Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](N)=[CH:6][C:5]=1[Cl:11].S(=O)(=O)(O)[OH:14].N([O-])=O.[Na+].NC(N)=O>O.[N+]([O-])([O-])=O.[Cu+2].[N+]([O-])([O-])=O>[Cl:11][C:5]1[CH:6]=[C:7]([OH:14])[CH:8]=[CH:9][C:4]=1[C:3]([OH:2])=[O:12]
Reactant: COC(=O)c1ccc(N)cc1Cl
Reactant: O=S(=O)(O)O
Agent: [Cu+2]
Agent: NC(N)=O
Agent: O=N[O-]
Solvent: O
Product: O=C(O)c1ccc(O)cc1Cl
Temperature: 0 °C
Yield: 73 %

Procedure:
4-Amino-2-chloro-benzoic acid methyl ester from Example E41b.1 (5.45 g, 29.4 mmol) was treated with a 35% solution of sulphuric acid (120 ml) and the mixture was stirred and heated until dissolution then cooled to 0° C. Sodium nitrite (4.30 g, 62.5 mmol) in water (25 ml) was added dropwise and the mixture was stirred for 15 min at 0° C. Urea was added to destroy the excess nitrite. Cop-per nitrate (200 mg, 0.83 mmol) was added and heated to 90° C. The reaction mixture was cooled to room temperature, extracted into ethyl acetate×3, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 30% EtOAc:70% hexane to 50% EtOAc:49% hexane:1% AcOH) to yield the title compound (3.7 g, 73%).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][C@H:9]1[C:20]([N:22]1[CH2:28][CH2:27][CH2:26][N:25]([CH:29]2[CH2:32][CH2:31][CH2:30]2)[CH2:24][CH2:23]1)=[O:21])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:13]([C@H:11]1[CH2:12][NH:8][C@H:9]([C:20]([N:22]2[CH2:28][CH2:27][CH2:26][N:25]([CH:29]3[CH2:32][CH2:31][CH2:30]3)[CH2:24][CH2:23]2)=[O:21])[CH2:10]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)N1CCCN(C2CCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C([C@@H]1C[C@@H](Cc2ccccc2)CN1)N1CCCN(C2CCC2)CC1
Reaction time: 16 h
Yield: 98.2 %

Procedure:
A solution of (2S,4R)-4-benzyl-2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (350.8 mg, 0.794 mmol) in CH2Cl2 (2 mL) was treated with TFA (0.5 mL). After 16 h, the mixture was concentrated and the residue was purified by FCC(CH2Cl2 to 10% MeOH/0.1% NH4OH in CH2Cl2) to give the title compound (266.3 mg, 98%). MS (ESI): mass calcd. for C21H31N3O, 341.25; m/z found, 342.3 [M+H]+. 1H NMR (CDCl3): 7.35-7.29 (m, 2H), 7.28-7.22 (m, 1H), 7.16 (d, J=7.9 Hz, 2H), 4.91-4.80 (m, 1H), 4.03-3.38 (m, 4H), 3.20-2.90 (m, 2H), 2.85-2.33 (m, 7H), 2.25-1.56 (m, 11H).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1(O)[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1.Cl.C(OCC)C>C1COCC1.O>[C:1]1([CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH2:15][C:14]2[C:9]([CH:8]=1)=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: Cc1ccccc1C1(O)Cc2ccccc2C1
Agent: Cl
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1C1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 63 %

