Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[S:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][C:19]=2[NH:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][CH:27]=[CH:26]3)[CH:14]=1>>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([NH:22][C:19]3[CH:18]=[CH:17][N:16]=[C:15]4[CH:14]=[C:13]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)[S:21][C:20]=34)=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Brc1cc2nccc(Nc3ccc4[nH]ccc4c3)c2s1
Product: COc1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from 4-methoxybenzeneboronic acid and (2-bromo-thieno[3,2-b]pyridin-7-yl)-(1H-indol-5-yl)-amine by a procedure analogous to example 17. 1H NMR (400 MHz, DMSO) d 11.3 (s, 1H), 10.6 (s, 1H), 8.21 (d, 1H), 7.65 (m, 5H), 7.00 (m, 5H), 6.43 (d, 1H), 3.80 (s, 3H); LC-MS: 372 (MH+); HPLC RT: 5.45 minutes.
Reaction SMILES: [CH2:1]1[O:17][C:4]2=[CH:5][C:6]3[NH:12][CH2:11][C:10]4=[N:13][CH:14]=[CH:15][N:9]4[CH2:8][C:7]=3[CH:16]=[C:3]2[O:2]1.[CH3:18][C:19]1[CH:36]=[CH:35][CH:34]=[CH:33][C:20]=1[C:21]([NH:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1)=[O:22].C(N(CC)CC)C>ClCCl>[CH2:1]1[O:17][C:4]2=[CH:5][C:6]3[N:12]([C:28]([C:27]4[CH:26]=[CH:25][C:24]([NH:23][C:21](=[O:22])[C:20]5[CH:33]=[CH:34][CH:35]=[CH:36][C:19]=5[CH3:18])=[CH:32][CH:31]=4)=[O:29])[CH2:11][C:10]4=[N:13][CH:14]=[CH:15][N:9]4[CH2:8][C:7]=3[CH:16]=[C:3]2[O:2]1
Reactant: c1cn2c(n1)CNc1cc3c(cc1C2)OCO3
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3nccn3Cc3cc4c(cc32)OCO4)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
As described for Example 125 a mixture of 1.0 mmol of 7,8-methylenedioxy-10,11-dihydro-5H-imidazo-[2,1-c][1,4]benzodiazepine, 1.1 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride and 1.5 mmol of triethylamine in 10 ml of dichloromethane is stirred at room temperature for 3 hours and worked up to give the desired product as a solid.
Reaction SMILES: C(OCC)(=O)[CH2:2][C:3](OCC)=[O:4].[Na].[CH3:13][O:14][C:15]1[C:16]([CH3:28])=[C:17]([CH:23]=[CH:24][C:25](=[O:27])[CH3:26])[C:18]([CH3:22])=[CH:19][C:20]=1[CH3:21].[OH-].[Na+]>C(O)C>[OH:4][C:3]1[CH2:2][CH:23]([C:17]2[C:18]([CH3:22])=[CH:19][C:20]([CH3:21])=[C:15]([O:14][CH3:13])[C:16]=2[CH3:28])[CH2:24][C:25](=[O:27])[CH:26]=1
Reactant: COc1c(C)cc(C)c(C=CC(C)=O)c1C
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Product: COc1c(C)cc(C)c(C2CC(=O)C=C(O)C2)c1C
Yield: 63 %

Procedure:
Diethyl malonate (21.0 g) was added to a solution of sodium metal (3.02 g) in anhydrous absolute ethanol (55 ml) and the mixture was heated to reflux temperature. 1-(3-Methoxy-2,4,6-trimethylphenyl)but-1-en-3-one (27.3 g) was added over a period of 2 minutes and the mixture was heated under reflux for a period of 2 hours. An aqueous solution of sodium hydroxide (16.0 g in 100 ml of water) was added and the mixture was heated under reflux for a further 41/2 hours. The aqueous mixture was cooled and washed with dichloromethane and the aqueous phase was warmed, acidified with dilute aqueous hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase was washed with water, dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure to give 3-hydroxy-5-(3-methoxy-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (20.5 g) as a colourless crystalline solid, mp 165°-166° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C@H:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C>C(O)C>[F:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:14][C@@H:13]1[NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CNCC[C@@H]1F
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CN(c2ccncc2[N+](=O)[O-])CC[C@@H]1F
Yield: 91 %

