Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=2)[C:10]2[CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[S:27][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[C:10]2[CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[S:27][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc2c(C3=CCCCC3)c(-c3ccccc3)n(Cc3ccccc3)c2s1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc2c(C3CCCCC3)c(-c3ccccc3)n(Cc3ccccc3)c2s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution (0.7 M) of methyl 6-benzyl-4-cyclohex-1-en-1-yl-5-phenyl-6H-thieno[2,3-b]pyrrole-2-carboxylate in TFA at 0° C. was treated with triethylsilane (1.5 eq.). The mixture was stirred at 0° C. for 1 h then concentrated to give a residue that was purified by flash chromatography on silica gel (1:30 acetone/toluene) affording methyl 6-benzyl-4-cyclohexyl-5-phenyl-6H-thieno[2,3-b]pyrrole-2-carboxylate as a solid that was dissolved in THF/MeOH (1:1). The resulting solution (0.04 M) was treated with aqueous KOH (1 N solution, 4 eq.) then the mixture was heated to 80° C. for 4 h. After cooling down, the mixture was concentrated then the resulting residue was diluted with water and pH was turned to neutral value by addition of aqueous ammonium chloride (saturated solution). The mixture was concentrated to give a residue that was purified by RP-HPLC (Conditions: Waters X-TERRA MS C18, 10 micron, 10×150 mm; flow: 20 mL/min; Gradient: A: H2O+0.05% TFA; B: MeCN+0.05% TFA; 50% A isocratic for 2 min then linear to 0% A in 10 min) to afford the title compound (58%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:27]=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=4)([OH:25])[C:19]4[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=4)[CH:16]=3)[NH:11][C:10](=[O:33])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[CH3:36]I>C1COCC1.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:26]4[CH:27]=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=4)([OH:25])[C:19]4[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=4)[CH:16]=3)[N:11]([CH3:36])[C:10](=[O:33])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)nc1)c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1
Reactant: CI
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc(Cl)nc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.4 %

Procedure:
To a solution of 4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1H-quinolin-2-one (351 mg, 0.737 mmol) in THF (15 ml) was added a 40% aqueous NaOH (2 ml), benzyltriethylammonium chloride (84 mg. 0.369 mmol) and a solution of methyl iodide (0.078 ml, 1.25 mmol) in THF (4 ml). The reaction mixture was stirred at ambient temperature for 4 hours after which time it was partitioned between CHCl3 and water. The organic layer was washed with brine, dried over MgSO4 and concentrated under vacuum to give the crude product. It was chromatographed on silica gel with MeOH—CHCl3—NH4OH (2:98:0.2 to 5:95:0.5) as eluents to afford the title compound as a white solid (200.3 mg, 0.408 mmol, 55% yield).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[Cl:9].[F:10][C:11]([F:22])([F:21])[C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:9][C:3]1[CH:4]=[C:5]([NH2:6])[CH:7]=[CH:8][C:2]=1[C:15]1[CH:16]=[CH:17][C:12]([C:11]([F:22])([F:21])[F:10])=[CH:13][CH:14]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(Br)c(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1ccc(-c2ccc(C(F)(F)F)cc2)c(Cl)c1
Temperature: 90 °C

Procedure:
4-bromo-3-chloroaniline (2.1 g, 10.2 mmol), (4-(trifluoromethyl)phenyl)boronic acid (2.7 g, 14.2 mmol), Pd(dppf)Cl2 (744 mg, 1.0 mmol), 2M aqueous Na2CO3 (15.3 mL, 30.5 mmol) were dissolved in 1,4-dioxane (30 mL) and the resulting mixture was heated to 90° C. After 16 h the resulting mixture was cooled to room temperature, was diluted with EtOAc, washed with water and brine. The organic layer was dried (Na2SO4), concentrated and diethyl ether was added. The resulting precipitate was filtered and dried in vacuo to yield the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([O:15][CH3:16])=[O:14])[C:9]([OH:11])=[O:10].[CH2:17](NC(C1C=CC=CC=1)C(O)=O)[CH3:18]>>[CH2:17]([N:12]([CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)[C:9]([OH:11])=[O:10])[C:13]([O:15][CH3:16])=[O:14])[CH3:18]
Reactant: COC(=O)NC(C(=O)O)c1ccccc1F
Reactant: CCNC(C(=O)O)c1ccccc1
Product: CCN(C(=O)OC)C(C(=O)O)c1ccccc1

Procedure:
(Ethyl-methoxycarbonyl-amino)-phenyl-acetic acid was prepared using the procedure used to prepare (2-Fluoro-phenyl)-methoxycarbonylamino-acetic acid using Ethylamino-phenyl-acetic acid. LCMS-ESI+: calc'd for C12H15NO4: 237.10 (M+); Found: 238.03 (M+H+).
Reaction SMILES: C([O:3][C:4](=[O:44])[CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][N:21]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:20]1)=[O:17])C.[OH-].[Na+].Cl>C(O)C>[C:36]([O:35][C:33]([N:21]1[CH2:22][C@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:24][C@H:19]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:16]([C:8]2[N:7]([CH2:6][CH2:5][C:4]([OH:44])=[O:3])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)=[O:17])[CH2:20]1)=[O:34])([CH3:37])([CH3:39])[CH3:38]
Reactant: CCOC(=O)CCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCC(=O)O)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100.1 %

