Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([O:17]C)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7].[OH-].[Na+]>CO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C:9]1([C:15]([OH:17])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7]
Reactant: COC(=O)C1(NC(=O)c2ccco2)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NC1(C(=O)O)CCCCC1)c1ccco1
Yield: 67.3 %

Procedure:
To the solution of methyl 1-[N-(furan-2-ylcarbonyl)amino]-1-cyclohexanecarboxylate (9.6 g) obtained in Step 1 in 100 ml of methanol, was added 2N-sodium hydroxide solution (50 ml). The reaction mixture was refluxed for 3 hours and concentrated. The resulting residue was diluted with 150 ml of water and washed with 100 ml of diethyl ether. 6N-hydrochloride was added dropwise to the resulting aqueous layer to adjust the pH of the solution to pH 3. The resulting white solid was filtered and dried to give the titled compound (6.1 g).
Reaction SMILES: C(OC([N:8]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:9]1[CH:23]=[CH:22][C:12]([CH:13]=[CH:14][C:15](N2C=CN=C2)=[O:16])=[CH:11][CH:10]=1)=O)(C)(C)C.[OH-].[Na+].[NH2:41][CH2:42][CH:43]([OH:46])[CH2:44][OH:45]>C(Cl)(Cl)Cl>[CH2:24]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH:13]=[CH:14][C:15]([NH:41][CH2:42][CH:43]([OH:46])[CH2:44][OH:45])=[O:16])=[CH:22][CH:23]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCCCCN(C(=O)OC(C)(C)C)c1ccc(C=CC(=O)n2ccnc2)cc1
Reactant: NCC(O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCNc1ccc(C=CC(=O)NCC(O)CO)cc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
To a mixture containing 4.3 g. of 1-[N-(t-butyloxycarbonyl)-4-(pentadecylamino)cinnamoyl] imidazole, 50 ml. of chloroform, and 50 ml. of 5 N sodium hydroxide is added 1.1 g. of 3-amino-1,2-propanediol. The solution is vigorously stirred for 24 hours, the layers are separated, and the chloroform solution is washed once with 50 ml. of 1 N sodium hydroxide. The solvent is evaporated and the residue is heated for 30 minutes at 40° C. in 50 ml. of anhydrous trifluoroacetic acid. The solvent is again evaporated and the oil is crystallized from acetone to yield light yellow crystals.
Reaction SMILES: NC1C=CC(SC(=O)N)=CC=1[N+]([O-])=O.[C:15]([S:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]([O:31][CH3:32])=[O:30])=[S:27])=[C:21]([N+:33]([O-])=O)[CH:20]=1)(=[O:17])[NH2:16].NC1C=CC(SC(=O)N)=CC=1N.[CH3:48][O:49][C:50]([N:52]=[C:53]=[S:54])=[O:51]>[Fe].CC(C)=O>[C:15]([S:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]([O:31][CH3:32])=[O:30])=[S:27])=[C:21]([NH:33][C:53]([NH:52][C:50]([O:49][CH3:48])=[O:51])=[S:54])[CH:20]=1)(=[O:17])[NH2:16]
Reactant: COC(=O)N=C=S
Reactant: COC(=O)NC(=S)Nc1ccc(SC(N)=O)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: NC(=O)Sc1ccc(N)c(N)c1
Agent: NC(=O)Sc1ccc(N)c([N+](=O)[O-])c1
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1ccc(SC(N)=O)cc1NC(=S)NC(=O)OC

