Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:4][CH:3]=1.Cl.Cl.[CH2:23]([O:25][C:26]([C@H:28]1[C@H:33]([N:34]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:35])[CH2:32][CH2:31][NH:30][CH2:29]1)=[O:27])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:23]([O:25][C:26]([C@H:28]1[C@H:33]([N:34]([CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH3:35])[CH2:32][CH2:31][N:30]([CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:29]1)=[O:27])[CH3:24]
Reactant: CCOC(=O)[C@@H]1CNCC[C@H]1N(C)Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(F)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)[C@@H]1CN(CCc2ccc(F)cc2)CC[C@H]1N(C)Cc1ccccc1
Yield: 65.3 %

Procedure:
A solution of toluene-4-sulfonic acid 2-(4-fluorophenyl)-ethyl ester (containing 10% by weight of 2-(4-fluorophenyl)ethanol; 206 mg, 630 μmol), trans-4-(benzyl-methyl-amino)-piperidine-3-carboxylic acid ethyl ester dihydrochloride (220 mg, 630 μmol) and potassium carbonate (261 mg, 1.9 mmol) in acetonitrile (6 mL) was heated at reflux for 17 hours. The mixture was cooled and filtered, the solid was washed with acetonitrile, and the filtrate was concentrated under vacuum. The residue was purified by flash chromatography, eluting with 20%, then 30% ethyl acetate in hexane, to provide an oil (164 mg, 65%). 1H NMR (300 MHz, CDCl3) δ7.28 (m, 5H), 7.16 (m, 2H), 6.98 (t, J=9 Hz, 2H), 4.20 (m, 2H), 3.75 (d, J=13 Hz, 1H), 3.48 (d, J=13 Hz, 1H), 3.14 (m, 2H), 2.88 (m, 2H), 2.80 (m, 2H), 2.62 (m, 2H), 2.29 (m, 1H), 2.20 (s, 3H), 1.87 (m, 1H), 1.70 (m, 2H), 1.28 (t, J=7 Hz, 3H).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([CH:24]=O)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1>>[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([CH:24]=[C:8]3[C:7]4[C:11](=[CH:12][CH:13]=[C:5]([S:2]([NH2:1])(=[O:4])=[O:3])[CH:6]=4)[NH:10][C:9]3=[O:14])=[CH:21][CH:22]=2)[CH:17]=[CH:16]1
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1ccc2[nH]ccc2c1
Product: NS(=O)(=O)c1ccc2c(c1)C(=Cc1ccc3[nH]ccc3c1)C(=O)N2

Procedure:
5-Aminosulfonyl-2-oxindole was condensed with indole-5-carbaldehyde to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:11][N:12]([CH:14]3[CH2:16][CH2:15]3)[CH:13]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([CH3:32])[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=1>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:23][C:24]2[CH:25]=[C:26]([CH3:32])[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=2)[C:9]2[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:11][N:12]([CH:14]3[CH2:16][CH2:15]3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(N)cn(C)c1=O
Reactant: CCOC(=O)c1nn(C2CC2)cc1C(O)c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(C2CC2)cc1C(Nc1cc(C)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-cyclopropyl-1H-pyrazole-3-carboxylate (Step 37.3) and 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2). tR: 4.31 min (HPLC 1); tR: 1.00 min (LC-MS 2); ESI-MS: 441 [M+H]+ (LC-MS 2); Rf=0.06 (EtOAc).
Reaction SMILES: [C:1]1([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][C:20]1[N:25]=[C:24](Cl)[C:23]([C:27]#[N:28])=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CC(O)C.CO>[NH2:19][C:20]1[N:25]=[C:24]([NH:18][CH:16]([C:8]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)[CH3:17])[C:23]([C:27]#[N:28])=[CH:22][N:21]=1
Reactant: N#Cc1cnc(N)nc1Cl
Reactant: CC(N)c1nc2cccnc2n1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: CO
Product: CC(Nc1nc(N)ncc1C#N)c1nc2cccnc2n1-c1ccccc1
Temperature: 90 °C
Yield: 45.5 %