Procedure:
Method 1 of Example 1 was followed using 1 eq each of 4-chloro-3-nitropyridine, tert-butyl(3S,4S)-4-fluoropiperidin-3-ylcarbamate and triethylamine in ethanol yielding tert-butyl(3S,4S)-4-fluoro-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate, (91%). LCMS (m/z): 341.0 (MH+); LC Rt=2.37 min.
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]([N:20]3[CH2:25][CH2:24][CH:23]([O:26][CH3:27])[CH2:22][CH2:21]3)=[CH:16][C:15]=2[C:28]2[CH2:33][CH2:32][C:31]3([CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:30][CH:29]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.C(OCC)(=O)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([O:26][CH3:27])[CH2:22][CH2:21]3)=[CH:16][C:15]=2[CH:28]2[CH2:29][CH2:30][C:31]3([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]3)[CH2:32][CH2:33]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC1CCN(c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(C3=CCC4(CCCCC4)CC3)c2)CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: COC1CCN(c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(C3CCC4(CCCCC4)CC3)c2)CC1
Yield: 98.3 %

Procedure:
4-[4-(4-Methoxypiperidin-1-yl)-2-spiro[5.5]undec-2-en-3-ylphenyl]piperazine-1-carb oxylic acid t-butyl ester (524 mg, 1.0 mmol) prepared in Example (39f) was used as the starting material. A mixed solution of methanol, tetrahydrofuran and ethyl acetate was used instead of a mixed solvent of methanol and tetrahydrofuran for reaction in a manner similar to Example (8a) and treated in a similar manner, to give 517 mg of the title compound as a colorless solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.CO.[CH3:8][CH2:9][OH:10].[C:11](O)(=O)[CH3:12]>[Pd].[Pt]=O>[C:9]1([OH:10])[CH:5]=[CH:4][CH:12]=[CH:11][CH:8]=1.[NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCO
Reactant: CC(=O)O
Agent: O=[Pt]
Agent: [Pd]
Agent: c1c[nH]cn1
Solvent: CO
Product: Oc1ccccc1

Procedure:
As shown in Method E, imidazole 10 (R8 =CH3) is treated with any ether cleaving reagent such as 48% HBr in acetic acid, pyridine-HCl, AlCl3 /C6H6, and BBr3 /CH2Cl2 at 0° to the reflux temperature of the solvent for about 1-24 hours to obtain imidazole phenol 11 (X=CH2). Imidazole 10 (R8 =CH2C6H5) is treated with a suitable solvent such as an alcohol (CH3OH, EtOH, and the like) or acetic acid at ambient temperature for a period of about 15 minutes to about 15 hours in the presence of a suitable catalyst such as 10% Pd on carbon, platinum oxide, and the like, at a pressure of up to about 60 psi to afford imidazole 11 (X=CH2 or X=O when m and n are >1). ##STR16##
Reaction SMILES: [CH3:1]OC1C(OC)=CC2C(=O)CCCCC=2C=1.C[O-].[Na+].[CH3:20][O:21][C:22]1[C:23]([O:37][CH3:38])=[CH:24][C:25]2[C:31](=[O:32])[CH:30]([C:33]([OH:35])=[O:34])[CH2:29][CH2:28][CH2:27][C:26]=2[CH:36]=1.[BH4-].[Na+]>CO.C(Cl)Cl>[CH3:1][O:34][C:33]([CH:30]1[CH2:29][CH2:28][CH2:27][C:26]2[CH:36]=[C:22]([O:21][CH3:20])[C:23]([O:37][CH3:38])=[CH:24][C:25]=2[CH:31]1[OH:32])=[O:35]
Reactant: COc1cc2c(cc1OC)C(=O)CCCC2
Reactant: COc1cc2c(cc1OC)C(=O)C(C(=O)O)CCC2
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1CCCc2cc(OC)c(OC)cc2C1O

