Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18](=[O:20])[CH3:19])=[CH:13][CH:12]=1>N1CCCCC1.C(O)(=O)C.C1(C)C=CC=CC=1>[C:4]1([CH:3]=[CH:2][CH:1]=[C:17]([C:14]2[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=2)[C:18](=[O:20])[CH3:19])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)Cc1ccncc1
Reactant: O=C/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CC(=O)C(=CC=Cc1ccccc1)c1ccncc1
Yield: 17 %

Procedure:
Trans-cinnamaldehyde (1.84 ml, 14.8 mmol), five drops of piperidine and five drops of acetic acid were added to a solution of 4-pyridyl acetone (2.0 g, 14.8 mmol) in toluene (25 ml). The mixture was heated to reflux for 48 hours with a Dean-Stark trap to remove water. The mixture was concentrated to give a black oil. The oil was purified by silica gel chromatography (eluted with 1:1 hexane/ethyl acetate). The desired fractions were collected, combined and concentrated to give 6-phenyl-3-(4-pyridinyl)hexa-3,5-dien-2-one (628 mg). The ketone was further purified by an additional column chromatography on silica gel (eluting with hexane-ethyl acetate-methylene chloride-methanol (1:1:2:0.12)) (380 mg, 27.3%): Anal. Calc'd for C17H15NO 0.4 H2O: C, 79.91; H, 5.84; N, 5.48. Found: C, 79.72; H, 5.91; N, 5.25. MS (M+H+): 250.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:6]2[C:11]([N:12]=[C:13]3[C:18]=1[CH:17]=[CH:16][CH2:15][CH2:14]3)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][CH3:3].[H-].[H-].[H-].[H-].[Li+].[Al+3].[H-].[NH4+].[Cl-].[OH-:28].[K+]>O1CCCC1.CCOCC>[CH2:1]([NH:4][C:5]1[C:6]2[C:11]([N:12]=[C:13]3[C:18]=1[CH:17]([OH:28])[CH2:16][CH2:15][CH2:14]3)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2][CH3:3]
Reactant: [OH-]
Reactant: CCCNc1c2c(nc3ccccc13)CCC=C2
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCNc1c2c(nc3ccccc13)CCCC2O
Yield: 75 %

Procedure:
In 50ml of dry tetrahydrofuran was suspended 2.49 g of 3,4-dihydro-9-(n-propylamino)acridin-1(2He-one. The mechanically stirred suspension was cooled in ice and 4.50ml (0.5 eq) of 1.1 M LiAlH4 solution in ether was added dropwise, whereupon a solution formed. After the addition, the reaction appeared complete based on thin layer chromatography analysis. The excess hydride was neutrilized with 0.5ml of saturated NH4Cl solution and therafter 30% potassium hydroxide was added to dissolve the salts. The supernatent tetrahydrofuran solution was separated and evaporated to a solid. The solid was recrystallized from 1:4 dichloromethane/EtOAc to yield 1.88 g (75%) of needles, melting point 164° C.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:30]([O:32][CH2:33][CH3:34])=[O:31]>C(Cl)Cl>[CH2:33]([O:32][C:30]([S:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1)=[O:31])[CH3:34]
Reactant: Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Temperature: 25 °C