Procedure:
In a similar manner, substituting 1-amino-4-carbamoylthio-2-nitrobenzene for the 4-carbamoylthio-1-(3-methoxycarbonyl-2-thioureido)-2-nitrobenzene in the iron reduction step, 1,2-diamino-4-carbamoylthiobenzene is prepared. 0.5 G. of this latter compound in 30 ml. acetone is treated overnight with 2 g. methoxy carbonyl isothiocyanate at room temperature. The solution is concentrated and the residue triturated with ether. Recrystallization yields 4-carbamoylthio-1,2-bis-(3-methoxycarbonyl-2-thioureido)-benzene.
Reaction SMILES: [OH:1][C@H:2]([C:26]#[C:27][CH3:28])[CH2:3][C@:4]1([CH3:25])[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([CH3:24])[C:8]([CH3:23])=[C:9]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[CH3:14])[O:5]1.N1C2C(=CC=CC=2)C=CC=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(OCC)(=O)C.CCCCCC>[OH:1][C@H:2](/[CH:26]=[CH:27]\[CH3:28])[CH2:3][C@:4]1([CH3:25])[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([CH3:24])[C:8]([CH3:23])=[C:9]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:10]=2[CH3:14])[O:5]1
Reactant: CC#C[C@@H](O)C[C@]1(C)CCc2c(C)c(OCc3ccccc3)c(C)c(C)c2O1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCCCCC
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: C/C=C\[C@@H](O)C[C@]1(C)CCc2c(C)c(OCc3ccccc3)c(C)c(C)c2O1

Procedure:
2.5 g. of 2(S)-[2(S)-hydroxy-3-pentynyl]-2,5,7,8-tetramethyl-6-benzyloxychroman and 0.25 g. of Lindlar catalyst in 15 ml. of ethyl acetate-hexane (2 = 1 parts by volume) containing 0.1 ml. of quinoline was hydrogenated at 25° C. and atmospheric pressure. The catalyst was filtered off and washed with ethyl acetate. The ethyl acetate solution was washed with 1.0 N aqueous HCl (3 × 50 ml.), dried over MgSO4 and concentrated in vacuo to give 2.508 g. of crude product. Crystallization of this material from pentane yield 2.053 g. of 2(S)-[2(S)-hydroxy-3(Z)-pentenyl]-2,5,7,8-tetramethyl-6-benzyloxychroman as white crystalls, m.p. 84°-86° C. [α]D25 - 30.57° (CHCl3).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)=[CH:8][CH:7]=1.[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][NH2:26])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][NH:26][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)=[CH:8][CH:7]=1)[CH3:22]
Reactant: CCN(CC)CCN
Reactant: CC1(C)OB(c2ccc(OCCCBr)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CC)CCNCCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Yield: 52.6 %

Procedure:
A solution of 2-[4-(3-bromopropoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (500 mL, 2.02 mmol), N1,N1-diethylethane-1,2-diamine (0.87 mL, 6.1 mmol), and potassium carbonate (550 mg, 4.0 mmol) in acetonitrile (15 mL) was heated to 50° C. for 3 h. The reaction mixture was cooled, filtered and the filtrate was concentrated to afford the desired product (400 mg, 53%) as a yellow oil: ESI MS m/z 377 [C21H37BN2O3+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:11][C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:12])[NH:5][C:4]=2[CH:3]=1.[Cl:13][CH2:14][CH2:15][C:16](Cl)=[O:17].[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C>[Cl:13][CH2:14][CH2:15][C:16]([C:3]1[C:4]2[NH:5][C:6](=[O:12])[CH2:7][CH2:8][CH2:9][C:10]=2[S:11][C:2]=1[CH3:1])=[O:17]
Reactant: O=C(Cl)CCCl
Reactant: Cc1cc2c(s1)CCCC(=O)N2
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: Cc1sc2c(c1C(=O)CCCl)NC(=O)CCC2
Reaction time: 3 h
Yield: 74.7 %

