Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[CH3:14][CH:15]([CH3:17])[O-:16].[Na+].[Na]>C(O)(C)C>[CH:15]([O:16][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1)([CH3:17])[CH3:14]
Reactant: Clc1ccc(N2CCNCC2)nn1
Reactant: CC(C)[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(C)O
Product: CC(C)Oc1ccc(N2CCNCC2)nn1

Procedure:
3-Chloro-6-piperazinopyridazine (4.0 g) (J. Med. Chem., 5, 541 (1963)) and sodium isopropoxide, prepared by addition of sodium (0.7 g) to dry isopropanol (70 ml), were heated in a bomb at 130°-140° C. for 10 hours. The solvent was evaporated in vacuo, the residue taken up in methylene chloride (300 ml) and the resulting solution washed with water (2×50 ml). The organic extract was dried (Na2SO4) and evaporated in vacuo to give 3-isopropoxy-6-piperazinopyridazine (3.3 g). A sample in ethyl acetate, was converted to the maleate salt by treatment with maleic acid in ethyl acetate. The resulting solid was re-crystallized from ethanol, m.p. 144°-145° C.
Reaction SMILES: [NH2:1][C:2]([CH2:9][CH3:10])([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3][OH:4].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:1][C@:2]([CH2:9][CH3:10])([CH2:5][CH2:6][CH2:7][CH3:8])[CH2:3][OH:4]
Reactant: CCCCC(N)(CC)CO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[C@](N)(CC)CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
The product from step (e) (20 g) was added to a 1M solution of lithium aluminium hydride (1.5 molar equivalents) in THF and the mixture reflexed for 3 hours, then stirred for 16 hours at room temperature. The mixture was cooled to about 0° C., then quenched with water and 1N aqu. NaOH added. The resulting solid was broken up with additional water and the suspension heated at 50° C. for 5 minutes, then cooled to room temperature, diethyl ether (100 ml) added and filtered. The filtrate was evaporated in vacuo to give the desired product as an oil (82% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:37])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH:17][CH:16]2[C:34]([OH:36])=O)[CH:12]=[CH:13][CH:14]=1.CC1(C)[O:43][C@H:42]([CH2:44][CH2:45][NH2:46])[CH2:41][O:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O1CCCC1>[OH:43][C@@H:42]([CH2:41][OH:40])[CH2:44][CH2:45][NH:46][C:34]([CH:16]1[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=2[F:37])[C:19]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)([C:20]#[N:21])[CH:18]([CH2:29][C:30]([CH3:33])([CH3:31])[CH3:32])[NH:17]1)=[O:36]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Reactant: CC1(C)OC[C@@H](CCN)O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCC[C@@H](O)CO)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1
Yield: 51.8 %

Procedure:
In a manner similar to the method described in Example 72a, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid (0.2 g, 0.36 mmol) was reacted with 2-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.15 g, 1.07 mmol), HATU (0.24 g, 0.64 mmol) and iPr2NEt (0.31 g, 1.78 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid ((R)-3,4-dihydroxy-butyl)-amide as a white solid (0.1 g, 54%).
Reaction SMILES: S1C2=CC=CC(O)=C2C=N1.C[O:12][C:13]1[C:21]2[S:20][N:19]=[CH:18][C:17]=2[CH:16]=[CH:15][CH:14]=1.Cl.N1C=CC=CC=1>>[S:20]1[C:21]2[C:13]([OH:12])=[CH:14][CH:15]=[CH:16][C:17]=2[CH:18]=[N:19]1
Reactant: COc1cccc2cnsc12
Agent: Cl
Agent: Oc1cccc2sncc12
Solvent: c1ccncc1
Product: Oc1cccc2cnsc12
Yield: 47.4 %

