Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:20][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].ClC1C=CC=C(C(OO)=[O:30])C=1>ClCCl>[CH2:11]([CH:10]1[O:30][CH:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:20][CH3:21])=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Solvent: ClCCl
Product: CCCCCCCCC1OC1CCCCCCCC(=O)OC

Procedure:
Methyl oleate (1) (5.0 g; 0.017 mol) (89%) (ITERG) and meta-chloroperbenzoic acid (mCPBA) (4.3 g; 0.025 mol) (Aldrich) were dissolved in dichloromethane (J. T. Baker) (100 mL) and the reaction mixture was mixed under agitation at ambient temperature for 5 hours. The reaction mixture was then filtered and the collected solution was washed with saturated aqueous sodium bicarbonate (3×50 mL) (Aldrich) then with water (3×50 mL). The organic layer was separated and dried over anhydrous sodium sulfate. Finally, the solvent was removed by evaporation under rotation to obtain the intermediate compound 2.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([O:27][C:28](=[O:30])[CH3:29])[CH:8]=[CH:9][C:10]=1[C:11]1[C:12](=[O:26])[O:13][C:14]2[C:19]([C:20]=1[CH3:21])=[CH:18][CH:17]=[C:16]([O:22][C:23](=[O:25])[CH3:24])[CH:15]=2)(=[O:3])[CH3:2].[Br:31]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.[W]>[C:1]([O:4][C:5]1[CH:6]=[C:7]([O:27][C:28](=[O:30])[CH3:29])[CH:8]=[CH:9][C:10]=1[C:11]1[C:12](=[O:26])[O:13][C:14]2[C:19]([C:20]=1[CH2:21][Br:31])=[CH:18][CH:17]=[C:16]([O:22][C:23](=[O:25])[CH3:24])[CH:15]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(-c2c(C)c3ccc(OC(C)=O)cc3oc2=O)c(OC(C)=O)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1ccc(-c2c(CBr)c3ccc(OC(C)=O)cc3oc2=O)c(OC(C)=O)c1

Procedure:
A mixture of acetic acid 3-acetoxy-4-(7-acetoxy-4-methyl-2-oxo-2H-chromen-3-yl)-phenyl ester (0.767 g, 1.87 mmol, 1 eq), N-bromosuccinimide (0.349 g, 1.962 mmol, 1.05 eq) and benzoyl peroxide (0.035 g, 0.145 mmol) in carbon tetrachloride (30 mL) was stirred and heated to reflux under nitrogen in presence of a 100W tungsten lamp for 20 hours. Reaction monitoring by MS and TLC showed the presence unreacted starting material, and additional N-bromosuccinimide (0.060 g, 0.34 mmol) and benzoyl peroxide (0.008 g) were added to the reaction mixture and the reaction was heated at reflux under nitrogen for an additional 2 hours. The mixture was evaporated to dryness, dissolved in hot dichloromethane and purified by column chromatography on silica gel using 3% ethyl acetate/hexane as an eluent to yield the title product as a tan crystalline solid.
Reaction SMILES: [CH3:1][S:2]([O:5][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:7])(=[O:4])=[O:3].[CH3:16]C(O)CCCCCCCCC.CS(Cl)(=O)=O.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][S:2]([O:5][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH3:7])(=[O:4])=[O:3]
Reactant: CCCCCCCCC(C)OS(C)(=O)=O
Reactant: CCCCCCCCCC(C)O
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCC(C)OS(C)(=O)=O
Reaction time: 3.5 h
Yield: 95 %

