Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([NH:10][C:11]2[N:12]=[C:13]([NH2:29])[C:14]3[N:15]=[CH:16][N:17]([C:27]=3[N:28]=2)[C@H:18]2[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[C@H:19]2[OH:20])([CH3:9])C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:30][C@H](N)CC1C=CC=CC=1.C1([C@H](N)CC)C=CC=CC=1.C1([C@@H](N)CC)C=CC=CC=1>>[C:1]1([CH:7]([NH:10][C:11]2[N:12]=[C:13]([NH2:29])[C:14]3[N:15]=[CH:16][N:17]([C:27]=3[N:28]=2)[C@@H:18]2[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[C@H:19]2[OH:20])[CH2:9][CH3:30])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(Nc1nc(N)c2ncn([C@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)c1ccccc1
Reactant: C[C@H](N)Cc1ccccc1
Agent: CC[C@@H](N)c1ccccc1
Agent: CC[C@H](N)c1ccccc1
Product: CCC(Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)c1ccccc1
Temperature: 130 °C
Reaction time: 4.5 h

Procedure:
In Scheme A, step b, the acetonide (2) is then treated with an appropriately substituted primary amine to provide the secondary amine of structure (3). More specifically, the acetonide (2) is combined with a large excess of an appropriately substituted primary amine, such as L-(-)-amphetamine, D-(+)-amphetamine, (R)-1-phenylpropylamine or (S)-1-phenylpropylamine, under an atmosphere of an inert gas such as nitrogen. The mixture is then heated to approximately 130° C. with stirring for approximately 3 to 6 hours. After cooling, the product can be isolated and purified by techniques well known to one skilled in the art. For example, the crude mixture can be directly purified by flash chromatography followed by radial chromatography using an appropriate eluent such as 3% to 6% methanol/chloroform to provide the secondary amine (3).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2Br)[N:3]=1.[CH3:40][S:41]([C:44]1[CH:45]=[C:46](B(O)O)[CH:47]=[CH:48][CH:49]=1)(=[O:43])=[O:42].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:29][CH2:28][C:11]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:13]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=2[C:48]2[CH:47]=[CH:46][CH:45]=[C:44]([S:41]([CH3:40])(=[O:43])=[O:42])[CH:49]=2)[N:3]=1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(OCc4ccc(Cl)cc4Br)nc(N)n3)CC2)CN1C(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(OCc4ccc(Cl)cc4-c4cccc(S(C)(=O)=O)c4)nc(N)n3)CC2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A mixture of (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((2-bromo-4-chlorobenzyl)oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (300 mg, 0.4 mmol), (3-(methylsulfonyl)phenyl)boronic acid (280 mg, 1 mmol), and Pd(dppf)Cl2 (62 mg, 0.09 mmol) in dioxane (5 mL)/aq. Na2CO3 solution (2.0 M, 5 mL) was heated to 90° C. for 4 h. The reaction was then cooled to RT, the solids filtered away, and the filtrate concentrated in vacuo. Purification on normal phase silica gel (CH2Cl2/MeOH) provided (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((5-chloro-3′-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)methoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as an off-white solid.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:46][C:47]1[S:48][CH:49]=[CH:50][N:51]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)[C:8]([NH:46][C:47]2[S:48][CH:49]=[CH:50][N:51]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSc1ccc(C(CC2CCCC2)C(=O)O)cc1
Reactant: Nc1nccs1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CSc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)propionic acid (200 mg, 0.76 mmol) and triphenylphosphine (198 mg, 0.76 mmol) in methylene chloride (2 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (150 mg, 0.84 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The reaction mixture was then treated with 2-aminothiazole (160 mg, 1.60 mmol), and the resulting reaction mixture was stirred at 25° C. for 15 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. The remaining residue was diluted with water and ethyl acetate. The organic layer was further washed with a 1N aqueous hydrochloric acid solution and a saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded crude 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiazol-2-yl-propionamide as a yellow solid. Recrystallization from 2/1 hexanes/ethyl acetate afforded pure 3-cyclopentyl-2-(4-methylsulfanyl-phenyl)-N-thiazol-2-yl-propionamide (114 mg, 44%) as a white solid: mp 195-196° C.; EI-HRMS m/e calcd for C18H22N2OS2 (M+) 346.1174, found 346.1171.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:10]([CH3:21])[CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]2[CH3:21])=[CH:19][CH:18]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC1CNCCN1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(4-Chloro-phenyl)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.83 g, 0.68 mmol) was dissolved in HCl/dioxane (4M, 8 mL) and stirred for 2 hr at rt. The mixture was then evaporated in vacuo, basified with aqueous sodium hydroxide (1M, 50 mL), and extracted with ethyl acetate (3×100 mL). The organic layers were evaporated and the crude residue used in the next step, (0.56 g, brown oil).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:32])[CH2:9][CH2:10][CH:11]2[C:14](=[O:15])[N:13]([C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[CH:12]2[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.N.[H][H]>C(O)C.[Ni]>[NH2:21][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([N:13]2[CH:12]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH:11]([CH2:10][CH2:9][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[OH:32])[C:14]2=[O:15])=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(C#N)cc2)cc1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: COc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(CN)cc2)cc1
Temperature: 60 °C

