Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][C:21]4[N:26]([CH2:27][CH2:28]C#N)[C:25](=[O:31])[CH2:24][O:23][C:22]=4[N:32]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O=C1COC2N=C(C3C=CC(C4(NC(=O)OC(C)(C)C)CCC4)=CC=3)C(C3C=CC=CC=3)=CC=2N1.[F:75]CCI>>[C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][C:21]4[N:26]([CH2:27][CH2:28][F:75])[C:25](=[O:31])[CH2:24][O:23][C:22]=4[N:32]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: FCCI
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCC#N)C(=O)CO4)cc2)CCC1
Agent: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCF)C(=O)CO4)cc2)CCC1

Procedure:
Following the procedure for tert-butyl(1-(4-(1-(2-cyanoethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate, tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (100 mg, 0.212 mmol) was reacted with 1-fluoro-2-iodoethane (111 mg, 0.636 mmol) to afford the title compound (85 mg. 1H NMR (500 MHz, CDCl3): 7.45 (1H, s), 7.24-7.31 (7H, m), 7.17-7.20 (2H, m,), 5.01 (1H, s), 4.94 (2H, s), 4.80 (1H, t), 4.70 (1H, t), 4.27 (1H, t), 4.22 (1H, t), 2.44-2.49 (4H, m), 2.06 (1H, m), 1.86 (1H, m), 1.2-1.43 (9H, br).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][CH:18]([CH2:35][CH2:36][CH3:37])[CH2:19][N:20]1[C:28]2[C:23](=[CH:24][C:25](/[C:29](/[CH3:34])=[CH:30]/[C:31](O)=[O:32])=[CH:26][CH:27]=2)[CH:22]=[CH:21]1>>[CH3:17][CH:18]([CH2:35][CH2:36][CH3:37])[CH2:19][N:20]1[C:28]2[C:23](=[CH:24][C:25](/[C:29](/[CH3:34])=[CH:30]/[C:31]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:32])=[CH:26][CH:27]=2)[CH:22]=[CH:21]1
Reactant: CCCC(C)Cn1ccc2cc(/C(C)=C/C(=O)O)ccc21
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: CCCC(C)Cn1ccc2cc(/C(C)=C/C(=O)Nc3ccccc3OCCCC(=O)O)ccc21

Procedure:
0.56 g of compound 14 was obtained in a similar manner to those described in the Examples 1 and 2 using 1.56 g of ethyl 4-(2-aminophenoxy)butyrate and 1.0 g of 3-[1-(2-methylpentyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([O:18]C)=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].C1COCC1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:15]3[CH:14]=[C:13]([C:16]([OH:18])=[O:17])[NH:12][C:11]=3[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)CCC2c1ccc(Cl)cc1
Yield: 48 %