Procedure:
A method similar to that used in the preparation of benzo[d]isothiazol-4-ol using 7-methoxy-benzo[d]isothiazole (60 mg, 0.363 mmol) and pyridine hydrochloride (500 mg, 4.33 mmol) gave the title compound (26 mg, 47%); Mass spectrum (ion-spray): m/z=151.9 (m+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])/[C:5]/2=[C:13]1\[CH:14]=[C:15]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=2)[C:16]([CH3:19])([CH3:18])[O:17]\1.[CH3:29][NH:30][CH2:31][CH:32]([OH:35])[CH2:33][OH:34].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])/[C:5]/2=[C:13]1\[CH:14]=[C:15]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([N:30]([CH2:31][CH:32]([OH:35])[CH2:33][OH:34])[CH3:29])=[O:26])=[CH:27][CH:28]=2)[C:16]([CH3:19])([CH3:18])[O:17]\1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)c(F)cc32)C=C1c1ccc(C(=O)O)cc1
Reactant: CNCC(O)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CC(O)CO)C(=O)c1ccc(C2=C/C(=C3\C(=O)Nc4cc(F)c(F)cc43)OC2(C)C)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]benzoic acid (50 mg, 0.13 mmol), 3-methylamino-1,2-propanediol (40 mg, 0.38 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 61 mg, 0.16 mmol) and diisopropylethylamine (37 mg, 0.29 mmol) in 6 mL of anhydrous DMF was stirred at room temperature for 10 minutes. The mixture was poured into 100 mL of water. The precipitates were filtered, washed with water, and dried in vacuum to give 4-[(5E)-5-(5,6-difluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]-N-(2,3-dihydroxypropyl)-N-methylbenzamide as yellow solid. Yield: 47 mg, 81%.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:13]=[C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9])[CH2:2][CH2:3][CH3:4].[CH3:19][N:20]([CH3:30])[C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](O)=[O:25]>C(OC(=O)C)(=O)C>[CH2:1]([O:5][C:6]1[CH:13]=[C:12]([N:14]([CH2:15][CH3:16])[CH2:17][CH3:18])[CH:11]=[CH:10][C:7]=1[CH:8]1[C:27]2[C:23](=[CH:22][C:21]([N:20]([CH3:30])[CH3:19])=[CH:29][CH:28]=2)[C:24](=[O:25])[O:9]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(N(CC)CC)ccc1C=O
Reactant: CN(C)c1cccc(C(=O)O)c1
Solvent: CC(=O)OC(C)=O
Product: CCCCOc1cc(N(CC)CC)ccc1C1OC(=O)c2cc(N(C)C)ccc21

Procedure:
Employing a procedure similar to that described in Example 1, part A above, 13.3 g of 2-butoxy-4-diethylaminobenzaldehyde and 9.7 g of m-dimethylaminobenzoic acid were refluxed in acetic anhydride to obtain 3-(2-butoxy-4-diethylaminophenyl)-6-dimethylaminophthalide (Formula I: R=CH3 ; X=Z=H; Y=2-C4H9O-4-(C2H5)2NC6H3) as a tarry residue.
Reaction SMILES: CC1C=CC(S(O[C@@H:12]2[CH2:25][C:24]3[C@@:15]([CH3:38])([C@@H:16]4[C@@H:21]([CH2:22][CH:23]=3)[C@@H:20]3[CH2:26][CH2:27][C@H:28]([C@@H:29]([CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH3:30])[C@@:19]3([CH3:37])[CH2:18][CH2:17]4)[CH2:14][CH2:13]2)(=O)=O)=CC=1.[CH2:39]([OH:50])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][OH:49]>O1CCOCC1>[CH3:36][CH:34]([CH2:33][CH2:32][CH2:31][C@H:29]([C@@H:28]1[C@:19]2([CH3:37])[C@H:20]([C@H:21]3[C@H:16]([CH2:17][CH2:18]2)[C@:15]2([CH3:38])[C:24]([CH2:25][C@@H:12]([O:50][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][OH:49])[CH2:13][CH2:14]2)=[CH:23][CH2:22]3)[CH2:26][CH2:27]1)[CH3:30])[CH3:35]
Reactant: OCCCCCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)cc1
Solvent: C1COCCO1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCCCCCO)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 78.2 %