Procedure:
2-Methanesulfonyloxyundecane was prepared as described for 2-methanesulfonyloxydecane from 2-undecanol (30.0 ml, 144 mmol), methanesulfonylchloride (15.5 ml, 200 mmol) and diisopropylethylamine (30.8 ml, 177 mmol) in dry CH2Cl2 (240 ml). After stirring for 3.5 hrs, the reaction was processed as previously stated but at 4 times the volumes to provide 2-methanesulfonyloxyundecane (31.35 g, 95%).
Reaction SMILES: [CH:1]1([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][NH:2]1.[CH3:16][C:17]1[S:18][C:19]([C:28](O)=[O:29])=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:21]=1>>[CH3:16][C:17]1[S:18][C:19]([C:28]([N:2]2[CH2:3][CH:4]3[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]3)[CH:1]2[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:29])=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:21]=1
Reactant: CCOC(=O)CC1NCC2CCCCC21
Reactant: Cc1nc(-c2ccccc2)c(C(=O)O)s1
Product: CCOC(=O)CC1C2CCCCC2CN1C(=O)c1sc(C)nc1-c1ccccc1

Procedure:
Ethyl 2-(2-(2-methyl-4-phenylthiazole-5-carbonyl)octahydro-1H-isoindol-1-yl)acetate was prepared according general procedure A from ethyl 2-(octahydro-1H-isoindol-1-yl)acetate and 2-methyl-4-phenylthiazole-5-carboxylic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47]OS(C)(=O)=O)=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:53][NH:54][CH3:55]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:18][CH:19]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][N:54]([CH3:55])[CH3:53])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCOS(C)(=O)=O)CCC3)cc1
Reactant: CNC
Solvent: CCO
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCN(C)C)CCC3)cc1

Procedure:
In analogy to the procedure described in example 8(c), the (3R,4R)-3-[1-(2-methanesulfonyloxy-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy -benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester [example 9(a)] was treated with dimethylamine in ethanol to yield the (3R,4R)-3-[1-(2-dimethylamino-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 688 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([O:23][CH3:24])[C:11](=[O:22])[N:12]([CH3:21])[C:13]=3[NH:17][C:18](=[O:20])[CH3:19])[C:8]2=[O:25])=[CH:4][CH:3]=1.[C:28]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([O:23][CH3:24])[C:11](=[O:22])[N:12]([CH3:21])[C:13]=3[N:17]([CH3:28])[C:18](=[O:20])[CH3:19])[C:8]2=[O:25])=[CH:26][CH:27]=1
Reactant: O=C([O-])[O-]
Reactant: COc1c2c(c(NC(C)=O)n(C)c1=O)CCN(Cc1ccc(F)cc1)C2=O
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c2c(c(N(C)C(C)=O)n(C)c1=O)CCN(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-[6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]acetamide (0.073 g, 0.196 mmol) in 2 mL DMF was added Cs2CO3 (0.084 g, 0.25 mmol) and methyl iodide (0.044 mL, 0.7 mmole) and the reaction was stirred overnight at room temperature. The solvent was removed and the residue was partitioned between CHCl3 and 10% KHSO4, the organic was dried with Na2SO4, filtered and evaporated to give the crude product.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[CH:11]=[CH:10][CH:9]=2)=[O:5])C.O.[OH-].[Li+].O1CCCC1>O>[CH3:21][N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:13]=2[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]3)[CH2:16][CH2:17]1
Reactant: CCOC(=O)c1cc2c(N3CCN(C)CC3)cccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(c2cccc3[nH]c(C(=O)O)cc23)CC1
Yield: 48.6 %