Procedure:
A mixture of 1-(3-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)ethylamine (68 mg, 0.29 mmol), 2-amino-4-chloropyrimidine-5-carbonitrile (44 mg, 0.29 mmol) and DIPEA (147 μL, 0.86 mmol) in IPA (1 mL) was heated at 90° C. in a sealed vial for 18 h. After cooling to RT, the reaction mixture was diluted with MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 50-100% EtOAc in cyclohexane) followed by trituration from EtOAc to afford 365 as an off-white solid (47 mg, 46%). LCMS (Method K): RT 2.58 min [M+H]+ 357.09. 1H NMR (DMSO-d6, 400 MHz): δ 8.25 (1H, dd, J=4.76, 1.48 Hz), 8.14 (1H, dd, J=7.98, 1.47 Hz), 8.09 (1H, s), 7.72 (1H, d, J=7.41 Hz), 7.55-7.43 (5H, m), 7.32 (1H, dd, J=7.99, 4.77 Hz), 7.16-6.68 (2H, m), 5.55 (1H, m), 1.49 (3H, d, J=6.81 Hz)
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24]/[CH:25]=[CH:26]\[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=1[O:38][CH3:39]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24]/[CH:25]=[CH:26]\[CH2:27][O:28][C:29]4[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=4[O:38][CH3:39])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(C)=O)ccc1OC/C=C\CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(C)=O)ccc1OC/C=C\CN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 65.4 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.2 g, 10 mmol), K2CO3 (1.8 g, 13 mmol) and (Z)-1-[4-[(4-chloro-2-butenyl)oxy]-3-methoxyphenyl]ethanone (3.43 g, 9.7 mmol) in acetonitrile (100 ml) was heated at reflux for 11/2 hours. At the end of the reaction, the solvent was removed and the inorganics were filtered after addition of dichloromethane (250 ml). The dichloromethane solvent was removed again. The crude oil was purified on two flash chromatography columns to give a colorless oil (2.78 g). The oil was solidified by vigorously drying on a vacuum pump. Recrystallization from ethanol (10 ml) and hexane (2 ml) gave analytically pure (Z)-[4-[4-[[4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-butenyl]oxy]-3-methoxy-phenyl]ethanone, 1.83 g,m.p.=57°-59° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.Cl.[N:8]1([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][O:26][C:27]4[CH:31]=[CH:30][O:29][N:28]=4)[O:22][C:21]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([N:11]1[CH2:10][CH2:9][N:8]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][O:26][C:27]4[CH:31]=[CH:30][O:29][N:28]=4)[O:22][C:21]3=[O:32])=[CH:16][C:15]=2[F:33])[CH2:13][CH2:12]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCNCC2)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Yield: 88.9 %

