Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH2:17]4)[N:13]([CH3:19])[C:12]=3[CH:20]=2)[C:4](=[O:21])[CH:3]=1.[Br:22][C:23]1[O:27][C:26]([CH2:28][OH:29])=[CH:25][CH:24]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[Br:22][C:23]1[O:27][C:26]([CH2:28][O:29][C:2]2[CH:7]=[CH:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]4[N:15]=[C:14]([CH:16]5[CH2:18][CH2:17]5)[N:13]([CH3:19])[C:12]=4[CH:20]=3)[C:4](=[O:21])[CH:3]=2)=[CH:25][CH:24]=1
Reactant: OCc1ccc(Br)o1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(Cl)cc3=O)cc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(Br)o4)cc3=O)cc21
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a solution of 4-chloro-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (150 mg) and (5-bromo-2-furyl)methanol (177 mg) in toluene (2.0 ml) was added potassium tert-butoxide (112 mg) at 100° C., and the mixture was stirred for 30 min. The mixture was quenched with water (2 ml), and the precipitate was collected. The resulting solid was recrystallized from EtOH—H2O to give the title compound (158 mg) as an off-white solid.
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][O:6][C:5]2[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:4]=2[C:3]1=O.[C:15]([NH2:22])(=[S:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(O)C>[CH2:19]([O:18][C:16]([C:15]1[S:21][C:2]2[CH2:8][CH2:7][O:6][C:5]3[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:4]=3[C:3]=2[N:22]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)C(N)=S
Reactant: O=C1c2cc(F)ccc2OCCC1Br
Solvent: CCO
Product: CCOC(=O)c1nc2c(s1)CCOc1ccc(F)cc1-2
Reaction time: 8 h
Yield: 62.5 %

Procedure:
Dissolved 4-bromo-7-fluoro-3,4-dihydrobenzo[b]oxepin-5(2H)-one (1.06 g, 4.09 mmol) in ethanol (100 mL) and added Ethyl Thioamidooxalate (1.09 g, 8.18 mmol). Heated to reflux with a vigreux condensation column attached. Allowed to stir a reflux overnight and confirmed complete reaction by LCMS. Concentrated in vacuo and purified by flash chromatography using ethyl acetate/heptanes (0 to 10% over 60 minutes) to give 0.75 g (62% yield) of 9-fluoro-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid ethyl ester
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].[H-].[Na+].Cl[C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[CH:23]=[C:24]([CH3:26])[S:25][C:16]=12>O1CCCC1>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([O:10][CH3:11])=[CH:5][C:3]=1[NH:4][C:15]1[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]2[CH:23]=[C:24]([CH3:26])[S:25][C:16]=12
Reactant: Cc1cc2ncc(C#N)c(Cl)c2s1
Reactant: COc1cc(N)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Nc2c(C#N)cnc3cc(C)sc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 22.5 %

Procedure:
A mixture of 2,4-dichloro-5-methoxyaniline (507 mg, 2.64 mmol) and 60% sodium hydride (105.6 mg, 2.64 mmol) in 15 mL of tetrahydrofuran is heated at reflux for 1 hour. The solution is cooled and 7-chloro-2-methylthieno[3,2-b]pyridine-6-carbonitrile (275.3 mg, 1.32 mmol) is added. The reaction mixture is heated at reflux for 6 hours, cooled to room temperature and partitioned between dichloromethane and water. The organic layer is washed with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of 5% ethyl acetate in hexane to 20% ethyl acetate in hexane followed by preparative thin layer chromatography developing with 20% ethyl acetate in dichloromethane, to provide 108 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-methylthieno[3,2-b]pyridine-6-carbonitrile as an off white solid, mp 213-214° C.; 1H NMR (DMSO-d6) δ 2.51 (s, 3H), 3.85 (s, 3H), 7.20 (s, 1H), 7.35 (s, 1H), 7.75 (s, 1H), 8.55 (s, 1H), 9.56 (s, 1H); MS 362.1, 364.3 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.Cl[C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH2:23][CH:24]2[CH2:26][CH2:25]2)=[C:16]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[N:15]=1.[CH3:33][NH:34][C:35]1[N:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=1>C(OCC)(=O)C.O>[CH:24]1([CH2:23][N:20]2[CH:19]=[N:18][C:17]3[C:21]2=[N:22][C:14]([C:38]2[CH:37]=[N:36][C:35]([NH:34][CH3:33])=[N:40][CH:39]=2)=[N:15][C:16]=3[N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH2:26][CH2:25]1
Reactant: Clc1nc(N2CCOCC2)c2ncn(CC3CC3)c2n1
Reactant: CNc1ncc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CNc1ncc(-c2nc(N3CCOCC3)c3ncn(CC4CC4)c3n2)cn1
Yield: 60.6 %