Procedure:
Using 2,3-dimethoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (10 g), powdery sodium methoxide [prepared by subjecting a 28% methanol solution of sodium methoxide (40 g) to concentration to dryness under reduced pressure] and dimethyl carbonate (150 g), a condensation reaction is carried out in a manner as that described in Example 42. The resulting methyl ester of 2,3-dimethoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-carboxylic acid is dissolved in a mixture of methanol (100 ml) and methylene chloride (100 ml). The solution is subjected to reduction in a manner as that described in Example 42, using sodium borohydride (2 g). The product is purified by silica gel column chromatography (hexane:ethyl acetate=2:1-1:1) to afford 2,3-dimethoxy-5-hydroxy-6,7,8,9-tetrahydro-5H-benzocycloheptene-6-carboxylic acid methyl ester (8 g) as a pale yellow oil.
Reaction SMILES: O[C:2]1[C:7](CC=C(C)C)=[C:6]([O:13][CH2:14][O:15][CH3:16])[CH:5]=[C:4](OCOC)[C:3]=1[C:21](=[O:23])C.[CH2:24]([OH:26])C>>[CH3:24][O:26][C:7]1[CH:2]=[C:3]([CH:4]=[CH:5][C:6]=1[O:13][CH2:14][O:15][CH3:16])[CH:21]=[O:23]
Reactant: COCOc1cc(OCOC)c(C(C)=O)c(O)c1CC=C(C)C
Reactant: CCO
Product: COCOc1ccc(C=O)cc1OC

Procedure:
In 95.0 ml of ethanol were dissolved 14.8 g of the 2'-hydroxy-4',6'-bis(methoxymethoxy)-3'-(3-methyl-2butenyl)acetophenone obtained in Production Example 1 and 9.0 g of the 3-methoxy-4-methoxymethoxybenzaldehyde obtained in Production Example 17, the solution was cooled to 0° C., and 138.0 ml of a saturated solution of potassium hydroxide in ethanol was added to the solution. The temperature was elevated to room temperature and the reaction liquid was stirred for 15 hours. The reaction liquid was made acidic by an addition of hydrochloric acid and extracted with diethyl ether. The ether layer was concentrated under a reduced pressure. The reaction mixture was subjected to the column chromatography [230-400 mesh Kieselgel 60; eluting solvent=hexane/ethyl acetate (3/1)] to obtain 13.1 g (yield=57.0%) of 2'-hydroxy-3-methoxy-4,4',6'-tris(methoxymethoxy)-3'-(3-methyl-2-butenyl)chalcone.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=3)[CH:10]=2)=[C:4]([CH3:29])[CH:3]=1.[CH2:30]([O:32][CH2:33][CH2:34]O)[CH3:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:30]([O:32][CH2:33][CH2:34][O:1][C:2]1[CH:3]=[C:4]([CH3:29])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:22]=3)[CH:10]=2)=[C:6]([CH3:8])[CH:7]=1)[CH3:31]
Reactant: CCOCCO
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(O)cc3C)c2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOCCOc1cc(C)c(-c2cccc(COc3ccc(CCC(=O)OC)cc3)c2)c(C)c1
Yield: 50.9 %

Procedure:
To a solution of methyl 3-[4-[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy]phenyl]propanoate (0.20 g, 0.51 mmol), 2-ethoxyethanol (0.099 mL, 1.02 mmol) and triphenylphosphine (0.18 g, 0.67 mmol) in tetrahydrofuran (4.0 mL) was added dropwise diethyl azodicarboxylate (40% toluene solution, 0.30 mL) at 0° C. with stirring and the mixture was stirred at room temperature for 12 hrs. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=3/1) to give the title compound (0.12 g, yield 51%) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][CH:14]([C:16]([F:19])([F:18])[F:17])[CH2:13][C:12](=[O:20])[CH:11]=1)([O-:3])=[O:2].O.O.O.O.O.O.O.[Cl-].[Ce+3].[Cl-].[Cl-].C(O)C.[BH4-].[Na+]>CCOC(C)=O>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH2:15][C@H:14]([C:16]([F:19])([F:17])[F:18])[CH2:13][C@H:12]([OH:20])[CH:11]=1)([O-:3])=[O:2]
Reactant: O=C1C=C(c2ccncc2[N+](=O)[O-])CC(C(F)(F)F)C1
Agent: [BH4-]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1cnccc1C1=C[C@@H](O)C[C@@H](C(F)(F)F)C1
Temperature: 25 °C
Yield: 66 %