Procedure:
A solution of 1-(2-(ethoxycarbonyl)-1H-indol-4-yl)-4-methylpiperazine (0.91 g, 3.17 mmol), lithium hydroxide hydrate (0.136 g, 3.17 mmol, 1.0 equivalent), tetrahydrofuran (20 mL), and water (4 mL) was heated at reflux under nitrogen for 16 hours. The resulting reaction mixture was evaporated under reduced pressure, and the residue was chromatographed using silica gel (approximately 30 g) and elution with methylene chloride/methanol/ammonium hydroxide [3:2:0.2] to afford the title compound (0.40 g, 1.54 mmol, 49%) as a white solid: mp, 272-273° C.; R, =0.05 in methylene chloride/methanol/ammonium hydroxide [5:1:0.1]; 13C NMR (D2O) δ169.4, 145.0, 137.5, 132.9, 124.7, 120.7, 108.2, 107.3, 103.7, 58.7, 53.7, 51.0; LRMS (m/z, relative intensity) 260 (18), 259 (M+, 100), 244 (9), 215 (7), 170 (24); HRMS calculated for C14H17N3O2 259.1322, found 259.1325.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:26]([CH3:37])[CH:25]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:1]([N:5]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:26]([CH3:37])[CH:25]=1)[C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cccc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: CCOC(=O)COc1ccc(CBr)cc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
To a solution of N-butyl-N-[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amine (73 mg, 0.25 mmol) in anhydrous acetonitrile (5 mL) was added ethyl [4-(bromomethyl)-2-methylphenoxy]acetate (75 mg, 0.25 mmol) and N,N-diisopropylethylamine (43 μL, 0.25 mmol). The resulting solution was heated at reflux under nitrogen for 2 h and then cooled to room temperature. The solvent was removed in vacuo and the residue diluted with water (10 mL) and extracted with CH2Cl2 (30 mL). The organic extract was separated by hydrophobic frit and the solvent removed in vacuo. Purification by SPE (Silica, 5 g) eluting 99:1 cyclohexane:EtOAc afforded the title compound as a pale yellow oil (105 mg).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]2[CH:18]=[N:17][CH:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=O)C.O.[NH2:20][NH2:21]>>[N:14]1[CH:15]=[CH:16][N:17]=[CH:18][C:13]=1[O:12][C@H:9]1[CH2:10][CH2:11][C@H:6]([C:4]([NH:20][NH2:21])=[O:3])[CH2:7][CH2:8]1
Reactant: CCOC(=O)[C@H]1CC[C@H](Oc2cnccn2)CC1
Reactant: NN
Solvent: O
Product: NNC(=O)[C@H]1CC[C@H](Oc2cnccn2)CC1
Temperature: 120 °C

Procedure:
A mixture of cis/trans-4-(pyrazin-2-yloxy)-cyclohexanecarboxylic acid ethyl ester (1.11 g, 4.41 mmol) and hydrazine hydrate (0442 g, 8.83 mmol) was heated at 120° C. for 72 h. After cooling to room temperature the reaction mixture was partitioned between ethyl acetate (50 ml) and water (30 ml). The organic layer was separated. The aqueous layer was extracted with two 50 ml portions of ethyl acetate. The combined organic layers were washed with brine (30 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The crude cis/trans-hydrazide was triturated in ethyl acetate (5 ml). The precipitate was collected by filtration and dried in vacuo to give the crude title compound (0.236 g, 23%) as white solid, which was used in the next step without further purification. MS m/e: 237 (M+H+)
Reaction SMILES: [F:1][CH:2]1[C:6](=[O:7])[O:5][CH:4]2[CH2:8][CH2:9][CH:10]([CH:11]=[CH:12][CH:13]([OH:20])[CH:14]([F:19])[CH2:15][CH2:16][CH2:17][CH3:18])[CH:3]12.[O:21]1[C:25](=O)[CH:24]=[C:23]2[CH:27]=[CH:28]C=C12>>[F:1][CH:2]1[C:6](=[O:7])[O:5][CH:4]2[CH2:8][CH2:9][CH:10]([CH:11]=[CH:12][CH:13]([O:20][CH:25]3[CH2:24][CH2:23][CH2:27][CH2:28][O:21]3)[CH:14]([F:19])[CH2:15][CH2:16][CH2:17][CH3:18])[CH:3]12
Reactant: O=C1C=C2C=CC=C2O1
Reactant: CCCCC(F)C(O)C=CC1CCC2OC(=O)C(F)C12
Product: CCCCC(F)C(C=CC1CCC2OC(=O)C(F)C12)OC1CCCCO1

