Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]Cl)[CH:33]=1.CCN(C(C)C)C(C)C.O>C(#N)C>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([NH:21][CH2:38][C:34]3[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=3)[C@@H:17]2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: ClCc1cccnc1
Reactant: C[C@@H](O[C@H]1CC[C@@H](N)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: C[C@@H](O[C@H]1CC[C@@H](NCc2cccnc2)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C

Procedure:
To a solution of 75 mg of non-racemic 1-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-2-(S)-(4-fluorophenyl)-3-(R)-aminocyclopentane from Example 39 in 2 mL of acetonitrile was added 34 mg of 3-picolyl chloride hydrochloride and 0.090 mL of DIPEA. The reaction was heated at 50° C. for 3 days and then poured into water and extract twice with ethyl acetate. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated. The residue was purified on a 3×1 mm preparative silica gel plates eluted with 5% methanol in methylene chloride to give 40 mg of title compound as an oil. Mass spec (NH3 /CI): 527 (M+1).
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:2]1.[CH3:11]OC(OC)N(C)C.O.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][NH2:29])=[CH:24][CH:23]=1>>[CH:1]1([C:4]2[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:11][N:28]([C:25]3[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)[N:29]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)CC(=O)C1CC1
Reactant: COC(OC)N(C)C
Reactant: COc1ccc(NN)cc1
Solvent: O
Product: COC(=O)c1cn(-c2ccc(OC)cc2)nc1C1CC1
Yield: 84 %

Procedure:
Using methyl 3-cyclopropyl-3-oxopropanoate (3.7 g), dimethylformamide dimethylacetal (3.6 mL) and p-methoxyphenylhydrazine monohydrate (4.7 g) and in the same manner as in Example 15(1), the title object compound (5.9 g, 84%) was obtained as an oil.
Reaction SMILES: C(O)(C)C.O.[C:6]([C@@:14]([C:29]([OH:31])=[O:30])([OH:28])[C@@:15]([C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([OH:19])[C:16]([OH:18])=[O:17])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[O:32]=[C:33]([N:47]1[CH2:52][CH2:51][N:50]2[C:53]([C:56]([F:59])([F:58])[F:57])=[N:54][N:55]=[C:49]2[CH2:48]1)[CH2:34][CH:35]([NH2:46])[CH2:36][C:37]1[CH:42]=[C:41]([F:43])[C:40]([F:44])=[CH:39][C:38]=1[F:45]>CO>[C:20]([C@@:15]([C:16]([OH:18])=[O:17])([OH:19])[C@@:14]([C:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:28])[C:29]([OH:31])=[O:30])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[O:32]=[C:33]([N:47]1[CH2:52][CH2:51][N:50]2[C:53]([C:56]([F:59])([F:58])[F:57])=[N:54][N:55]=[C:49]2[CH2:48]1)[CH2:34][C@H:35]([NH2:46])[CH2:36][C:37]1[CH:42]=[C:41]([F:43])[C:40]([F:44])=[CH:39][C:38]=1[F:45]
Reactant: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: O=C(O)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)O)C(=O)c1ccccc1
Solvent: CC(C)O
Solvent: CO
Solvent: O
Product: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 62.5 °C
Reaction time: 0.38 h

Procedure:
In a 25 mL round bottom flask Isopropanol (1.25 mL) and Dibenzoyl-L-tartaric acid monohydrate (0.462 g) were taken. It was heated to 60-65° C. 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (0.5 g) dissolved in methanol (1.0 mL) was added into reaction mixture at 60-65° C. over a period of 15 min. It was stirred for 15-30 min. at 60-65° C. Solid salt was precipitated. It was gradually cooled to room temperature and stirred for 30-60 min. The salt was filtered and washed with a mixture of IPA: MeOH (2:1, 3 mL). An enantiomerically enriched desired Dibenzoyl-L-tartaric acid salt off (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine was obtained (Wt.-0.358 g, % Y-37.8%, Purity by HPLC-97.5%, % Chiral purity by HPLC of R-isomer 99.6%). % of weight loss by TGA-4.7%. m.p.-156-160° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][C:13](=O)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C(OC([N:35]([CH3:37])C)N(C)C)(C)(C)C.O.[NH2:39]N>CO>[CH2:1]([O:8][C:9](=[O:18])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][C:13]2[NH:39][N:35]=[CH:37][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: NN
Reactant: O=C1CCCC(NC(=O)OCc2ccccc2)C1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(NC1CCCc2[nH]ncc21)OCc1ccccc1
Yield: 72.5 %

