Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([OH:12])[CH:8]=[CH:7]2.C([O-])(O)=O.[Na+].[Cl:18][CH2:19][C:20](Cl)=[O:21]>>[Cl:18][CH2:19][C:20]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[CH:5]=[CH:4][CH:3]=1)=[O:21]
Reactant: Nc1cccc2ccc(O)cc12
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(CCl)Nc1cccc2ccc(O)cc12
Reaction time: 1 h

Procedure:
To a solution of 8-amino-2-naphthol (10.0 g, 62.8 mmol) in 240 mL of 1:1EtOAc/saturated NaHCO3 solution was added chloroacetyl chloride dropwise (5.5 mL, 69.1 mmol). After one hour, the solution was filtered, the layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH2:16][CH2:17][NH:18][CH2:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH2:16][CH2:17][N:18]([S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])[CH2:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2CCNC3)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2CCN(S(=O)(=O)c2ccccc2)C3)CC1

Procedure:
4-(1,2,3,4-Tetrahydroisoquinolin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester as a viscous oil (150 mg) from Step 3 was reacted with benzenesulfonyl chloride (60 microliters) using the Schotten-Baumann procedure (50 mL diethyl ether (Et2O) and 50 mL aqueous sodium carbonate). The ether layer was separated, dried over MgSO4, and concentrated in vacuo. The residue was chromatographed to provide 1.76 mg of 4-(2-benzenesulfonyl-1,2,3,4-tetrahydroisoquinolin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester as a white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:18]([NH:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[CH:29]1[CH:34]=[CH:33][C:32]([CH2:35][O:36][C:37]([NH:39][C@H:40]([C:45](OC2C=CC([N+]([O-])=O)=CC=2)=[O:46])[CH2:41][C:42]([NH2:44])=[O:43])=[O:38])=[CH:31][CH:30]=1>CN(C)C=O>[NH:39]([C:37]([O:36][CH2:35][C:32]1[CH:33]=[CH:34][CH:29]=[CH:30][CH:31]=1)=[O:38])[C@H:40]([C:45]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:18]([NH:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:19])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:46])[CH2:41][C:42](=[O:43])[NH2:44]
Reactant: CC(C)(C)OC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
20.93 g of H-Asn-Phe-NH-NH-BOC are dissolved in 45 ml of dimethylformamide with warming, mixed with 22.7 g of Z-Asn-ONP at room temperature, and stirred until the mixture solidifies. After standing overnight, the solid mass is dissolved in 160 ml of dimethylformamide with warming, precipitated by adding dropwise to 1 liter of ether, and the product is filtered off and washed with acetone until free of nitrophenol. Rf = 0.24 in chloroform-methanol (8:2).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH:16]1[CH2:20][CH2:19][CH2:18][C:17]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[N:16]1([C:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=3)[CH2:4][CH:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: N#Cc1ccc(N2CCC(=O)CC2)cc1
Reactant: O=C1CCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: N#Cc1ccc(N2CC=C(N3CCCC3)CC2)cc1
Yield: 66 %

Procedure:
A solution of 24 g (0.1199 mol) of the compound of (b), 15 ml (12.78 g/0.1796 mol) of pyrrolidone, 240 mg of p-toluenesulfonic acid, and 100 ml of benzene is stirred at reflux with the azeotropic removal of water for 6 hours. After cooling, the resulting precipitate is collected and triturated with ethyl ether to afford 20 g (66%) of title compound: m.p. 126°-129° C.; IR (KBr) 2200, 1635, and 1600 cm-1 ; 'H NMR (CDCl3) δ 7.48 (d, 2H), 6.7 (d, 2H), 4.3-4.1 (m, 1H), 3.95-3.45 (m, 4H), 3.2-2.85 (m, 4H), 2.65-2.25 (m, 2H), and 1.95-1.75 (m, 4H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]1[C:12](=[O:13])[CH2:11][C:10]([CH3:14])=[N:9]1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([F:25])[C:23]=1F)[C:19]#[N:20]>CN(C)C=O>[CH3:7][N:8]1[C:12]([O:13][C:23]2[C:16]([F:15])=[CH:17][C:18]([C:19]#[N:20])=[CH:21][C:22]=2[F:25])=[CH:11][C:10]([CH3:14])=[N:9]1
Reactant: N#Cc1cc(F)c(F)c(F)c1
Reactant: CC1=NN(C)C(=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2c(F)cc(C#N)cc2F)n(C)n1
Temperature: 75 °C
Yield: 92.3 %