Procedure:
The title compound was synthesized from methyl 4-(4-chlorophenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.0492 g, 0.18 mmol) and sodium hydroxide (0.45 mL, 10M, 25 equiv), according to General Procedure 7. A 1:4 mixture of THF and methanol (5 mL) was used. The resulting product was purified by preparative HPLC using the Chromeleon purification system. A 0.1% formic acid/1% acetonitrile mixture in water (aqueous phase) and methanol (no modifier added—organic phase) using a 50 mm Dynamax HPLC C-18 column at 28 mL/min (initial gradient of 40% methanol and increasing to 100% over 7 minutes) afforded the title compound (22.6 mg, 48%) with purity by HPLC of 93.6% (UV) and 100% (ELSD). LCMS m/e 260 (M−H). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.23-7.28 (m, 2H), 7.15-7.19 (m, 2H), 6.52 (s, 1H), 4.18 (t, J=7.17 Hz, 1H), 2.70-2.97 (m, 3H), 2.20 (dddd, J=12.75, 8.60, 6.53, 6.41 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[C:29]([Cl:31])[C:28]([O:32][CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[C:27]([Cl:38])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[Cl:38][C:27]1[CH:26]=[C:25]([C:23]2[N:24]=[C:20]([NH:19][C:17](=[O:18])[CH2:16][N:10]3[C:6]4[C:5](=[O:12])[N:4]([CH3:13])[C:3](=[O:14])[N:2]([CH3:1])[C:7]=4[CH:8]=[CH:9]3)[S:21][CH:22]=2)[CH:30]=[C:29]([Cl:31])[C:28]=1[O:32][CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Reactant: CC(C)(C)COc1c(Cl)cc(-c2csc(NC(=O)CBr)n2)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3cc(Cl)c(OCC(C)(C)C)c(Cl)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (50 mg, 0.110 mmol) with 2-bromo-N-{4-[3,5-dichloro-4-(2,2-dimethylpropoxy)phenyl]-1,3-thiazol-2-yl}acetamide (23 mg, 0.128 mmol) in the presence of NaH (7 mg, 0.291 mmol) in dry DMF (5.0 mL) to give 30 mg of the product as an off-white solid; 1H NMR (δ ppm, DMSO-d6, 300 MHz) 1.08 (s, 9H), 3.17 (s, 3H), 3.39 (s, 3H), 3.67 (s, 2H), 5.32 (s, 2H), 6.22 (s, 2H), 7.35 (s, 1H), 7.85 (s, 1H), 8.00 (s, 2H), 12.68 (br s, 1H); APCI-MS (m/z) 550.20 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:12])[CH2:10][NH2:11])=[CH:5][CH:4]=1.[Cl:13][C:14]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][C:15]=1[CH:16]=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.CCOCC>[Cl:13][C:14]1[C:21]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH:11][CH2:10][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:12]
Reactant: COc1ccc(C(C)CN)cc1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: COc1ccc(C(C)CNCc2cccc(C(F)(F)F)c2Cl)cc1
Reaction time: 0.5 h
Yield: 77 %

Procedure:
A solution of 2-(4-methoxyphenyl)propylamine (183 mg, 1.11 mmole) and 2-chloro-3-trifluoromethylbenzaldehyde (230 mg, 1.11 mmole) in 10 mL of MeOH was treated with a crystal of p-toluenesulfonic acid hydrate, and stirred for 30 minutes. The reaction was diluted with Et2O, and washed with aqueous NaHCO3. The extracts were dried, and the solvent removed. A solution of the residue in 10 mL of MeOH was cooled to 0° and treated with excess NaBH4. The reaction was warmed to 23° and stirred for 30 minutes. The reaction was diluted with H2O and extracted with Et2O. The extracts were washed with H2O, dried and the solvent removed, and gave the titled compound, 305 mg (77% yield). MS (ESI) 358 (MH+)
Reaction SMILES: [O:1]1[CH2:4][CH:3]([CH:5]=O)[CH2:2]1.[CH3:7][C:8]([S@@:11]([NH2:13])=[O:12])([CH3:10])[CH3:9]>ClCCl.S([O-])([O-])(=O)=O.[Cu+2]>[O:1]1[CH2:4][CH:3](/[CH:5]=[N:13]/[S@:11]([C:8]([CH3:10])([CH3:9])[CH3:7])=[O:12])[CH2:2]1
Reactant: O=CC1COC1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/C1COC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 29 %