Procedure:
3-(3-Nitropyridin-4-yl)-5-(trifluoromethyl)cyclohex-2-enone (1.0 eq) was mixed with cerium(III) chloride heptahydrate (1.0 eq) and absolute ethanol (0.17) was added. The mixture was stirred at ambient temperature until all solids dissolved. The mixture was cooled on an ice bath and NaBH4 (1.2 eq) was added portion wise. The reaction was stirred on the ice bath for 1 h. The mixture was diluted with EtOAc, washed with water, dried over MgSO4, filtered and concentrated. The residue was purified by column (1:1 ethyl acetate and hexanes) to give cis-3-(3-nitropyridin-4-yl)-5-(trifluoromethyl)cyclohex-2-enol (66%). LC/MS (m/z): MH+=289.2, Rt=0.72 min.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:21]C)=[C:17]([F:20])[CH:18]=3)[C:13]([C:23]#[N:24])=[CH:12]2)=[CH:7][CH:6]=1)C.B(Br)(Br)Br.O>ClCCl>[C:23]([C:13]1[C:14]2[C:19](=[CH:18][C:17]([F:20])=[C:16]([OH:21])[CH:15]=2)[N:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:25])=[O:3])=[CH:6][CH:7]=2)[CH:12]=1)#[N:24]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(OC)c(F)cc32)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: N#Cc1cn(-c2ccc(C(=O)O)cc2)c2cc(F)c(O)cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.9 %

Procedure:
To a solution of 4-(3-cyano-6-fluoro-5-methoxyindol-1-yl)benzoic acid ethyl ester (1.2 g) in dichloromethane (20 mL) was added boron tribromide (1.0 mol/L dichloromethane solution) (10 mL) in a dropwise manner under ice cooling, and this mixture was stirred at room temperature for 12 hours. This reaction mixture was poured into water, and this mixture was extracted with ethyl acetate, concentrated under reduced pressure to give the title compound (0.44 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:13])=[CH2:12])[CH:8]=[CH:7][C:6]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16][CH2:15]1)([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[OH-].[Pd+2].[OH-]>[C:1]([C:5]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16][CH2:15]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C=C(C)c1ccc(N2CCN(C(=O)C(=O)OCC)CC2)c(C(C)(C)C)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=O)N1CCN(c2ccc(C(C)C)cc2C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
A suspension of ethyl {4-[2-tert-butyl-4-(1-methylethenyl)phenyl]piperazin-1-yl}(oxo)acetate (Example 166, 0.17 g, 0.474 mmol) and palladium hydroxide (20% on carbon, wetted with ca. 50% water, 20 mg) in ethyl acetate (3 mL) was stirred under hydrogen at room temperature for 30 minutes. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to provide ethyl {4-[2-tert-butyl-4-(1-methylethyl)phenyl]piperazin-1-yl}(oxo)acetate (0.133 g, 78%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])=[CH:4][CH:3]=1.[NH:17]1[CH2:26][CH2:25][CH2:24][C@H:18]1[C:19]([O:21]CC)=[O:20].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([N:17]2[CH2:26][CH2:25][CH2:24][C@H:18]2[C:19]([OH:21])=[O:20])=[O:14])=[O:7])=[CH:15][CH:16]=1
Reactant: CCOC(=O)[C@@H]1CCCN1
Reactant: O=C(O)CCCNC(=O)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NCCCC(=O)N1CCC[C@H]1C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-aminobutyric acid and ethyl L-prolinate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-(p-chlorobenzoyl)-4-aminobutyryl]-L-proline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:9]=[CH2:10])[CH:6]=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].FC(F)(F)C(O)=O.[CH2:21]([N:28]([CH2:34]OC)[CH2:29][Si](C)(C)C)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl.C(OC(=O)C)C>[CH2:21]([N:28]1[CH2:29][CH2:10][CH:9]([C:7]2[CH:6]=[CH:5][C:4]([N+:11]([O-:13])=[O:12])=[C:3]([O:2][CH3:1])[CH:8]=2)[CH2:34]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=Cc1ccc([N+](=O)[O-])c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1cc(C2CCN(Cc3ccccc3)C2)ccc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 127.8 %