Procedure:
1.22 g of 4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzonitrile are dissolved in 90 ml of ethanol, 10 ml of conc. ammonia solution and an excess of Raney nickel are added and the mixture is stirred at 60° C. and a hydrogen pressure of 10 bar for 8 h. Overnight, the reaction mixture cools to room temperature. The next day, the catalyst is separated off, the filtrate is concentrated under reduced pressure and the residue is purified chromatographically on silica gel using dichloromethane/methanol/ammonia solution 10/1/0.1. This gives 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)azetidin-2-one of molecular weight 434.51 (C26H27FN2O3); MS (ESI): 418.2 (MH+-NH3).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:11]3[C:12]([CH3:18])=[C:13]([C:15]([OH:17])=O)[O:14][C:10]=3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[CH3:19][O:20][C:21](=[O:43])[C@@H:22]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=2)=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH:23]([CH3:25])[CH3:24].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>[Cl-].[Na+].O.CN(C=O)C>[CH3:19][O:20][C:21](=[O:43])[C@@H:22]([NH:26][S:27]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:15]([C:13]3[O:14][C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([C:3]5[CH:4]=[CH:5][O:1][CH:2]=5)[C:11]=4[C:12]=3[CH3:18])=[O:17])=[CH:40][CH:41]=2)=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH:23]([CH3:25])[CH3:24]
Reactant: Cc1c(C(=O)O)oc2cccc(-c3ccoc3)c12
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4cccc(-c5ccoc5)c4c3C)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.6 %

Procedure:
To 4-furan-3-yl-3-methyl-benzofuran-2-carboxylic acid (114 mg, 0.47 mmol) was added (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester (170 mg, 0.47 mmol), BOP (249 mg, 1.2 eq), N,N-diisopropylethylamine (0.1 mL, 1.2 eq) and 4 mL of DMF. The mixture was stirred at room temperature overnight. The reaction mixture was poured into brine, and extracted with ethyl acetate. The combined organic solution was washed with brine and water. Removal of the solvent gave the crude product, which was purified by column chromatography on silica gel to give 258 mg of (S)-2-{4′-[(4-furan-3-yl-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester, obtained as white solid.
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]CO.C(OC(C)C)(C)C>>[C:1]([O:9][CH2:10][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH2:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1
Reactant: NCCCCCCCCCCO
Solvent: CC(C)OC(C)C
Product: NCCCCCCCCCCOC(=O)c1ccccc1
Yield: 90 %

Procedure:
In an argon atmosphere, a mixture of methyl benzoate (3.0 mmol), 10-aminodecan-1-ol (3.6 mmol), Zn4(OCOCF3)6O (1.25 mol % in terms of mole number) and diisopropyl ether (5.0 ml) was heated to reflux for 20 hours, and as a result, 10-aminodecyl benzoate was obtained at a yield of 90%. The yield of 10-benzoylaminodecyl benzoate was 7%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[CH2:9][CH2:8][CH2:7]2.[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl.[OH-].[Na+].O>COCCO>[O:1]=[C:2]1[C:11]2[C:10]([O:12][CH2:13][CH:15]3[O:17][CH2:16]3)=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: O=C1CCCc2cccc(O)c21
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCO
Product: O=C1CCCc2cccc(OCC3CO3)c21