Procedure:
To a solution of tert-butyl (3S,5R)-3-[{[1-(3-ethoxy-3-oxopropyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (225 mg) in ethanol (5 ml) was added 2M aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 3 days. The reaction mixture was adjusted to pH 7 with 1M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object product (215 mg).
Reaction SMILES: C([SiH](CC)CC)C.[CH:8]1([NH:11][C:12](=[O:24])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[CH:16]=2)[CH2:10][CH2:9]1>CO.[Pd]>[NH2:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[O:14][CH2:13][C:12]([NH:11][CH:8]1[CH2:9][CH2:10]1)=[O:24]
Reactant: O=C(COc1cccc([N+](=O)[O-])c1)NC1CC1
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: CO
Product: Nc1cccc(OCC(=O)NC2CC2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 81.9 %

Procedure:
Triethylsilane (27.0 ml, 169 mmol) was added dropwise to a suspension of N-cyclopropyl-2-(3-nitrophenoxy)acetamide (4 g, 16.93 mmol) and Pd/C (10%, 400 mg) in MeOH (50 ml). Resulting suspension was stirred at RT for 20 min. and filtered through celite. The filtrate was evaporated under vacuum and triturated in hexane to obtain the crystals which were collected by filtration to afford 2-(3-aminophenoxy)-N-cyclopropylacetamide (2.86 gm).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[O:35][C@H:34]([CH2:36][OH:37])[C@@H:32]([OH:33])[C@H:12]2[O:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:4](N)[N:3]=1.CS(C)=[O:41].[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[CH2:14]([O:13][C@@H:12]1[C@H:32]([OH:33])[C@@H:34]([CH2:36][OH:37])[O:35][C@H:11]1[N:8]1[C:9]2[N:10]=[C:2]([NH2:1])[NH:3][C:4](=[O:41])[C:5]=2[N:6]=[CH:7]1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCCCCCCCCCO[C@H]1C(n2cnc3c(N)nc(N)nc32)O[C@H](CO)[C@H]1O
Reactant: CS(C)=O
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: CCCCCCCCCCCCCCCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21
Reaction time: 216 h

Procedure:
2,6-Diamino-9-(2-O-octadecyl--D-ribofuranosyl) purine (10 g) in 0.1 M sodium phosphate buffer (50 mL, pH 7.4), 0.1 M tris buffer (1000 mL, pH 7.4) and DMSO (1000 mL) was treated with adenosine deaminase (1.5 g) at RT. At day 3, day 5 and day 7 an additional aliquot (500 mg, 880 mg and 200 gag, respectively) of adenosine deaminase was added. The reaction was stirred for a total of 9 day and purification by silica gel chromatography yielded the product (2 g). An analytical sample was recrystallized from MeOH 1H NMR (DMSO-d6)δ 0.84 (t, 3, CH3), 1.22 [s, 32, O--CH2 --CH2 --(CH2)16 ], 5.07 (m, 2, 3'-OH and 5'-OH); 5.78 (d, 1, 1'-H); 6.43 (s, 2, NH2), 7.97 (s, 1, 8-H) and 10.64 (s, 1, NH2). Anal. Calcd. for C28H49N5O5 : C, 62.80; H, 9.16; N, 12.95. Found: C, 62.54; H, 9.18; N, 12.95.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7](=[NH:14])[S:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]([CH:19]1[CH2:23][CH2:22][C:21]([CH3:27])([C:24](O)=[O:25])[C:20]1([CH3:29])[CH3:28])=[O:18]>C(N(CC)CC)C>[CH2:10]([C:8]1=[CH:9][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6]/[C:7]/1=[N:14]\[C:24]([C:21]1([CH3:27])[CH2:22][CH2:23][CH:19]([C:17]([O:16][CH3:15])=[O:18])[C:20]1([CH3:29])[CH3:28])=[O:25])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1cn(C(C)(C)C)sc1=N
Reactant: COC(=O)C1CCC(C)(C(=O)O)C1(C)C
Solvent: CCN(CC)CC
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(C)CCC(C(=O)OC)C1(C)C
Temperature: 60 °C