Procedure:
To a solution of 2-(o-tolyl)-2-indanol (10.0 g, 44.6 mmol) in THF (200 mL) was added a solution of concentrated hydrochloric acid (40 mL) in water (60 mL). The solution was stirred at room temperature overnight (12 h). Diethyl ether (200 mL) and water added. Aqueous layer was extracted with diethyl ether (3* 200 mL). All etheral layers were combined, washed with water (50 mL), brine (50 mL), dried over anhydrous magnesium sulphate, and concentrated. Kugelrohr distillation yielded 5.8 g of 2-(o-tolyl)-1H-indene (150° C./0.3 mm Hg). 1H-N.M.R. (CDCl3) d 2.49(s, 3H), d 3.78 (d, J=0.90 Hz, 2H), d 6.94(br s, 1H), d 7.18-7.50(m, 8H).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.NC1[N:25]2[CH2:26][CH2:27]N=[C:24]2[C:23]2[CH:22]=CC(O)=C(OC)C=2N=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:38][O:39][C:40]1[C:49]2[N:48]=[C:47]([NH2:50])[N:46]3[CH2:51][CH2:52][N:53]=[C:45]3[C:44]=2[CH:43]=[CH:42][C:41]=1[O:54][CH2:55][C@H:56]1[CH2:58][O:57]1.N1CCCCC1>CN(C=O)C>[OH:57][C@H:56]([CH2:58][N:25]1[CH2:24][CH2:23][CH2:22][CH2:27][CH2:26]1)[CH2:55][O:54][C:41]1[CH:42]=[CH:43][C:44]2[C:45]3[N:46]([CH2:51][CH2:52][N:53]=3)[C:47]([NH2:50])=[N:48][C:49]=2[C:40]=1[O:39][CH3:38]
Reactant: COc1c(O)ccc2c1N=C(N)N1CCN=C21
Reactant: COc1c(OC[C@H]2CO2)ccc2c1N=C(N)N1CCN=C21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: COc1c(OC[C@H](O)CN2CCCCC2)ccc2c1N=C(N)N1CCN=C21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.3 %

Procedure:
To a slurry of 5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-ol bis(trifluoroacetate) (Intermediate E, 3.00 g, 6.52 mmol) in DMF (72 mL) was added caesium carbonate (10.62 g, 32.6 mmol, 10.0 equiv.) and the resulting slurry was stirred at room temperature for 1.5 hr, followed by the addition of (R)-glycidyl methanesulfonate (Intermediate F, Step 1, 45 mL, 0.29 M in DMF, 13.0 mmol, 2.0 equiv.). This mixture was stirred at 60° C. for 12 hr and concentrated under reduced pressure to a volume of approximately 50 mL and divided into 3 portions. Each portion was treated with 2.15 mL piperidine (6.45 mL total, 65.2 mmol, 10 equiv.) and was heated in a microwave reactor for 45 min. at 140° C. The combined resulting mixtures were concentrated under reduced pressure. The resulting solids (1.93 g) were purified by MPLC to give N-(8-{[(2R)-2-hydroxy-3-(piperidin-1-yl)propyl]oxy}-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)amine (1.93 g, 79%): 1H NMR (DMSO-d6+1 drop TFA-d) δ 1.30-1.43 (m, 1H), 1.56-1.70 (m, 2H), 1.70-1.84 (m, 2H), 2.88-3.04 (m, 2H), 3.11-3.32 (m, 2H), 3.42-3.52 (m, 2H), 3.82 (s, 3H), 4.09-4.17 (m, 4H), 4.28-4.38 (m, 3H), 7.24 (d, J=9.4 Hz, 1H), 7.83 (d, J=9.1 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[C:4]([F:12])[CH:3]=1.O.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[C:36]([O:40][C:41](=[O:53])[NH:42][C:43]([C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([NH2:52])[CH:47]=1)([CH3:45])[CH3:44])([CH3:39])([CH3:38])[CH3:37]>CC=C(C)C.ClCCl.C(Cl)(Cl)Cl>[C:36]([O:40][C:41](=[O:53])[NH:42][C:43]([C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([NH:52][C:9](=[O:11])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:12])[CH:47]=1)([CH3:45])[CH3:44])([CH3:37])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1cccc(N)c1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Agent: CC=C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)NC(C)(C)c1cccc(NC(=O)Cc2ccc(Br)cc2F)c1
Reaction time: 0.67 h
Yield: 71 %

Procedure:
Dissolve (4-bromo-2-fluoro-phenyl)acetic acid (1.49 g, 6.39 mmol) in 25 mL amylene-stabilized chloroform and add hydroxybenzotriazole hydrate (0.95 g, 7.03 mmol), to give a slurry. Add 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.47 g, 7.67 mmol) and stir the resulting clear solution at room temperature for 15 minutes. Add [1-(3-amino-phenyl)-1-methyl-ethyl]-carbamic acid tert-butyl ester and stir for 90 minutes at room temperature. Dilute reaction with 20 mL dichloromethane and wash with saturated NaHCO3, 1 N NaHSO4, and dilute aqueous saturated sodium chloride, then dry over MgSO4 and concentrate to give a brittle tan foam. Purify the foam on a 120 g silica cartridge with 100% CH2Cl2 for 5 minutes followed by a gradient of 0→10% EtOAc in CH2Cl2 over 40 minutes. Concentrate and dry clean fractions to provide 2.11 g (71%) of the title compound as a brittle white foam. LCMS (ES) m/z 463/465 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:7](N)=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15]C)[CH:5]=[CH:4][N:3]=1.S(=O)(=O)(O)O.CC([N+]([O-])=O)(C)C>C(O)(=O)C>[Cl:1][C:2]1[C:7]2[O:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccccc1-c1ccnc(Cl)c1N
Agent: CC(C)(C)[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Clc1nccc2c1oc1ccccc12
Temperature: 45 °C
Yield: 40.9 %