Procedure:
Potassium carbonate (1.38 g, 10 mmol) was added to a solution of 2,4-dihydro-2,5-dimethyl-3H-pyrazol-3-one (0.70 g, 6.3 mmol) in N,N-dimethylformamide (15 mL). 3,4,5-Trifluorobenzonitrile (0.94 g, 6.0 mmol) was added, and the reaction mixture was heated at 75° C. under a nitrogen atmosphere for 16 h, then allowed to cool. The reaction mixture was partitioned between water (60 mL) and ethyl acetate (30 mL). The organic phase was washed with water (2×30 mL) and brine (30 mL), dried over MgSO4, and concentrated to give the title compound as a yellow oil (1.38 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:16])=O.CN(C)C=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([Cl:16])=[O:6]
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4,5-Trifluorobenzoic acid (0.176 g, 1.0 mmol) in dichloromethane (1.5 mL) was treated with a solution of oxalyl chloride (1.5 mL of 2 M in dichloromethane, 3 mmol) and a catalytic amount of N,N-dimethylformamide. The reaction was stirred overnight at ambient temperature. The excess oxalyl chloride was removed in vacuo to afford 3,4,5-trifluorobenzoyl chloride.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[C:10]1([C:2]2[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: OB(O)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(-c2ccccc2)o1
Temperature: 150 °C
Yield: 55.5 %

Procedure:
A solution of 5-bromofuran-2-carboxylic acid (381 mg, 2 mmol), phenylboronic acid (488 mg, 4 mmol) in DMF (3 ml) was place in a microwave reaction tube and treated with a 2 M K3PO4(aq) (2 ml, 4 mmol). The solution was purged with nitrogen for 10 minutes before adding Pd(PPh3)4 (1.5 mg) catalyst. The mixture was again purged with nitrogen for 5 minutes before the reaction tube was sealed. The mixture was heated in a microwave oven at 150° C. for 30 minutes. The reaction mixture was filtered and the filtrate poured into 1N HCl (100 ml) with stirring. The precipitate was filtered and air-dried to give 209 mg of 5-phenylfuran-2-carboxylic acid. MS (ES−) found: (M−H)−=187.13.
Reaction SMILES: [OH-].[K+].O.[C:4]([C:8]1[S:9][CH:10]=[CH:11][C:12]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:26])[CH2:22][CH2:23][CH2:24][OH:25])=[CH:17][CH:16]=1)([O:6]C)=[O:5]>C(O)C>[C:4]([C:8]1[S:9][CH:10]=[CH:11][C:12]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:26])[CH2:22][CH2:23][CH2:24][OH:25])=[CH:17][CH:16]=1)([OH:6])=[O:5]
Reactant: COC(=O)c1sccc1COc1ccc(C(C)CCCO)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(CCCO)c1ccc(OCc2ccsc2C(=O)O)cc1
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a stirred solution of 14.59 g of potassium hydroxide, 15 ml of water, and 60 ml of 95% ethanol was added a solution of 8.68 g of 4-[4-(2-carbomethoxy-3-thienylmethoxy)phenyl]pentanol and 30 ml of 95% ethanol. The stirred solution was heated under reflux for five hours, allowed to stand overnight at ambient temperature, and concentrated. The residue was diluted with 500 ml of water, and the solution was acidified with concentrated hydrochloric acid. An oil separated. The mixture was extracted with ether (2×250 ml) and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. A solution of the residue and toluene was filtered through anhydrous sodium sulfate and the filtrate was concentrated to afford 6.89 g (82.7%) of product as an oil, dried at 60° C. in vacuo.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:12][CH2:11][CH:10]([CH3:13])[C:9]2[CH:8]=[C:7]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:6]=[CH:5][C:4]1=2.[Si]([O:33][CH2:34][CH:35]=O)(C(C)(C)C)(C)C.Cl>O1CCOCC1>[CH3:2][CH:3]1[CH2:12][CH2:11][CH:10]([CH3:13])[C:9]2[CH:8]=[C:7]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][CH:22]([NH:25][CH2:35][CH2:34][OH:33])[CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: CC1CCC(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: CC1CCC(C)c2cc(-c3csc(N4CCC(NCCO)CC4)n3)ccc21