Procedure:
To a mixture of 5 g of 2-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepin-5-one and 4.5 g of 3-chloropropionyl chloride in 50 ml of dichloroethane was added 9.2 g of aluminum chloride and the mixture was stirred for 3 hours. The mixture was poured into ice-cold water and extracted with chloroform. The organic layer was washed with saline solution, dried over magnesium sulfate and concentrated. The residue was recrystallized from ethanol to give 5.6 g of 3-(3-chloropropionyl)-2-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepin-5-one as white crystals, m.p. 86°-87° C.
Reaction SMILES: [C:1]([CH:4]([C:12](=O)[CH3:13])[CH:5]([C:9](=[O:11])[CH3:10])[C:6](=O)[CH3:7])(=[O:3])[CH3:2].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:23])[C:17]=1[CH3:24]>>[C:9]([C:5]1[C:4]([C:1](=[O:3])[CH3:2])=[C:12]([CH3:13])[N:15]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:23])[C:17]=2[CH3:24])[C:6]=1[CH3:7])(=[O:11])[CH3:10]
Reactant: Cc1c(N)ccc(O)c1C
Reactant: CC(=O)C(C(C)=O)C(C(C)=O)C(C)=O
Product: CC(=O)c1c(C(C)=O)c(C)n(-c2ccc(O)c(C)c2C)c1C

Procedure:
Utilizing the general procedure outlined in Example 48, 1,1,2,2-tetraacetylethane (300 mg, 1.5 mol) and 4-amino-2.3-xylenol (206 mg, 1.5 mmol) reacted to give 1-[4-acetyl-1-(4-hydroxy-2,3-dimethyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone as yellow solid: MS (ESI) 300 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:15])[C:6]=2[CH:5]=[C:4]([C:16]([OH:18])=[O:17])[CH:3]=1.[C:19](=O)([O-])[O-].[K+].[K+].CN(C)C=O.CI>O>[CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:15])[C:6]=2[CH:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:3]=1
Reactant: Cc1cc(C(=O)O)cc2c1-c1ccccc1C2=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)C(=O)c1ccccc1-2
Reaction time: 0.25 h
Yield: 96.2 %

Procedure:
Under anhydrous calcium chloride drying conditions, 4-methyl-9-oxo-9H-fluorene-2-carboxylic acid (1.745 g), potassium carbonate (3.03 g) and dimethylformamide (20 ml) were mixed. To this mixture was added methyl iodide (0.92 ml) at room temperature, and the mixture was stirred for 3 hr 15 min. To the reaction mixture was added water (60 ml), and the mixture was stirred at room temperature for 30 min. The mixture was filtered and the obtained solid was air-dried and dried under reduced pressure at 80° C. to give the title compound (1.778 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]([O:13][CH3:14])[CH2:9][S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]([OH:17])=O.[CH3:18][C:19]1[C:20]([NH2:24])=[N:21][O:22][N:23]=1.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:1][C:2]1[C:7]2[CH:8]([O:13][CH3:14])[CH2:9][S:10](=[O:11])(=[O:12])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]([NH:24][C:20]1[C:19]([CH3:18])=[N:23][O:22][N:21]=1)=[O:17]
Reactant: Cc1nonc1N
Reactant: COC1CS(=O)(=O)c2ccc(C(=O)O)c(Cl)c21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1CS(=O)(=O)c2ccc(C(=O)Nc3nonc3C)c(Cl)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.00 g (3.14 mmol) of 4-chloro-3-methoxy-2,3-dihydro-1-benzothiophene-5-carboxylic acid 1,1-dioxide and 0.33 g (3.15 mmol) of 4-methyl-1,2,5-oxadiazol-3-yl-amine were dissolved at room temperature (RT) in 35 ml of CH2Cl2, 3.02 g (4.74 mmol) of 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in THF) were added and the mixture was stirred at RT for 1 h. Subsequently, 2.18 ml (15.64 mmol) of triethylamine and 75 mg (0.61 mmol) of 4-dimethylaminopyridine (DMAP) were added and the whole mixture was stirred at RT for 16 h. This was followed by washing with water and twice with 6N hydrochloric acid, drying of the organic phase over Na2SO4 and filtration with suction through silica gel, washing through with 1:2 heptane/ethyl acetate and concentration. Yield 708 mg (63%).
Reaction SMILES: OC[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH3:19])=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].[OH-].[K+].ClC(O)C(O)C.C[O-].[Na+]>CO>[CH3:19][C:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:18][O:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1
Reactant: COC(=O)CCCCC=C(C)CCCCCCCO
Agent: CC(O)C(O)Cl
Agent: C[O-]
Agent: [K+]
Solvent: CO
Product: CC1=CCCCCC(=O)OCCCCCCC1
Yield: 39.2 %