Procedure:
To an ice bath cooled solution containing 1.0 g 3.4mmole) of 2-(4-mercaptophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazole prepared as in Example 16 and 0.5 ml (3.6mmole) of triethylamine in 10 ml of methylene chloride is added 0.33 ml (3.5 mmole) of ethyl chloroformate. The reaction is allowed to warm to room temperature and stirred for several hours. Workup and chromatography in a manner analogous to that outlined in Example 18 affords the desired titled compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[CH3:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[NH:21][NH2:22]>CO.C(O)(=O)C>[CH3:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[NH:21][N:22]=[C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: Cn1c(NN)nc2ccccc21
Reactant: CC(=O)c1cc(Cl)ccn1
Solvent: CO
Solvent: CC(=O)O
Product: CC(=NNc1nc2ccccc2n1C)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 2-acetyl-4-chloropyridine (0.50 g, 3.20 mmol) and 1-methyl-2-hydrazinobenzimidazole (0.52 g, 3.20 mmol) in 5 ml of methanol is stirred for 4 days at room temperature after the addition of 6 drops of glacial acetic acid. The reaction is monitored by means of thin layer chromatography (Polygram Sil G/UV254 prefabricated foils; eluting agent: CH2Cl2:MeOH (12:1)). Subsequently, the reaction mixture is diluted with distilled water until a precipitate forms and stored for 24 hours in the refrigerator at approximately 5° C. The precipitate is filtered, washed several times with water, and dried. The product is recrystallized from a mixture of methanol and water. Yield: 0.60 g (62% of theory).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]2[NH:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:7]=[CH:6][N:5]=1.[CH2:26](Br)[CH:27]=[CH2:28].[Cl-].[NH4+]>CN(C)C=O>[CH2:28]([N:18]1[C:17]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:10]1[C:8]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:3])[CH:9]=1)[CH:27]=[CH2:26]
Reactant: Fc1ccc(-c2c(-c3ccnc(Cl)c3)[nH]c3cccnc23)cc1
Reactant: C=CCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C=CCn1c(-c2ccnc(Cl)c2)c(-c2ccc(F)cc2)c2ncccc21
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
Sodium hydride (120 mg, 3 mmole 60% in oil) is added to a solution of 323.5 mg (1 mmole) of 2-(2-Chloro-pyridin-4-yl)-3-(4-fluoro-phenyl)-1H-pyrrolo[3,2-b]pyridine in 8 mL of dimethylformamide at room temperature. After 30 min. at room temperature, 1.2 g of allyl bromide (10 mmoles) is added to the reaction mixture. After 1 hour at room temperature, the reaction mixture is poured into ammonium chloride solution and extracted with ethyl acetate. The organic phase is washed with water and dried over magnesium sulfate. After concentration the solid residue is purified by chromatography on silica gel (ethyl acetate/hexane 1/1) to give 270 mg of 1-Allyl-2-(2-chloro-pyridin-4-yl)-3-(4-fluoro-phenyl)-1H-pyrrolo[3,2-b]pyridine as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23]([O:25]C)=O)[CH:5]=[CH:6][CH:7]=1.Cl.[OH-].[NH4+:29]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:29])[CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(Cl)c1
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(Cl)c1
Yield: 47 %

Procedure:
A solution of the 9-[(3-chlorophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (156.2 mg, 0.43 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was sonicated for 5 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 69.7 mg (47%) of the 9-[(3-chlorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a white solid. 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (dd, 1H, J=1 and 8 Hz), 7.45 (m, 2H), 7.3 (m, 3H), 7.2 (s, 1H), 7.1 (d, 1H, J=8 Hz), 6.95 (s, 1H), 6.6 (d, 1H, J=8 Hz), and 5.7 (s, 2H). IR (CHCl3, cm−1) 3433, 3202 (br), 1630, 1600, 1580, 1564, 1433, 1330, 1261, and 776. MS (ES) m/e 349, 351, 353.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[C:4]([Cl:24])[C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1>CCOCC>[NH2:1][C:2]1[CH:3]=[C:4]([Cl:24])[C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:14])([CH3:15])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc(N)c(Cl)c(Cl)c21
Solvent: CCOCC
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc(N)cc(Cl)c21

Procedure:
From 4.75 g (0.014 mol) of 7-amino-9-chloro-5-(o-fluorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one there is obtained, in analogy to the details in Example 30, 7-amino-8,9-dichloro-5-(o-fluorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one of melting point 169°-172° (ether).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[C:11]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=3[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=3)[C:11]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=4[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Clc1nc(NCc2ccc(Cl)c(Cl)c2)c2c3c(sc2n1)CCCC3
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1-c1nc(NCc2ccc(Cl)c(Cl)c2)c2c3c(sc2n1)CCCC3

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-dichlorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5,6,7,8-tetrahydro-4-(3,4-dichlorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[SH:12].[CH3:13][C:14]1([C:20](Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>N1C=CC=CC=1>[CH3:13][C:14]1([C:20]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][C:3]=2[S:12][C:20]([C:14]2([CH3:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:21])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Nc1c(S)ccc2ccccc12
Reactant: CC1(C(=O)Cl)CCCCC1
Solvent: c1ccncc1
Product: CC1(C(=O)Nc2c(SC(=O)C3(C)CCCCC3)ccc3ccccc23)CCCCC1
Temperature: 60 °C