Procedure:
Chloroacetyl chloride (114 mg, 1 mmol) was added to a stirred solution of 3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one dihydrochloride (435 mg, 1 mmol) and triethylamine (302 mg, 3 mmol) in dichloromethane (10 ml) at ambient temperature. After 10 minutes the reaction was purified by direct chromatography on a 10 g silica Mega Bond Elut® column, eluting with dichloromethane. Relevant fractions were combined and evaporated to give the desired product (390 mg). MS (ESP): 439 (MH+) for C19H20ClFN4O5;
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:39])[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]2[O:38][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[C:32](=[O:33])[C:31]([O:34][CH3:35])=[CH:30][C:29](=[O:36])[C:28]=2[OH:37])=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1.Cl(O)(=O)(=O)=[O:41].C(OCC)C>O1CCCC1>[CH3:35][O:34][C:31]1[C:32](=[O:33])[C:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH:19]([OH:41])[CH:18]([OH:38])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:5]2[C:4](=[O:39])[C:3]([O:2][CH3:1])=[CH:8][C:7](=[O:9])[C:6]=2[OH:10])=[C:28]([OH:37])[C:29](=[O:36])[CH:30]=1
Reactant: COC1=CC(=O)C(O)=C(CCCCCCCC2OC2CCCCCCCC2=C(O)C(=O)C=C(OC)C2=O)C1=O
Reactant: [O-][Cl+3]([O-])([O-])O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC1=CC(=O)C(O)=C(CCCCCCCC(O)C(O)CCCCCCCC2=C(O)C(=O)C=C(OC)C2=O)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
37 Milligrams of 1,16-bis(5-methoxy-2-hydroxy-1,4-benzoquinon-3-yl)-8,9-epoxyhexadecane was dissolved in 2 ml of tetrahydrofuran, to this solution was added 0.5 ml of 5% perchloric acid aqueous solution and the mixture was stirred at room temperature for 4 hours. Then, 30 ml of diethyl ether was added to the reaction mixture, and the organic layer was washed with a saturated sodium chloride aqueous solution in several times, and dried over anhydrous sodium sulfate. This extract was purified by means of a preparative thin layer chromatography [adsorbent: "Silica gel 60 F254 " manufactured by E. Merck A. G., developing solvent: chloroform-methanol (85:15 mixture by volume/volume)], then recrystallized from ethyl acetate-n-hexane to obtain 12 mg of 1,16-bis(5-methoxy-2-hydroxy-1,4-benzoquinon-3-yl)-8,9-dihydroxyhexadecane. Yellow powdery crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:19]=2)[NH:16][C:15]([C:27]([NH2:29])=O)=[CH:14]3)=[CH:6][CH:5]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1.C(OCC)(=O)C.CCCCCC>O1CCCC1>[CH3:1][O:2][CH2:3][C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[C:18]([O:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:19]=2)[NH:16][C:15]([C:27](=[S:39])[NH2:29])=[CH:14]3)=[CH:6][CH:5]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COCc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(N)=O)cc3c2)cn1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COCc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(N)=S)cc3c2)cn1
Yield: 99.4 %

Procedure:
To a solution of 5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indole-2-carboxamide (1.45 g) in tetrahydrofuran (20 mL) was added a Lawesson's reagent (1.6 g), and the mixture was stirred with heating under reflux for 1 hr. The reaction mixture was cooled, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio) to give the title compound (1.5 g, yield 99%) as a yellow amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:16])[C:5]([O:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH2:17]([O:19][C:20]([C:22]1([NH2:31])[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)=[O:21])[CH3:18].CCN(C(C)C)C(C)C.CC(O)C.C(Cl)Cl>C(Cl)Cl>[CH2:17]([O:19][C:20]([C:22]1([NH:31][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]([CH3:16])[C:5]=2[O:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)=[O:21])[CH3:18]
Reactant: Cc1cc(Br)cc(C(=O)O)c1OC1CCC1
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Solvent: ClCCl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cc(Br)cc(C)c2OC2CCC2)Cc2ccccc2C1
Reaction time: 0.08 h

Procedure:
A 100 mL round bottom flask which contains a stirring bar is charged with 2-cyclobutoxyl-3-methyl-5-bromo-benzoic acid 317 (695 mg, 2.44 mmol) and dry DCM (8 mL). Stirring is initiated. After dissolution is complete, HTBU (924 mg, 2.44 mmol) is added. After 5 min, 2-amino-indane-2-carboxylic acid ethyl ester (500 mg, 2.44 mmol) is added followed by DIPEA (1.1 mL, 6.1 mmol). The reaction is allowed to stir for 15 days. Analysis by tlc of the reaction mixture (silica, 5% iPrOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are transferred to a separatory funnel and diluted with EtOAc (50 mL). The organic phase is washed consecutively with dilute aqueous HCl (3%, 25 mL), saturated aqueous NaHCO3 (25 mL) and brine (25 mL), and then dried over MgSO4, filtered and evaporated in vacuo to give 1.42 g of light orange solid. This solid is dissolved in 10 mL of DCM. This material is purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 10% EtOAc in heptanes over 3 column volumes followed by a linear gradient to 60% EtOAc in heptanes over 10 column volumes. 17 mL fractions of UV active eluent are collected. Fractions 4 through 9 are combined and evaporated in vacuo. This yields white solid material (0.8 g, 70%).
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.[CH3:31][N:32]([CH2:34][CH3:35])[CH3:33].Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:31][N:32]([CH3:33])[CH2:34][CH2:35][O:28][C:25]1[CH:24]=[CH:23][C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][C:5]3[N:4]([CH2:3][C:2]([CH3:30])([CH3:29])[CH3:1])[C:8]4[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=4[CH:6]=3)[CH2:21][CH2:20]2)=[CH:27][CH:26]=1
Reactant: CCN(C)C
Reactant: CC(C)(C)Cn1c(CN2CCN(c3ccc(O)cc3)CC2)cc2cnc(C#N)nc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CN(C)CCOc1ccc(N2CCN(Cc3cc4cnc(C#N)nc4n3CC(C)(C)C)CC2)cc1