Procedure:
2-Methoxy-1-nitro-4-vinyl-benzene (435 mg, 2.43 mmol) was dissolved in dichloromethane (2 ml), trifluoro acetic acid (80 μl, 1.0 mmol) was added, followed by slow addition of N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (715 mg, 3.01 mmol). Stirring was continued for 2 h at room temperature. Another portion of N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethylamine (300 mg, 1.26 mmol) was added and stirring continued for another 30 minutes. The reaction mixture was diluted with ethylacetate (25 ml), washed with aqueous NaHCO3 (15 ml). The organic layer was dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure to yield an oil (970 mg). The crude product was purified via silica gel chromatography with cyclohexane/ethyl acetate (gradient 0-50%). Fractions containing the product were combined, the solvent evaporated to yield an oil (320 mg, 46%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[CH3:14][N:15]([CH:17](OC)OC)[CH3:16]>>[CH3:14][N:15]([CH3:17])/[CH:16]=[CH:2]/[C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)Nc1cccc(C(C)=O)c1
Product: CC(=O)Nc1cccc(C(=O)/C=C/N(C)C)c1
Yield: 90 %

Procedure:
A solution of N-(3-acetylphenyl)acetamide (1.77 g, 10.0 mmol) in DMF-DMA (6 mL) with molecular sieve (10 portions) was stirred at 100° C. under N2 for 2 hr. the mixture was concentrated and washed with MTBE (30 mL) to afford 2.1 g (90%) of (E)-N-(3-(3-(dimethylamino)acryloyl)phenyl)acetamide as a yellow solid.
Reaction SMILES: [C:1]([O:9][C:10]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]([C:18]2([CH3:41])[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:20][N:19]2C(OCC2C=CC=CC=2)=O)=[N:12][C:11]=1[C:42]([O:44][CH3:45])=[O:43])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.[Pd]>[C:1]([O:9][C:10]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]([C:18]2([CH3:41])[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:21][CH2:20][NH:19]2)=[N:12][C:11]=1[C:42]([O:44][CH3:45])=[O:43])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(C2(C)CN(C(=O)OC(C)(C)C)CCN2C(=O)OCc2ccccc2)n(C)c(=O)c1OC(=O)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(C2(C)CN(C(=O)OC(C)(C)C)CCN2)n(C)c(=O)c1OC(=O)c1ccccc1

Procedure:
1-Benzyl 4-tert-butyl 2-[5-(benzoyloxy)-4-(methoxycarbonyl)-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl]-2-methylpiperazine-1,4-dicarboxylate was dissolved in AcOEt (20 ml/mmol) and hydrogenated at atm pressure on 10% (w/w) Pd/C over night. After filtration of the catalyst, solvent was evaporated to give crude product.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[O:23]=[C:24]1[NH:32][C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:26]2[N:25]1[CH:33]1[CH2:38][CH2:37][N:36]([C:39]2[N:44]=[CH:43][N:42]=[C:41]([C:45]([OH:47])=O)[CH:40]=2)[CH2:35][CH2:34]1.Cl.Cl.[CH3:50][C:51]1([CH3:60])[CH2:56][NH:55][CH2:54][C:53]2[CH:57]=[N:58][NH:59][C:52]1=2.C(N(CC)CC)C>CN(C=O)C>[CH3:50][C:51]1([CH3:60])[CH2:56][N:55]([C:45]([C:41]2[N:42]=[CH:43][N:44]=[C:39]([N:36]3[CH2:37][CH2:38][CH:33]([N:25]4[C:26]5[C:27](=[N:28][CH:29]=[CH:30][CH:31]=5)[NH:32][C:24]4=[O:23])[CH2:34][CH2:35]3)[CH:40]=2)=[O:47])[CH2:54][C:53]2[CH:57]=[N:58][NH:59][C:52]1=2
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Reactant: CC1(C)CNCc2cn[nH]c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(C)CN(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)Cc2cn[nH]c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.26 mmol) TBTU were added to 80 mg (0.24 mmol) 6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 70.0 mg (0.31 mmol) 7,7-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine dihydrochloride, 120.0 μL (0.86 mmol) triethylamine in 1.0 mL DMF and the mixture was stirred overnight at RT. The reaction mixture was purified by preparative HPLC, the product fractions were combined and then lyophilised.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.Cl>CC(N(C)C)=O.N1C=CC=CC=1>[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([C:8](=[CH:7][C:6]2[CH:5]=[CH:4][C:3]([NH2:2])=[CH:13][CH:12]=2)[C:9]([OH:11])=[O:10])=[O:20])=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1ccc(C=CC(=O)O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: Nc1ccc(C=C(C(=O)O)C(=O)c2ccc(F)cc2)cc1
Temperature: 0 °C
Yield: 90 %

