Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][NH2:15]>C(O)CCC>[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][N:15]1[C:6]([CH3:8])=[CH:7][C:2]([OH:1])=[CH:3][C:4]1=[O:9]
Reactant: Cc1cc(O)cc(=O)o1
Reactant: NCc1cccc(F)c1
Solvent: CCCCO
Product: Cc1cc(O)cc(=O)n1Cc1cccc(F)c1
Yield: 18.4 %

Procedure:
A mixture of 4-hydroxy-6-methyl-2-pyrone (2.5 g, 0.02 mol) and 3-fluorobenzylamine (2.5 g, 0.02 mol) in n-butanol (15.0 mL) was heated to reflux for 16 h under argon atmosphere. Butanol wad distilled in vacuo, the residue was triturated with EtOAc, cooled and filterd the precipitate. It was washed with cold EtOAc, and dried to give 0.86 g of the title compound as a pale yellow powder: 1H-NMR (CD3OD/400 MHz) δ 7.31 (m, 1H), 7.0-6.85 (m, 2H), 6.83 (d, 1H, J=9.6 Hz), 5.96 (d, 1H, j=2.0 Hz), 5.80 (d, 1H, J=2.0 Hz), 5.30 (s, 2H), and 2,24 (s, 3H); ES MS m/z 234 (MH+). Step 2: Preparation of 3-bromo-1-(3-fluorobenzyl)-4-hydroxy-6-methylpyridin-2(1H)-one
Reaction SMILES: [CH3:1][N:2]([CH3:59])[CH2:3][CH2:4][C@@H:5]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][N:41]4[CH2:46][CH2:45][N:44](C(OC(C)(C)C)=O)[CH2:43][CH2:42]4)=[CH:35][C:34]=3[O:54][CH3:55])=[CH:29][CH:28]=2)=[O:26])(=[O:23])=[O:22])=[CH:17][C:16]=1[N+:56]([O-:58])=[O:57])[CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCOCC1.Cl>[CH3:59][N:2]([CH3:1])[CH2:3][CH2:4][C@@H:5]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][N:41]4[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]4)=[CH:35][C:34]=3[O:54][CH3:55])=[CH:29][CH:28]=2)=[O:26])(=[O:22])=[O:23])=[CH:17][C:16]=1[N+:56]([O-:58])=[O:57])[CH2:6][S:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1cc(CCN2CCN(C(=O)OC(C)(C)C)CC2)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(N[C@H](CCN(C)C)CSc3ccccc3)c([N+](=O)[O-])c2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc(CCN2CCNCC2)ccc1-c1ccc(C(=O)NS(=O)(=O)c2ccc(N[C@H](CCN(C)C)CSc3ccccc3)c([N+](=O)[O-])c2)cc1

Procedure:
A solution of Example 491F (284 mg, 0.34 mmol) in 1,4-dioxane (1.5 mL) and 4M HCl (1.5 mL) at room temperature was stirred for 16 hours. The solution was purified by flash column chromatography on silica gel with 80:20:0.5 dichloromethane/methanol/concentrated ammonium hydroxide to provide the desired product. MS (ESI) m/e 745, 747 (M−H)−, (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 2.11 (m, 2H), 2.62 (s, 6H), 2.67 (m, 4H), 2.77 (m, 2H), 3.00 (m, 2H), 3.06 (m, 4H), 3.16 (d, 2H), 3.33 (t, 2H), 3.75 (s, 3H), 4.09 (m, 1H), 6.88 (d, 1H), 6.95 (d, 1H), 6.98 (s, 1H), 7.15-7.22 (m, 2H), 7.24-7.33 (m, 4H), 7.38 (d, 2H), 7.82 (dd, 1H), 7.88 (d, 2H), 8.17 (d, 1H), 8.47 (d, 1H).
Reaction SMILES: [B-](F)(F)(F)F.[CH3:6][CH2:7][O+](CC)CC.[CH3:13][O:14][C:15]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH2:19])=[O:18]>C(Cl)Cl>[CH3:13][O:14][C:15]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](=[NH:19])[O:18][CH2:6][CH3:7]
Reactant: COc1c(C)cccc1C(N)=O
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(=N)c1cccc(C)c1OC
Reaction time: 72 h