Procedure:
In a round-bottomed flask, oxetane-3-carbaldehyde (452 mg, 3.15 mmol) was dissolved in dichloromethane (18 ml) and (S)-2-methylpropane-2-sulfinamide (435 mg, 3.59 mmol) and anhydrous copper (II) sulfate (1.11 g, 6.93 mmol) were added. The reaction mixture was stirred at room temperature for 48 h then filtered through a glass microfiber filter, rinsing with dichloromethane. The filtrate was concentrated and the residue was chromatographed over silica gel with EtOAc/hexanes (gradient: 0-30% EtOAc) to afford 173 mg (29%) of (S)-2-methyl-propane-2-sulfinic acid 1-oxetan-3-yl-meth-(E)-ylideneamide as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.28 (d, J=4.9 Hz, 1H), 4.74-5.00 (m, 4H), 4.00-4.19 (m, 1H), 1.23 (s, 9H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2=[CH:17][C:18]([F:26])=[C:19]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:12]3=[C:13]2[N:8]([CH:9]([CH3:28])[CH2:10][C:11]3=[O:27])[CH:7]=1)=[O:5])C.[OH-].[Na+].C(O)(=O)C>C(O)C>[F:26][C:18]1[CH:17]=[C:14]2[C:13]3[N:8]([CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15]2=[O:16])[CH:9]([CH3:28])[CH2:10][C:11](=[O:27])[C:12]=3[C:19]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)c1cn2c3c(c(N4CCNCC4)c(F)cc3c1=O)C(=O)CC2C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC1CC(=O)c2c(N3CCNCC3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reaction time: 2 h
Yield: 81 %

Procedure:
3.87 g (0.01 mole) of 9-fluoro-5-methyl-8-(1-piperazinyl)-6,7-dihydro-1,7-dioxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid ethyl ester was suspended in 12 ml of ethanol, 50 ml of a 2N aqueous solution of sodium hydroxide was added thereto, and this mixture was stirred at 20°-25° C. for 2 hours to hydrolyze the starting material. The resulting reaction solution was adjusted to pH 4-5 by the addition of acetic acid under cooling with ice. The precipitate which separated out was collected by filtration and recrystallized from ethanol to obtain 2.91 g (81.0% yield) of 9-fluoro-5-methyl-8-(1-piperazinyl)-6,7-dihydro-1,7-dioxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid in the form of yellow crystals. These crystals had a melting point of 261°-263° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:32]=2)[CH2:27][CH2:26]1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:30]5[CH:29]=[C:28]6[C:33](=[CH:32][CH:31]=5)[N:25]([CH3:24])[CH2:26][CH2:27]6)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CN1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc5c(c4)CCN5C)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.106 mmol) and 1-methylindoline-5-boronic acid pinacol ester (Maybridge, Basel, Switzerland, 34 mg, 0.127 mmol) to give the title compound as a yellow solid. (HPLC: tR 2.52 min (Method A); M+H=425 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.87 (s, 1H), 8.16 (s, 1H), 8.00-7.97 (m, 1H), 7.83-7.81 (m, 1H), 7.41-7.40 (m, 1H), 7.20-7.17 (m, 1H), 7.14-7.13 (m, 1H), 6.57-6.55 (m, 1H), 3.94 (s, 3H), 3.56 (s, 3H), 3.33-3.29 (m, 2H), 2.92 (t, 2H), 2.73 (s, 3H), 1.94 (s, 3H))
Reaction SMILES: [C:1]1([CH2:7][S:8](Cl)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([NH2:20])CCCCCCC>C(Cl)Cl>[C:1]1([CH2:7][S:8]([NH2:20])(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCCCCCCN
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: ClCCl
Product: NS(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.3 %

Procedure:
The synthesis of the sulfonamide containing carboxylic acid precursor corresponding to the autoinducer analog 10 was accomplished by the two step sequence described below. Accordingly, a solution of α-toluenesulfonyl chloride (10 mmol) in CH2Cl2 (5 mL) was added dropwise to a stirred solution of octylamine (20 mmol) in CH2Cl2 (20 mL) at 0° C. The resulting mixture was subsequently stirred at room temperature for 30 min and was then extracted with H2O (3×24 mL) The organic phase was dried (MgSO4) and the solvent was evaporated in vacuo to provide the corresponding α-toluenesulfonamide (262 mg, 93%) as a colorless solid. Subsequent oxidative degration of the phenyl moiety within this compound via the procedure of Sharpless, et. al. [e.g., cat. RuCl3 hydrate, NaIO4, H2O/CH3CN/CCl4 (vide supra)] furnished the α-sulfonamidoacetic acid corresponding to homoserine lactone 10. Accordingly, a mixture of the above α-toluenesulfonamide (1.00 mmol), CCl4 (2 mL), CH3CN (2 mL), H2O (3 mL) and NaIO4 (14.50 mmol) was vigorously stirred at room temperature and RuCl3 hydrate (5 mg) was added. The reaction mixture was vigorously stirred for a further 2 h at room temperature and then CH2Cl2 (10 mL) was added and the phases were separated. The upper aqueous phase was extracted with three portions of CH2Cl2 and the combined organic phases were dried (MgSO4) and the solvents were removed in vacuo. Recrystallization of the residue from EtOH provided the α-sulfonamidoacetic acid (181 mg, 72%) as a colorless solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].OO.S(S([O-])=O)([O-])(=O)=[O:18].[Na+].[Na+]>C(O)(=O)C>[CH3:1][S:2]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13])=[O:18]
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: CSc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CS(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 96 h
Yield: 89 %