Procedure:
2-chloro-4-(2-methoxyphenyl)pyridin-3-amine (4.3 g, 18 mmol) was dissolved in 91 mL glacial acetic acid and conc. sulfuric acid (0.503 ml, 18.11 mmol). 2-methyl-2-nitropropane (6.22 g, 54.3 mmol) was added dropwise to the reaction mixture at room temperature. Reaction mixture was stirred at 45° C. until the starting material disappears in GC. After complete reaction, most of the acetic acid was distilled out under vacuum and the crude was diluted with DCM. Organic residue was partitioned between DCM and Na2CO3 solution. Organic layer was isolated, washed with brine, dried over anhd. Na2SO4 and solvents were evaporated under vacuum. Crude product was purified by silica gel column chromatography using 10-30% ethyl acetate/hexanes as eluent. 1.5 g 1-chlorobenzofuro[2,3-c]pyridine was isolated as white solid in 41% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH:10]([F:12])[F:11])[NH2:5].C(N(CC)CC)C.[CH3:20][C:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1.O>C(Cl)Cl>[F:12][CH:10]([F:11])[O:9][C:8]1[CH:7]=[CH:6][C:4]([NH:5][C:24]([C:21]2([CH3:20])[CH2:23][CH2:22]2)=[O:25])=[CH:3][C:2]=1[F:1]
Reactant: CC1(C(=O)Cl)CC1
Reactant: Nc1ccc(OC(F)F)c(F)c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C(=O)Nc2ccc(OC(F)F)c(F)c2)CC1
Yield: 83.9 %

Procedure:
To a solution of 3-fluoro-4-difluoromethoxyaniline (1.8 g) in methylene chloride (50 ml), triethylamine (1.1 g) was added, and a solution of 1-methylcyclopropanecarbonyl chloride (1.2 g) in methylene chloride was dropwise added thereto while stirring and ice-cooling. After stirring at room temperature for 1 hour, the reaction mixture was admixed with water and extracted with ether. The extract was washed with 1 N hydrochloric acid, sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The oily residue (2.5 g) was chromatographed on silica gel and eluted with a mixture of hexane and acetone to give N-(4-difluoromethoxy-3-fluorophenyl)-1-methylcyclopropanecarboxamide (2.2 g). nD24 1.5061.
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[C:11]2[CH:10]=[C:9]([C:12](=[O:31])[CH:13]=[CH:14][C:15]3[CH:29]=[CH:28][C:18]([C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])=[CH:17][C:16]=3[F:30])[CH:8]=[CH:7][C:6]=2[C:5]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[CH:4]C1.CC1(C)C2C(=CC=C(C(=O)C)C=2)C(C2C=CC(C)=CC=2)=C1>>[CH3:1][C:2]1([CH3:39])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](=[O:31])[CH:13]=[CH:14][C:15]3[CH:29]=[CH:28][C:18]([C:19]([O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])=[CH:17][C:16]=3[F:30])[CH:10]=2)[C:5]([C:32]2[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=2)=[CH:4]1
Reactant: Cc1ccc(C2=CCC(C)(C)c3cc(C(=O)C=Cc4ccc(C(=O)OCC[Si](C)(C)C)cc4F)ccc32)cc1
Agent: CC(=O)c1ccc2c(c1)C(C)(C)C=C2c1ccc(C)cc1
Product: Cc1ccc(C2=CC(C)(C)c3cc(C(=O)C=Cc4ccc(C(=O)OCC[Si](C)(C)C)cc4F)ccc32)cc1
Yield: 38 %