Procedure:
The preparation is carried out as described starting from 104 mg (0.26 mmol) of 1-[4-(5,8-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine hydrochloride and 55 μl (0.26 mmol) of (tert-butyldimethylsilanyloxy)acetaldehyde. The protecting group is cleaved off using a 4N HCl solution in dioxane. The purification is carried out by means of preparative HPLC. The product is in the form of the hydrochloride.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>C1COCC1>[CH2:11]([O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]([C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1)[OH:22])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1ccccc1OCc1ccccc1
Reactant: CSc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CSc1ccc(C(O)c2ccccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
In a nitrogen stream, a solution of 4-methylsulfanyl-phenylmagnesium bromide in THF (0.5 M, 35 mL) was added dropwise to a solution of 2-benzyloxybenzaldehyde (2.60 g, 12.2 mmol) in THF (24 mL) at 0° C. and the mixture was stirred at room temperature for two hours, and then a saturated ammonium chloride aqueous solution was added thereto under cooling with ice and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:4)] to obtain the title compound (3.91 g, 95%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH2:19]([C:26]1[O:27][C:28]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:29]([C:31](O)=[O:32])[N:30]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:31]([C:29]3[N:30]=[C:26]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[O:27][C:28]=3[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1nc(Cc2ccccc2)oc1-c1ccccc1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(Cc4ccccc4)oc3-c3ccccc3)cn2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-benzyl-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.06 min; [M+H]+=467.69.
Reaction SMILES: [O:1]1C[CH:2]1[CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][CH:11]=[CH:12][CH:13]=[C:6]2[C:5]1=[O:14].[N+:16]([C:19]1[NH:20][CH:21]=[CH:22][N:23]=1)([O-:18])=[O:17]>>[OH:1][CH:2]([N:20]1[CH:21]=[CH:22][N:23]=[C:19]1[N+:16]([O-:18])=[O:17])[CH2:3][N:4]1[C:8](=[O:9])[C:7]2[C:6](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]1=[O:14]
Reactant: O=C1c2ccccc2C(=O)N1CC1CO1
Reactant: O=[N+]([O-])c1ncc[nH]1
Product: O=C1c2ccccc2C(=O)N1CC(O)n1ccnc1[N+](=O)[O-]

Procedure:
According to the General Reaction Scheme, N-(2,3-epoxypropyl)phthalimide (1) is reacted with 2-nitro-imidazole (2) to obtain 2-[2-Hydroxy-2-(2-nitro-1H-imidazol-1-yl)ethyl]-1H-isoindole-1,3(2H)-dione (3). This product is then reacted with N -hydroxyphthalimide, preferably in the presence of a tertiary amine such as triphenylphosphine, to obtain the intermediate of Formula II, 2-{2-(1,3-dioxoisoindolin -2-yl)-1-[(2-nitroimidazolyl)methyl]ethoxy}isoindoline-1,3-dione (4). This intermediate is then reacted with hydrazine to obtain 1-[3-amino-2-(aminooxy)propyl]-2-nitro-1H -imidazole dihydrochloride (5), which is then reacted with the compound of Formula III to yield the compound of Formula I. A preferred compound of Formula III is 3-chloro-3-methyl-2-nitrosobutane, which, when used contacted with 1-[3-amino-2-(aminooxy)propyl]-2-nitro -1H-imidazole dihydrochloride (5), yields 3,3,9,9-tetramethyl-6-[(2-nitro-1H-imidazol-1-yl)methyl]-5-oxa-4,8-diazaundecane-2,10-dione dioxime (7).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([OH:16])=[O:15])[CH:8]=2)[NH:3]1.[O:20]=[C:21]1[C:26]2=[CH:27][NH:28][C:29]([CH:30]=O)=[C:25]2[CH2:24][CH2:23][O:22]1>>[O:1]=[C:2]1[C:10](=[CH:30][C:29]2[NH:28][CH:27]=[C:26]3[C:21](=[O:20])[O:22][CH2:23][CH2:24][C:25]=23)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14]([OH:16])=[O:15])[CH:8]=2)[NH:3]1
Reactant: O=C1Cc2cc(-c3cccc(C(=O)O)c3)ccc2N1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: O=C1Nc2ccc(-c3cccc(C(=O)O)c3)cc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
3-(2-Oxo-2,3-dihydro-1H-indol-5-yl)-benzoic acid was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:28][C:29]1[CH:51]=[CH:50][C:32]([CH2:33][N:34]2[C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=3[N:36]=[C:35]2[NH:43][CH:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)=[CH:31][CH:30]=1>>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:47]2[CH2:48][CH2:49][CH:44]([NH:43][C:35]3[N:34]([CH2:33][C:32]4[CH:50]=[CH:51][C:29]([F:28])=[CH:30][CH:31]=4)[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=3)[CH2:45][CH2:46]2)([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:9]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCC1(Cc2ccccc2)CCN(Cc2ccccc2)C1=O
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Product: O=C1N(Cc2ccccc2)CCC1(CCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1)Cc1ccccc1