Procedure:
4-Methylthio-3-nitrobenzoic acid (4.36 g, 20 mM) was dissolved in acetic acid (200 ml), and treated at ambient temperature with H2O2 (2.5 ml, 30%, 22 mM). After stirring at ambient temperature for 4 days, excess peroxide was decomposed with sodium metabisulfite, and solvent evaporated. The residue was purified by chromatography on silica, eluting with methanol, to give 4-methanesulphinyl-3-nitrobenzoic acid (4.1 g, 89%), mp 238-239°. Nmr (DMSO-d6): δ 2.90 (s, 3H); 8.29 (d, 1H); 8.56 (dd, 1H); 8.68 (d, 1H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:26]([O:28]C(C)(C)C)=[O:27])=[C:15]([CH2:18][S:19][C:20]4[N:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>ClCCl.C1(OC)C=CC=CC=1.O.[Ti](Cl)(Cl)(Cl)Cl>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:26]([OH:28])=[O:27])=[C:15]([CH2:18][S:19][C:20]4[N:25]=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C1=C(CSc2ncccn2)CS[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O
Product: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3ncccn3)CS[C@H]12
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 127.9 %

Procedure:
A stirred solution of tert-butyl (6R,7R)-7-phenylacetamido-3-(pyrimidin-2-yl)thiomethyl-ceph-3-em-4-carboxylate (3.5 g, purity 53%, 3.71 mmol) in dichloromethane (150 ml) and anisole (4.65 ml) was cooled to O° C. A solution of titanium tetrachloride (2.3 ml, 21 mmol) in dichloromethane (10 ml) was added. After stirring for 3.5 h at 0° C., the suspension was mixed with a chilled 2 M solution of hydrochloric acid in water. The organic phase was separated and washed with a 1 M solution of hydrochloric acid in water, water, and brine. The organic phase was dried over magnesium sulphate and concentrated to give 2.10 g of (6R,7R)-7-phenylacetamido-3-(pyrimidin-2-yl)thiomethyl-ceph-3-em-4-carboxylic acid (purity 75%, yield 50.9%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:14]([CH:17]2[CH2:22][N:21]([CH:23]=[O:24])[CH2:20][CH2:19][O:18]2)(=[O:16])=[O:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([S:14]([CH:17]2[CH2:22][N:21]([CH:23]=[O:24])[CH2:20][CH2:19][O:18]2)(=[O:16])=[O:15])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:9]=1
Reactant: O=CN1CCOC(S(=O)(=O)c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)C1
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(C(F)(F)F)cc(S(=O)(=O)C2CN(C=O)CCO2)c1
Reaction time: 72 h