Procedure:
Following a procedure similar to that for the preparation of 2-trimethylsilanyl-ethyl 4-[3-(8,8-dimethyl-5-p-tolyl-7,8-dihydro-naphthalen-2-yl)-3-oxo-propenyl]-3-fluoro-benzoate (Compound 8) while using 1-(3,3-dimethyl-1-p-tolyl-3H-inden-5-yl)-ethanone (Compound 14, 200 mg, 0.72 mmol) as the starting material yielded the title compound (145 mg, 38% yield) as a yellow solid:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[C:10]1([N:16]=[C:17]=[N:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1>[C:19]1([NH:18][C:17]([NH:9][NH:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[N:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C(=Nc1ccccc1)=Nc1ccccc1
Reactant: Cc1ccc(NN)cc1
Solvent: C1CCOC1
Product: Cc1ccc(NNC(=Nc2ccccc2)Nc2ccccc2)cc1
Reaction time: 2 h
Yield: 26.5 %

Procedure:
In 250 ml of tetrahydrofuran were dissolved 8.6 g of 4-methylphenylhydrazine and 15.0 g of 1,3-diphenylcarbodiimide and after stirring the solution for 2 hours under ice-cooling, tetrahydrofuran was distilled off under reduced pressure. When 40 ml of benzene and 80 ml of n-hexane were added to the oily product thus formed, crystals deposited. By collecting the crystals thus deposited by filtration, 5.9 g of 1,2-diphenyl-3-(4-methylphenylamino)guanidine was obtained.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.C1N2CCN(CC2)C1.[H-].[Na+].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[C:38]([CH2:39][OH:40])=[CH:37][C:36]2[C:31](=[C:32]([CH3:41])[CH:33]=[CH:34][CH:35]=2)[N:30]=1.N1C=C2C(N=CN2)=NC=1.C1N2CCN(CC2)C1>CS(C)=O>[N:10]1[C:2]([O:40][CH2:39][C:38]2[C:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[O:22][CH3:21])=[N:30][C:31]3[C:36]([CH:37]=2)=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:41])=[C:3]2[C:7]([NH:6][CH:5]=[N:4]2)=[N:8][CH:9]=1
Reactant: COc1ccccc1-c1nc2c(C)cccc2cc1CO
Reactant: Clc1ncnc2nc[nH]c12
Agent: C1CN2CCN1CC2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccccc1-c1nc2c(C)cccc2cc1COc1ncnc2[nH]cnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Prepared according to modified Procedure L. 6-Chloropurine (0.077 g, 0.5 mmol, 2 eq) and DABCO (0.112 g, 1 mmol, 4 eq) were stirred in DMSO (0.7 mL) at room temperature for 5 h. In a separate flask, sodium hydride (0.040 g, 1 mmol, 4 eq) was added portion-wise to a stirring solution of (2-(2-methoxyphenyl)-8-methyl-quinolin-3-yl)methanol (0.070 g, 0.25 mmol) in DMSO (0.5 mL), and after 30 minutes, the purine-DABCO salt was added to this mixture. The reaction stirred at room temperature 18 h. 3-((9H-purin-6-yloxy)methyl)-2-(2-methoxyphenyl)-8-methylquinoline [PI3Kδ IC50=38 nM] was isolated as a white solid after purification on a silica column. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.41 (1 H, s), 8.51 (1 H, s), 8.39 (1 H, s), 7.87 (1 H, d, J=7.8 Hz), 7.65 (1 H, d, J=7.0 Hz), 7.49-7.56 (1 H, m), 7.34-7.46 (2 H, m), 7.12 (1 H, d, J=8.2 Hz), 7.03 (1 H, t, J=7.2 Hz), 5.58 (2 H, s), 3.72 (3 H, s), 2.69 (3 H, s) Mass Spectrum (ESI) m/e=398.2 (M+1)
Reaction SMILES: [CH:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:16]1[CH:17]=[CH:18][N:19]2[CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[NH:22][CH2:21][C:20]=12.C(N(CC)C(C)C)(C)C>S(Cl)(Cl)=O.ClCCl>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:11]([N:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[CH2:25][N:19]4[CH:18]=[CH:17][CH:16]=[C:20]4[CH2:21]3)=[O:13])=[CH:14][CH:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(c1ccc(C2CCCCC2)cc1)N1Cc2cccn2Cc2ccccc21
Reaction time: 2 h
Yield: 66.1 %