Procedure:
Sodium carbonate (2.40 g, 22.7 mmol) and tetrakis triphenylphosphine palladium (0.44 g, 0.38 mmol) were added to a 1,4-dioxane (44.0 ml)-water (22.0 ml) mixture solution of 2-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purine (2.22 g, 7.56 mmol) and 2-methylaminopyrimidine-5-boronic acid pinacol ester (2.31 g, 9.82 mmol) at room temperature and the resulting mixture was heated to reflux for 3.5 hours in an argon atmosphere. The reaction mixture was left standing to cool and then poured into water and ethyl acetate was added to separate the layers. The solid precipitated in the aqueous layer was collected by filtration, washed with water, and then dried at 50° C. under reduced pressure. Meanwhile, the organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, then the filtrate was concentrated under reduced pressure, and the resulting solid was washed with dichloromethane and collected by filtration. These solids were combined to give the title compound (1.68 g, 61%) as a white solid.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[SH:19][C:20]1[N:24]([CH3:25])[N:23]=[N:22][N:21]=1.P(Cl)(Cl)(OP(Cl)(Cl)=O)=O.N>C(#N)C.O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:19][C:20]3[N:24]([CH3:25])[N:23]=[N:22][N:21]=3)[CH2:15][S:14][C@H:9]12
Reactant: Cn1nnnc1S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: N
Agent: O=P(Cl)(Cl)OP(=O)(Cl)Cl
Solvent: O
Solvent: CC#N
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: -40 °C
Yield: 87.2 %

Procedure:
In 5.4 ml of acetonitrile were suspended 0.909 g of 7-ACA and 0.504 g of 5-mercapto-1-methyl-1H-tetrazole, and 0.256 g of water was added. The suspension was cooled at -40° C. under stirring, and 3.58 g of diphosphoryl tetrachloride was added dropwise to it at -50° to -35° C. The reaction mixture was stirred at -35° to 0° C. for 5 minutes after the dropwise addition and placed in a warm water bath at 40° C. to warm, followed by stirring at the same temperature for 20 minutes. The reaction solution was cooled over an ice water bath and, after the addition of 11 ml of cold water, it was adjusted to pH 4.0 with aqueous concentrated ammonia. The separated-out precipitate was recovered by filtration, washed with water and dried, thereby affording 0.956 g of 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4 -carboxylic acid. The yield was 87.2%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([N+:37]([O-])=O)[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl>C(O)C>[NH2:37][C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][CH:32]=1)[CH2:29][N:28]([C:26]([C:10]1[CH:11]=[C:12]([CH:23]([CH3:25])[CH3:24])[C:13]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:27])[CH2:36]2
Reactant: CC(C)c1cc(C(=O)N2Cc3ccc([N+](=O)[O-])cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CC(C)c1cc(C(=O)N2Cc3ccc(N)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Yield: 87.7 %

Procedure:
A solution of (2,4-bis-benzyloxy-5-isopropyl-phenyl)-(5-nitro-1,3-dihydro-isoindol-2-yl)methanone (460 mg; 0.88 mmol) in ethanol (25 ml) was treated with tin (II) chloride dihydrate (1 g; 5 equiv.) then heated at reflux overnight then evaporated in vacuo. The residue was partitioned between EtOAc and saturated NaHCO3, the EtOAc layer was separated, dried (MgSO4) and evaporated to give 380 mg of (5-amino-1,3-dihydro-isoindol-2-yl)-(2,4-bis-benzyloxy-5-isopropyl-phenyl)-methanone.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[CH:6][C:7]([O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:8]([CH:10]=1)[NH2:9].[CH3:22][S:23](Cl)(=[O:25])=[O:24].N1C=CC=CC=1.Cl.C(=O)([O-])O.[Na+]>ClCCl>[CH3:22][S:23]([NH:9][C:8]1[CH:10]=[C:4]([CH:5]=[CH:6][C:7]=1[O:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[CH:3]=[O:2])(=[O:25])=[O:24]
Reactant: COC(OC)c1ccc(OCCN2CCOCC2)c(N)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(C=O)ccc1OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 93.7 %