Procedure:
To an argon purged solution of (3-nitro-5-(trifluoromethyl)phenyl)-(sulfonylmorpholino)methanone (658 mg, 1.87 mmol) in EtOH (20 mL) was added Pd/C (198 mg, 0.187 mmol, 10%). The resulting mixture was allowed to stir under an atmosphere of hydrogen gas for 3 days. The reaction was purged with argon, filtered through Celite and concentrated under reduced pressure to afford (3-amino-5-(trifluoromethyl)phenyl)-(sulfonylmorpholino)methanone which was used without further purification. MS m/z=323 [M+H]+. Calc'd for C12H13F3N2O3S: 322.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:7](=[S:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.[N+:35]([C:38]1[CH:45]=[CH:44][C:41]([CH2:42]Br)=[CH:40][CH:39]=1)([O-:37])=[O:36]>COCCO>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:7]([S:10][CH2:42][C:41]2[CH:44]=[CH:45][C:38]([N+:35]([O-:37])=[O:36])=[CH:39][CH:40]=2)=[N:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCCCc1n[nH]c(=S)n1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: COCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1nnc(SCc2ccc([N+](=O)[O-])cc2)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
A mixture of 209 mg (0.6 mmole) of 5-n-butyl-4-[(2'cyanobiphenyl-4-yl)methyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione (from Example 15, Step C), 209 μl (155 mg, 1.2 mmole) of N,N-diisopropylethylamine, 259 mg (1.2 mmole) of 4-nitrobenzyl bromide, and 2 ml of 2-methoxyethanol was stirred under N2 at room temperature for 2 hours. The solution was then concentrated in vacuo at 30° C. to small volume and then partitioned between a mixture of 25 ml of ether, 5 ml of ethyl acetate, and 25 ml of 0.2 N HCl. The organic phase was washed with an additional portion of 0.2 N HCl and then with saturated NaCl solution. The organic solution was dried (MgSO4), filtered, and concentrated. The residue was purified by column chromatography on silica gel (gradient elution with 0-1.6% methanol in CH2Cl2). Concentration of the combined product fractions yielded 252 mg (84%) of the title compound as a sticky foam, homogeneous by TLC in 19:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 484 (M+1)+.
Reaction SMILES: [K].CCSC(N(CC(C)C)CC(C)C)=O.[O:16]1[C:20]2([CH2:25][CH2:24][CH:23]([CH:26]3[CH2:31][CH2:30][CH:29]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=4)[CH2:28][CH2:27]3)[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1.[Cl-].[Na+]>CS(C)=O>[O:16]1[C:20]2([CH2:25][CH2:24][CH:23]([C@H:26]3[CH2:31][CH2:30][C@H:29]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=4)[CH2:28][CH2:27]3)[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1
Reactant: Fc1cccc(C2CCC(C3CCC4(CC3)OCCO4)CC2)c1
Agent: CCSC(=O)N(CC(C)C)CC(C)C
Agent: [Cl-]
Agent: [K]
Solvent: CS(C)=O
Product: Fc1cccc([C@H]2CC[C@H](C3CCC4(CC3)OCCO4)CC2)c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
23.7 g of potassium t.-butylate were added to a solution of 125.3 g of 4-(1,4-dioxaspiro[4,5]dec-8-yl)-1-(3-fluorophenyl)-cyclohexane (cis/trans 50/47) in 630 ml of dimethyl sulphoxide, the mixture was stirred at 100° C. for 2 hrs., cooled and poured into 2500 ml of 5 percent sodium chloride solution. The reaction mixture was extracted with methylene chloride, the organic phase was dried over sodium sulfate, filtered and the filtrate was evaporated. Crystallization of the residue from isopropanol gave 121.9 g of trans-4-(1,4-dioxaspiro[4,5]dec-8-yl)-1-(3-fluorophenyl)cyclohexane as colorless crystals (trans content 99.8%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8]CC=C)[C:5]([O:12][CH3:13])=[CH:4][N:3]=1.N1CCOCC1>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([O:12][CH3:13])=[CH:4][N:3]=1
Reactant: C=CCOc1nc(Cl)ncc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1COCCN1
Product: COc1cnc(Cl)[nH]c1=O
Yield: 68.2 %