Procedure:
In a 500 mL round-bottomed flask was cholesteryl tosylate (10.0 g, 18.5 mmol) and 1,10-Decanediol (48.3 g, 277 mmol) suspended in Dioxane (200 ml) to give a white suspension. The flask was fitted with a temperature sensor and reflux condenser. The mixture was heated to reflux and allowed to stir at reflux overnight. The reaction mixture was cooled to room temperature and the solids were filtered off. The solution was concentrated in vacuo. The mixture was re-dissolved in methanol (250 mL) and water (ca. 40 mL) was added to precipitate out the crude product. The precipitate was filtered and dried in vacuo. The residue was further purified via column chromatography on a 100 g Biotage SNAP column eluting over 2 L of a 0-25% EtOAc in Hexanes gradient. Pure fractions were combined and concentrated to give 7.85 g (82%) of a white solid. 1H NMR (300 mHz, CDCl3) δ0.69 (3H, s); 0.85-1.66 (50H, m); 1.75-2.09 (5H, m); 2.14-2.29 (1H, m); 2.32-2.43 (1H, m); 3.14 (1H, tt, J=11.2, 4.4 Hz); 3.46 (2H, dt, J=6.9, 0.4 Hz); 3.65 (2H, t, J=6.6 Hz); 5.36 (1H, d, J=5.3 Hz).
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>C(Cl)(Cl)Cl>[C:4]([O:11][C:10](=[O:12])[C@@H:9]1[CH2:13][CH2:14][CH2:15][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
N-BOC-Proline tert-Butyl Ester (24) was synthesized from N-BOC-proline (14) according to the general procedure: yield, 90%; [α]25D -50.5° (c 3.4, CHCl3); 1H NMR δ 4.12 (dd, 1H, J=3.4, 8.9), 3.60-3.39 (m, 2H), 2.29-2.16 (m, 1H), 2.00-1.80 (m, 3H), 1.51 (s, 9H), 1.46 (s, 9H). Anal. Calcd for C14H26NO4 : C, 61.7; H, 9.6,; N, 5.1. Found: C, 61.7; H, 9.6; N, 5.4.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:21][C:10]3([CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]3)[CH2:9]2)=[CH:4][CH:3]=1.Br[C:23]1[C:24](=[O:31])[N:25]([CH3:30])[N:26]=[C:27]([Cl:29])[CH:28]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl.[O-]S([O-])(=O)=O.[Na+].[Na+].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:17]([O:16][C:14]([N:12]1[CH2:13][C:10]2([CH2:9][N:8]([C:5]3[CH:6]=[N:7][C:2]([NH:1][C:23]4[C:24](=[O:31])[N:25]([CH3:30])[N:26]=[C:27]([Cl:29])[CH:28]=4)=[CH:3][CH:4]=3)[CH2:21]2)[CH2:11]1)=[O:15])([CH3:18])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CC2(C1)CN(c1ccc(N)nc1)C2
Reactant: Cn1nc(Cl)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1nc(Cl)cc(Nc2ccc(N3CC4(CN(C(=O)OC(C)(C)C)C4)C3)cn2)c1=O
Temperature: 100 °C
Reaction time: 20 h
Yield: 24.6 %

Procedure:
In a 250 mL round-bottomed flask, tert-butyl 6-(6-aminopyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (870 mg, 3.00 mmol), 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (670 mg, 3.00 mmol), xantphos (260 mg, 449 μmol), Cs2CO3 (2.93 g, 8.99 mmol) and Pd2(dba)3 (137 mg, 150 μmol) were combined with dioxane (25.0 ml) to give a dark brown solution. The reaction mixture was heated to 100° C. under argon and stirred for 20 h. The reaction was cooled to 25° C., diluted with DCM, and Na2SO4 was added. The mixture was filtered over celite, the filter cake was washed with DCM and the filtrate was conc. in vacuo to a dark brown semisolid. The crude material was purified by flash chromatography (silica gel, 220 g, 0% to 5% MeOH in DCM). The impure material was repurified by flash chromatography (silica gel, 220 g, 0% to 4% MeOH in DCM) to afford 0.320 g (25%) of the title compound as a light yellow powder. (M+H)+=433/435 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ: 8.12 (s, 1H), 8.08 (s, 1H), 7.65 (s, 1H), 6.82 (d, J=1.5 Hz, 2H), 4.12 (s, 4H), 4.01 (s, 3H), 3.80 (s, 4H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:15])=[C:7]([N+:12]([O-])=O)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[OH-].[NH4+].[H][H]>[Pd].CO>[NH2:12][C:7]1[CH:8]=[N:9][C:10]2[C:5]([C:6]=1[OH:15])=[CH:4][CH:3]=[C:2]([CH3:1])[CH:11]=2
Reactant: [H][H]
Reactant: Cc1ccc2c(O)c([N+](=O)[O-])cnc2c1
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc2c(O)c(N)cnc2c1
Yield: 84.1 %