Procedure:
Stir a mixture of (3-Oxo-cyclohexyl)-carbamic acid benzyl ester (12.3 g, 49.8 mmol), toluene (60 mL) and tert-butoxybis(dimethylamino)methane (9.53 g, 54.77 mmol) at 90° C. for 1.5 hour. Cool the reaction and remove the solvent in vacuo. To the residue, add methanol (60 mL) and hydrazine hydrate (2.74 g, 54.77 mmol). Stir the reaction at room temperature for 3 hours. Remove the solvent in vacuo. To the residue, add ethyl acetate and wash with water. After drying the organic layer over sodium sulfate, filter and concentrate to afford 9.8 g of the title compound with 80% purity.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[N:5]([C:12]1([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:22](Cl)(=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].CO>C1COCC1>[CH3:20][C:12]1([N:5]2[C:4](=[O:21])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:22](=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19]
Reactant: CC1(N2C(=O)c3cccc(N)c3C2=O)CCC(=O)NC1=O
Reactant: CCCCCCC(=O)Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCC(=O)Nc1cccc2c1C(=O)N(C1(C)CCC(=O)NC1=O)C2=O
Reaction time: 0.25 h
Yield: 71.5 %

Procedure:
To a suspension of 4-amino-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione (0.10 g, 0.35 mmol) in THF (15 ml) was added heptanoyl chloride (0.10 g, 0.70 mmol). The mixture was heated to reflux for 18 h. The reaction mixture was allowed to cool and to the solution was added methanol (2 ml). The reaction mixture was stirred for an additional 15 minutes followed by solvent evaporation in vacuo. The resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.10 g (74%) of product as an off-white solid: mp 172-174° C.; 1H NMR (DMSO-d6) 11.05 (s, 1H), 9.65 (s, 1H), 8.50 (d, J=8.3 Hz, 1H), 7.79 (t, J=7.6 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 2.77-2.43 (m, 5H), 2.08-2.03 (m, 1H), 1.90 (s, 3H), 1.61 (t, J=6.4 Hz, 2H), 1.29 (bs, 6H), 0.87 (t, J=6.3 Hz, 3H); 13C NMR (DMSO-d6) 172.12, 172.02, 168.74, 167.36, 136.41, 135.90, 131.20, 125.70, 117.71, 116.31, 58.81, 36.51, 30.93, 29.07, 28.54, 28.12, 24.69, 21.94, 20.98, 13.86; Anal. Calcd. For C21H21N3O5: C, 62.83; H, 6.33; N, 10.47 Found: C, 62.45; H, 6.18; N, 10.24+0.50H2O.
Reaction SMILES: [C:1](OCC)(=O)[CH2:2][C:3](OCC)=O.[OH-].[Na+].[N+:14]([C:17]1[CH:18]=CC(Cl)=[N:21][CH:22]=1)([O-:16])=[O:15].Cl>CN(C)C=O>[N+:14]([C:17]1[CH:18]=[CH:3][C:2]([CH3:1])=[N:21][CH:22]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])cn1
Reaction time: 0.25 h