Procedure:
0.24 g 7-(2,2-dimethyl-propyl)-6-[4-(4-hydroxy-phenyl)-piperazin-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile and 0.128 g dimethylaminoethane.HCl were stirred in 2 ml of acetone in the presence of 0.41 g of potassium carbonate. After 18 hours the mixture was extracted with ethyl acetate/water, dried over Magnesium sulfate and evaporated. The residue was chromatographed on silicagel using CH2Cl2/MeOH yielding 6-{4-[4-(2-dimethylamino-ethoxy)-phenyl]-piperazin-1-ylmethyl}-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile as colorless wax.
Reaction SMILES: [C:1]([C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[O:24][CH3:25])(C)[C:4]([O:6]CC)=[O:5])#N.Cl>C(O)(=O)C>[CH3:25][O:24][C:11]1[C:12]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:13][CH:14]=[CH:15][C:10]=1[CH:3]([CH3:1])[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)C(C)(C#N)c1cccc(Oc2ccccc2Cl)c1OC
Agent: Cl
Solvent: CC(=O)O
Product: COc1c(Oc2ccccc2Cl)cccc1C(C)C(=O)O
Yield: 54.6 %

Procedure:
A mixture of ethyl 2-cyano-2-[2-methoxy-3-(2-chlorophenoxy)phenyl]propionate (5.8 g), conc. hydrochloric acid (20 ml) and acetic acid (40 ml) was refluxed under heating for 26 hours. After cooling, the reaction mixture was evaporated, and water was added to the residue. The mixture was evaporated again, and the oily residue was dissolved in saturated aqueous sodium bicarbonate under warming. After cooling, the aqueous solution was washed with diethyl ether, acidified with conc. hydrochloric acid and extracted with diethyl ether. The extract was washed with water, dried and then evaporated to give oily 2-[2-methoxy-3-(2-chlorophenoxy)phenyl]propionic acid (2.7 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[C:8]([F:10])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([F:16])[CH:5]=1.[C:17]([C:21]1[N:26]=[CH:25][C:24]([CH:27]=[CH:28][C:29](O)=[O:30])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[N:26]=[CH:25][C:24]([CH:27]=[CH:28][C:29]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]([F:16])[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:8]([F:10])[CH:9]=2)=[O:30])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(C=CC(=O)O)cn1
Reactant: CS(=O)(=O)Nc1c(F)cc(CN)cc1F
Agent: Cl
Product: CC(C)(C)c1ccc(C=CC(=O)NCc2cc(F)c(NS(C)(=O)=O)c(F)c2)cn1
Yield: 78.7 %

Procedure:
N-(4-Aminomethyl-2,6-difluoro-phenyl)-methanesulfonamide HCl salt (50 mg, 0.18 mmol) was reacted with 3-(6-tert-butyl-pyridin-3-yl)-acrylic acid (37 mg) to give the title compound (60 mg, 79%) after purification by column chromatography (Hex/EtOAc=1/2).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].[CH2:9]=[C:10]1[O:14][C:12](=[O:13])[CH2:11]1>O1CCCC1>[OH:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][N:1]1[C:12](=[O:13])[CH2:11][C:10](=[O:14])[CH3:9]
Reactant: OCC1CCCCN1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N1CCCCC1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of 25 g (0.22 mol) 2-piperidinemethanol in 200 ml tetrahydrofuran was added dropwise to a solution of 18 g of diketene (0.2 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue purified by column chromatography. This gave 32.40 g (0.17 mol, 76% yield) of a colorless oil.
Reaction SMILES: [CH3:1][CH:2]([CH2:23][CH3:24])[CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20].[H][H]>[Pt]=O.C(O)(=O)C>[CH3:1][CH:2]([CH2:23][CH3:24])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: CCC(C)C=CCCCCCCCCCCCCCCC(=O)OC
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCC(C)CCCCCCCCCCCCCCCCC(=O)OC
Yield: 56.3 %