Procedure:
By the procedure of Example 5 [3aR-[3aα,4α(1E,3R*,4R*)6aα]]-hexahydro-3-fluoro-4-(3-hydroxy-4-fluoro-1-octenyl]-2H-cyclopenta[b]furan-2-one was converted to [3aR-[3aα,4α(1E,3R*,4R*)6aα]]-hexahydro-3-fluoro-4[3-(tetrahydro-2H-pyran-2-yl)oxy]-4-fluoro-1-octenyl]-2H-cyclopenta[b]furan-2-one.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[CH:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH2:22](I)[I:23]>C1COCC1>[I:23][CH2:22][C:13]1([C:18]([O:20][CH3:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)C1CCCC1
Reactant: ICI
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C1(CI)CCCC1
Temperature: -10 °C
Reaction time: 1 h
Yield: 51.9 %

Procedure:
To a stirred solution of HN(iPr)2 (1.31 mL, 9.36 mmol) in THF (5 mL) was added n-BuLi (1.58 M in hexane, 5.43 mL, 8.58 mmol) with keeping −10° C. under N2, and the mixture was stirred at −10° C. for 1 h. Then, to this mixture was added a solution of methyl cyclopentanecarboxylate (1.00 g, 7.80 mmol) in THF (3 mL) dropwise at 0° C., and the mixture was stirred at 0° C. for 2 h. Finally, to this mixture was added CH2I2 (0.628 mL, 7.80 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with sat. NH4Cl aq. (50 mL), extracted with Et2O (75 mL) for two times, and the combined organic layer was washed with brine (75 mL). The organic layer was dried over Na2SO4, filtered and concentrated. Removal of the solvent gave a residue, which was chromatographed on a column of silica gel eluting with EtOAc/hexane (1:20→1:10) to give 1.085 g (52%) of title compound as a colorless oil.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:15][CH2:16][N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][C:18]1=[O:26].CC1C=CC=CC=1>O>[C:1]1([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:26])[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=c1[nH]c2ccccc2n1CCCl
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1[nH]c2ccccc2n1CCN1CCN(Cc2ccccc2)CC1

Procedure:
A mixture of 70.4 parts of 1-(phenylmethyl)piperazine, 39.4 parts of 1-(2-chloroethyl)-1,3-dihydro-2H-benzimidazol-2-one and 360 parts of methylbenzene is stirred and refluxed overnight. The reaction mixture is cooled, water is added and the layers are separated. The methylbenzene-phase is washed three times with water, dried, filtered and evaporated. The solid residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is boiled in 2,2'-oxybispropane. The whole is cooled on an ice-bath. The product is filtered off and crystallized from a mixture of 2,2'-oxybispropane and a small amount of 2-propanol, yielding 1,3-dihydro-1-{2-[4-(phenylmethyl)-1-piperazinyl]ethyl}-2H-benzimidazol-2-one; mp. 136.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[C:35]([C:36](Cl)=[O:37])=[C:34]([CH3:39])[O:33][N:32]=1>C1COCC1.C(Cl)Cl>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[C:35]([C:36]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH2:7][CH2:8][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:13]=3)[CH2:10][CH2:11]2)=[O:37])=[C:34]([CH3:39])[O:33][N:32]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN)CC2)c1
Reactant: Cc1onc(-c2ccccc2Cl)c1C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2Cl)c1C(=O)NCCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-{3-[1-(4-aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3-(2-chlorophenyl)-5-methyl-4-isoxazolecarbonyl chloride: ESMS m/e: 537.0 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:10][CH2:11][CH3:12])(=[O:9])[C:4]([O:6]CC)=O.[C:13]1(=[O:25])[C:23]2=[C:24]3[C:19](=[CH:20][CH:21]=[CH:22]2)[CH2:18][CH2:17][CH2:16][CH:15]3[CH2:14]1.Cl>O1CCOCC1>[C:4]([CH:14]1[CH:15]2[C:24]3[C:19]([CH2:18][CH2:17][CH2:16]2)=[CH:20][CH:21]=[CH:22][C:23]=3[C:13]1=[O:25])([C:3]([O:10][CH2:11][CH3:12])=[O:9])=[O:6]
Reactant: O=C1CC2CCCc3cccc1c32
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(=O)C1C(=O)c2cccc3c2C1CCC3
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.5 %