Procedure:
206 g (1.29 mol) of diethyl malonate are added to 600 ml of dimethylformamide, and 51.2 g (1.28 mol) of freshly powdered NaOH are introduced, with cooling. The mixture is subsequently stirred after 15 minutes and a solution of 94.8 g (0.6 mol) of 5-nitro-2-chloropyridine in 600 ml of dimethylformamide is then added dropwise at room temperature. The deep red solution formed is stirred until the reaction is complete, 36% strength HCl is then added dropwise until the color changes to orange and the mixture is evaporated to dryness in vacuo. The residue is taken up in 400 ml of CHCl3, washed with 500 ml of water and evaporated again. The residue is now dissolved in a mixture of 1,200 ml of 36% strength HCl and 870 ml of water and the solution is boiled under reflux until the evolution of gas has ended. Thereafter, it is evaporated in vacuo, the residue is dissolved in 500 ml of water, the solution is extracted with methylene chloride and the organic phase is washed again with water. After the solvent has been stripped off, 72 g (87%) of 5-nitro-2-picoline remain.
Reaction SMILES: Br.Br.[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH:4]1[CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][NH2:21])[CH2:16][CH2:15]1.CS([C:26]1[S:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][C:29]=2[N:34]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH:4]1[CH2:13][N:14]1[CH2:15][CH2:16][CH:17]([CH2:20][NH:21][C:26]2[S:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][C:29]=3[N:34]=2)[CH2:18][CH2:19]1
Reactant: NCC1CCN(CC2COc3ccccc3O2)CC1
Reactant: CS(=O)(=O)c1nc2cnccc2s1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: c1ccc2c(c1)OCC(CN1CCC(CNc3nc4cnccc4s3)CC1)O2
Temperature: 150 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
A mixture of 6.7 parts of 1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinemethanamine dihydrobromide, 3.26 parts of 2-(methylsulfonyl)thiazolo[4,5-c]pyridine, 4.25 parts of sodium carbonate and 18 parts of N,N-dimethylacetamide was stirred for 2 hours at 150° C. The reaction mixture was poured into ice water. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1,1'-oxybisethane. The product was filtered off and dried, yielding 1.15 parts (20%) of N-[[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]thiazolo[4,5-c]pyridin-2-amine; mp. 147.1° C. (compound 58).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(O[C:41](=[O:47])[O:42][C:43](Cl)(Cl)Cl)Cl.[F:49][C:50]1[CH:59]=[CH:58][CH:57]=[CH:56][C:51]=1[O:52][CH2:53]CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:42][CH2:43][CH2:53][O:52][C:51]2[CH:56]=[CH:57][CH:58]=[CH:59][C:50]=2[F:49])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: OCCOc1ccccc1F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCOc4ccccc4F)cc3)c2cc1OC
Temperature: 25 °C
Yield: 53.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (60 mg) was added to toluene/triethylamine=10/1 (6 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (91 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-(2-fluorophenoxy)-1-ethanol (47 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (52 mg, yield 50%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])[CH:4]=[CH:3]1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:24]=[N:25][C:26]([C:29]3[CH:30]=[C:31]([CH2:35]O)[CH:32]=[CH:33][CH:34]=3)=[N:27][CH:28]=2)[CH2:19][CH2:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>CN(C=O)C>[CH3:16][N:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:28]=[N:27][C:26]([C:29]3[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=3)[CH2:35][N:7]3[C:2](=[O:1])[CH:3]=[CH:4][C:5]([C:8]4[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=4)[C:11]#[N:12])=[N:6]3)=[N:25][CH:24]=2)[CH2:21][CH2:22]1
Reactant: CN1CCN(c2cnc(-c3cccc(CO)c3)nc2)CC1
Reactant: N#Cc1cccc(-c2ccc(=O)[nH]n2)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CN1CCN(c2cnc(-c3cccc(Cn4nc(-c5cccc(C#N)c5)ccc4=O)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
149 mg (0.76 mmol) of 3-(6-oxo-1,6-dihydropyridazin-3-yl)benzonitrile and 256 mg (0.76 mmol) of {3-[5-(4-methylpiperazin-1-yl)pyrimidin-2-yl]phenyl}-methanol are suspended in 5 ml of DMF with 378 mg (1.13 mmol) of polymer-bound triphenylphosphine (about 3 mmol of triphenylphosphine per g) and shaken at room temperature for 30 min. 266 mg (1.134 mmol) of di-tert-butyl azodicarboxylate are added. The reaction mixture is shaken at room temperature for 2 h. A further 378 mg (1.13 mmol) of polymer-bound triphenylphosphine (about 3 mmol of triphenylphosphine per g) and 266 mg (1.134 mmol) of di-tert-butyl azodicarboxylate are added, and the reaction mixture is shaken at room temperature for 2 h. The reaction mixture is filtered, the filtrate is evaporated, and the residue is purified by means of column chromatography on silica gel; yield: 59 mg of “A287”; HPLC: Rt=2.38 min (method C); LC-MS: 464 (M+H).
Reaction SMILES: [NH:1]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:2]([C:5]([OH:7])=O)[CH2:3][OH:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:39][C:40]([F:70])([F:69])[C:41]1[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:68])[O:49][CH2:50][C:51]2([C:57](=[O:67])[NH:58][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=3[Cl:66])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)=[CH:43][CH:42]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:70][C:40]([F:39])([F:69])[C:41]1[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:68])[O:49][CH2:50][C:51]2([C:57](=[O:67])[NH:58][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=3[Cl:66])[CH2:52][CH2:53][N:54]([C:5](=[O:7])[C@@H:2]([NH:1][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][OH:4])[CH2:55][CH2:56]2)=[CH:43][CH:42]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)OCC1(C(=O)NCc2ccccc2Cl)CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)N1CCC(COC(=O)Nc2ccc(C(F)(F)F)cc2)(C(=O)NCc2ccccc2Cl)CC1
Reaction time: 8 h
Yield: 56.6 %