Procedure:
A solution of 5-dimethoxymethyl-2-(2-morpholinoethoxy)aniline obtained in Step 3 (0.27 g, 0.91 mmol) in dichloromethane (2.00 mL) was added with methanesulfonyl chloride (0.11 mL, 1.42 mmol) and pyridine (0.50 mL, 6.18 mmol), followed by stirring at room temperature for 10 hours. The reaction mixture was added with hydrochloric acid (3 mol/L, 3.00 mL), was stirred at room temperature for 20 minutes, was neutralized with a saturated aqueous sodium hydrogencarbonate solution (50 ml) and was extracted with ethyl acetate (50 mL×3). The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. the crude product was purified by silica gel column chromatography (chloroform, then methanol/chloroform=1/6) to obtain 3-methanesulfonylamino-4-(2-morpholinoethoxy)benzaldehyde (0.28 g, 95%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22](O)=[O:23])[C:15]=4[N:14]=3)=[C:9]([C:25]([F:28])([F:27])[F:26])[CH:8]=2)[CH2:3][CH2:2]1.CN(C(ON1N=[N:44][C:39]2[CH:40]=[CH:41][CH:42]=[N:43][C:38]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.NC1C=NC=CC=1>CN(C=O)C.O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:17][C:16]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([NH:44][C:39]5[CH:38]=[N:43][CH:42]=[CH:41][CH:40]=5)=[O:23])[C:15]=4[N:14]=3)=[C:9]([C:25]([F:27])([F:26])[F:28])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cccc2[nH]c(-c3ccc(N4CCOCC4)cc3C(F)(F)F)nc12
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1cccnc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)c1cccc2[nH]c(-c3ccc(N4CCOCC4)cc3C(F)(F)F)nc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.2 %

Procedure:
A mixture of 2-(4-morpholino-2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxylic acid (20; 157 mg, 0.40 mmol), HATU (304 mg, 0.80 mmol), DIEA (207 mg, 1.60 mmol) and 3-aminopyridine (173; 37 mg, 0.40 mmol) in DMF (2 mL) was stirred at room temperature for 12 h. Water (20 mL) was added and stirred for 30 min. The mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography to give 2-(4-morpholino-2-(trifluoromethyl)phenyl)-N-(pyridin-3-yl)-1H-benzo[d]imidazole-4-carboxamide (Compound 430) (64 mg, 34%) as a pale yellow solid. MS (ESI) calcd for C24H20F3N5O2: 467.16; found: 468 [M+H].
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]([CH2:13][C@@H:14]3[CH2:18][O:17]C(C)(C)[O:15]3)[CH:8]=[N:7][C:6]=2[N:5]([CH3:21])[C:4](=[O:22])[C:3]=1[CH3:23].[F:24][C:25]1[CH:31]=[C:30]([I:32])[CH:29]=[CH:28][C:26]=1[NH2:27].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:15][C@@H:14]([CH2:18][OH:17])[CH2:13][N:9]1[C:10](=[O:12])[C:11]2[C:2]([NH:27][C:26]3[CH:28]=[CH:29][C:30]([I:32])=[CH:31][C:25]=3[F:24])=[C:3]([CH3:23])[C:4](=[O:22])[N:5]([CH3:21])[C:6]=2[N:7]=[CH:8]1
Reactant: Nc1ccc(I)cc1F
Reactant: Cc1c(Cl)c2c(=O)n(C[C@@H]3COC(C)(C)O3)cnc2n(C)c1=O
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1c(Nc2ccc(I)cc2F)c2c(=O)n(C[C@@H](O)CO)cnc2n(C)c1=O
Temperature: 70 °C
Yield: 31 %