Procedure:
5.3 gm of methyl 18-methyl-16-eicosenoate charged into an autoclave together with 0.3 gm of platinum oxide and 30 ml of acetic acid were reduced under 100 atm hydrogen pressure at 100° C. for 5 hours. After the reaction, the catalyst was removed by filtration and the solvent was evaporated to obtain 3 gm of methyl 18-methyleicosanoate, which was purified by flash column chromatography (chloroform). The product was dissolved into 150 ml of a 5% sodium hydroxide-ethanol solution and stirred at room temperature for 8 hours. Then, 95 ml of 2N sulfuric acid was added to obtain a solid. The solid material was filtered and washed with water to obtain 3.1 gm of 18-methyleicosanoic acid (yield: 59% from methyl 18-methyl-16-eicosenoate).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[O:22]1[CH2:24][CH:23]1[CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[OH:22][CH:23]([CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[CH2:24][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: C1CN(CC2CO2)CCO1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CC(O)CN3CCOCC3)CC1)O2

Procedure:
Compound 166 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 4-(oxiran-2-ylmethyl)morpholine and conditions outlined in procedure X. M.P.=75-78° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 3.9 (m, 1H), 3.7 (m, 5H), 2.95 (s, 1H), 2.9 (t, 2H), 2.7-2.3 (m, 11H), 2.15 (d, 2H), 1.9 (q, 2H); LCMS: 445 [M+H].
Reaction SMILES: FC1C=CC(C2C=NC(N3CCN(S(C[C@H](C(C)C)C(O)=O)(=O)=[O:21])CC3)=NC=2)=CC=1.C([C@@H]1COC(=O)N1[C:44](=[O:73])[CH:45]([CH2:49][S:50]([N:53]1[CH2:58][CH2:57][CH:56]([O:59][C:60]2[CH:65]=[CH:64][C:63]([C:66]3[CH:71]=[CH:70][C:69]([F:72])=[CH:68][CH:67]=3)=[CH:62][N:61]=2)[CH2:55][CH2:54]1)(=[O:52])=[O:51])[CH:46]([CH3:48])[CH3:47])C1C=CC=CC=1>>[F:72][C:69]1[CH:68]=[CH:67][C:66]([C:63]2[CH:64]=[CH:65][C:60]([O:59][CH:56]3[CH2:57][CH2:58][N:53]([S:50]([CH2:49][C@H:45]([CH:46]([CH3:47])[CH3:48])[C:44]([OH:73])=[O:21])(=[O:51])=[O:52])[CH2:54][CH2:55]3)=[N:61][CH:62]=2)=[CH:71][CH:70]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)O
Reactant: CC(C)C(CS(=O)(=O)N1CCC(Oc2ccc(-c3ccc(F)cc3)cn2)CC1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Product: CC(C)[C@@H](CS(=O)(=O)N1CCC(Oc2ccc(-c3ccc(F)cc3)cn2)CC1)C(=O)O
Yield: 47 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methylbutyric acid, from 4-(R)-benzyl-3-(2-{4-[5-(4-fluorophenyl)pyridin-2-yloxy]piperidine-1-sulfonyl methyl}-3-methyl-butyryl)oxazolidin-2-one (0.70 g) to yield the title compound as a cream solid (0.24 g, 47%).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[C:8]3[C:13]([NH:14][C:15](=[O:16])[C:6]2=[N:5][CH:4]=[C:3]1[C:17]([OH:19])=O)=[CH:12][CH:11]=[CH:10][CH:9]=3.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:33][NH2:34]>CN(C)C=O>[O:1]=[C:2]1[N:7]2[C:8]3[C:13]([NH:14][C:15](=[O:16])[C:6]2=[N:5][CH:4]=[C:3]1[C:17]([NH:33][NH2:34])=[O:19])=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: O=C(O)c1cnc2c(=O)[nH]c3ccccc3n2c1=O
Reactant: NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: NNC(=O)c1cnc2c(=O)[nH]c3ccccc3n2c1=O
Yield: 95 %

