Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:36]([S:38](Cl)(=[O:40])=[O:39])[CH3:37]>>[CH2:36]([S:38]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]3)=[O:15])=[CH:11][CH:12]=2)[CH2:2][CH2:3]1)(=[O:40])=[O:39])[CH3:37]
Reactant: CCS(=O)(=O)Cl
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCNCC4)cc3)cc(=O)c2c1
Product: CCS(=O)(=O)N1CCN(c2ccc(NC(=O)c3cc(=O)c4cc(OC)cc(N5CCN(C)CC5)c4o3)cc2)CC1

Procedure:
This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially available ethanesulfonyl chloride (Aldrich) via the parallel synthesis described above. MS—base peak at m/z=570 by positive ion CI, mp=232-234° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[N:27]1[C:40]2C(=CC=C3[C:39]=2[N:38]=[CH:37]C=C3)C=CC=1.N1C=CN=C1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:38]3[CH:39]=[CH:40][N:27]=[CH:37]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(I)cc2)CC1
Reactant: c1cnc2c(c1)ccc1cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-n3ccnc3)cc2)CC1
Temperature: 110 °C
Yield: 156.3 %

Procedure:
4-(4-Iodo-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.194 g, 0.5 mmol), Cul (0.01 g), Cs2CO3 (0.326 g, 1.0 mmol), [1,10]Phenanthroline (0.027 g, 0.15 mmol) and imidazole (0.034 g, 0.5 mmol) were mixed in 3 mL dry DMF in a pressure vessel. The vessel was heated at 110° C. overnight. After cooling to rt, the insoluble was filtered and washed with CH2Cl2. The filtrate was concentrated and the crude was purified with prep TLC (7.5% MeOH-2M NH3/CH2Cl2) to yield the title compound (0.077 g). M+H 328.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:18]([O:20]CC)=[O:19])[CH:6]=[C:7]2[C:11]=1[N:10](C1CCCCO1)[N:9]=[CH:8]2.[Li+].[OH-]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:18]([OH:20])=[O:19])[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[CH:8]2
Reactant: CCOC(=O)c1cc(OC)c2c(cnn2C2CCCCO2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)cc2cn[nH]c12
Temperature: 40 °C
Reaction time: 8 h
Yield: 75.1 %

Procedure:
A mixture of ethyl 7-methoxy-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-5-carboxylate (980 mg, 4.45 mmol) in THF (10 mL), water (10 mL) and LiOH (560 mg, 13.4 mmol) was heated at 40° C. for 3 hours and then stirred at room temperature overnight. The reaction was not complete so the mixture was heated to 45° C. and heated overnight. The mixture was then concentrated to dryness, acidified to pH 6 with conc. HCl and partitioned between EtOAc and water. The resultant solids were collected by vacuum filtration, rinsed with EtOAc and dried under high vacuum to afford a white solid. The organic layer was washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to provide an off-white solid. Both batches of white solid were combined to afford the title compound (642 mg, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[O:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[C:22]3[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=3)[CH2:25][NH2:26])[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:30](OC(=O)C)(=[O:32])[CH3:31].O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[O:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[C:22]3[CH:23]=[C:24]([CH2:25][NH:26][C:30](=[O:32])[CH3:31])[CH:27]=[CH:28][CH:29]=3)[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(-c2cc3nccc(-c4cccc(CN)c4)c3o2)cc(OC)c1OC
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(-c2cc3nccc(-c4cccc(CNC(C)=O)c4)c3o2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 96 h
Yield: 45 %

Procedure:
3-[2-(3,4,5-Trimethoxy-phenyl)-furo[3,2-b]pyridin-7-yl]-benzylamine (0.036 mmol) is dissolved in acetic acid (1.00 ml) and acetic acid anhydride (0.159 mmol) is added. The reaction solution is stirred 4 d at RT. Water is added and extracted with ethyl acetate. The combined organic layers are washed with brine and dried over MgSO4. The product is isolated after removal of the solvent in vacuo as yellow solid (45% yield). HPLC (method A): Rt 2.52 min (purity 99.4%); LCMS (ESI+) (method E): Rt 1.87 min, M+H+ 433.1 m/z; 1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.57 (d, J=5.1, 1H), 8.44 (t, J=5.7, 1H), 8.09 (d, J=12.1, 1H), 7.97 (d, J=7.8, 1H), 7.76 (d, J=2.8, 1H), 7.69-7.56 (m, 2H), 7.44 (t, J=9.5, 1H), 7.33 (d, J=7.8, 2H), 4.39 (d, J=5.9, 2H), 3.91 (d, J=11.1, 6H), 3.78-3.70 (m, 3H), 1.91-1.77 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24])C(OC(C)(C)C)=O)[CH3:2]>ClCCl.FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24])[CH3:2]
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)c1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cc1cc(Cl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 50.5 %