Procedure:
To a solution of 1-amino-naphthalene-2-thiol in pyridine are added two mol equivalents of 1-methyl-cyclohexanecarbonyl chloride at room temperature. After completion of the addition, the reaction mixture is heated to 60° C. for 2 hours. The pyridine is then removed under reduced pressure, water is added and the mixture is extracted with ethyl acetate. The combined extracts are washed with sat. NaHCO3-solution, diluted hydrochloric acid and brine, dried (Na2SO4) and concentrated to obtain crude 1-methyl-cyclohexanecarbothioic acid S-{1-[(1-methyl-cyclohexanecarbonyl)-amino]-naphthalen-2-yl}ester.
Reaction SMILES: [Cl:1][C:2]1[S:28][C:5]2=[N:6][C:7](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[O:22][CH2:23][C:24](C)([CH3:26])[CH3:25])=[C:8](I)[C:9](=[O:10])[N:4]2[CH:3]=1.[H-].[Na+].C(OC1C(OC)=CC=CC=1C=O)C(C)C.C1(COC2C(OC)=CC=CC=2/C=C/C2N=C3SC=CN3C(=O)C=2I)CC1>CS(C)=O>[Cl:1][C:2]1[S:28][C:5]2=[N:6][C:7](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[O:22][CH2:23][CH:24]([CH3:25])[CH3:26])=[CH:8][C:9](=[O:10])[N:4]2[CH:3]=1
Reactant: COc1cccc(/C=C/c2nc3sc(Cl)cn3c(=O)c2I)c1OCC(C)(C)C
Agent: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Agent: COc1cccc(C=O)c1OCC(C)C
Agent: [H-]
Solvent: CS(C)=O
Product: COc1cccc(/C=C/c2cc(=O)n3cc(Cl)sc3n2)c1OCC(C)C
Yield: 583.4 %

Procedure:
Step 2 intermediate from Intermediate 19 (1.2 g, 2.412 mmol) was reacted with NaH (60% dispersion in mineral oil, 105 mg, 2.610) and 2-isobutoxy-3-methoxybenzaldehyde (546 mg, 2.412 mmol) in dry DMSO (10 ml) according to the procedure outlined in Intermediate 2, Step 3 to yield 5.5 g of the desired compound as a white solid; 1H NMR (300 MHz, CDCl3) δ 1.03 (d, J=6.6 Hz, 6H), 1.98-2.06 (m, 1H), 3.68 (d, J=6.6 Hz, 2H), 3.79 (s, 3H), 6.30 (s, 1H), 6.98-7.16 (m, 3H), 7.30-7.33 (m, 1H), 8.05 (d, J=16.2 Hz, 1H), 8.23 (s, 1H).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:16](OCC)=[O:17].C(O)(=O)C>COCCOC>[CH:16]([CH:10]([CH2:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:17]
Reactant: CCOC(=O)CCc1ccccc1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CC(=O)O
Product: CCOC(=O)C(C=O)Cc1ccccc1
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of NaH (2.338 g, 58.5 mmol) in DME (20 mL) was added dropwise a solution of ethyl 3-phenylpropanoate (3.2 g, 19.49 mmol) and ethyl formate (6.28 mL, 78 mmol) in DME (20 mL) at room temperature. The reaction mixture was then stirred overnight. It was neutralized with acetic acid (4 mL), then extracted with EtOAc. The organic phase was collected, washed with brine, dried over Na2SO4, filtered, and concentrated affording the crude title compound (4.02 g, 100% yield). LCMS: rt=2.82 and 3.51 min (a mixture of ketone and enol isomer), [M+H+]=207.1
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH:31]1([CH2:37][NH2:38])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:31]1([CH2:37][NH:38][C:14]([C:11]2([C:17]3[CH:18]=[C:19]([C:27]([F:29])([F:28])[F:30])[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=3)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: NCC1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCCCC1)C1(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(3,5-bis-trifluoromethylphenyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (0.5 mmol; 220.7 mg) in DMF (2 mL) was added cyclohexylmethylamine (0.6 mmol; 0.078 mL), N, N-diisopropyl-N-ethylamine (1 mmol; 0.174 mL) and HBTU (0.6 mmol; 228 mg), and the resulting mixture was stirred at room temperature overnight. The mixture was then purified via reverse phase HPLC. The desired fractions were combined and lyophilized. The resulting residue was dissolved in 1,4-dioxane (3 mL) and a 4N HCl solution in 1,4-dioxane (3 mL) was added. The resulting mixture was stirred for 2 hours at room temperature, then evaporated to yield 4-(3,5-bis-trifluoromethylphenyl)-piperidine-4-carboxylic acid cyclohexylmethylamide as a hydrochloride salt. MS (ESI) m/z 437.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=O)[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.Cl.[NH2:30][OH:31].C(=O)([O-])O.[Na+]>>[OH:31]/[N:30]=[C:9](/[C:4]1[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=1)\[CH2:10][CH:11]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1