Procedure:
A solution of triethyloxonium borofluoride (23 g.) in anhydrous methylene chloride (60 ml.) was added to a solution of 2-methoxy-3-methylbenzamide [19.7 g; prepared as described in French Patent M.21] in anhydrous methylene chloride (200 ml.). The mixture was kept at room temperature for 3 days, concentrated to about 120 ml. and diluted with anhydrous diethyl ether (300 ml.). The solid which separated was filtered off and washed with anhydrous diethyl ether to give ethyl 2-methoxy-3-methylbenzimidate borofluoride (28.7 g.), m.p. 93°-96° C., which was pure enough for use in the next stage of the synthesis. An aliquot was recrystallised from a mixture of anhydrous methylene chloride and anhydrous diethyl ether to give pure ethyl 2-methoxy-3-methylbenzimidate borofluoride, m.p. 102°-104° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:16]2[CH:15]=[CH:14][C:13]3[CH:17]=[CH:18][CH:19]=[C:20](I)[C:12]=3[C:11](=O)[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=O)C.O.[NH2:24][NH2:25]>>[N:24]1[NH:25][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][OH:4])=[C:16]3[CH:15]=[CH:14][C:13]4[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=4[C:11]=1[C:10]=23
Reactant: CC(=O)OCc1cccc2c(=O)c3c(I)cccc3ccc12
Reactant: NN
Solvent: O
Product: OCc1ccc2[nH]nc3c2c1C=Cc1ccccc1-3

Procedure:
The mixture of (6-iodo-5-oxo-5H-dibenzo[a,d]cyclohepten-1-yl)methyl acetate with its 4-iodo form prepared in Example 6-h was treated with hydrazine monohydrate by the procedure of Example 1-h, and purified and separated by silica gel column chromatography (ethyl acetate:hexane=3:7), to give 320 mg and 1.1 mg of the title compounds as yellow powders, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([F:19])[C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[F:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH2:32][NH2:33]>>[Cl:1][C:2]1[CH:18]=[C:17]([F:19])[C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:33][CH2:32][C:31]1[CH:34]=[CH:35][CH:36]=[C:29]([F:28])[CH:30]=1
Reactant: NCc1cccc(F)c1
Reactant: O=C(N1CCc2c(F)cc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: O=C(N1CCc2c(F)cc(Cl)c(NCc3cccc(F)c3)c2CC1)C(F)(F)F
Yield: 27.9 %

Procedure:
Use a method similar to the General Procedure 5-1 to couple 7-chloro-9-fluoro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (130 mg, 0.3 mmol) with 3-fluorobenzylamine (100 □L, 0.89 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 and 4:1) followed by SCX chromatography to give 7-chloro-9-fluoro-6-(3-fluorobenzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (35 mg, 28%). MS (ES+) m/z: 401 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([O:19][CH2:20][CH2:21][S:22][CH3:23])[CH:3]=1.Cl.I([O-])(=O)(=O)=[O:26].[Na+].[OH-].[Na+]>O.C(Cl)Cl>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])=[O:7])=[C:4]([O:19][CH2:20][CH2:21][S:22]([CH3:23])=[O:26])[CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCSC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCCS(C)=O
Reaction time: 2 h
Yield: 93.3 %