Procedure:
Para-aminocinnamic acid hydrochloride (0.1 mol, 19.96 g) was dissolved in 100 milliliters (ml) of dimethylacetamide and 30 ml pyridine, then 0.1 mol of para-fluorobenzoylchloride was added dropwise while the solution was maintained at 0° C. The solution was allowed to react for about 5 hours at room temperature, and then neutralized to a pH of 6 to 7 with hydrochloric acid. The solution was filtered to obtain a reaction intermediate. The intermediate was washed with water, dried under a vacuum and recrystallized in a solution of dimethylacetamide (10%) and water (90%). A yield of 90% N (para-fluorbenzoyl)-para-aminocinnamic acid in was obtained. Thionyl chloride (1.2 equivalents) and 50 ml of methylene chloride were added. The solution was allowed to react until clear. After the reaction, the solvent and thionyl chloride were removed under a vacuum, and the remaining product was dried. N-(para-fluorbenzoyl)- para-aminocinnamic acid was obtained.
Reaction SMILES: [CH2:1]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][N:4]=1)[CH3:2].[Br:12]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:12][CH:1]([C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][N:4]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1noc2ccccc12
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1noc2ccccc12

Procedure:
A mixture of 5.3 g of 3-ethyl-1,2-benzisoxazole, 6.4 g of N-bromosuccinimide and 50 ml of carbon tetrachloride is refluxed for 1 h. Afterwards c. 50 mg of α,α-azoisobutyro-nitrile are added and the mixture is refluxed for a further 1 h. After cooling and filtering the mixture, the filtrate is concentrated under vacuum. The crude product is purified by chromatography over silica gel with ethyl acetate/hexane (1:1) to give 3-(1-bromoethyl)-1,2-benzisoxazole as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[CH:5]2.[OH:13][C:14]1[CH:27]=[CH:26][C:17]([O:18][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:26][CH:27]=1)[CH:6]=[CH:5]2
Reactant: Clc1ccc2cc(Br)ccc2n1
Reactant: CCOC(=O)C(C)Oc1ccc(O)cc1
Product: CCOC(=O)C(C)Oc1ccc(Oc2ccc3cc(Br)ccc3n2)cc1

Procedure:
was prepared from 6-bromo-2-chloroquinoline and ethyl 2-(4-hydroxyphenoxy)propionate following essentially the same procedure as that described in Example 1. The compound had a melting point of 85° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH3:26])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1.[CH3:27][N:28]1[CH:32]=[C:31]([S:33](Cl)(=[O:35])=[O:34])[N:30]=[CH:29]1.N1C=CC=CC=1>O1CCCC1>[CH2:25]([O:24][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:33]([C:31]2[N:30]=[CH:29][N:28]([CH3:27])[CH:32]=2)(=[O:35])=[O:34])=[CH:7][C:6]=1[C:8]1[NH:13][C:12](=[O:14])[C:11]2=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:10]2[N:9]=1)[CH3:26]
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: CCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOc1ccc(NS(=O)(=O)c2cn(C)cn2)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
150 mg (0.424 mmol) of the compound from example 42A are reacted with 307 mg (1.70 mmol) of 1-methylimidazole-4-sulfonyl chloride and 0.34 ml (4.24 mmol) of pyridine in 5 ml of tetrahydrofuran.