Procedure:
4-Cyclohexylbenzoic acid (0.50 g, 2.45 mmol) was suspended in thionyl chloride (3 mL) and heated at reflux for 30 minutes. After cooling, the thionyl chloride was removed in vacuo. The residue was dissolved in toluene and concentrated in vacuo to give the crude acid chloride as a yellow oil which was then dissolved in dichloromethane (5 mL) and slowly added to a solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.67 g, 3.64 mmol) and N,N-diisopropylethyl amine (0.94 mL, 5.4 mmol) in dichloromethane (15 mL). After stirring for 2 hours, the reaction was quenched with water. The organic layer was washed with 1 N hydrochloric acid, 1 N sodium hydroxide and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a yellow oil. Purification by flash chromatography using a solvent system of 50% dichloromethane in hexane followed by 25% ethyl acetate in hexane gave a white foam which crystallized upon sonication from hexane/ethyl acetate to provide the title compound (0.60 g) as a white solid, m.p. 127–129° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14]C(=O)OC(C)(C)C)[CH2:9]1.C(OC([NH:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43](O)=[O:44])=O)(C)(C)C>>[NH2:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH2:14])[CH2:9]1)=[O:44]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccncc2N)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnccc1N1CCC[C@H](N)C1

Procedure:
Following the procedures as described in EXAMPLE 1 and starting with (R)-tert-butyl 1-(3-aminopyridin-4-yl)piperidin-3-ylcarbamate and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid, the title compound was obtained as a white solid (8 mg, 7.2%). 1H NMR (400 MHz, DMSO) δ 9.37 (s, 1H), 8.21 (d, J=5.2, 1H), 7.67 (s, 2H), 7.54 (ddd, J=14.7, 8.4, 6.3, 1H), 7.29 (t, J=8.9, 2H), 7.12 (d, J=5.3, 1H), 3.12 (d, J=7.6, 2H), 3.05-2.91 (m, 2H), 1.93-1.79 (m, 1H), 1.72 (s, 2H), 1.29-1.08 (m, 1H). ESIMS m/z=431.1 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:14])=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH3:15][NH:16][CH3:17]>CO>[Cl:14][C:5]1[N:4]=[N:3][C:2]([N:16]([CH3:17])[CH3:15])=[C:7]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=1
Reactant: CNC
Reactant: Clc1cc(N2CCNCC2)c(Cl)nn1
Solvent: CO
Product: CN(C)c1nnc(Cl)cc1N1CCNCC1
Reaction time: 4 h
Yield: 113.2 %

Procedure:
23 g 3,6-dichloro-4-piperazin-1-yl-pyridazine and 45 g dimethylamine are suspended in 200 ml of methanol and autoclaved for 4 hours at 100° C. The reaction mixture is evaporated to dryness and the product is extracted with chloroform and washed with sodium hydroxide solution. The hydrochloride is precipitated with an ethereal HCl solution. 27 g product are obtained. M.p.=291° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:16]/[C:17](/[CH3:24])=[CH:18]\[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][C:17]([CH3:24])=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(N=C=O)ccc1Cl
Reactant: CCOC(=O)/C=C(/C)N
Product: CCOC(=O)C=C(C)NC(=O)Nc1ccc(Cl)c(C(=O)OCC)c1

Procedure:
using ethyl 2-chloro-5-isocyanatobenzoate and ethyl 3-aminocrotonate there is obtained ethyl 2-chloro-5-{3-[2-(ethoxycarbonyl)-1-methylvinyl]ureido}-benzoate, using isopropyl 2-chloro-4-fluoro-5-isocyanatobenzoate and ethyl 3-aminocrotonate there is obtained isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-1-methylvinyl]ureido}benzoate, m.p. 147°-150° C.,
Reaction SMILES: [CH2:1]([Li])CCC.[Si:6]([O:13][C:14]1[C:19]([CH2:20][CH2:21][CH3:22])=[CH:18][C:17]([CH:23]=O)=[CH:16][C:15]=1[CH2:25][CH2:26][CH3:27])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C(OCC)(=O)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[Si:6]([O:13][C:14]1[C:19]([CH2:20][CH2:21][CH3:22])=[CH:18][C:17]([CH:23]=[CH2:1])=[CH:16][C:15]=1[CH2:25][CH2:26][CH3:27])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: [Li]CCCC
Reactant: CCCc1cc(C=O)cc(CCC)c1O[Si](C)(C)C(C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C=Cc1cc(CCC)c(O[Si](C)(C)C(C)(C)C)c(CCC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
To a solution of 1.0 g (2.80 mmol) of methyl triphenylphosphonium bromide in 5.0 mL of ether at 0° C. was added 1.12 mL (2.5M, 2.80 mmol) of butyllithium. The reaction mixture was stirred for 30 minutes at 0° C. and then 756 mg (2.33 mmol) of the title compound from Example 14 (Step A) was added. After stirring for 1 h at room temperature, the reaction mixture was poured into ethyl acetate and washed with water and then saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash chromotography (silica gel, hexane/ethyl acetate 97:3) gave 411 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:20])=[C:4]([CH:14]2[CH2:18][O:17][C:16](=[O:19])[NH:15]2)[C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH:8](O)[CH3:9])[CH:7]=1.CN(C)C=O.S(Cl)([Cl:28])=O>ClCCl>[Cl:1][C:2]1[C:3]([F:20])=[C:4]([CH:14]2[CH2:18][O:17][C:16](=[O:19])[NH:15]2)[C:5]([O:11][CH2:12][CH3:13])=[C:6]([CH2:8][CH2:9][Cl:28])[CH:7]=1
Reactant: CCOc1c(C(C)O)cc(Cl)c(F)c1C1COC(=O)N1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1c(CCCl)cc(Cl)c(F)c1C1COC(=O)N1