Procedure:
To a solution of 2-chloro-5-methoxy-4-(prop-2-en-1-yloxy)pyrimidine (95.0 g, 475 mmol) in anhydrous DCM (2 L) under nitrogen atmosphere was added morpholine (124 mL, 1.425 moL) and then Pd(Ph3P)4 (13.7 g, 11.9 mmol) and the reaction mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated until thick, then poured into EtOAc. The precipitate was collected and dried to give 52 g of a mixture of 2-chloro-5-methoxypyrimidin-4(3H)-one and morpholine (1:1). 1H-NMR (CDC3, 400 MHz) δ 7.45 (s, 1H), 3.67 (s, 3H). MS (ESI) m/z (M+H)+ 161.0.
Reaction SMILES: [H-].[Na+].[CH:3]([N:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][OH:14])[CH2:8][CH2:7]1)([CH3:5])[CH3:4].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[CH:17]=1.[Cl-].[Na+]>COCCOCCOC.CCCCCC.CCOCC.C1COCC1.O>[CH:3]([N:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][O:14][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH2:22])[CH:17]=2)[CH2:10][CH2:11]1)([CH3:5])[CH3:4]
Reactant: CC(C)N1CCN(CCO)CC1
Reactant: Nc1cc(Cl)ccn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)N1CCN(CCOc2ccnc(N)c2)CC1
Temperature: 40 °C
Yield: 41.5 %

Procedure:
Sodium hydride (60% in mineral oil; 21.00 g; 525 mmol) was added to a 4-neck (2 L) flask under nitrogen with mechanical stirrer, condenser, thermocouple and addition funnel attached. Dry diglyme (450 mL) was added. A solution of 2-(4-isopropylpiperazin-1-yl)ethanol (90.45 g; 525 mmol) in diglyme (150 mL) was added slowly with stirring. The temperature was slowly increased to 40° C. until effervescence had ceased. The mixture was allowed to cool and 4-chloropyridin-2-amine (45.00 g; 350 mmol) was added. The mixture was heated at 157° C. for 16 hours and allowed to cool. Water (300 mL) was added followed by THF (750 mL). Sodium chloride was added (sufficient to saturate the aqueous phase). The phases were separated and the aqueous phase was further extracted with THF (3×600 mL). The combined organic phases were dried with sodium sulfate (600 g) for 16 hours and then filtered. The solvent was removed under vacuum (8 mm Hg, bath temperature at 60° C., to remove the diglyme). The residue was dissolved in THF (1000 mL) and filtered (Celite) to remove some fine particulates. The solvent was removed under vacuum to give a pale brown oil. The material was placed under high vacuum. A solid slowly formed (about 130 g). Ether (200 mL) was added and the material was physically broken up. Hexane (about 200 mL) was added, and the resulting solids were mechanically stirred to break them up. The solids were collected by filtration and washed (hexane/ether 1:1). The material was dried under vacuum to give the desired product (38.4 g) as a cream colored solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[CH2:10][C:11](=[O:24])[CH2:12][O:13][C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][N:27]([CH:29]=O)[CH3:28]>O>[CH2:1]([O:8][C:9](=[O:25])[C:10]([C:11](=[O:24])[CH2:12][O:13][C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2)=[CH:26][N:27]([CH3:29])[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(COC12CC3CC(CC(C3)C1)C2)CC(=O)OCc1ccccc1
Reactant: CN(C)C=O
Solvent: O
Product: CN(C)C=C(C(=O)COC12CC3CC(CC(C3)C1)C2)C(=O)OCc1ccccc1

Procedure:
A solution of 4-(adamantan-1-yloxy)-3-oxo-butyric acid benzyl ester (1.133 g, 3.3 mmol) and DMF dimethylacetal (0.56 mL, 3.96 mmol) in DMF (20 mL) was heated at 100° C. for 3 h. The mixture was diluted with H2O (80 mL) and extracted with EtOAc (2×30 mL). The combined extracts were washed with brine (2×30 mL), and dried (MgSO4). Filtration and evaporation of the solvent afforded the product, (0.647 g, 49%).