Procedure:
A mixture of 500 mg of 1,5-dioxo-1,6-dihydropyrimido[1,2-a]-quinoxalin-2-carboxylic acid and 400 mg of carbonyldiimidazole in 20 ml of dimethylformamide was warmed over a steam bath for 15 minutes and then was cooled in an ice-bath and treated with 1.0 ml of a solution in dimethylformamide containing 1.1 g/10 ml of hydrazine hydrate overnight. The resultant mixture was filtered to obtain 500 mg (95% yield) of 1,5-dioxo-1,6-dihydropyrimido[1,2-a]quinoxaline-2-carbohydrazide melting at >300° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)(=[O:21])=[O:20])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:28][CH:29]1[CH2:34][CH2:33][N:32]([CH:35]([CH3:37])[CH3:36])[CH2:31][CH2:30]1.[Cl:38][C:39]1[CH:44]=[C:43](B(O)O)[CH:42]=[CH:41][N:40]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:14][CH2:15][N:16]([S:19]([N:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)(=[O:21])=[O:20])[CH2:17][CH2:18]3)=[O:12])[N:8]2[C:43]2[CH:42]=[CH:41][N:40]=[C:39]([Cl:38])[CH:44]=2)=[CH:4][C:3]=1[O:28][CH:29]1[CH2:30][CH2:31][N:32]([CH:35]([CH3:37])[CH3:36])[CH2:33][CH2:34]1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(S(=O)(=O)N5CCCCC5)CC4)[nH]c3cc2Br)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(S(=O)(=O)N5CCCCC5)CC4)n(-c4ccnc(Cl)c4)c3cc2Br)CC1
Temperature: 35 °C
Reaction time: 18 h
Yield: 47.5 %

Procedure:
A suspension of 0.15 g (0.25 mmol) [6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-[4-(piperidine-1-sulfonyl)-piperazin-1-yl]-methanone (example 1), 119 mg (0.76 mmol) 2-chloropyridine-4-boronic acid, 91 mg (0.50 mmol) copper(II) acetate and 80 μL (78 mg, 1.0 mmol) pyridine in 4 ml chloroform was stirred 18 h at 35° C. The volatile components were evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel with a gradient of dichloromethane:methanol (100:0 to 50:50 v/v) as eluant to afford 84 mg (47%) of the title compound as a light-yellow solid.
Reaction SMILES: CO[C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[C:14]([F:16])[F:15].[CH3:18][Si:19]([CH3:28])([CH3:27])[C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[CH3:18][Si:19]([CH3:28])([CH3:27])[C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:3](=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[C:14]([F:15])[F:16])=[CH:22][CH:21]=1
Reactant: C[Si](C)(C)c1ccc(N)cc1
Reactant: COC(=O)CCCCCCCCCC=C(F)F
Solvent: Cc1ccccc1
Product: C[Si](C)(C)c1ccc(NC(=O)CCCCCCCCCC=C(F)F)cc1
Reaction time: 2 h

Procedure:
2.5 g of 12,12-difluorododec-11-enoic acid methyl ester are added at room temperature to 1.53 g of 4-trimethylsilylaniline in 25 ml of toluene. The mixture is stirred for 2 hours at 80° and then concentrated by evaporation in vacuo. The residue is taken up in toluene, the toluene phase is washed with water, dried over sodium sulfate and concentrated to dryness by evaporation. The residue is taken up in hexane:ethyl acetate (9:1) and filtered over silica gel. Evaporation of the filtrate yields the title compound (nD24 =1.5038; compound no. 1-2).