Procedure:
Prepare by the method of Example 2.6 using 1-benzyl-3-(phenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine (0.99 g, 2.6 mmol) and (1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (0.80 g, 2.6 mmol) to give the title compound: Rf=0.22 (silica gel, 5% methanol/ethyl acetate/2% triethylamine).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:27])[CH2:6][C@@H:5]1[CH2:28][CH3:29])(=[O:3])[CH3:2].CCN(C(C)C)C(C)C.[CH2:39]([O:42][C:43](Cl)=[O:44])[CH2:40][CH3:41]>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:27][C:43](=[O:44])[O:42][CH2:39][CH2:40][CH3:41])[CH2:6][C@@H:5]1[CH2:28][CH3:29])(=[O:3])[CH3:2]
Reactant: CCCOC(=O)Cl
Reactant: CC[C@H]1C[C@@H](N)c2cc(-c3ccc(CN4CCCCC4)cc3)ccc2N1C(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCOC(=O)N[C@@H]1C[C@H](CC)N(C(C)=O)c2ccc(-c3ccc(CN4CCCCC4)cc3)cc21
Reaction time: 0.67 h

Procedure:
(cis)-1-Acetyl-2-ethyl-6-[4-(1-piperidinylmethyl)phenyl]-1,2,3,4-tetrahydro-4-quinolinamine (for a preparation see Intermediate 5) (50 mg, 0.128 mmol) was dissolved in dichloromethane (DCM) (2 mL), mixed with DIPEA (0.045 mL, 0.255 mmol) and propylchloroformate (0.019 mL, 0.166 mmol, Aldrich) and stirred under nitrogen. After 40 minutes the reaction was loaded onto a 5 g SCX-column, eluting with MeOH (70 mL) followed by 2M MeOH/NH3 (70 mL). Product-containing fractions were evaporated to dryness to give a colourless solid (38 mg). This was purified on a 12+M Biotage silica column, eluting with 0 to 8% 2M methanolic ammonia in DCM. Product-containing fractions were evaporated to dryness to give a clear, colourless solid (16 mg). LCMS (Method C): Rt=0.83, MH+=478
Reaction SMILES: Cl.[CH2:2]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]2[NH:24][C:25](=[S:27])[O:26][C:22]=2[CH:21]=1>C(O)(C)C>[CH2:2]([CH:9]1[CH2:10][CH2:11][N:12]([CH2:15][C:16]([NH:19][C:20]2[CH:29]=[CH:28][C:23]3[NH:24][C:25](=[S:27])[O:26][C:22]=3[CH:21]=2)=[O:18])[CH2:13][CH2:14]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)CN1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccc2[nH]c(=S)oc2c1
Agent: Cl
Solvent: CC(C)O
Product: O=C(CN1CCC(Cc2ccccc2)CC1)Nc1ccc2[nH]c(=S)oc2c1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-acetic acid hydrochloride and 6-amino-3H-benzoxazole-2-thione according to the method described in Example 161c. Melting Point: 183-184° C. (isopropanol)
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:27])[C:7]([CH2:16][C:17]1[C:25]2[C:20](=[C:21]([Cl:26])[CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)([NH:13][CH:14]=[O:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:4].[CH3:28]I>CS(C)=O>[CH2:11]([O:10][C:8](=[O:9])[C:7]([CH2:16][C:17]1[C:25]2[C:20](=[C:21]([Cl:26])[CH:22]=[CH:23][CH:24]=2)[N:19]([CH3:28])[CH:18]=1)([NH:13][CH:14]=[O:15])[C:6]([O:5][CH2:3][CH3:4])=[O:27])[CH3:12]
Reactant: CI
Reactant: CCOC(=O)C(Cc1c[nH]c2c(Cl)cccc12)(NC=O)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOC(=O)C(Cc1cn(C)c2c(Cl)cccc12)(NC=O)C(=O)OCC
Reaction time: 4 h
Yield: 75.4 %

