Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)CO.O>C1C=CC=CC=1>[O:1]=[C:2]1[CH2:7][CH2:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:3]1
Reactant: CCOC(=O)CC1CCC(=O)C=C1c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: OCCO
Product: CCOC(=O)CC1=C(c2ccccc2)CC(=O)CC1
Reaction time: 2.5 h
Yield: 72.4 %

Procedure:
A stirred solution of ethyl (4-keto-2-phenyl cyclohex-2-enyl)acetate (12.91 g.), p-toluene sulphonic acid monohydrate (0.95 g.) and ethylene glycol (2.93 ml.) in benzene (258 ml.) was heated under reflux using a Dean and Stark water separator for 2.5 hours. A further aliquot of ethylene glycol (0.7 ml.) was then added and the mixture heated under reflux for a further 3 hours. The reaction mixture was then cooled and the benzene evaporated. The residual mixture was dissolved in ether (500 ml.). The solution was extracted with saturated sodium bicarbonate solution (2×100 ml.). The combined extracts were washed with water (2×100 ml.), dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by flash chromatography on silica, eluting with ether/hexane (3:1 v/v), to give the ethylene ketal of ethyl (4-keto-2-phenylcyclohex-1-enyl)acetate (9.35 g.) NMR (90 MHz): 1.20 (3H,t), 1.88 (2H,t). 2.38 (2H,t), 2.9 (2H,s), 4.0 (4H,s), 4.1 (2H,q) and 7.1-7.4 (5H,)ppm.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[N:14]([CH:25]([N:36]=[N+]=[N-])[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:13]1=[O:39])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].C(O)=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[CH:15]([S:16][C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[N:14]([CH:25]([NH2:36])[C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[C:13]1=[O:39])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=NC(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SC(=O)OCC(Cl)(Cl)Cl
Agent: [Pd]
Solvent: O=CO
Product: NC(C(=O)OCc1ccccc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C

Procedure:
A mixture of benzyl 2-[3-phenoxyacetamido-4-(2,2,2-trichloroethoxycarbonylthio)-2-oxo-1-azetidinyl]-2-azidoacetate (2.856 g.) and 10% palladium on carbon (600 mg.) in formic acid (27 ml.) was stirred at room temperature under hydrogen atmosphere. After stirring for an hour, to the mixture was added 5% palladium on carbon (600 mg.) in formic acid (8 ml.) and stirred under hydrogen atmosphere for additional 2.5 hours. The resultant mixture was filtered through a pad of Celite and the filter cake was washed with methylene chloride. The filtrate and washings were combined and concentrated in vacuo to a volume of 15 ml. A part of this concentrate was evaporated to dryness to give benzyl 2-[3-phenoxyacetamido-4-(2,2,2-trichloroethoxycarbonylthio)-2-oxo-1-azetidinyl]-2-aminoacetate.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)=[CH:8][C:9]=2[CH2:11][N:12]2[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][CH2:14][C:13]2(C)[CH3:20])[NH:4][N:3]=1.CC1C2C(C(O)=O)=CC(C3C=CC(OC4CCCCO4)=CC=3)=NC=2N(C2CCCCO2)N=1.C(N1CC(C)NCC1(C)C)C1C=CC=CC=1>>[CH3:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:22]3[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=3)=[CH:8][C:9]=2[CH2:11][N:12]2[CH2:17][C:16]([CH3:18])([CH3:19])[NH:15][CH2:14][CH:13]2[CH3:20])[NH:4][N:3]=1
Reactant: Cc1n[nH]c2nc(-c3ccc(O)cc3)cc(CN3CC(C)(C)NCC3(C)C)c12
Agent: CC1CN(Cc2ccccc2)C(C)(C)CN1
Agent: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OC4CCCCO4)cc3)cc(C(=O)O)c12
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3)cc(CN3CC(C)(C)NCC3C)c12