Procedure:
84.5 g (0.31 mol) of methyl 14-hydroxy-7-methyl-tetradec-6-enoate, 21 g of 86 percent potassium hydroxide in 220 ml of methanol, 72 g of chloropropane- 1,2-diol and 9 ml of 5.4M methanolic sodium methylate solution were mixed according to the procedure in Example 6. The product was distilled (b.p. 114° C.) in a high vacuum (0.1 Torr) and subsequently chromatographed. 29 g (38%) of 8-methyloxacyclopentadec-7-en-2-one were obtained having the following characteristics, Z/E=60/40;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].[CH3:16][N:17]([CH3:21])[C:18](Cl)=[S:19].CCCCCCCC.CCCCCC.C(OCC)(=O)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([Br:9])[C:7]=1[O:8][C:18](=[S:19])[N:17]([CH3:21])[CH3:16]
Reactant: CN(C)C(=S)Cl
Reactant: CCOC(=O)Cc1cc(Br)c(O)c(Br)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)Cc1cc(Br)c(OC(=S)N(C)C)c(Br)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 61.7 %

Procedure:
Following the procedure of Newman and Karnes, J. Org. Chem. 31, 3980 (1966), a mixture of ethyl 3,5-dibromo-4-hydroxyphenylacetate (20 g, 0.06 mol), from Preparation B, N,N-dimethylthiocarbamoyl chloride (10.9 g, 0.088 mol), and 1,4-diazabicyclo[2 2.2]octane (Dabco™) (13.4 g, 0.12 mol) in 250 mL DMF was heated, with stirring, at 70° C. for one hour. The reaction mixture was cooled and the precipitate (Dabco-HCl salt) removed by filtration and washed well with ethyl acetate. The filtrate was concentrated on a rotary evaporator and the solid collected by filtration, washed well with water and dried in vacuum to obtain ethyl 3,5-dibromo-4-(N,N-dimethylthiocarbamoyloxy)phenylacetate (16 g, 0.037 mol, 62% yield), MP: 93°-95° C. (hexane/ethyl acetate).
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([CH:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:24]([CH3:26])[CH3:25])[S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:6][CH:5]=1.[Li+].[OH-]>O1CCCC1>[C:30]([O:29][C:27]([CH:23]([N:11]([CH2:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:34])=[O:2])=[CH:9][CH:8]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:24]([CH3:26])[CH3:25])=[O:28])([CH3:32])([CH3:33])[CH3:31]
Reactant: COC(=O)c1ccc(CN(C(C(=O)OC(C)(C)C)C(C)C)S(=O)(=O)c2ccc(OC)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(Cc2ccc(C(=O)O)cc2)C(C(=O)OC(C)(C)C)C(C)C)cc1
Temperature: 60 °C

Procedure:
The diester (Compound 7*) (151 mg, 0.31 mmol) was dissolved in tetrahydrofuran (2 ml) and 4N LiOH (250 μl) was added at ambient temperature. The mixture was heated to 60° C. for 5 hours when HPLC monitoring showed the hydrolysis was completed. The mixture was cooled to ambient temperature and the solvent was evaporated. The residue was dissolved in water and the clear solution extracted with once with diethyl ether. Then the aqueous phase was cooled to 5° C. (ice/water) and neutralised with 1N HCl and after which it was extracted with ethyl acetate (3×5 ml). The combined ethyl acetate phases was extracted with water (5 ml) and brine (5 ml), dried with (Na2SO4), filtered and evaporated to afford the product as white foam. Yield 133 mg (90%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([N:14]=[C:15]([NH2:17])[N:16]=2)[CH:13]=1)([O-:3])=[O:2].[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1.O>CN(C)C(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:18]=[CH:19][CH:20]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([N:14]=[C:15]([NH:17][C:24]([CH:21]3[CH2:23][CH2:22]3)=[O:25])[N:16]=2)[CH:13]=1)([O-:3])=[O:2]
Reactant: Nc1nc2ccc(Oc3cccc([N+](=O)[O-])c3)cn2n1
Reactant: O=C(Cl)C1CC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(Nc1nc2ccc(Oc3cccc([N+](=O)[O-])c3)cn2n1)C1CC1
Yield: 88.2 %