Procedure:
7-Methyl-3-nitro-4-quinolinol (11.8 g, 58 mmol), methanol (about 300 mL), ammonium hydroxide (50 mL), and palladium on carbon (1 g of 10%) were combined. The mixture was placed on a Parr apparatus under a 35-40 psi (2.4-2.8 Kg/cm2) hydrogen atmosphere for about 1 hour. The reaction mixture was filtered through a layer of Celite® filter agent and the filter cake was rinsed well with methanol. The filtrate was treated with charcoal and then concentrated under vacuum to provide a fluffy pale green solid. This material was triturated with acetonitrile to provide 8.5 g of 3-amino-7-methyl-4-quinolinol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[C:12]3[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=3[CH2:14][N:15]3[CH:19]=[CH:18][CH:17]=[C:16]3[C:10]2=[N:9][N:8]=1.[Br:24]N1C(=O)CCC1=O.S(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.C(Cl)Cl>[Br:24][C:19]1[N:15]2[C:16]([C:10]3[N:11]([C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:8][N:9]=3)[C:12]3[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=3[CH2:14]2)=[CH:17][CH:18]=1
Reactant: c1ccc(-c2nnc3n2-c2ccccc2Cn2cccc2-3)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)([O-])[O-]
Agent: O=S([O-])O
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Brc1ccc2n1Cc1ccccc1-n1c(-c3ccccn3)nnc1-2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 3 g of 3-(2-pyridinyl)-9H-pyrrolo[2,1-c]-1,2,4-triazolo[4,3-a][1,4]benzodiazepine in 50 mL of tetrahydrofuran is added 1.8 g of N-bromosuccinimide. The reaction mixture is allowed to stir at room temperature for 3 hours during which time a heavy white precipitate forms. A solution of aqueous sodium bisulfite is added to the reaction mixture and, after stirring for an additional 1 hour, the solid is collected and washed with 100 ml of water. The filtrate is evaporated to dryness under reduced pressure to yield a white solid. The combined solids are dissolved in 150 mL of methylene chloride, the solution is drived over anhydrous magnesium sulfate, filtered, and the solvent is evaporated under reduced pressure to yield 11-bromo-3-(2-pyridinyl)-9H-pyrrolo[2,1-c]-1,2,4-triazolo[4,3-a][1,4]benzodiazepine, m.p. 228°-229° (d). Product is recrystallized from a mixture of methylene chloride and diethyl ether.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1.[Br:20]C1C(OC)=C(C=CC=1)C=O>>[Br:20][C:4]1[C:5]([O:18][CH3:19])=[C:6]([CH:8]([OH:17])[C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:2][CH:3]=1
Reactant: COc1c(Br)cccc1C=O
Reactant: COc1ccc(F)cc1C(O)C#Cc1ccccc1
Product: COc1c(Br)cccc1C(O)C#Cc1ccccc1
Yield: 92 %

Procedure:
Following the procedure used to prepare 1-(5-fluoro-2-methoxy-phenyl)-3-phenyl-prop-2-yn-1-ol, 3-bromo-2-methoxy-benzaldehyde was reacted to give the title compound as an oil (3.70 g, 92%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:16][CH:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][C@H:26]([CH2:28][OH:29])[O:25][C:24]4=[O:30])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][C@H:26]([CH2:28][O:29][S:39]([CH3:38])(=[O:41])=[O:40])[O:25][C:24]4=[O:30])=[CH:19][CH:18]=3)[CH2:15][CH2:16]2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OCc1ccccc1)N1CC=C(c2ccc(N3C[C@H](CO)OC3=O)cc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(C3=CCN(C(=O)OCc4ccccc4)CC3)cc2)C(=O)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (R)-(-)-3,6-dihydro-4-[4-[5-(hydroxymethyl)-2-oxo-3-oxazolidinyl]phenyl]-1(2H)-pyridinecarboxylic acid phenylmethyl ester (EXAMPLE 17, Step 3, 970 mg) and triethylamine (0.50 mL) in dry methylene chloride (9.5 mL) at 0° C. under N2 is treated with methanesulfonyl chloride (0.20 mL) dropwise. The resulting mixture is stirred at 0° C. for one hour, diluted with methylene chloride (40 mL), washed with water (10 mL), saturated aqueous sodium bicarbonate (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound, mp 166-168° C.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[C:20](Cl)(=[O:24])[C:21]([CH3:23])=[CH2:22]>C(Cl)Cl>[CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][C:20](=[O:24])[C:21]([CH3:23])=[CH2:22])=[CH:8][CH:7]=1)(=[O:4])=[O:5]
Reactant: C=C(C)C(=O)Cl
Reactant: CNS(=O)(=O)c1ccc(O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Oc1ccc(S(=O)(=O)NC)cc1
Reaction time: 3 h
Yield: 79.3 %