Procedure:
To the solution heated to 80° C. of 3.2 g of 8-hydroxy 1-tetralone and 20 ml of epichlorohydrin in 20 ml of 2-methoxy ethanol is added 1.8 g of sodium hydroxide and the mixture is heated to reflux for 1 hour. Water is added and the mixture is extracted with methylene chloride. The organic phase is separated, dried and the solvent is evaporated.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=1[NH:29][CH2:30][C:31]1[N:32]=[N:33][N:34]([CH3:36])[N:35]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:29]([C:23]3[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=3[CH3:21])[CH2:30][C:31]3[N:32]=[N:33][N:34]([CH3:36])[N:35]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: Cc1ccc(NCc2nnn(C)n2)c(C)c1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2nnn(C)n2)c2ccc(C)cc2C)[C@H]1O
Yield: 57 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using the epoxide compound (250 mg, 0.89 mmol) obtained in step 1 of example 2 and N-(2,4-dimethylphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=2:1), to give desired compound (256 mg, yield: 57%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6](Cl)[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].O.[NH2:20][NH2:21]>O>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([NH:20][NH2:21])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: NN
Reactant: COc1c(Cl)nc(SC)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1c(Cl)nc(SC)nc1NN
Reaction time: 0.5 h

Procedure:
A mixture of 48.1 g (0.21 mol) of 4,6-di-chloro-2-methylthio-5-methoxypyrimidine, 29.5 g (0.21 mol) of potassium carbonate, 80 ml of hydrazine monohydrate, and 80 ml of water was prepared and heated at reflux with stirring for about 30 min at which time the reaction appeared by high pressure liquid chromatography to be complete. The mixture was allowed to cool and was extracted with methylene chloride. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was mixed with hexane and the solids removed by filtration and dried to obtain 34.7 g of the title compound as a tan solid melting at 118°-119° C.
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:4]([CH3:17])[C:3]=1[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19].[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][N:34]=1>>[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36]([C:2]2[N:6]=[C:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[N:4]([CH3:17])[C:3]=2[C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])=[CH:35][N:34]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: Cn1c(-c2ccc(C(F)(F)F)cc2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Product: COc1ncc(-c2nc(-c3ccc(C(F)(F)F)cc3)n(C)c2C(=O)N2CCC(N3CCCC3)CC2)cn1

Procedure:
In analogy to the procedure described for example 7, [5-iodo-3-methyl-2-(4-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 104) was reacted with 2-methoxy-pyrimidin-5-yl-boronic acid to give the title compound as light yellow solid. MS: 515.3 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=O)[NH:10][N:9]=[CH:8][N:7]=1)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:15]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][N:9]=[N:10][C:11]=1[Cl:15])=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1ncn[nH]c1=O
Product: CCOC(=O)c1ncnnc1Cl
Yield: 90 %

Procedure:
6-Oxo-1,6-dihydro-[1,2,4]triazine-5-carboxylic acid ethyl ester (115 mg, 0.68 mmol) in POCl3 (1.5 ml) was heated to 100° C. for 2 h. All volatiles were then removed and the remaining residue was diluted with cold CHCl3 and carefully neutralized with sat. NaHCO3-solution. This mixture was extracted with cold CHCl3. The organic phase was then washed with cold brine, dried (Na2SO4) and evaporated to give the crude title compound (115 mg, 90%) as brown gum, which was used in the next reaction step without further purification. MS: m/e=188.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([S:16]([CH3:19])(=[O:18])=[O:17])[CH2:12][CH2:11]2)[CH:5]=[N:6][C:7]=1Cl.[NH2:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1>>[Cl:1][C:2]1[C:7]([NH:20][C:21]2[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=2)=[N:6][CH:5]=[C:4]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([S:16]([CH3:19])(=[O:18])=[O:17])[CH2:12][CH2:11]2)[CH:3]=1
Reactant: CS(=O)(=O)N1CCN(Cc2cnc(Cl)c(Cl)c2)CC1
Reactant: Nc1cccc(O)c1
Product: CS(=O)(=O)N1CCN(Cc2cnc(Nc3cccc(O)c3)c(Cl)c2)CC1