Procedure:
4-[3-Methyl-4-(2,5,5-trimethyl-piperazin-1-ylmethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-phenol was synthesized in analogy to Example 49 (4-[3-Methyl-4-(2,2,5,5-tetramethyl-piperazin-1-ylmethyl)-1H-pyrazolo[3,4-b]pyridin-6-yl]-phenol) starting from 3-methyl-1-(tetrahydro-pyran-2-yl)-6-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid and 1-benzyl-2,2,5-trimethyl-piperazine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18](B(O)O)[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.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>[C:10]1([C:9]#[C:8][C:4]2[CH:3]=[C:2]([C:18]3[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=3)[CH:7]=[CH:6][CH:5]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OB(O)c1cccnc1
Reactant: Brc1cccc(C#Cc2ccccc2)c1
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: [K+]
Solvent: CN(C)C=O
Product: C(#Cc1cccc(-c2cccnc2)c1)c1ccccc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
1-Bromo-3-(phenylethynyl)benzene (3 g, 11.7 mmol), 3-pyridylboronic acid (1.6 g, 13.0 mmol), Tetrakis(triphenylphosphine)palladium (0.3 g, 0.26 mmol) and potassium carbonate (3.2 g, 23.2 mmol) were dissolved in N,N-dimethylformamide and the reaction was stirred at 100° C. overnight under nitrogen. The mixture was extracted with dichloromethane and the combined organic phases were washed with water, dried over sodium sulfate and concentrated in vacuo to give the title compound as oil (1.3 g, 43% yield).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[CH:7][C:6]=1[C:21]1[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=1.[NH2:27][C:28]1[N:32]=[CH:31][NH:30][N:29]=1.[H-].[Na+]>CC(N(C)C)=O>[F:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:27][C:28]2[N:32]=[CH:31][NH:30][N:29]=2)=[C:6]([C:21]2[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=2)[CH:7]=1)=[O:20]
Reactant: Nc1nc[nH]n1
Reactant: Cn1nccc1-c1cc(NC(=O)c2cccc(F)c2)ccc1OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cn1nccc1-c1cc(NC(=O)c2cccc(F)c2)ccc1OCCNc1nc[nH]n1
Reaction time: 2 h
Yield: 48.1 %

Procedure:
To a solution of N-(4-(2-bromoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-fluorobenzamide (62.3 mg, 0.149 mmol) and 3-amino-1H-1,2,4-triazole (38.8 mg, 0.461 mmol) in DMA (4 mL) was added NaH (58.8 mg, 60% dispersion in mineral oil) and the reaction was stirred for two hours. The resulting material was purified by HPLC. The product was dried under reduced pressure to afford the title compound as a white solid (30.2 mg, 48%). LCMS m/z (%)=422 (M+H, 100).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[CH2:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O)[CH3:17].[F-].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O1CCOCC1.O.CC(OC)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13])[CH3:17]
Reactant: COC(=O)c1ccc(Br)c(C(F)(F)F)c1
Reactant: CCc1ccccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Solvent: O
Product: CCc1ccccc1-c1ccc(C(=O)OC)cc1C(F)(F)F

Procedure:
A mixture of methyl 4-bromo-3-(trifluoromethyl)benzoate (3.0 g, 10.6 mmol), 2-ethylphenylboronic acid (2.38 g, 15.9 mmol), cesium fluoride (4.83 g, 31.8 mmol), palladium acetate (48 mg, 0.21 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (261 mg, 0.64 mmol) was prepared in dioxane (30 mL) and water (15 mL), and then heated at 90° C. for 2.5 hours. The reaction mixture was diluted with MTBE (150 mL) and washed with water (50 mL) and brine (50 mL). The aqueous layers were extracted with MTBE (75 mL). The organic layers were combined, dried (MgSO4) and concentrated under vacuum. After purification by flash chromatography (silica, heptane/EtOAc), the title compound was obtained as a colorless oil (3.05 g, 93%). HPLC (Method A) Rt 5.6 min (Purity: 97.3%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([N:21]3[C@@H:30]4[C@@H:25]([CH2:26][CH2:27][CH2:28][CH2:29]4)[CH2:24][CH2:23][CH2:22]3)=[O:20])[CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:21]1([C:19]([C:17]2[CH:18]=[C:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[S:15][CH:16]=2)=[O:20])[C@@H:30]2[C@@H:25]([CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(C(=O)N3CCC[C@@H]4CCCC[C@@H]43)cs2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(c1csc(C2CCNCC2)c1)N1CCC[C@@H]2CCCC[C@@H]21
Yield: 77.3 %

