.