Procedure:
A solution of 2-(5-chloro-2,4-dinitro-phenyl)-malonic acid tert-butyl ester ethyl ester (0.4 g) in a mixture of dichloromethane (3 mL) and trifluoroacetic acid (0.5 mL) was heated at 70° C. for 30 minutes in a sealed tube. The reaction mixture was then evaporated under reduced pressure and the residue was purified by flash chromatography (EtOac/hexane, 10/90) to afford 150 mg of (5-chloro-2,4-dinitro-phenyl)-acetic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14](OCC2C=CC=CC=2)=O)=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:26]=[CH:27][C:28]([S:31]([OH:34])(=[O:33])=[O:32])=[CH:29][CH:30]=1>CO>[S:31]([C:28]1[CH:29]=[CH:30][C:25]([CH3:24])=[CH:26][CH:27]=1)([OH:34])(=[O:33])=[O:32].[F:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[CH3:14])=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@H]1COc1ccc(F)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CN1CC[C@H]1COc1ccc(F)nc1

Procedure:
The title compound was prepared by the procedure of example 98c, except substituting 6-fluoro-3-(1-Cbz-2-(S)-azetidinylmethoxy)pyridine for the R enantiomer thereof. The product was obtained as a white solid: mp 124-126° C.; [α]D =+15.93 (c 0.5, MeOH); 1H NMR (300 MHz, D2O) δ 7.92 (s, 1H), 7.68 (m, 3H), 7.38 (d, 2H, J=8.0 Hz), 7.11 (dd, 1H, J=2.5,8.5 Hz), 4.8 (br s, 1H), 4.45 (m, 2H), 4.27 (br s, 1H), 4.02 (br s, 1H), 2.99 (s, 3H), 2.68 (m, 2H), 2.40 (s, 3H); MS (CI/NH3); m/z 197 (M+H)+. Anal. Calcd for C10H13FN2O.TsOH: C, 55.42; H, 5.75; N, 7.60. Found: C, 55.33; H, 5.74; N, 7.59.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[NH:15][C:16]([CH:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)=[CH:17][C:10]=23)O1.Br[C:33]1[N:38]=[C:37]([NH2:39])[CH:36]=[N:35][CH:34]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>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.O1CCOCC1>[NH2:39][C:37]1[N:38]=[C:33]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[NH:15][C:16]([CH:18]4[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]4)=[CH:17][C:10]=23)[CH:34]=[N:35][CH:36]=1
Reactant: Nc1cncc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3c(B4OC(C)(C)C(C)(C)O4)ccnc3[nH]2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3c(-c4cncc(N)n4)ccnc3[nH]2)CC1
Temperature: 100 °C

Procedure:
A mixture of Example 21A (500 mg, 1.2 mmol), 6-bromopyrazin-2-amine (244 mg, 1.4 mmol), bis(triphenylphosphine)palladium(ii) chloride (82 mg, 0.1 mmol), tricyclohexylphosphine (33 mg, 0.1 mmol) and cesium carbonate (1.2 g, 3.5 mmol) was purged with nitrogen, then anhydrous dioxane (60 ml) was added. The mixture was heated at 100° C. overnight. The reaction was cooled to room temperature and filtrated, and the solid was washed with dichloromethane (200 mL). The filtrate was concentrated and purified by flash chromatography on silica gel using an ISCO Companion eluting with heptanes/ethyl acetate (30%) to provide the title compound. MS (ESI+) m/z 395 (M+H)+.
Reaction SMILES: [C:1]([O:9][C:10]1[C:19]2[N:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13](=[O:20])[NH:12][C:11]=1[C:21]([O:23][CH3:24])=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH2:26][C:27]([N:29]([CH3:31])[CH3:30])=[O:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.Cl>C1COCC1>[C:1]([O:9][C:10]1[C:11]([C:21]([O:23][CH3:24])=[O:22])=[N:12][C:13]([O:20][CH2:26][C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[C:14]2[C:19]=1[N:18]=[CH:17][CH:16]=[CH:15]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1[nH]c(=O)c2cccnc2c1OC(=O)c1ccccc1
Reactant: CN(C)C(=O)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1nc(OCC(=O)N(C)C)c2cccnc2c1OC(=O)c1ccccc1