Procedure:
The title compound was prepared in an analogous manner to that described above in Example 22, Step 2 using 1-((5,6-dichloropyridin-3-yl)methyl)-4-(methylsulfonyl)piperazine and 3-aminophenol under microwave irradiation conditions (150° C., 30 min), and isolated as a pale yellow solid (70%). LCMS (API-ES) m/z 398 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][N:13]=[N:12][N:11]=2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH:14]1[C:10]([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)=[N:11][N:12]=[N:13]1
Reactant: O=[N+]([O-])c1ccc(-c2nnn[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-(4-nitro-phenyl)-1H-tetrazole (1.0 g, 5.2 mmol) in MeOH (30 mL) was added 10 wt % Pd/C (0.1 equiv by wt) under argon atmosphere. The mixture was evacuated, refilled with hydrogen (3 cycles) and stirred at room temperature for 1.5 h. The heterogeneous reaction mixture was filtered through a pad of Celite, washed with MeOH and concentrated in vacuo. The crude amino-compound was used in the next step without purification. MS (ES+): m/z 162 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:16]([O:18]C)=[O:17])[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=[N:3]1.[OH-].[K+]>C1COCC1.O>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:16]([OH:18])=[O:17])[S:10][C:11]=2[C:12]([F:13])([F:14])[F:15])=[CH:5][CH:4]=[N:3]1
Reactant: COC(=O)c1cc(-c2ccnn2C)c(C(F)(F)F)s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(C(=O)O)sc1C(F)(F)F
Temperature: 50 °C
Yield: 110.5 %

Procedure:
To a solution of methyl 4-(1-methyl-1H-pyrazol-5-yl)-5-(trifluoromethyl)-2-thiophenecarboxylate (250 mg, 0.77 mmol), in THF/H2O (3 mL/0.3 mL), was added KOH (217 mg, 3.88 mmol). The reaction mixture was heated to 50° C. for 4 h. After the mixture was concentrated and diluted with H2O, the pH was adjusted to 3. The mixture was extracted with DCM (5 mL×3). The collected organic layers were concentrated under vacuum to give crude acid (235 mg, 80% pure) which was used directly in the next step without further purification: LC-MS (ES) 277 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.CO.C#C>C(Cl)Cl.CCOCC.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH2:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Agent: [Pd]
Agent: C#C
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(CCCO)cc2c1O
Reaction time: 0.42 h
Yield: 14 %