Procedure:
(R)-5-Chloro-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (9.2 g, 27.1 mmol, 1 eq, compound 8E), 2-fluoro-4-iodoaniline (12.9 g, 54.2 mmol, 2 eq), tris(dibenzylideneacetone)dipalladium(0) (1.99 g, 2.17 mmol, 0.08 eq), 9,9-Dimethyl-4,5-bis(diphenylphosphino)xanthene (1.25 g, 2.17 mmol, 0.08 eq) and sodium tert-butoxide (7.81 g, 81.4 mmol, 3 eq) were heated in degassed anhydrous 1,4-dioxane (80 mL) at 100° C. for 1 hour. Upon cooling, the solution was filtered and the solid washed with DCM. The filtrate was evaporated in vacuo and the residue (crude 8F) was taken up in H2O (20 mL) and THF (20 mL). 1N HCl (15 mL) was added and the solution heated at 70° C. for 30 minutes. Upon cooling an off-white solid precipitated which was collected by filtration, washed with water and dried. The solid was purified by HPLC to give 4.2 g of title compound (31%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.63 (s, 3H) 3.38 (t, J=6.06 Hz, 1H) 3.41-3.51 (m, 1H) 3.61 (s, 3H) 3.62-3.68 (m, 1H) 3.75 (br. s., 1H) 4.81 (t, J=5.56 Hz, 1H) 5.11 (d, J=5.31 Hz, 1H) 6.60 (t, J=8.72 Hz, 1H) 7.45 (d, J=9.60 Hz, 1H) 7.66 (d, J=10.61 Hz, 1H) 8.48 (s, 1H) 10.16 (s, 1H). [M+H] calc'd for C18H18FIN4O4, 501. found, 501.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:14][N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.C=O.[BH3-][C:27]#N.[Na+]>CO>[Br:1][C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:19][CH2:20][N:21]([CH3:27])[CH2:22][CH2:23]3)=[CH:14][N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: [BH3-]C#N
Reactant: Brc1cn2ccnc2c(Nc2ccc(N3CCNCC3)cn2)n1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1CCN(c2ccc(Nc3nc(Br)cn4ccnc34)nc2)CC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 99.1 %

Procedure:
A mixture of 106b (210 mg, 0.52 mmol), formaldehyde (150 mg, 5 mmol), and NaBH3CN (220 mg, 3.5 mmol) in methanol (8 mL) was stirred at 20° C. for 3 hours. The solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column-chromatography eluting with CH2Cl2/methanol (20:1) to afford 106c (200 mg, 90%). MS: [M+H]+ 388.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:25])[CH:12]=[C:13]([S:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[O:14]2)=[C:9]([OH:26])[C:8]=1[O:27][CH3:28])[CH2:4][CH3:5])[CH3:2].Cl.Cl.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:47]=[CH:46][C:42]([CH2:43][O:44]Cl)=[CH:41][CH:40]=2)[CH2:34][CH2:33]1.C(N(CC)CC)C>ClCCl>[CH2:1]([CH:3]([O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:25])[CH:12]=[C:13]([S:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:43](=[O:44])[C:42]4[CH:41]=[CH:40][C:39]([CH2:38][N:35]5[CH2:34][CH2:33][N:32]([CH3:31])[CH2:37][CH2:36]5)=[CH:47][CH:46]=4)=[CH:20][CH:19]=3)[O:14]2)=[C:9]([OH:26])[C:8]=1[O:27][CH3:28])[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1cc2oc(Sc3ccc(O)cc3)cc(=O)c2c(O)c1OC
Reactant: CN1CCN(Cc2ccc(COCl)cc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)Oc1cc2oc(Sc3ccc(OC(=O)c4ccc(CN5CCN(C)CC5)cc4)cc3)cc(=O)c2c(O)c1OC
Yield: 33.7 %

Procedure:
150 ml in dichloromethane of 4.46 g of 7-(1-ethylpropoxy)-5-hydroxy-2-(4-hydroxyphenylthio)-6-methoxychromone obtained in Example 33, 7.21 g of 4-(4-methylpiperazinomethyl)benzoxychloride dihydrochloride, 7.78 ml of triethylamine was stirred over 3 hours at room temperature. The solution thus reacted was concentrated, and an aqueous solution of sodium bicarbonate was added to the resulting residues, and the product was extracted with ethyl acetate. The organic layer was concentrated, and the residues thus obtained were purified by flash column chromatography (chloroform: methanol =30:1 ), whereby 2.31 g of 7-(1-ethylpropoxy)-5-hydroxy-2-{4-[4-(4-methylpiperazinomethyl)benzoyloxy]phenylthio}-6-methoxychromone was obtained.
Reaction SMILES: C(N=S(C1C=CC(CN)=CC=1)(C)=O)#N.[C:15]([N:17]=[S:18]([C:22]1[CH:39]=[CH:38][C:25]([CH2:26][N:27]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:24][CH:23]=1)([CH2:20][CH3:21])=[O:19])#[N:16]>>[C:15]([N:17]=[S:18]([C:22]1[CH:39]=[CH:38][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1)([CH2:20][CH3:21])=[O:19])#[N:16]
Reactant: CCS(=O)(=NC#N)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: CS(=O)(=NC#N)c1ccc(CN)cc1
Product: CCS(=O)(=NC#N)c1ccc(CN)cc1