Procedure:
To a suspension of 50% sodium hydride (7.4 g) in anhydrous dioxane (50 ml), under nitrogen, a solution of diethyl oxalate (34.5 g) in anhydrous dioxane (20 ml) and then a solution of 2a,3,4,5-tetrahydro-acenaphthen-1-one (20.4 g) in anhydrous dioxane (130 ml) are added under stirring at room temperature. The reaction mixture is kept under stirring at a temperature varying between about 25° C. and about 45° C. for 4 hours, then it is diluted with ice water (1500 ml) and acidified to pH=4 with 2N HCl. The precipitate is filtered, washed with water and then purified by treatment with methanol to give 2-ethoxalyl-2a,3,4,5-tetrahydroacenaphthen-1-one (30.8 g), m.p. 92°-94° C., which is reacted with methylhydrazine (5.7 g) in acetic acid (300 ml) at 50° C. for 1 hour.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[NH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[Cl:29])[N:20]=1>O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:18][C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[Cl:29])[N:20]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccc2c(Cl)cccc2n1
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(Nc1ccc2c(Cl)cccc2n1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 8.5 %

Procedure:
Pyridine (1 ml) and 4-chlorobenzenesulfonyl chloride (255 mg) were added to 2-amino-5-chloroquinoline (119 mg, Preparation Example 2) at room temperature. After stirring at room temperature for 3 days, water was added thereto and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and concentrated. Then, the resulting solid was washed with methanol, to give the title compound (20 mg).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH2:9][C:10]([NH:12][C:13]1[NH:14][C:15]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=[CH:16][C:17]=1[C:18]([NH2:20])=[O:19])=[O:11].O>CN(C)C=O>[NH2:9][C:10]([NH:12][C:13]1[NH:14][C:15]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=[C:16]([Cl:1])[C:17]=1[C:18]([NH2:20])=[O:19])=[O:11]
Reactant: O=C1CCC(=O)N1Cl
Reactant: NC(=O)Nc1[nH]c(-c2ccc(Br)cc2)cc1C(N)=O
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)Nc1[nH]c(-c2ccc(Br)cc2)c(Cl)c1C(N)=O
Yield: 51 %

Procedure:
N-Chlorosuccinimide (48 mg, 0.36 mmol) was added to a solution of 2-aminocarbonylamino-5-(4-bromophenyl)pyrrole-3-carboxamide (Compound No. 1-1, 97 mg, 0.30 mmol) in anhydrous N,N-dimethylformamide (2 mL), and the mixture was stirred overnight at 50° C. After cooling, water (4 mL) was added thereto, the precipitated solid was filtered off, and washed with water (5 mL). The obtained solid was dried under reduced pressure to give the target compound (54 mg) as a pale brown solid (Yield 51%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7](Cl)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[O:23]=[S:24]1(=[O:29])[CH2:28][CH2:27][CH2:26][NH:25]1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:1]([C:5]1[N:6]=[C:7]([N:25]2[CH2:26][CH2:27][CH2:28][S:24]2(=[O:29])=[O:23])[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S1(=O)CCCN1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)c1nc(N2CCCS2(=O)=O)c2nnn(Cc3ccccc3Cl)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.6 %