Procedure:
To a solution of Boc-Ser-OH (162 mg, 0.79 mmol, 2 equiv.) in DMF (2 mL) were added HATU (300 mg, 0.79 mmol, 2 equiv.), followed by addition of (4-(2-chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-(trifluoromethyl)phenylcarbamate (200 mg, 0.39 mmol, 1 equiv.) and DIEA (140 μL, 0.79 mmol, 2 equiv.). The reaction mixture was stirred overnight and purified on RP-HPLC using a mixture of acetonitrile and H2O to give (S)-(1-(2-(tert-butoxycarbonyl)amino-3-hydroxypropanoyl)-4-(2-chlorobenzylcarbamoyl)piperidin-4-yl)methyl 4-(trifluoromethyl)phenylcarbamate (145 mg, 56%). LRMS (M+H+-Boc) m/z 557.1.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH:34]([F:36])[F:35])=[N:32][CH:33]=1>C(#N)C.O>[F:35][CH:34]([F:36])[C:31]1[N:32]=[CH:33][C:28]([CH2:27][O:1][C:2]2[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=2[O:17][CH3:18])=[CH:29][CH:30]=1
Reactant: COc1cc(CNC(=O)OC(C)(C)C)ccc1O
Reactant: FC(F)c1ccc(CCl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(CNC(=O)OC(C)(C)C)ccc1OCc1ccc(C(F)F)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.7 %

Procedure:
To a stirred solution of tert-butyl 4-hydroxy-3-methoxybenzylcarbamate (4.70 g, 18.56 mmol) and potassium carbonate (7.64 g, 55.28 mmol) in acetonitrile (50 mL) was added 5-(chloromethyl)-2-(difluoromethyl)pyridine hydrochloride (4.58 g, 21.40 mmol). The mixture was heated to reflux. After 3 h, the off-white suspension was allowed to cool to room temperature and was diluted with water (200 mL). The mixture was extracted with dichloromethane (3×75 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 7.74 g (>100%) of tert-butyl 4-((6-(difluoromethyl)pyridin-3-yl)methoxy)-3-methoxybenzylcarbamate as a waxy yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[C:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=1)([CH3:29])[CH3:28].Cl.C(=O)([O-])[O-].[NH4+:44].[NH4+]>C(O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[C:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37](=[NH:44])[NH2:38])=[CH:33][CH:32]=1)([CH3:28])[CH3:29]
Reactant: [NH4+]
Reactant: CCOC(=O)CN(c1ccc2c(c1)nc(C(C)(C)Oc1ccc(C#N)cc1)n2C)S(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CN(c1ccc2c(c1)nc(C(C)(C)Oc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1ccccc1

Procedure:
Prepared analogously to Example 1e from 1-methyl-2-[1-(4-cyanophenoxy)-1-methyl-ethyl]-5-[N-(ethoxycarbonylmethyl)-benzenesulphonylamino]-benzimidazole and ethanolic hydrochloric acid, ethanol and ammonium carbonate.
Reaction SMILES: [C:1]([N:11]1[CH2:17][CH2:16][CH2:15][C@H:12]1[CH:13]=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:25][C:26](=[O:28])[CH3:27])C=CC=CC=1>C(Cl)Cl>[C:1]([N:11]1[CH2:17][CH2:16][CH2:15][C@H:12]1[CH:13]=[CH:25][C:26](=[O:28])[CH3:27])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: ClCCl
Product: CC(=O)C=C[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a 350 mg (1.50 mmol) sample of CBZ-L-prolinal, from step 23b above, dissolved in 5 mL of methylene chloride was added 576 mg of 1-triphenylphosphoranylidene-2-propanone (Aldrich, 1.81 mmol). The reaction was stirred at room temperature for 45 min, then heated at reflux for 1.3 hr. The solution was cooled, and a precipitate formed. The mixture was extracted with methylene chloride (3×10 mL). The combined organics were washed with brine and dried over MgSO4. The residue was chromatographed on silica gel, eluting with 25-35% ether in hexane, The title compound was isolated by removal of solvent (279 mg). Anal. Calcd for C16H19NO3 : C, 70.31; H, 7.01; N, 5.12; Found: C, 70.20; H, 7.02; N, 5.10.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](Cl)=[O:11])=[CH:7][C:6]=2[CH:13]=1.[CH2:14]([N:16](C(C)C)[CH:17](C)[CH3:18])[CH3:15].C1(C)C=CC=CC=1.C(NCC)C>O>[CH2:14]([N:16]([CH2:17][CH3:18])[C:10]([C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=2[CH:7]=1)=[O:11])[CH3:15]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)c1cc2cc(Br)ccc2o1
Solvent: CCNCC
Solvent: O
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1cc2cc(Br)ccc2o1
Reaction time: 0.08 h
Yield: 88 %