Procedure:
To a solution of 15.00 g (0.08 mole) of N-methyl-4-hydroxybenzenesulfonamide, 8.11 g (0.08 mole) of triethylamine and 200 ml of methylene chloride cooled to 0° C. was added a solution of 8.37 g (0.08 mole) of methacryloyl chloride in 100 ml of methylene chloride over a period of approximately 30 minutes. The solution was then stirred for another 3 hours with cooling; washed once with 100 ml of 2 percent HCl solution, and twice with water; dried over magnesium sulfate and concentrated in vacuo in a warm water bath. The resultant solid was recrystallized from 150 ml of ethyl alcohol:water (1:1) with filtering through diatomaceous earth. Collection of the white solid and drying at room temperature in vacuo gave 16.20 g (79.9 percent of theory) of N-methyl-4-methacryloyloxybenzenesulfonamide; m.p.=106° to 107° C.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30](Cl)Cl)=[CH:25][CH:24]=1>>[C:26]1([NH:29][C:30]2[S:17][C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]3[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:9]=3)=[N:18][N:19]=2)[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=1
Reactant: NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Reactant: ClC(Cl)=Nc1ccccc1
Product: c1ccc(Nc2nnc(NCCCOc3cccc(CN4CCCCC4)c3)s2)cc1

Procedure:
The compound is prepared by a method analogous to that of Example 29 from N-[3-[3-(1-piperidinylmethyl) phenoxy]propyl]-hydrazine carbothioamide and phenyl isocyanide dichloride. The analytical values are summarized in Table II.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:27][C:26]3[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=3[C:24]([F:23])([F:33])[F:34])[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: FC(F)(F)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2n1Cc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (577 mg) in DMF (6 mL) was added potassium carbonate powder (890 mg) and 2-(trifluoromethyl)benzyl bromide (1.54 g). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (5%-40% EtOAc/hexanes), followed by recrystallization with hexanes to yield the title compound as an orange-brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH2:12].[CH3:13][O:14][CH:15]([CH3:19])[CH2:16][C:17]#[CH:18].C(NC(C)C)(C)C>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:10]=[C:9]([C:18]#[C:17][CH2:16][CH:15]([O:14][CH3:13])[CH3:19])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH2:12]
Reactant: C#CCC(C)OC
Reactant: Nc1c(Cl)cc(I)c2c1OCO2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COC(C)CC#Cc1cc(Cl)c(N)c2c1OCO2
Reaction time: 1.5 h
Yield: 91.5 %

Procedure:
5-chloro-7-iodo-1,3-benzodioxol-4-amine (600 mg, 2.02 mmol) and 4-methoxypent-1-yne (500 mg, 5.10 mmol) in ethyl acetate (8 ml) were cooled in ice-methanol, under an atmosphere of nitrogen, then treated with bis(triphenylphosphine)palladium(II) dichloride (141 mg, 10 mol %) followed by copper(I) iodide (38 mg, 10 mol %) and diisopropylamine (407 mg, 5.69 mmol). The reaction was allowed to warn to room temperature and stirred 90 min then filtered through Celite. The filtrate was purified by column chromatography on silica using a 1:1 mixture of methyl tert-butyl ether and iso-hexane as eluent to give 5-chloro-7-(4-methoxypent-1-yn-1-yl)-1,3-benzodioxol-4-amine (495 mg, 92%) as a dark brown oil;
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:23]([C:27]1[N:28]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=3[S:59](=[O:62])(=[O:61])[NH2:60])=[CH:49][CH:48]=2)[C:29](=[O:45])[N:30]([C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][C:33]=2[C:41]([F:44])([F:43])[F:42])[N:31]=1)[CH2:24][CH2:25][CH3:26].C1CCN2C(=NCCC2)CC1>>[CH2:23]([C:27]1[N:28]([CH2:46][C:47]2[CH:52]=[CH:51][C:50]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=3[S:59](=[O:62])(=[O:61])[NH:60][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])=[CH:49][CH:48]=2)[C:29](=[O:45])[N:30]([C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][C:33]=2[C:41]([F:42])([F:44])[F:43])[N:31]=1)[CH2:24][CH2:25][CH3:26]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CCCCc1nn(-c2ccc([N+](=O)[O-])cc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2ccc([N+](=O)[O-])cc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1

Procedure:
The title compound was prepared from 2-chlorobenzoic acid (2.0 equivalents), CDI (2.0 equiv), 5-n-butyl-2,4-dihydro-2-(4-nitro-2-trifluoromethyl)phenyl-4-[(2'-sulfamoylbiphenyl-4-yl)methyl]-3H-1,2,4-triazol-3-one (from Step C) (1.0 eq), and DBU (2.0 equiv) according to the procedure of Example 51, to give a 43% yield of the desired material after flash chromatography, as a glassy solid, mp 179°-181° C., homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 714 (M+1)+.