Procedure:
To a solution of 6-(3-nitrophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-amine (3.49 g, 12.9 mmol) in N,N-dimethylacetamide (20 mL) was added with stirring under ice-cooling cyclopropanecarbonyl chloride (2.46 mL, 27.0 mmol), and the mixture was stirred at room temperature for 15 hr. Water (40 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water and dried to give the title compound (3.86 g, 88%) as a white solid.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH2:9][C:10]([C:12]1[CH:22]=[CH:21][C:15]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:14][CH:13]=1)=[O:11])C1C=CC=CC=1.O.Cl.[H][H]>[Pd].CO>[NH2:8][CH2:9][CH:10]([C:12]1[CH:22]=[CH:21][C:15]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:14][CH:13]=1)[OH:11]
Reactant: CS(=O)(=O)Nc1ccc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(C(O)CN)cc1

Procedure:
4'-(2-Dibenzylaminoacetyl)methanesulfonanilide (XXVI) (32.7 g) and Pd/C catalyst (1.5 g) were combined in MeOH (200 ml), H2O (25 ml), and concentrated HCl (6.6 ml) and shaken for 24 hours at 35° C. and 3 atmospheres pressure of hydrogen gas in a Parr hydrogenator, by which time three equivalents of hydrogen had been consumed. The catalyst was filtered off and the filtrate was evaporated to a white solid, which was recrystallized twice from 2-PrOH/H2O. This yielded 4.3 g of Compound (XXV).HCl, m.p. 178°-180°, whose elemental analysis for C, H, and N, NMR, and mass spectra were consistent with the indicated structure.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:23]([C:26]1[CH:27]=[C:28]([O:36][CH3:37])[C:29]([OH:35])=[C:30](B(O)O)[CH:31]=1)[CH:24]=[CH2:25]>>[OH:22][C:15]1[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:14]=1[C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:30]3[CH:31]=[C:26]([CH2:23][CH:24]=[CH2:25])[CH:27]=[C:28]([O:36][CH3:37])[C:29]=3[OH:35])[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: C=CCc1cc(OC)c(O)c(B(O)O)c1
Reactant: COc1ccc(O)c(-c2cccc(-c3cccc(Br)n3)n2)c1
Product: C=CCc1cc(OC)c(O)c(-c2cccc(-c3cccc(-c4cc(OC)ccc4O)n3)n2)c1
Yield: 42 %

Procedure:
6-(2-Hydroxy-5-methoxyphenyl)-6′-(5-allyl-2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine and 5-allyl-2-hydroxy-3-methoxyphenylboronic acid in 42% yield using method F; δH [2H6]-DMSO 13.41,(1H, s), 12.52,(1H, s), 8.38,(1H, d), 8.27,(1H, d), 8.24-8.12,(4H, m), 7.65,(1H, s), 7.52,(1H, s), 6.99,(1H, d), 6.93,(2H, m), 6.05,(1H, m), 5.14,(1h, d), 5.07,(1H, d), 3.83,(6H, s), 3.40,(2H, d).
Reaction SMILES: [CH2:1]([C@H:8]([N:17]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:35][CH:34]=1)[C:18](=[O:31])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)[C:9](=[O:16])[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[CH:50]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH2:1]([C@H:8]([N:17]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[CH:37][CH:38]=1)[C:18](=[O:31])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)[C:9](=[O:16])[N:10]1[CH2:11][CH2:12][N:13]([CH2:50][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][N:44]=2)[CH2:14][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)N2CCNCC2)cc1
Reactant: O=Cc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Product: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccn3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.6 %