Procedure:
To a cold (0° C.) suspension of methyl 8-(benzoyloxy)-5-oxo-5,6-dihydro[1,6]-naphthyridine-7-carboxylate (3.24 g, 10 mmol), 2-hydroxy-N,N-dimethylacetamide (1.13 g, 11 mmol), and triphenylphosphine (5.24 g, 20 mmol) in THF (100 mL), diethyl azodicarboxylate (3.1 mL, 19.6 mmol) was added over a period of 3 minutes. The resultant mixture was stirred at room temperature for two days. The product mixture was treated with 1 M aq HCl and extracted with methylene chloride. The organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residual oil was subject to column chromatography on silica gel eluting with 1-2% methanol in ethyl acetate. Collection and concentration of the appropriate fractions provided the slower eluting o-alkylated isomer as white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][N:31]=2)[CH2:26][CH2:25]1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:33]3[CH:32]=[N:31][C:30]([N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)=[CH:35][CH:34]=3)[C:16]2=[CH:15][N:14]=1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc(N5CCN(C)CC5)nc4)n[nH]c3n2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine. LCMS (M+H)+=468.0.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:23])[C:3]=1[CH3:24].[CH3:25][O:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:32]5[C:27]([O:26][CH3:25])=[N:28][CH:29]=[CH:30][CH:31]=5)[C:3]([CH3:24])=[C:4]([CH3:23])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: COc1ncccc1B(O)O
Reactant: Cc1cc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc(Cl)c1C
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: CCOC(C)=O
Solvent: COCCOC
Product: COc1ncccc1-c1nc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)cc(C)c1C
Temperature: 80 °C
Yield: 93 %

Procedure:
To N-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide (100 mg, 0.29 mmol), 2-methoxypyridin-3-ylboronic acid (67 mg, 0.44 mmol) and tetrakis(triphenylphosphine)palladium (0) (34 mg, 0.029 mmol) in 1,2-dimethoxyethane (3.0 mL), 2 M Na2CO3 (438 μL, 0.88 mmol) was added. The reaction mixture was stirred and heated at 80° C. for 68 hours under N2 atmosphere. The reaction mixture was diluted with ethyl acetate (5 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield 1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-3,4-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide as a pale yellow solid (112 mg, 92.4%). ESI-MS m/z calc. 415.5. found 416.5 (M+1)+. Retention time 1.68 minutes.
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:7][CH2:6][CH:5]([C:8]2[S:25][C:11]3[N:12]=[C:13]([CH3:24])[N:14]=[C:15]([CH2:16][NH:17][C:18]([CH3:23])([CH3:22])[CH2:19][O:20][CH3:21])[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.N1(CO)C2C=CC=C[C:30]=2N=N1.ClCCCl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>O>[F:26][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[S:25][C:11]3[N:12]=[C:13]([CH3:24])[N:14]=[C:15]([CH2:16][N:17]([CH3:30])[C:18]([CH3:23])([CH3:22])[CH2:19][O:20][CH3:21])[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1
Reactant: COCC(C)(C)NCc1nc(C)nc2sc(C3CCC(F)(F)CC3)cc12
Reactant: OCn1nnc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: COCC(C)(C)N(C)Cc1nc(C)nc2sc(C3CCC(F)(F)CC3)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
To a mixture of N-{[6-(4,4-difluorocyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}-1-methoxy-2-methylpropan-2-amine (110 mg), 1H-benzotriazole-1-methanol (86 mg), and DCE was added NaBH(OAc)3 (182 mg), followed by stirring at room temperature for 4 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by basic silica gel column (hexane/EtOAc) to obtain N-{[6-(4,4-difluorocyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}-1-methoxy-N,2-dimethylpropan-2-amine (93 mg). This product was dissolved in MeOH, and fumaric acid (27 mg) was added thereto, followed by concentration under reduced pressure to obtain N-{[6-(4,4-difluorocyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}-1-methoxy-N,2-dimethylpropan-2-aminefumarate (117 mg).
Reaction SMILES: ClCC([NH:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[NH:21]C(=O)CCl)[C:11](=[O:26])[C:10]=2[CH:9]=[CH:8][CH:7]=1)=O.[N+](C1C2C(=O)C3C(=CC=CC=3[N+]([O-])=O)C(=O)C=2C=CC=1)([O-])=O.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].[OH-].[Na+]>C(O)C>[NH2:5][C:6]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[NH2:21])[C:11](=[O:26])[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=C(CCl)Nc1cccc2c1C(=O)c1c(NC(=O)CCl)cccc1C2=O
Agent: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1cccc2c1C(=O)c1c(N)cccc1C2=O