Procedure:
A mixture of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Example No. 134 (231.0 mg) and Pd/C (10%, 46.2 mg) are dissolved in 40 mL 3:1 CH2Cl2 :MeOH. The reaction mixture is placed under the Parr hydrogenator at 26 psi and monitored with the OAMS for complete reduction of the acetylene. The reaction is complete in 25 min and filtered over celite to remove the palladium. The filtrate is condensed to obtain a solid. The solid is suspended in ether, filtered, and collected to yield 31.8 mg (14%) of the desired product as a white solid.
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][C:16](=[O:18])[CH:15]=[C:6]1[C:7]1[CH:8]=[CH:9][C:10]([OH:14])=[CH:11][C:12]=1[CH2:13]2)[CH2:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.[CH3:28][O:29][CH2:30]Cl>CN(C=O)C.CCOC(C)=O>[CH2:1]([C:5]12[CH2:17][C:16](=[O:18])[CH:15]=[C:6]1[C:7]1[CH:8]=[CH:9][C:10]([O:14][CH2:28][O:29][CH3:30])=[CH:11][C:12]=1[CH2:13]2)[CH2:2][CH2:3][CH3:4]
Reactant: COCCl
Reactant: CCCCC12CC(=O)C=C1c1ccc(O)cc1C2
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC12CC(=O)C=C1c1ccc(OCOC)cc1C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 8a-butyl-6-hydroxy-8,8a-dihydrocyclopenta[a]inden-2(1H)-one (300 mg, 1.2 mmol) in anhydrous DMF (3 mL) was placed under a N2 atmosphere and stirred at room temperature while N,N-diisopropylethylamine (0.63=L, 3.6 mmol) and chloromethyl methyl ether (0.183 mL, 2.4 mmol) were added successively. After stirring at room temperature overnight, the mixture was diluted with EtOAc (100 mL) and washed with 1N HCl. The acid wash was back-extracted with EtOAc. The combined organics were washed with 5% NaHCO3, water and brine, dried over MgSO4, filtered, and concentrated under vacuum to a brown oil. The crude product was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 40S (4×7 cm) silica gel column, eluting with 5:1 hexane-EtOAc, to provide 8a-butyl-6-(methoxymethoxy)-8,8a-dihydrocyclopenta[a]inden-2(1H)-one as an oil.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:28]([O:32][C:33]([NH:35][C@H:36]([C:41]([OH:43])=[O:42])[CH2:37][CH:38]([CH3:40])[CH3:39])=[O:34])([CH3:31])([CH3:30])[CH3:29].O[C:45]1[CH:52]=[CH:51][C:48]([CH:49]=[O:50])=[CH:47][CH:46]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CN(C)C1C=CN=CC=1.ClCCl>[CH:49]([C:48]1[CH:51]=[CH:52][C:45]([O:42][C:41](=[O:43])[CH:36]([NH:35][C:33]([O:32][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:34])[CH2:37][CH:38]([CH3:39])[CH3:40])=[CH:46][CH:47]=1)=[O:50]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=Cc1ccc(O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)CC(NC(=O)OC(C)(C)C)C(=O)Oc1ccc(C=O)cc1

Procedure:
BOP (13.0 mmol) was added to a solution of N-tert-butyloxycarbonyl-L-leucine (10.9 mmol) and 4-hydroxybenzaldehyde (13.0 mmol) in dry DMF (12 mL), and stirred to dissolve. N,N-Diisopropylethylamine (43.0 mmol) and 4-dimethylaminopyridine (1 mmol) were added with stirring. The resulting solution was stirred for 2.5 hours. The reaction mixture was covered with dichloromethane (100 mL) and washed with water, saturated aqueous sodium bicarbonate, and saturated brine. The dichloromethane was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting red oil was purified by column chromatography on silica gel with dichloromethane as an eluant.
Reaction SMILES: C(O)CCCCC.[H-].[Na+].[C:10]1([O:16][C:17](=[O:51])[O:18][CH2:19][N:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]4[CH2:40][CH2:39][N:38]([C:41]5[C:49]6[CH:48]=[CH:47][S:46][C:45]=6[CH:44]=[CH:43][CH:42]=5)[CH2:37][CH2:36]4)[CH:28]=3)[CH:23]=[CH:22][C:21]2=[O:50])C=CC=CC=1.C[O-].[Na+]>O1CCCC1.O>[CH3:10][O:16][C:17](=[O:51])[O:18][CH2:19][N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][N:38]([C:41]4[C:49]5[CH:48]=[CH:47][S:46][C:45]=5[CH:44]=[CH:43][CH:42]=4)[CH2:37][CH2:36]3)[CH:28]=2)[CH:23]=[CH:22][C:21]1=[O:50]
Reactant: O=C(OCn1c(=O)ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21)Oc1ccccc1
Agent: C[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCCO
Product: COC(=O)OCn1c(=O)ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc21
Yield: 19.6 %

Procedure:
To a solution of n-hexylalcohol (50.5 mg) in tetrahydrofuran (5 ml) was added with stirring under ice-cooling 60% sodium hydride (18 mg) by small portions, and the mixture was stirred at the same temperature for 0.5 hr, to a solution of carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester phenyl ester (240 mg) in tetrahydrofuran (1 ml) was added with stirring under ice-cooling sodium methoxide (30 mg), and the mixture was stirred for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) to give carbonic acid 7-[4-(4-benzo[b]thiophen-4-ylpiperazin-1-yl)butoxy]-2-oxo-2H-quinolin-1-ylmethyl ester methyl ester (42 mg).