Procedure:
In analogy to example 1, step 2, from 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a colourless oil, MS (ESI+): m/z=391.3 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][C@H:10]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:14][CH2:13]1)[CH3:11])([CH3:4])([CH3:3])[CH3:2].C1([O:33][C:34](=O)[NH:35][O:36][CH3:37])C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][C@H:10]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]([CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:34]([NH:35][O:36][CH3:37])=[O:33])[CH2:14][CH2:13]1)[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](CCNC(=O)OC(C)(C)C)N1CCC(NCC2CCCCC2)CC1
Reactant: CONC(=O)Oc1ccccc1
Solvent: C1CCOC1
Product: CONC(=O)N(CC1CCCCC1)C1CCN([C@H](C)CCNC(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 72 h
Yield: 50.7 %

Procedure:
To a solution of {(R)-3-[4-(cyclohexylmethyl-amino)-piperidin-1-yl]-butyl}-carbamic acid tert-butyl ester (174 mg, 0.47 mmol) in THF (5 ml) was added methoxy-carbamic acid phenyl ester (94.7 mg, 0.56 mmol). The mixture was stirred at 60° C. for 3 d then concentrated in vacuo. The crude product was purified by flash chromatography (CH2Cl2, 7% MeOH, 1% NH4OH) to afford {(R)-3-[4-(1-cyclohexylmethyl-3-methoxy-ureido)-piperidin-1-yl]-butyl}-carbamic acid tert-butyl ester (105 mg, 50%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14]OS(C)(=O)=O)[N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1>[I-].[K+].C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:20])=[C:11]([CH2:13][CH2:14][N:30]3[CH2:31][CH2:32][CH2:33][C@H:29]3[CH3:28])[N:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCOS(C)(=O)=O
Reactant: C[C@@H]1CCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Yield: 103.4 %

Procedure:
Prepare using the method of Example 102 with 2-[2-(4-bromophenyl)-5-methyl-1,3-oxazol-4-yl]ethyl methanesulfonate (See Intermediate 13) (0.65 g, 1.80 mmole), anhydrous acetonitrile (6 mL), potassium carbonate (0.87 g, 6.32 mmol), potassium iodide (0.03 g, 0.18 mmol) and (2R)-2-methylpyrrolidine hydrochloride (salt) (See Intermediate 7) (0.25 g, 2.08 mmol) to give the title compound as a pale orange oil (0.65 g): MS (m/e) (79Br/81Br): 349, 351(M+1)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([OH:10])=O.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)[N:20]1[CH2:24]CC[CH2:21]1.CNC.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:21][N:20]([CH3:24])[C:8]([C:4]1[S:5][CH:6]=[CH:7][C:3]=1[O:2][CH3:1])=[O:10]
Reactant: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: COc1ccsc1C(=O)O
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccsc1C(=O)N(C)C
Reaction time: 36 h
Yield: 193.6 %

Procedure:
To a suspension of 3-methoxythiophene carboxylic acid (1.84 g, 11.61 mmol), from step A, in 60 mL of acetonitrile at room temperature was added bromotripyrroli-dinophosphonium hexafluorophosphate (PyBrop, 5.40 g, 11.60 mmol), dimethyl amine (2.0 M in THF, 14.5 ml, 29.0 mmol) and diisopropylethyl amine (5.0 mL, 28.63 mmol) successively. After stirred for 1.5 day, the mixture was concentrated under reduced pressure to a yellow oil, which was purified by preparative TLC (CH2Cl2—MeOH=40:1). The silica was extracted with CH2Cl2 and methanol, the extracts were filtered and concentrated to an oil, which was further dried on high vacuum, yielding 4.16 g of N,N-dimethyl 3-methoxythiophene amide (contaminated by PyBrop impurity) (MH+=186.0).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH:18]=[C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:40])[N:13]2[C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:39]>C(OCC)(=O)C.O.[Pt](=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:40])[N:13]2[C:32]1[C:33]([Cl:39])=[CH:34][CH:35]=[CH:36][C:37]=1[Cl:38]
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CC1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Cc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of tert-butyl 4-{[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]methylene}piperidine-1-carboxylate (EXAMPLE AAA18, STEP C, 150 mg, 0.25 mmol) in ethyl acetate (4 mL) was purged and filled with nitrogen. To this was added platinum (IV) oxide hydrate (30 mg, 20% weight). The mixture was evacuated and filled with hydrogen via balloon. Then the reaction was stirred at rt under hydrogen for 1 h, filtered through celite and rinsed with ethyl acetate and methanol. Removal of the solvent provided tert-butyl 4-{[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]methyl}piperidine-1-carboxylate as a white solid used directly for the next step.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[O:11][C:12]1[C:13]2[N:14]([C:21]([CH3:25])=[C:22]([CH3:24])[N:23]=2)[CH:15]=[C:16]([C:18](O)=[O:19])[CH:17]=1.F[B-](F)(F)F.N1(O[C:41](N(C)C)=[N+:42](C)[CH3:43])C2C=CC=CC=2N=N1.CNC.C(=O)([O-])O.[Na+]>ClCCl>[OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[O:11][C:12]1[C:13]2[N:14]([C:21]([CH3:25])=[C:22]([CH3:24])[N:23]=2)[CH:15]=[C:16]([C:18]([N:42]([CH3:43])[CH3:41])=[O:19])[CH:17]=1
Reactant: Cc1nc2c(O[C@@H]3c4ccccc4C[C@H]3O)cc(C(=O)O)cn2c1C
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Product: Cc1nc2c(O[C@@H]3c4ccccc4C[C@H]3O)cc(C(=O)N(C)C)cn2c1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.7 %