Procedure:
A mixture of 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (15.9 mg, 47.2 μmol), 1,1-dioxo-isothiazolidine (11.4 mg, 94.4 μmol) and DBU (14.2 μL, 94.4 μmol) in DMF (250 μL) was stirred at the room temperature overnight. The reaction mixture was directly purified by preparative HPLC (column: Gemini Sum C18 110A 75×30 mm. mobile phase: water (0.05% Et3N): acetonitrile 75:25% to 5:95%. WL: 230 nm Flow: 30 mL/min.) to afford the title compound as white solid (3.10 mg, 16%). MS (m/e): 387.3 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][NH:22][CH2:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1.CCN(C(C)C)C(C)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[C:13]3[CH2:24][CH2:23][N:22]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:21][C:14]3=[N:15][C:16]=2[NH:17][CH:18]([CH3:20])[CH3:19])[CH2:7][CH2:6]1
Reactant: CC(C)Nc1nc2c(nc1N1CCN(Cc3ccc(F)cc3F)CC1)CCNC2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1nc2c(nc1N1CCN(Cc3ccc(F)cc3F)CC1)CCN(S(C)(=O)=O)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a solution of 2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine (50 mg, 0.124 mmol) and DIPEA (0.032 mL, 0.186 mmol) in DCM (1 mL) was added methanesulfonyl chloride (10.6 μL, 0.137 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hr and concentrated via rotary evaporation. The resulting crude material was partitioned between EtOAc (2 mL) and water (1 mL). The organic phase was washed with brine, dried over Na2SO4, filtered, rinsed with EtOAc, and concentrated via rotary evaporation. The crude material was dissolved in EtOAc and MeOH, adsorbed on silica gel (0.75 g), and purified via medium pressure chromatography using a gradient eluant of 50% to 100% EtOAc in heptane on a 4 g silica gel column (Single Step™) to give the title compound (50.6 mg, 85%) as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.12-1.19 (m, 6H), 2.53-2.61 (m, 4H), 2.74 (t, J=5.9 Hz, 2H), 2.97 (s, 3H), 3.00 (d, J=7.3 Hz, 4H), 3.44-3.48 (m, 1H), 3.59 (s, 2H), 4.02-4.10 (m, 1H), 4.16 (s, 2H), 5.41 (d, J=7.8 Hz, 1H), 7.08 (td, J=8.4, 2.2 Hz, 1H), 7.22 (td, J=9.9, 2.7 Hz, 1H), 7.44-7.54 (m, 1H); ESI-MS m/z [M+H]+ 480.9.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=[O:8].B(O)(O)[C:11]1[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=1>>[C:14]1([CH3:17])[CH:15]=[CH:16][C:11]([C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([OH:9])=[O:8])=[CH:12][CH:13]=1
Reactant: O=C(O)c1sccc1Br
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2ccsc2C(=O)O)cc1

Procedure:
prepared by reaction of 3-bromo-thiophene-2-carboxylic acid with p-tolylboronic acid. LC-MS (basic): tR=0.50 min; [M−H]−=217.2.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:2]([CH:7]=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccccc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2-c2ccccc2)CC1
Reaction time: 3 h
Yield: 102.1 %

Procedure:
To a solution of biphenyl-2-carbaldehyde (5.01 g, 27.5 mmol) in dichloromethane (150 ml) at rt under nitrogen was added piperazine-1-carboxylic acid tert-butyl ester (5.63 g, 30.2 mmol) followed by glacial acetic acid (1.90 ml, 33.2 mmol). The reaction was stirred for 1 h before sodium triacetoxyborohydride (11.65 g, 55.0 mmol) was introduced. After 3 h, a solution of 5% NaOH (˜15 ml) was added and the mixture was extracted with dichloromethane. The organic layer was separated, washed with H2O (×2), brine, dried (Na2SO4), filtered and concentrated under reduced pressure to give 4-biphenyl-2-ylmethyl-piperazine-1-carboxylic acid tert-butyl ester as an oil (9.9 g, 100%) which was used without further purification. HPLC-MS 353 [M+1]+.