Procedure:
To a stirred solution of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[2-(methylthio)ethoxy]benzamide (1.0 g, 2.28 mmoles) (prepared in Example 20) and 1.4N HCl solution (3.97 ml, 5.56 mmoles) in 15 ml of H2O at 0°-5°, was added sodium metaperiodate (0.625 g, 2.92 mmoles). The mixture, which soon began to darken, was stirred at 0°-5° to 2 hours. The mixture was then diluted to 50 ml and made alkaline (pH=12) with NaOH solution. Methylene chloride (50 ml) was added, the mixture was shaken well, and the layers were separated. The aqueous layer was extracted with 3 portions of methylene chloride and the combined organic solutions were dried (anhydrous MgSO4) and evaporated. A dark oil (0.96 g) which solidified upon standing was obtained. The crude product was flash chromatographed on silica, eluting with CH2Cl2 :CH3OH:NH4OH, 80:20:0.5. Appropriate fractions were combined and evaporated to give 0.80 g (77%) of the title compound as a yellow resin which crystallized upon standing, mp. 110°-114°.
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][C:4]1[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[C:6]([CH3:12])=[CH:7][C:8]=1[C:9](Cl)=[O:10]>C1COCC1>[CH3:3][C:4]1[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[C:6]([CH3:12])=[CH:7][C:8]=1[C:9]([NH2:2])=[O:10]
Reactant: [NH4+]
Reactant: Cc1cc(C(=O)Cl)c(C)n1-c1ccccc1C(F)(F)F
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C(N)=O)c(C)n1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Yield: 96.2 %

Procedure:
To conc ammonium hydroxide (28%, 9.8 mL, 70 mmol) at 0° C. was added cautiously a solution of 2,5-dimethyl-1-(2-trifluoromethyl-phenyl)-1H-pyrrole-3-carbonyl chloride (2.1 g, 7.0 mmol) in THF (10 mL). After 10 min the reaction mixture was removed from the ice-bath and allowed to stir at ambient temperature. After 1 h the mixture was added to satd NH4Cl (30 mL) and extracted with DCM (3×30 mL). The combined extracts were washed with water (2×50 mL) and brine (50 mL), dried (anhyd Na2SO4) and concentrated under reduced pressure to afford the title compound (1.9 g, 96%) as a pale brown solid, which was used without purification in the next step. 1H-NMR (DMSO-d6) δ 7.98 (1H, d, J=7.8), 7.88 (1H, app t, J=7.8), 7.78 (1H, app t, J=7.8), 7.44 (1H, d, J=7.8), 7.17 (1H, brs), 6.66 (1H, brs), 6.35 (1H, s), 2.07 (3H, s), 1.81 (3H, s).
Reaction SMILES: O1CCCC1.[S:6]1[CH2:11][CH2:10][CH2:9][S:8][CH2:7]1.C([Li])CCC.[C:17]([C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][CH2:28][C:29]2=[O:34])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCCCCC>[C:17]([C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][CH2:28][C:29]2([CH:7]1[S:8][CH2:9][CH2:10][CH2:11][S:6]1)[OH:34])(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: C1CSCSC1
Reactant: O=C1CCc2c1cccc2C(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(c1ccccc1)c1cccc2c1CCC2(O)C1SCCCS1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