Procedure:
The title compound is prepared in analogy to preparation 6d, substituting 2-(4-(N-cyano-S-methylsulfonimidoyl)benzyl)isoindoline-1,3-dione with 2-(4-(N-cyano-S-ethylsulfonimidoyl)benzyl)isoindoline-1,3-dione (preparation 13b). ESI mass spectrum: [M+H]+=224; r.t. HPLC: 0.52 min (Z011_S03).
Reaction SMILES: C[C@H]1N[C@@H](C)[CH2:5][N:4]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:14]([C:25]4[CH:33]=[C:32]([F:34])[CH:31]=[C:30]5[C:26]=4[CH:27]=[CH:28][NH:29]5)=[N:13][C:12]=3[CH:11]=2)[CH2:3]1.[N:35]1([CH:40]2[CH2:45]CNC[CH2:41]2)[CH2:39][CH2:38][CH2:37][CH2:36]1>>[F:34][C:32]1[CH:31]=[C:30]2[C:26]([CH:27]=[CH:28][NH:29]2)=[C:25]([C:14]2[N:15]=[C:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:17]3[S:18][C:10]([CH2:9][N:4]4[CH2:3][CH2:45][CH:40]([N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)[CH2:41][CH2:5]4)=[CH:11][C:12]=3[N:13]=2)[CH:33]=1
Reactant: C[C@@H]1CN(Cc2cc3nc(-c4cc(F)cc5[nH]ccc45)nc(N4CCOCC4)c3s2)C[C@H](C)N1
Reactant: C1CCN(C2CCNCC2)C1
Product: Fc1cc(-c2nc(N3CCOCC3)c3sc(CN4CCC(N5CCCC5)CC4)cc3n2)c2cc[nH]c2c1

Procedure:
Prepared according to the method used in the preparation of 6-(cis-3,5-dimethyl-piperazin-1-ylmethyl)-2-(6-fluoro-1H-indol-4-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, using 4-pyrrolidin-1-yl-piperidine in place of 2,6-dimethyl-piperazine. The title compound was obtained as a white solid (31.5 mg, 48%).
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:11]2[C:12](=[O:25])[N:13]([CH2:23][CH3:24])[C:14]3[C:19]([CH:20]=2)=[CH:18][N:17]=[C:16]([NH:21][CH3:22])[CH:15]=3)[CH:3]=1.[Li]CCCC.[C:31]1([N:37]=[C:38]=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[C:6]([C:5]1[C:4]([C:11]2[C:12](=[O:25])[N:13]([CH2:23][CH3:24])[C:14]3[C:19]([CH:20]=2)=[CH:18][N:17]=[C:16]([NH:21][CH3:22])[CH:15]=3)=[CH:3][C:2]([NH:1][C:38]([NH:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:39])=[C:9]([F:10])[CH:8]=1)#[N:7]
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2C#N)cc2cnc(NC)cc21
Reactant: O=C=Nc1ccccc1
Agent: [Li]CCCC
Solvent: ClCCl
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2C#N)cc2cnc(NC)cc21
Temperature: -60 °C
Reaction time: 0.67 h
Yield: 16.3 %