Procedure:
N—((S)-1-Benzyl-2-oxo-2-piperazin-1-yl-ethyl)-N-(4-pentyl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide (50 mg, 0.084 mmol) was dissolved in acetonitrile (1 mL) and pyridine-2-carbaldehyde (10 mg, 0.092 mmol) and sodium triacetoxyborohydride (26.7 mg, 0.126 mmol) was added. The mixture was stirred at rt for 16 h, filtered and directly purified by prep. HPLC to give 29 mg of N—[(S)-1-Benzyl-2-oxo-2-(4-pyridin-2-ylmethyl-piperazin-1-yl)-ethyl]-N-(4-pentyl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide. LC-MS: tR=1.02 min; [M+H]+=683.58.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][C:26]=1[C:34]([F:37])([F:36])[F:35]>>[CH3:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][CH2:2][C@H:3]2[N:8]([C:9]([C:11]3[N:12]=[C:13]([CH3:23])[S:14][C:15]=3[C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)=[O:10])[CH2:7][C@H:6]3[C@@H:4]2[CH2:5]3)=[O:30])=[CH:27][C:26]=1[C:34]([F:35])([F:36])[F:37]
Reactant: Cc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2ccc(C)c(C(F)(F)F)c2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 4-Methyl-3-trifluoromethyl-benzoic acid. LC-MS (basic): tR=1.00 min; [M+H]+=514.1.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][S:13]2(=[O:18])=[O:17])[CH:3]=1.[CH2:19]([O:26][CH2:27][C@@H:28]1[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[NH:29]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][CH2:27][C@@H:28]1[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[N:29]1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([N:12]2[CH2:16][CH2:15][CH2:14][S:13]2(=[O:18])=[O:17])[CH:3]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(Br)cc1N1CCCS1(=O)=O
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Product: COC(=O)c1ccc(N2[C@H](COCc3ccccc3)CCS2(=O)=O)cc1N1CCCS1(=O)=O
Yield: 87.1 %

Procedure:
Using methyl 4-bromo-2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoate (334 mg) described in Preparation Example 13 and (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (241 mg) described in Preparation Example 1 and by the reaction and treatment in the same manner as in Preparation Example 12, the title compound (430 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[Cl:14][C:15]1[CH:16]=[C:17]([S:22]([N:25]([CH2:35][P:36](=[O:43])([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[C:26]2[CH:27]=[C:28]3[C:32](=[CH:33][CH:34]=2)[NH:31][CH2:30][CH2:29]3)(=[O:24])=[O:23])[CH:18]=[C:19]([Cl:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>S(Cl)(Cl)=O.ClCCl.CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:31]1[C:32]3[C:28](=[CH:27][C:26]([N:25]([CH2:35][P:36](=[O:43])([O:37][CH2:38][CH3:39])[O:40][CH2:41][CH3:42])[S:22]([C:17]4[CH:16]=[C:15]([Cl:14])[CH:20]=[C:19]([Cl:21])[CH:18]=4)(=[O:24])=[O:23])=[CH:34][CH:33]=3)[CH2:29][CH2:30]1)=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CCOP(=O)(CN(c1ccc2c(c1)CCN2)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOP(=O)(CN(c1ccc2c(c1)CCN2C(=O)c1cc2cc(Cl)ccc2[nH]1)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Temperature: 80 °C
Reaction time: 2 h

Procedure:
50 mg 5-chloro-1H-indole-2-carboxylic acid are dissolved in 2 ml of thionyl chloride and heated to 80° C. for 1 hour. The solvent is eliminated in vacuo and the residue is twice combined with dichloromethane and this is again eliminated in vacuo. The residue is taken up in 5 ml dichloromethane and the solution is added dropwise to a mixture of 100 mg diethyl {[(3,5-dichloro-phenylsulphonyl)-(2,3-dihydro-1H-indol-5-yl)-amino]-methyl}-phosphonate and 60 mg potassium carbonate in 2 ml dimethylformamide. The mixture is stirred for 2 hours at ambient temperature, diluted with ethyl acetate and washed with 1 N HCl and saturated sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo and the residue is chromatographed on silica gel (dichloromethane/methanol 95:5 to 70:30).