In 100 ml. of dry tetrahydrofuran is dissolved 3.6 g. of 1,3-dithian and while the solution is chilled to -30°C in nitrogen gas streams and stirred, 10 ml. of a 20 % solution of n-butyl lithium in hexane is added dropwise over a period of about 15 minutes. After the dropwise addition has been completed, the solution is stirred at that temperature for 2 hours and, then, at -5°C for 30 minutes. The solution is chilled again to -20°C and, under stirring, a solution of 7.1 g. of 4-benzoylindan-1-one in 75 ml. of dry tetrahydrofuran is added dropwise. After the dropwise addition has been completed, the mixture is stirred at that temperature for 1 hour, after which it is allowed to stand at 0°C overnight. Then, the solvent is distilled off undr reduced pressure. To the residue is added 15 ml. of dilute hydrochloric acid, followed by extraction with ether. The extract is washed with water and aqueous sodium chloride and, then, dried. The solvent is distilled off under reduced pressure and the residue is purified by column chromatography on silica gel (500 g. silica gel, eluted with a 20:1 mixture of benzene and ethyl acetate). The described procedure gives 2-(4-benzoyl-1-hydroxy-1-indanyl)-1,3-dithian as an oily product. The infrared absorption spectrum (neat) of this product is in good agreement with the assumed structure, absorbing at 1660 cm-1 (ketone) and 3450 cm-1 (hydroxyl).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:16][NH:15][CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1.[F:26][C:27]([F:44])([F:43])[C:28]1[CH:29]=[CH:30][C:31]([N:34]2[CH2:39][CH2:38][CH:37]([C:40](O)=[O:41])[CH2:36][CH2:35]2)=[N:32][CH:33]=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>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:25])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[CH2:16][N:15]([C:40]([CH:37]3[CH2:38][CH2:39][N:34]([C:31]4[CH:30]=[CH:29][C:28]([C:27]([F:44])([F:26])[F:43])=[CH:33][N:32]=4)[CH2:35][CH2:36]3)=[O:41])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Reactant: O=C(O)C1CCN(c2ccc(C(F)(F)F)cn2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C(F)(F)F)cn3)CC2)C[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
A mixture of 125 mg (0.456 mmol) rac-[(3S,4R)-4-(4-Chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester, 198 mg (0.547 mmol) 1-(5-(trifluoromethyl)pyridin-2-yl)piperidine-4-carboxylic acid, 208 mg (0.547 mmol) HATU and 353 mg (2.73 mmol) DIPEA in 10 mL DMF and stirred for 1 h ar room temperature. The mixture was concentrated and DMF and DIPEA was added and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 187 mg (66%) of the title compound as light brown viscous oil. MS m/e: 619.4 [M+H]+.
Reaction SMILES: C(P(=O)(OCC)OCC)#N.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH2:27][O:28][CH3:29])=[C:21]([CH3:30])[C:20]=2[CH3:31])=[CH:14][C:13]=1[N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].[O:41]=[C:42]1[NH:46][C:45](=[O:47])[CH:44]([CH2:48][C:49]2[CH:59]=[CH:58][C:52]([O:53][CH2:54][C:55](O)=[O:56])=[CH:51][CH:50]=2)[S:43]1.C(N(CC)CC)C>O1CCCC1>[O:41]=[C:42]1[NH:46][C:45](=[O:47])[CH:44]([CH2:48][C:49]2[CH:50]=[CH:51][C:52]([O:53][CH2:54][C:55]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[C:23]([CH3:25])[C:22]([O:26][CH2:27][O:28][CH3:29])=[C:21]([CH3:30])[C:20]=4[CH3:31])=[CH:14][C:13]=3[N:32]([CH3:40])[C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:56])=[CH:58][CH:59]=2)[S:43]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: COCOc1c(C)cc(Oc2ccc(N)c(N(C)C(=O)OC(C)(C)C)c2)c(C)c1C
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCOc1c(C)cc(Oc2ccc(NC(=O)COc3ccc(CC4SC(=O)NC4=O)cc3)c(N(C)C(=O)OC(C)(C)C)c2)c(C)c1C
Temperature: 25 °C
Reaction time: 17 h
Yield: 75.9 %