Procedure:
A −70° C. solution of 4-amino-2-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-5-fluorobenzonitrile (100 mg, 0.296 mmol) in DCM was treated drop-wise with n-BuLi (0.47 mL, 1.17 mmol), stirred at −60° C. for 40 min, treated with phenyl isocyanate (70.6 mg, 0.593 mmol), warmed to RT and stirred for 12 h. The mixture was concentrated and purified by HPLC to afford 1-(4-cyano-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (22 mg, 16% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.28 (s, 1H), 9.08 (s, 1H), 8.46 (s, 1H), 8.42 (d, J=8.0 Hz, 1H), 7.94 (s, 1H), 7.91 (s, 1H), 7.45-7.43 (m, 2H), 7.31-7.27 (m, 2H), 7.18-7.13 (q, J=4.8 Hz, 1H), 7.02-6.98 (m, 1H), 6.26 (s, 1H), 4.16 (q, J=7.2 Hz, 2H), 2.87 (d, J=4.8 Hz, 3H), 1.22 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 457.3 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]4[C:20]([C:24]5[CH:29]=[C:28]([Cl:30])[N:27]=[CH:26][C:25]=5[CH:31]([N:33](C)[C:34](=O)OC(C)(C)C)[CH3:32])=[CH:21][CH:22]=[CH:23][C:17]=4[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=[N:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1([CH2:6][CH2:7][NH:8][C:9]2[N:14]=[C:13]([C:15]3[S:19][C:18]4[C:20]([C:24]5[C:25]([CH:31]([NH:33][CH3:34])[CH3:32])=[CH:26][N:27]=[C:28]([Cl:30])[CH:29]=5)=[CH:21][CH:22]=[CH:23][C:17]=4[CH:16]=3)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: CC(c1cnc(Cl)cc1-c1cccc2cc(-c3ccnc(NCCn4ccnn4)n3)sc12)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(C)c1cnc(Cl)cc1-c1cccc2cc(-c3ccnc(NCCn4ccnn4)n3)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
Combine tert-butyl 1-(4-(2-(2-(2-(1H-1,2,3-triazol-1-yl)ethylamino)pyrimidin-4-yl)benzo[b]thiophen-7-yl)-6-chloropyridin-3-yl)ethyl(methyl)carbamate (300 mg, 0.5 mmol) and dry TFA (2.0 mL) in dry DCM (6 mL). Stir the solution at RT for 1 h. Dilute the resulting residue with DCM and wash with saturated sodium bicarbonate solution, water, and saturated aqueous sodium chloride. Separate the organic layer and dry over magnesium sulfate. Filter and concentrate in vacuo to give a residue. Purify the residue by column chromatography [0.1% to 2% 2 M ammonia in methanol/DCM] to afford the title compound (175 mg, 70%). MS (ES) m/z 491 [M+1]+.
Reaction SMILES: ClC(OC(Cl)C)=O.C1(C[N:15]2[CH2:20][CH:19]=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]4[C:31]([C:36]5[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=5)=[CH:32][CH:33]=[CH:34][CH:35]=4)=[O:29])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)C=CC=CC=1>ClCCCl>[NH:15]1[CH2:16][CH:17]=[C:18]([C:21]2[CH:22]=[CH:23][C:24]([NH:27][C:28]([C:30]3[C:31]([C:36]4[CH:37]=[CH:38][C:39]([C:42]([F:43])([F:44])[F:45])=[CH:40][CH:41]=4)=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:29])=[CH:25][CH:26]=2)[CH2:19][CH2:20]1
Reactant: O=C(Nc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: O=C(Nc1ccc(C2=CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 126.2 %

Procedure:
1-Chloroethyl chloroformate (0.078 mol) was added dropwise to a stirring mixture of intermediate (20) (0.039 mol) in 1,2-dichloro-ethane (500 ml). The mixture was stirred for 30 minutes and then stirred and refluxed overnight. The solvent was evaporated. Methanol (500 ml) was added. The mixture was stirred and refluxed overnight. The solvent was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried, yielding 20.8 g of N-[4-(1,2,3,6-tetrahydro-4-pyridinyl)phenyl]-4′-(trifluoro-methyl)-[1,1′-biphenyl]-2-carboxamide (intermediate 21).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[NH:17]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:19]=[N:18]1>C(#N)C>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:17]2[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:19]=[N:18]2)=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cnn(Cc2ccc(OC)cc2)c1
Yield: 99.1 %

Procedure:
According to Scheme 1 Step 1: K2CO3 (803 mmol, 111 g) followed by 1-(chloromethyl)-4-methoxybenzene (562 mmol, 76.0 mL) were added slowly to a solution of ethyl 1H-pyrazole-4-carboxylate (535 mmol, 75.0 g) in acetonitrile (500 mL) at room temperature. Then the suspension was heated under reflux for 4 hours. At room temperature, the reaction mixture was filtered, was concentrated under reduced pressure and was slurried in petroleum ether to yield ethyl 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (530 mmol, 138 g, 99%) as a white solid.