Procedure:
2.0 g (5.7 mmol) 8-(trans-2,3-dihydro-2-hydroxy-1-indenyloxy)-2,3-dimethyl-imidazo[1,2-a]pyridine-6-carboxylic acid and 2.4 g (7.4 mmol) O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU) are suspended in 100 ml dichloromethane and 2.1 ml (11.4 mmol) dimethylamine (5.6 M in ethanol) are added to the reaction mixture. After stirring for 3 h at room temperature, the reaction mixture is hydrolyzed with saturated aqueous sodium hydrogen carbonate. The organic phase is separated and the aqueous layer is extracted with dichloromethane The combined organic phases are dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using dichloromethane:methanol (20:1) and crystallization from methanol/light petroleum ether yields 1.18 g (57%) of the title compound as a colourless solid (m.p. 182-184° C.).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.CO.[CH2:13](Cl)CCl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:13][O:9][C:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=1)=[O:10]
Reactant: ClCCCl
Reactant: Cc1cccc(C(=O)O)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cccc(C)n1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a suspension of 6-methyl-pyridine-2-carboxylic Acid (10 g, 72.9 mmol) in CH2Cl2 (200 mL) cooled to 0° C. is added MeOH (10 mL), 4-dimethylaminopyridine (11.6 g, 94.8 mmol), and EDC (18.2 g, 94.8 mmol). The mixture is stirred at RT for 6 h, washed with water and brine, and dried over Na2SO4. The mixture is filtered and concentrated in vacuo and the residue is chromatographed on silica gel (50% EtOAc/Hexanes) to yield the title compound, 9.66 g (92%), as a colorless liquid.
Reaction SMILES: Br[CH2:2][C@H:3]([F:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].FC(F)(F)S(O[C:17]1[C:22]([F:23])=[CH:21][C:20]([CH:24]2[CH2:29][CH2:28][Si:27]([CH2:36][CH2:37][CH2:38][CH:39]=[CH2:40])(C3C=CC=CC=3)[CH2:26][CH2:25]2)=[CH:19][C:18]=1[F:41])(=O)=O>>[CH2:36]([Si@H:27]1[CH2:28][CH2:29][C@H:24]([C:20]2[CH:21]=[C:22]([F:23])[C:17]([CH2:2][C@H:3]([F:10])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[C:18]([F:41])[CH:19]=2)[CH2:25][CH2:26]1)[CH2:37][CH2:38][CH:39]=[CH2:40]
Reactant: C=CCCC[Si]1(c2ccccc2)CCC(c2cc(F)c(OS(=O)(=O)C(F)(F)F)c(F)c2)CC1
Reactant: CCCCCC[C@@H](F)CBr
Product: C=CCCC[Si@H]1CC[C@H](c2cc(F)c(C[C@H](F)CCCCCC)c(F)c2)CC1

Procedure:
The general procedure of Example 18 was repeated-using (R)-1-bromo-2-fluorooctane and (2,6-difluoro-4-(4-(4-pentenyl)-4-phenyl-4-silacyclohexyl)phenyl) trifluoromethanesulfonate, thereby obtaining the intended compound.