Procedure:
7.34 g of diethyl cyanophosphonate were added to a mixture of 18.7 g of t-butyl N-[2-amino-5-(4-methoxymethoxy-2,3,5-trimethylphenoxy)phenyl]-N-methylcarbamate, 12.6 g of 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid, 4.55 g of triethylamine and 300 ml of anhydrous tetrahydrofuran. The resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated by evaporation. Water was then added to the concentrate. After extraction with ethyl acetate, the extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography through a silica gel column (eluting solvent: n-hexane/ethyl acetate=1/1), whereby 23.1 g of the desired compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][CH:11]=[CH:12][CH3:13])[CH2:7][N:6]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:4].[O:21]=O>CN(C=O)C.O.[Pd](Cl)Cl.[Cu]Cl>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([CH2:10][CH2:11][C:12](=[O:21])[CH3:13])[CH2:7][N:6]1[C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[O:4]
Reactant: O=O
Reactant: CC=CCC1CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Agent: Cl[Cu]
Agent: Cl[Pd]Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1CC(CCC(C)=O)CN1C(=O)OC(C)(C)C
Yield: 71 %

Procedure:
To a solution of 4-but-2-enyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (149 mg, 0.42 mmol, 1 equiv) in DMF (1.4 mL) and water (0.2 mL) were added palladium(II)chloride (7.4 mg, 0.042 mmol, 0.1 equiv) and copper(I) chloride (41.1 mg, 0.42 mmol, 1 equiv). The mixture was stirred at 50° C. overnight with oxygen bubbling into the mixture. The mixture was filtered and the filtrate was concentrated under high vacuum. The residue was diluted with ethyl acetate, washed with water (1×), brine (1×), dried and concentrated. The residue was purified by preparative TLC to give 4-(3-oxo-butyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (110 mg, 71%).
Reaction SMILES: B.C1COCC1.C(O[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH:15]1[C:27]([OH:29])=O)=[O:13])(C)(C)C.[H-].[Na+]>C1COCC1>[O:13]=[C:12]1[N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:16][CH:15]2[CH2:27][O:29]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(=O)O)C1
Agent: B
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN2C(=O)OCC2C1
Temperature: 50 °C
Reaction time: 1 h
Yield: 20.2 %

Procedure:
Borane-THF complex (1.0 M solution in THF, 200 mL, 200 mmol) was added slowly to a solution of 1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (30.3 g, 91.7 mmol) in THF (100 mL). Upon complete addition, the reaction mixture was heated to 50° C. for 2 h. Upon cooling to rt, the reaction mixture was carefully quenched by the dropwise addition of MeOH. After gas evolution ceased, the reaction mixture was concentrated under reduced pressure. The material was dissolved in EtOAc (300 mL) and washed with 1 N NaOH (2×200 mL) and brine (200 mL). The organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. The material was twice dissolved in THF (50 mL) and concentrated under reduced pressure. The material was dissolved in THF (200 mL) and NaH (60% dispersion in mineral oil, 0.366 g, 0.916 mmol) was added portionwise. The reaction mixture was heated to reflux. After 1 h, the reaction mixture was allowed to cool to rt and was concentrated under reduced pressure. The material was dissolved in EtOAc (300 mL), washed with water (2×200 mL) and brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting solid was dissolved in EtOAc (200 mL) with heating, diluted with hexanes (200 mL) and allowed to cool to rt. The white, crystalline solid was collected by filtration after 5 h, washed with hexanes (2×), and dried under vacuum. This gave 13.29 g (60%) of the product. The filtrate was concentrated under reduced pressure, dissolved in EtOAc (50 mL) with heating, and diluted with hexanes (200 mL). This was allowed to cool to rt and sit over the weekend. The white, crystalline solid was collected by filtration, washed with hexanes (2×), and dried under vacuum. This gave an additional 4.49 g (20%) of the product. Analytical data: Rf=0.43 in 80% EtOAc/Hexanes; 1H NMR (400 MHz, CDCl3) δ 4.41 (t, J=8.4 Hz, 1H), 4.35-3.98 (br, 2H), 3.92 (dd, J=5.6 and 8.8 Hz, 1H), 3.80-3.72 (m, 2H), 2.98 (dt, J=3.6 and 12.4 Hz, 1H), 2.86-2.70 (br, 1H), 2.70-2.55, (br, 1H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 156.7, 154.2, 81.1, 65.5, 52.9, 47.7 (br), 43.4 (br), 41.1, 28.7. LC-MS: RT=6.46 min; [M+Na]+=264.9. Anal. Calcd for C11H18N2O4: C, 54.53; H, 7.49; N, 11.56. Found: C, 54.38; H, 7.44; N, 11.35.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5]([C:9]([OH:11])=O)=[N:6][C:7]=1[CH3:8].[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[O:14][C:9](=[O:11])[C:5]2=[N:6][C:7]=1[CH3:8])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(C(=O)O)c(C(=O)O)cc1O
Product: CC(=O)Oc1cc2c(nc1C)C(=O)OC2=O
Temperature: 140 °C