Procedure:
cis-4-[4-(octahydro-quinoline-1-carbonyl)-thiophen-2-yl]-piperidine-1-carboxylic acid t-butyl ester (0.06 g, 0.14 mmol) was dissolved in DCM (3 mL) and TFA (3 mL) and the reaction stirred at room temperature for 5 hours. The solvent was evaporated and the residue product was purified by flash chromatography on a SCX-2 cartridge, washing with acetonitrile and then eluting with 2 M ammonia in methanol. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.036 g). LCMS m/z 333.20 [M+H]+ RT=6.44 min (Analytical Method 2). 1H NMR (400 MHz, CHCl3-d): δ 7.2 (s, 1H), 6.9 (s, 1H), 4.6 (m, 1H), 3.8 (m, 1H), 3.2 (m, 2H), 3.1 (m, 1H), 2.9 (m, 1H), 2.7 (m, 2H), 2.0-1.1 (m 18H).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][OH:22])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:25][N:26]=[C:27]=[O:28]>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][O:22][C:27]([NH:26][CH3:25])=[O:28])=[O:11])=[CH:23][CH:24]=1)([O-:3])=[O:2]
Reactant: CN=C=O
Reactant: CC(=O)S[C@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: C1CCOC1
Product: CNC(=O)OC[C@@H]1C[C@H](SC(C)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
(2S,4S)-1-(p-Nitrobenzyloxycarbonyl)-2-hydroxymethyl-4-acetylthiopyrrolidine (200 mg) was dissolved in 2 ml of dry tetrahydrofuran. Methyl isocyanate (0.168 ml) was added thereto. The mixture was refluxed for 10 hours and distilled to remove the solvent. The residue was purified by silica gel chromatography to obtain (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-methylaminocarbonyloxymethyl-4-acetylthiopyrrolidine.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].Cl[C:23]1C(Cl)=C(C(=O)CCC)C=CC=1OCCCC(O)=O>>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([C:16](=[O:21])[C:17](=[CH2:23])[CH2:18][CH2:19][CH3:20])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: CCCC(=O)c1ccc(OCCCC(=O)O)c(Cl)c1Cl
Reactant: CCCCC(=O)c1ccc(OCCCC(=O)O)c(Cl)c1Cl
Product: C=C(CCC)C(=O)c1ccc(OCCCC(=O)O)c(Cl)c1Cl

Procedure:
By conducting the reaction as described in Example 2, Step B, except that an equimolar amount of 4-(2,3-dichloro-4-valerylphenoxy)butyric acid was substituted for the 4-(2,3-dichloro-4-butyrylphenoxy)butyric acid, there was obtained 4-[2,3-dichloro-4-(2-methylenevaleryl)phenoxy]butyric acid, m.p. 85°-87° C.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)[CH3:14]>>[Cl:1][C:2]1[N:3]([C:18]2[CH:19]=[CH:20][C:15]([CH2:13][CH3:14])=[CH:16][CH:17]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CCc1ccc(B(O)O)cc1
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Product: CCc1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Yield: 73 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 4-ethylphenylboronic acid as described in Step 1 of Example 29 to afford 2-chloro-1-(4-ethyl-phenyl)-1H-indole-3-carboxaldehyde (73% yield) as a light yellow solid. ESI/MS 284 (M+H); RT 4.04 min; NMR 10.12 (1H, s); 8.20 (1H, d, J=9 Hz); 7.54 (4H, m); 7.38 (2H, m); 7.28 (1H, d); 2.77 (2H, q); 1.28 (3H, t).
Reaction SMILES: [O:1]=[C:2]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH2:3][N:4]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[S:5]1.C(Cl)(=O)O.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:26]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:9]=[C:8]1[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[S:5][N:4]1[CH2:3][C:2]([N:14]1[CH2:19][CH2:18][N:17]([C:25]([O:27][C:28]2[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=2)=[O:26])[CH2:16][CH2:15]1)=[O:1]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cn1sc2ccccc2c1=O)N1CCNCC1
Agent: CN(C)c1ccncc1
Agent: O=C(O)Cl
Solvent: ClCCl
Product: O=C(Cn1sc2ccccc2c1=O)N1CCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Yield: 54.6 %