Procedure:
In the step S1, a manufacturing method of 1,8-bis(chloroacetamido)anthraquinone includes the steps of: add 1,8-dinitroanthraquinone with ethanol, and then add sodium sulfide nonahydrate and sodium hydroxide solution into the mixture to be mixed and reflux heated. After standing and filtration, 1,8-diaminoanthraquinone is obtained by recrystallization of the solution. Next the 1,8-diaminoanthraquinone is dissolved in N,N-dimethylform amide, and pyridine is added for catalyzing, and then chloroacetyl chloride is added into and mixed with the mixture to react. Pour the solution into ice water, 1,8-bis(chloroacetamido) anthraquinone is obtained after filtration and recrystallization of the solution. The step of adding pyridine for catalyzing is run under an ice-bath while in the step of adding and mixing chloroacetyl chloride into the mixture, the ice bath is removed, the nitrogen gas is introduce and the step is run under light protection condition. The step of adding and mixing chloroacetyl chloride into the mixture is run at the room temperature for 24 hours.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=2)[CH2:3][CH2:2]1.Br[CH:19]([CH3:27])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[C@H:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:27])=[CH:7][C:8]=1[C:14]([F:15])([F:16])[F:17])#[N:11]
Reactant: N#Cc1ccc(NCC2CC2)cc1C(F)(F)F
Reactant: CC(Br)C(=O)OC(C)(C)C
Product: C[C@@H](C(=O)OC(C)(C)C)N(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized in manner similar to example 1 using 4-[(cyclopropylmethyl)amino]-2-(trifluoromethyl)benzonitrile and 1,1-dimethylethyl 2-bromopropanoate: 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=8.8 Hz, 1H), 7.04 (d, J=2.6 Hz, 1H), 6.86 (dd, J=8.9, 2.7 Hz, 1H), 4.33 (q, J=7.1 Hz, 1H), 3.30 (m, 2H), 1.54 (d, J=7.1 Hz, 3H), 1.39 (s, 9H), 0.99 (m, 1H), 0.63 (m, 2H), 0.29 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:21])(=[O:20])[NH:18][CH3:19])=[CH:13][CH:12]=2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:23]>O1CCOCC1>[NH2:23][C:6]1[C:7]([C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:21])(=[O:20])[NH:18][CH3:19])=[CH:13][CH:12]=2)=[O:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: N
Reactant: CNS(=O)(=O)c1ccc(OC(=O)c2c(Cl)ncnc2Cl)cc1
Solvent: C1COCCO1
Product: CNS(=O)(=O)c1ccc(OC(=O)c2c(N)ncnc2Cl)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 69 %