Procedure:
4-[3-chloro-6-ethoxy-2-fluoro-5-(1-hydroxyethyl)phenyl]-1,3-oxazolidin-2-one (150 mg, 0.49 mmol) (from Step 10) was stirred in dichloromethane (4 mL) with N,N-dimethylformamide (96 μL) and thionyl chloride (110 μL, 1.5 mmol) was added. The mixture was evaporated. Water was added and the mixture was extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give the desired compound, 159 mg, 100%.
Reaction SMILES: ClS(O)(=O)=O.[N+:6]([C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[O:11]/[C:12](=[CH:16]\[C:17]([OH:19])=O)/[C:13]([OH:15])=[O:14])([O-:8])=[O:7].[N+](C1C=CC=CC=1O/C(=C/C(O)=O)/C(O)=O)([O-])=O>>[N+:6]([C:9]1[C:10]2[O:11][C:12]([C:13]([OH:15])=[O:14])=[CH:16][C:17](=[O:19])[C:20]=2[CH:21]=[CH:22][CH:23]=1)([O-:8])=[O:7]
Reactant: O=C(O)/C=C(\Oc1ccccc1[N+](=O)[O-])C(=O)O
Agent: O=C(O)/C=C(/Oc1ccccc1[N+](=O)[O-])C(=O)O
Agent: O=S(=O)(O)Cl
Product: O=C(O)c1cc(=O)c2cccc([N+](=O)[O-])c2o1
Temperature: 60 °C
Reaction time: 6 h
Yield: 70 %

Procedure:
After a reaction container equipped with a stirrer, a cooling tube and a thermometer was charged with 25 parts by weight of chlorosulfonic acid, 5 parts by weight of a mixture (content: 65.7% by weight) containing 2-(2-nitrophenoxy)fumaric acid and 2-(2-nitrophenoxy)maleic acid was added. After that, the inner temperature was raised to 60° C. and the mixture was stirred and kept at the same temperature for 6 hours to obtain a reaction solution containing 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran (reaction yield: 70%). After cooled to room temperature, the reaction solution was gradually added into 50 parts by weight of water and the mixture was gradually cooled to an inner temperature of 0° C. Precipitated crystals were filtered and dried to obtain 2.2 parts by weight of 8-nitro-2-carboxy-4-oxo-4H-1-benzopyran as crystals (content: 96.9% by weight, yield: 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[C:9](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)(Cl)Cl.ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](/[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)\[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(/C(=C/C=C/C(=O)O)c2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(/C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 55.6 %

Procedure:
As in Example 115, (E,E)-5-(4-methoxyphenyl)-5-phenyl-2,4-pentadienoic acid (5.2 g) and 4-nitrophenol (3.14 g) in 30 mL of carbon tetrachloride and 10 mL of dichloromethane was treated with 1.3-dicyclohexylcarbodiimide (3.8 g). The mixture was stirred at room temperature for 2 days. After the usual work up. the ester was crystallized from ether-hexane to yield 4.14 g of (E,E)-5-(4-methoxyphenyl)-5-phenyl-2,4-pentadienoic acid 4-nitrophenyl ester, mP 113°-115° C.