Procedure:
Compound 10 (81.5 mg, 0.29 mmol) was treated with 4-nitrophenyl chloroformate carbonochloridate (213 mg, 1.06 mmol) and DMAP (108 mg, 0.88 mmol) in anhydrous CH2Cl2 (4 mL) at room temperature for 16 h. The mixture was washed successively with saturated NaHCO3(aq.) and 1 M HCl(aq) until the solution became transparent. The organic phase was dried over MgSO4, filtered, concentrated, and purified by flash chromatography on a silica gel column with elution of CH2Cl2/MeOH (100:0.5 to 9:1) to give the title compound (70 mg, 56% yield). C20H18N4O6S; pale yellow solid; mp 114-118° C.; IR vmax (neat) 2923, 2854, 1725, 1655, 1520, 1346, 1259, 1163, 1111, 1056, 1024, 862, 748 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.22 (2H, d, J=10.2 Hz), 8.02 (1H, d, J=8.0 Hz), 7.62 (2H, t, J=8.0 Hz), 7.55 (1H, d, J=8.0 Hz), 7.40 (1H, t, J=8.0 Hz), 7.27 (1H, d, J=10.2 Hz), 4.73 (2H, s), 3.70 (6H, br s), 3.62 (2H, br s); 13C NMR (100 MHz, CDCl3) δ 165.4, 165.1, 155.5, 151.7, 144.7, 141.0, 132.1, 126.5, 125.4, 124.9 (2×), 123.0, 122.0 (2×), 120.2, 44.7, 44.5, 44.2, 43.8, 43.6; ESI-HRMS calcd for C20H19N4O6S: 443.1025. found: m/z 443.1042 [M+H]+.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21](=[O:26])[NH:22][CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=1[CH3:37]>>[Si:1]([O:18][CH2:19][C:20]1[C:21](=[O:26])[N:22]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=2[CH3:37])[CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCc1ccc[nH]c1=O)(c1ccccc1)c1ccccc1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Product: Cc1cc([N+](=O)[O-])ccc1-n1cccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1=O

Procedure:
Analogously to Example 4A, 1.50 g (4.13 mmol) of the compound from Example 3A are reacted with 704 mg (4.54 mmol) of 2-fluoro-5-nitrotoluene. This gives 570 mg (28% of theory) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:40][CH2:41][CH2:42][CH3:43])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:34]4[N:35]=[N:36][N:37]([CH3:39])[N:38]=4)[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:44]>C(Cl)Cl.O1CCOCC1>[ClH:44].[ClH:44].[CH2:40]([C:18]1[N:17]=[N:16][C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:20][C:19]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[C:23]([C:34]2[N:35]=[N:36][N:37]([CH3:39])[N:38]=2)[CH:22]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(-c2nnn(C)n2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)c(-c2nnn(C)n2)c1
Reaction time: 1 h

Procedure:
To a solution of 4-{6-butyl-5-[4-cyclohexyloxy-3-(2-methyl-2H-tetrazol-5-yl)-phenyl]-pyridazin-3-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (Example 70, 0.156 mmol, 92.1 mg) in DCM (1.5 mL) was added 4 N HCl in dioxane (0.5 mL) and the reaction mixture was stirred for 1 h. The organic solvents were removed in vacuo and the residue was triturated with anhydrous diethyl ether and hexanes. The yellow solid was dried overnight under high vacuum to give 3-butyl-4-[4-cyclohexyloxy-3-(2-methyl-2H-tetrazol-5-yl)-phenyl]-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (65.8 mg).
Reaction SMILES: [CH3:1][C@H:2]([C:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20]CC2C=CC=CC=2)=[CH:16][CH:15]=1)=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>[Pd].C(OCC)(=O)C>[CH3:1][C@H:2]([C:11]([O:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCC[C@H](C)C(=O)Oc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCC[C@H](C)C(=O)Oc1ccc(O)cc1
Reaction time: 6 h
Yield: 88.2 %

Procedure:
{circle around (2)}: A mixture comprising 3.0 g of (S)-4-(1′-methylnonylcarbonyloxy)-1-benzyloxybenzene, 0.3 g of palladium/carbon and 20 g of ethyl acetate was stirred for 6 hours under hydrogen atmosphere. Then, palladium/carbon was filtered off, followed by distilling off ethyl acetate from the filtrate, whereby 2.0 g of (S)-4-(1′-methylnonylcarbonyloxy)phenol was obtained in the form of a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2Cl)=[CH:4][CH:3]=1.[C:13]([N:20]1[CH2:26][CH2:25]C[NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[N:23]2[CH2:22][CH2:21][N:20]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:26][CH2:25]2)=[CH:4][CH:3]=1
Reactant: Clc1nccc2ccc(Br)cc12
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nccc3ccc(Br)cc23)CC1
Temperature: 110 °C
Yield: 53.5 %