Procedure:
4-(N-methylsulfamoyl)phenyl 4,6-dichloropyrimidine-5-carboxylate (1.4 g, 3.18 mmol) was dissolved in dioxane (16 ml) and cooled in an ice bath. Ammonia (2.27 ml, 7N in MeOH) was dropwise added and the mixture was stirred at 0° C. for 6 h. The solvent was removed and ethyl acetate added. The solid precipitate was filtered and washed with ethyl acetate to give 750 mg (69% yield) of the title compound. Purity 100%
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=2)[CH:30]=1>C(#N)C>[CH3:1][O:2][C:3](=[O:18])[CH2:4][N:5]([S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:7])=[O:8])[CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=2)[CH:30]=1
Reactant: COC(=O)CNS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CN(Cc1ccnc(-c2cc(OC)c(OC)c(OC)c2)c1)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
N-(2-Nitrobenzenesulfonyl)glycine methyl ester (5.60 g) was dissolved in acetonitrile (100 mL), and to the solution potassium carbonate (3.10 g) and potassium iodide (2.29 g) were added. To the mixture, 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (6.00 g) was then added, and the resultant mixture was stirred at 80° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the resultant mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate, water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=50:1) to obtain the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[CH2:21][CH2:22][N:23]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=2)[CH2:24][CH2:25]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NCc1ccc(CN2CCN(c3ccccn3)CC2)cc1
Yield: 152.3 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (1.0 g), 1-(2-pyridyl)piperazine (1.4 g) and potassium carbonate (4.2 g) in dimethylformamide (20 ml) was stirred at 60-70° C. for 2.5 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown oil. The obtained brown oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=20:1) to give a pale-yellow oil (2.5 g). The obtained pale-yellow oil was crystallized from ethyl acetate and the crystals were recrystallized from ethyl acetate to give the title compound (1.4 g) as white crystals, m.p.=100-101° C.
Reaction SMILES: C1(C)C=CC(S(OCC([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=O)(C)C)(=O)=O)=CC=1.[OH-].[Na+]>CCOCC>[C:19]([O:18][C:16](=[NH:15])[CH:20]=[C:19]([CH3:22])[CH3:21])([CH3:20])([CH3:21])[CH3:22]
Reactant: Cc1ccc(S(=O)(=O)OCC(C)(C)NC(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)=CC(=N)OC(C)(C)C
Yield: 145.7 %

Procedure:
A stirred mixture of 2-tert-butoxycarbonylamino-2-methyl-1-propyl p-toluenesulfonate (8.2 g, 23.88 mmol) and powdered NaOH (6.7 g, 0.151 mol) in Et2O (200 mL) was heated under reflux for 10 hr. After cooling, the mixture was filtered. And the filtrate was washed with water, brine, dried over Na2SO4, and evaporated. The residue was chromatographed on silica-gel with n-hexane:EtOAc (6:1 v/v) as eluent to give 2.7 g (66.2%) 1-tert-butoxycarbonyl-2-methylpropylene imine as an oil. 1H-NMR (CDCl3) δ 1.29 (s, 61H), 1.47 (s, 9H), 2.05 (s, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([N:12]=[C:13]=[O:14])[CH2:4][CH2:3]1.[OH-].[NH4+:16]>O1CCCC1>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13]([NH2:16])=[O:14])[CH2:4][CH2:3]1
Reactant: O=C=NC1CCC(=O)c2ccccc21
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)NC1CCC(=O)c2ccccc21

Procedure:
A solution of 1,2,3,4-Tetrahydro-4-oxo-1-naphthylisocyanate (5.0 g) in tetrahydrofuran is added to a rapidly stirred aqueous concentrated ammonium hydroxide solution (excess) to afford 1,2,3,4-tetrahydro-4-oxo-1-naphthylurea.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([NH2:13])=[N:9][NH:10][C:11]=1[NH2:12].[N:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH:23]=O)[CH:21]=O)=[CH:16][CH:15]=1>C(O)C.C(O)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([NH2:12])=[N:10][N:9]2[CH:23]=[C:20]([C:17]3[CH:18]=[CH:19][N:14]=[CH:15][CH:16]=3)[CH:21]=[N:13][C:8]=12
Reactant: O=CC(C=O)c1ccncc1
Reactant: Nc1n[nH]c(N)c1-c1ccccn1
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1nn2cc(-c3ccncc3)cnc2c1-c1ccccn1
Yield: 61.6 %

Procedure:
A mixture of 4-pyridin-2-yl-1H-pyrazole-3,5-diamine (290 mg, 1.66 mmol) and 2-pyridin-4-yl-malonaldehyde (247 mg, 1.66 mmol) were placed in ethanol (5 mL) with a catalytic amount of acetic acid (6 drops). The reaction mixture was submitted to microwave irradiations at 140° C. for 15 minutes. The crude mixture was cooled down to room temperature and the resulting precipitate was filtered and washed with more ethanol to provide the title as a golden yellow solid (295 mg, 62%). MS (ES+) 289, (ES−) 287. δH (DMSO-d6) 7.16 (1H, dd), 7.21 (2H, m), 7.84 (1H, m), 7.89 (2H, m), 8.57 (2H, br m), 8.65 (2H, d), 8.98 (1H, d), 9.44(1H, d).