Procedure:
1.3 g. of 5-bromobenzofuran-2-carbonyl chloride, 1 mL [sic] of ethyldiisopropylamine and 30 mL [sic] of toluene are mixed and 0.62 ml of diethylamine is added to the brown-coloured solution with stirring. A precipitate is formed with a slightly exothermic reaction. After 5 minutes, the mixture was treated with 30 ml of completely deionized water and the phases were separated. The organic phase was washed with 1.) 20 ml of iN HCl 2.) 20 ml of iN NaOH 3.) 20 ml of water and then with 20 ml of saturated NaCl solution and then freed of solvent components in vacuo. After chromatography on silica gel the residual, yellowish oil forms in the eluent MtB ether/heptane 2:1 [sic]. Final weight: 1.3 g of colourless crystals [sic] (yield: 88%), m.p. 79-81°.
Reaction SMILES: O=S(Cl)[Cl:3].[Cl:5][C:6]1[N:11]=[N:10][C:9]([CH2:12]O)=[C:8]([O:14][CH3:15])[CH:7]=1>C(Cl)Cl>[Cl:5][C:6]1[N:11]=[N:10][C:9]([CH2:12][Cl:3])=[C:8]([O:14][CH3:15])[CH:7]=1
Reactant: COc1cc(Cl)nnc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cc(Cl)nnc1CCl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Excess SOCl2 is added to a stirred solution of (6-chloro-4-methoxy-pyridazin-3-yl)-methanol (140 mg, 0.8 mmol) in CH2Cl2 (4 mL). The reaction mixture is stirred at room temperature for 4 hours. The solvent is removed in vacuo; toluene (4 mL) is added and evaporated to dryness. Flash column chromatography (silica gel) purification of the residue provides 6-chloro-3-chloromethyl-4-methoxy-pyridazine as a clear oil.
Reaction SMILES: [O:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:8].[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][C:11]=1[CH3:18].[OH-:19].[K+]>C1(C)C=CC=CC=1.O>[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][O:1][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]([OH:8])=[O:19])=[CH:12][C:11]=1[CH3:18]
Reactant: O=C1CCCCCO1
Reactant: Cc1cc(CBr)ccc1F
Reactant: [OH-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(COCCCCCC(=O)O)ccc1F
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of oxepan-2-one (0.562 g, 4.925 mmol) and 4-fluoro-3-methylbenzyl bromide (3.000 g, 14.774 mmol) in 20 mL of toluene, was added KOH (1.382 g, 24.625 mmol). The mixture was refluxed for 86 h. After cooling to room temperature, the reaction mixture was diluted with water (80 mL) and washed with ether. The aqueous layer was acidified with concentrated HCl to pH=2 and extracted with ether (50 mL×3). The combined organic extracts dried (Na2SO4), filtered, and concentrated under reduced pressure to give the title compound as colorless oil which was used directly in the next step without further purification (1.173 g, 94% yield). LC-MS: tR=8.0 min, m/z 277 (M+H)+.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][CH:5]1[O:17][CH2:16][CH2:15][O:14][CH:6]1[CH2:7][CH:8]1[O:13][CH2:12][CH2:11][O:10][CH2:9]1.[C:18]1([P:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCOCC>C1C=CC=CC=1>[I-:1].[CH2:15]1[CH2:16][O:17][CH:7]([CH:8]2[O:13][CH2:12][CH2:11][O:10][CH2:9]2)[CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][P+:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:14]1
Reactant: ICCCC1OCCOC1CC1COCCO1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: [I-]
Product: c1ccc([P+](CCCCC2OCCOC2C2COCCO2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 16 h

Procedure:
The iodide from Example XX (8.2 g, 0.023 mol) and triphenylphosphine (10 g, 0.038 mol) were dissolved in benzene (70 ml). The solution was boiled with stirring for 16 hours. After cooling, the benzene layer was decanted and the viscous residue was dissolved in a little acetone. Addition of ether gave 5.01 g (35% by weight yield) of a crystalline product, melting point 102°-104° C., while dilution of the mother liquor with ether gave a further 6.0 g (42% by weight yield) of less pure product (oil).