Procedure:
To a suspension of 7-bromo-1-chloroisoquinoline (3.14 g, 13 mmol) in DMSO (20 mL) at room temperature was added either carboxylic acid tert-butyl (BOC)piperazine (7.23 g, 38.8 mmol) or BOC-homopiperazine (7.77 g, 38.8 mmol) and then potassium carbonate (5.36 g, 39 mmol). The mixture was heated to 110° C. for 24 h. On cooling, the mixture was poured onto ice/water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with water 50 mL) and brine (50 mL). Before drying over anhydrous sodium sulfate. Removal of solvent under reduced pressure gave crude product. Purification was performed by applying the crude material to a plug of silica in a filter funnel and eluting with heptane/ethyl acetate (2:1) and gave 2.73 g (54%) yellow oil. 1H NMR (CDCl3) δ 8.20-8.22 (m, 1H), 8.13-8.18 (d, J=6 Hz, 1H), 7.65-7-71 (dd, J=12, 3 Hz, 1H), 7.59-7.65 (d, J=12 Hz, 1H), 7.21-7.25 (m, 1H), 3.64-3.73 (m, 4H), 7.27-7.36 (m, 4H), 1.49 (s, 9H); LCMS: 392, 394, 395.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Fc1ccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)cc1
Product: Fc1ccc(CNc2nc(-n3cccn3)nc3sc(C(F)(F)F)cc23)cc1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-trifluoromethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-trifluoromethyl-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(O[C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:11])(=O)C.[Na].[C:21]([OH:24])(=[S:23])[CH3:22]>O1CCOCC1.C(OCC)(=O)C.O.[Br-].[Zn+2].[Br-]>[C:21]([S:23][C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[CH3:11])(=[O:24])[CH3:22]
Reactant: CC(O)=S
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: [Br-]
Agent: [Na]
Agent: [Zn+2]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)S[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 40 °C
Reaction time: 4 h
Yield: 89.1 %

Procedure:
To a solution of 4-(R)acetoxy-3(R)-[1(R)t-butyldimethylsilyloxyethyl]azetidin-2-one (2.87 g) in dioxane (40 ml) the sodium salt of thioacetic acid (1.2 g) was added. Zinc bromide (2.7 g) was added to the resulting suspension and the reaction mixture was stirred for 4 hours at 40° C. The reaction mixture was then cooled at room temperature and poured in a mixture of ethyl acetate and water. The organic layer was separated, washed twice with water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography to give 2.7 g of the title product (89% yield).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][NH:35][CH:36]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:23][N:20]1[CH2:21][CH2:22][CH:17]([C:14]2[CH:15]=[CH:16][C:11]([C:4]3[N:3]=[C:2]([C:32]4[CH:33]=[N:34][NH:35][CH:36]=4)[N:7]4[CH:8]=[CH:9][N:10]=[C:6]4[CH:5]=3)=[CH:12][CH:13]=2)[CH2:18][CH2:19]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CN1CCC(c2ccc(-c3cc4nccn4c(Cl)n3)cc2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CN1CCC(c2ccc(-c3cc4nccn4c(-c4cn[nH]c4)n3)cc2)CC1
Temperature: 100 °C
Yield: 23.6 %

Procedure:
5-Chloro-7-(4-(1-methylpiperidin-4-yl)phenyl)imidazo[1,2-c]pyrimidine (0.120 g, 0.367 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.107 g, 0.551 mmol) and potassium carbonate (0.152 g, 1.10 mmol) were suspended in a mixture of DME (5 mL) and water (2 mL) and purged with argon for 5 minutes. Tetrakis(triphenylphosphine)palladium (0) (0.02121 g, 0.01836 mmol) was added and the reaction sealed and heated at 100° C. for 18 hours. The reaction mixture was cooled to ambient temperature and diluted with water and filtered. The solids were washed with acetone and then dried under high vacuum to afford 7-(4-(1-methylpiperidin-4-yl)phenyl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (0.0310 g, 0.0865 mmol, 23.55% yield). MS (apci) m/z=359.2 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]=[CH2:4].Br[CH2:6]/[CH:7]=[CH:8]/[CH:9]=[CH2:10]>>[CH:9]12[CH2:10][NH:1][CH2:2][CH:3]1[CH2:4][CH2:6][CH:7]=[CH:8]2
Reactant: C=CCN
Reactant: C=C/C=C/CBr
Product: C1=CC2CNCC2CC1

Procedure:
The starting material is 228 g (4.0 mol) of 1-amino-2-propene. 58.8 g (0.4 mol) of (E)-1-bromo-2,4-pentadiene (title compound of Example A.1.) are added dropwise, with stirring. The internal temperature is kept in the range 20°-30° C. by cooling. The reaction mixture is stirred for 5 h at room temperature and concentrated at 150 mbar. A solution of 20 g (0.5 mol) of sodium hydroxide in 200 ml of water is added, the mixture is extracted with twice 100 ml of methylene chloride, the extracts are dried over sodium sulphate, 0.1 g of 4-hydroxyanisole is added and the mixture is concentrated and distilled at 40 mbar. The distillate is stabilized by the addition of 10-20 ppm of 4-hydroxyanisole.