Procedure:
To a suspension of DMSO (5 mL) and KOH (229 mg, 4.1 mmol) was added 2-(7-Chloro-1H-indol-3-ylmethyl)-2-formylamino-malonic acid diethyl ester (500 mg, 1.4 mmol), followed by MeI (0.127 mL, 2 mmol) at 0° C. The reaction mixture was stirred for 4 hr. After the usual workup the product was purified by column chromatography on silica gel using 30% ethyl acetate-hexane to give 2-(7-Chloro-1-methyl-1H-indol-3-ylmethyl)-2-formylamino-malonic acid diethyl ester (402 mg, 77%): mp 83-87° C., 1H NMR (500 MHz, CDCl3): 1.28 (t, J=7.5 Hz, 6H), 3.81 (s, 2H), 4.08 (s, 3H), 4.17-4.31 (m, 4H), 6.71 (s, 1H), 6.93 (dd, J=7.5 and 7.5 Hz, 1H), 7.10 (d, J=7.5 Hz, 1H), 7.35 (d, J=7.5 Hz, 1H), 8.18 (d, J=1.0 Hz, 1H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:32])([CH3:31])[O:9][C:10](=[O:30])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)=[CH:14][CH:13]=1)(=O)=O.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([C:7]2[C:8]([CH3:31])([CH3:32])[O:9][C:10](=[O:30])[C:11]=2[C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:16][CH:17]=2)=[CH:39][CH:38]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC1(C)OC(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C1OS(=O)(=O)C(F)(F)F
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C2=C(c3ccc(OCc4ccc5ccccc5n4)cc3)C(=O)OC2(C)C)cc1
Reaction time: 0.5 h
Yield: 0 %

Procedure:
To a stirred solution of 2,2-dimethyl-5-oxo-4-(4-(quinolin-2-ylmethoxy)phenyl)-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (250 mg, 0.5 mol) in 1,4-Dioxane (10 mL) were added 4-methoxyphenylboronic acid (92 mg, 0.6 mol), Na2CO3 (127 mg, 1.5 mol) and water (4 mL) at RT under an inert atmosphere. The mixture was stirred for 30 min followed by addition of Pd(PPh3)4 (58 mg, 0.05 mol) and then refluxed for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water and brine, and then dried over Na2SO4 and concentrated in vacuo to afford 4-(4-methoxyphenyl)-5,5-dimethyl-3-(4-(quinolin-2-ylmethoxy)phenyl)furan-2(5H)-one- (40 mg, 18%) as a yellow solid. 1H NMR (500 MHz, d6-DMSO): δ 8.43-8.41 (m, 1 H), 8.02-7.98 (m, 2 H), 7.78 (t, J=7.8 Hz, 1 H), 7.68-7.52 (m, 2 H), 7.25-7.21 (m, 4 H), 7.02-6.98 (m, 4 H), 5.40 (s, 2 H), 5.25 (s, 2 H), 3.79 (s, 3 H). MS: M+H: m/z=452.2; M+Na: m/z=474.3. HPLC: 91%, (Condition-B).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)([C:14]#[N:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CO.O1CCOCC1>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][C:11]2([CH2:14][NH2:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NCC1(Cc2ccc(Cl)cc2)CCNCC1
Reaction time: 19 h

Procedure:
To a solution of 4-(4-chlorobenzyl)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester (0.500 g, 1.493 mmol) in methanol (3 ml) was added 4M HCl in dioxane (10 ml). After stirring for 19 hours, the solution was concentrated to give the deprotected amine as the hydrochloride salt (0.405 g).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:4]=2[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=1.[CH3:27][S:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH3:27][S:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:2]1[C:3]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:4]=2[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=1
Reactant: CSc1ccccc1B(O)O
Reactant: O=c1ccc2c(Cl)nc(NC(CO)CO)nc2n1-c1c(F)cccc1F
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: C1COCCO1
Solvent: O
Product: CSc1ccccc1-c1nc(NC(CO)CO)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 150 °C
Yield: 89 %

Procedure:
A solution of 4-Chloro-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2,6-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (50 mg, 0.13 mmol) in dioxane/H2O (3:1, 4.8 mL) was mixed with 2-methylthiophenyl boronic acid (33.8 mg, 0.20 mmol) and K2CO3 (54.3 mg, 0.39 mmol). The resultant mixture was bubbled with argon for 5 minutes, and added by Pd(PPh3)4 (3.0 mg, 0.0026 mmol). The reaction tube was sealed and heated with “Smith Creator” (microwave, 150° C.) for 15 minutes. The mixture was concentrated under vaco. Flash chromatography (EtOAc/Hexane, 3:1) then provided the title compound (89%): MS (ES) m/z 471 (M+H)+; 1H-NMR(CDCl3) δ 2.45 (s, 3H), 2.55 (s, br, 2H), 3.72 (m, br, 5H), 6.25 (m, br, 1H), 6.41 (m, 1H), 7.11 (m, 2H), 7.30 (m, 2H), 7.45 (m, 2H), 7.51 (m, 2H).