Procedure:
A suspension of 1.0 g (5.1 mmol) 5-hydroxy-6-methylpyridine-2,3-dicarboxylic acid and 5 ml acetic acid anhydride are heated at a bath temperature of 140° C. until a clear solution is produced. After compressing, the desired product is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:11]=2[CH2:12][NH:13][CH2:14][CH3:15])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH:24]1([C:27]([OH:29])=O)[CH2:26][CH2:25]1>>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:11]=2[CH2:12][N:13]([CH2:14][CH3:15])[C:27]([CH:24]2[CH2:26][CH2:25]2)=[O:29])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: O=C(O)C1CC1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(Br)cnc1OC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(Br)cnc1OC)C(=O)C1CC1

Procedure:
[2-(5-Bromo-2-methoxy-pyridin-3-yl)-5-trifluoromethyl-benzyl]-ethyl-amine and cyclopropanecarboxylic acid were reacted as described in Example 8, Step 6 to provide cyclopropanecarboxylic acid [2-(5-bromo-2-methoxy-pyridin-3-yl)-5-trifluoromethyl-benzyl]-ethyl-amide.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]([CH3:12])[CH2:9][C:10]#[CH:11])(=O)=O.[F:13][C:14]([F:24])([F:23])[CH2:15][CH2:16][S:17]([CH2:20][C:21]#[N:22])(=[O:19])=[O:18].[H-].[Na+].Cl>CS(C)=O>[CH3:12][CH:8]([CH2:9][C:10]#[CH:11])[CH2:7][CH2:6][CH:20]([S:17]([CH2:16][CH2:15][C:14]([F:13])([F:23])[F:24])(=[O:18])=[O:19])[C:21]#[N:22]
Reactant: C#CCC(C)CCOS(C)(=O)=O
Reactant: N#CCS(=O)(=O)CCC(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C#CCC(C)CCC(C#N)S(=O)(=O)CCC(F)(F)F
Temperature: 90 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
To a solution of 1.0 g of 3-methyl-5-hexynyl methanesulfonate and 1.1 g of (3,3,3-trifluoropropylsulfonyl)acetonitrile in 30 ml of dimethyl sulfoxide was added 0.2 g of sodium hydride (60% in oil) at room temperature. The reaction mixture was stirred at 60° C. for 3 days and at 90° C. for 2 hours. The reaction mixture was allowed to stand to cool to nearly room temperature. To the reaction mixture was added 10% hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.69 g of 5-methyl-2-(3,3,3-trifluoropropylsulfonyl)-7-octynenitrile (hereinafter referred to as the present compound (27)).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[C:9]12(O)[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>O>[C:9]12([S:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc(SC23CC4CC(CC(C4)C2)C3)cc1
Yield: 91.2 %

Procedure:
3.78 g (20 mmol) of p-bromothiophenol, 3.04 g (20 mmol) of 1-adamantanol and 10 ml of trifluoroacetic acid are stirred at ambient temperature for 8 hours and then poured into water. Sodium bicarbonate is added until the mixture is neutral at which time it is extracted with methylene chloride. The organic phase is dried and evaporated. After recrystallization in isooctane, 5.9 g of the expected product are obtained. Yield - 92%. Melting point: 121°-122° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]Cl)=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2].[SH:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][S:16][C:17]2[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=2[C:19]([OH:21])=[O:20])=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Reactant: O=C(O)c1ccccc1S
Product: O=C(O)c1ccccc1SSc1ccc([N+](=O)[O-])cc1C(Cl)(Cl)Cl
Yield: 87.1 %

Procedure:
61.4 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride are reacted with 32 g of 2-mercaptobenzoic acid by a method similar to that of Example 1. 74 g (87% of theory) of o-(4-nitro-2-trichloromethylphenyldithio)-benzoic acid of melting point 224° C., are obtained.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][OH:6].[CH2:7]=[C:8]1[O:12][C:10](=[O:11])[CH2:9]1>O1CCCC1>[OH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[C:10](=[O:11])[CH2:9][C:8](=[O:12])[CH3:7]
Reactant: CNCCCO
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N(C)CCCO
Temperature: 0 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of 20 g (0.23 mol) of 3-methylamino-1-propanol in 50 ml tetrahydrofuran was added dropwise to a solution of 18 g of diketene (0.21 mol) in 200 ml tetrahydrofuran −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 29.2 g (0.17 mol, 79% yield) of a colorless oil.