Procedure:
To a 20-mL scintillation vial containing a magnetic stir bar were added the product from Example 92B (637 mg, 3.00 mmol), racemic 3-(methoxycarbonyl)-1,2,2-trimethylcyclopentanecarboxylic acid (Maybridge, 771 mg, 3.60 mmol), and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (TBTU, Bachem, 1.16 g, 3.60 mmol). Anhydrous acetontirile (8 mL) was added to form a white slurry. Neat triethylamine (Aldrich, 1.09 g, 10.8 mm0l) was added via syringe to form a tan solution. The reaction flask was heated to 60° C. in a shaker block and mixed for 2 hours. The volatiles were removed by rotary evaporator to give a brown oil. The product was purified by flash chromatography (silica gel: 2-20% ethyl acetate in hexanes) to afford the title compound. 1H NMR (DMSO-d6) δ ppm 0.50 (s, 3H), 0.90 (t, J=7.5 Hz, 3H), 1.21 (s, 3H), 1.24-1.36 (m, 2H), 1.30 (s, 3H), 1.41-1.51 (m, 1H), 1.57 (s, 9H), 1.57-1.67 (m, 2H), 1.73-1.87 (m, 1H), 2.01-2.11 (m, 1H), 2.62-2.67 (m, 2H), 2.70-2.81 (m, 1H), 2.85-2.91 (m, 1H), 3.60 (s, 3H), 8.50 (s, 1H). MS (ESI+) m/z 409 (M+H)+. Anal. calcd. for C22H36N2O3S: C, 64.67; H, 8.88; N, 6.86. Found: C, 64.20; H, 8.71; N, 6.59.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][OH:18].C(N(CC)CC)C.Cl>C(Cl)(Cl)Cl>[C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([O:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][Cl:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: OCCOCCCl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOCCCl)cc1
Temperature: 0 °C

Procedure:
In a round bottom flask 9.53 g (50 mmol) of p-Toluenesulfonylchloride were mixed with 7.47 g (60 mmol) 2-(2-Chloroethoxy)ethanol in 50 ml CHCl3. The mixture was stirred and cooled below 5° C. and 10.1 g (100 mmol) triethylamine were added drop-wise at this temperature. After the addition was completed, the mixture was stirred for another 3 h at room temperature. At which point, a mixture of 50 g ice and 20 ml conc. HCl was added carefully and stirred for 30 min. The chloroform phase was separated, washed three times with 30 ml water, dried with Na2SO4 and the solvent removed in vacuo upon which 12.5 g (90%) of a yellowish oil was obtained. The product was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([C:8]2[N:16]3[C:11]([CH:12]=[CH:13][C:14]([NH:17]C(=O)OC(C)(C)C)=[CH:15]3)=[C:10]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:9]=2[CH3:33])=[O:7])=[CH:4][C:3]=1[O:36][CH3:37].FC(F)(F)C(O)=O>>[NH2:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([C:8]2[N:16]3[C:11]([CH:12]=[CH:13][C:14]([NH2:17])=[CH:15]3)=[C:10]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[C:9]=2[CH3:33])=[O:7])=[CH:4][C:3]=1[O:36][CH3:37]
Reactant: COc1ccc(-c2c(C)c(C(=O)c3ccc(N)c(OC)c3)n3cc(NC(=O)OC(C)(C)C)ccc23)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2c(C)c(C(=O)c3ccc(N)c(OC)c3)n3cc(N)ccc23)cc1

Procedure:
This compound is prepared according to the same method as that described in Example 49 by unblocking tert-butyl [3-(4-amino-3-methoxybenzoyl)-1-(4-methoxyphenyl)-2-methylindolizin-6-yl]carbamate with trifluoroacetic acid.
Reaction SMILES: [Mg].[C:2](=[O:4])=[O:3].Cl[C:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:20])[CH2:16][CH2:17][CH2:18][Cl:19])=[CH:11][CH:10]=1)([CH3:8])[CH3:7].Cl>[Cl-].C([N+](CC)(CC)CC)C.CN(C)C=O.[Ag]>[Cl:19][CH2:18][CH2:17][CH2:16][C:15]([C:12]1[CH:11]=[CH:10][C:9]([C:6]([CH3:8])([CH3:7])[C:2]([OH:4])=[O:3])=[CH:14][CH:13]=1)=[O:20]
Reactant: CC(C)(Cl)c1ccc(C(=O)CCCCl)cc1
Reactant: O=C=O
Agent: [Ag]
Agent: CC[N+](CC)(CC)CC
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C(=O)O)c1ccc(C(=O)CCCCl)cc1
Temperature: -10 °C
Yield: 72 %

Procedure:
Fit a jacketed glass cell of 50 mL capacity with an expanded silver mesh cathode (14 cm2 geometric area), a roughly concentric magnesium sacrificial anode, a tube to deliver carbon dioxide gas, and a magnetic stir bar. Cool the cell to −10° C. under carbon dioxide. Add a solution of tetraethylammonium chloride (40 mL of a 0.02M solution in dimethylformamide) and 1-[4-(1-chloro-1-methyl-ethyl)-phenyl]-4-chloro-butan-1-one (2.91 g, 85% pure by NMR, 9.81 mmol) and carry out electrolysis for 178 minutes at an average current density of 12.4 mA cm−2: the total charge passed is equal to 98% of the calculated theoretical two electron value. Warm the contents of the cell to ambient temperature, drain the contents, acidify with chilled aqueous 6M hydrochloric acid, extract and evaporate the solvent in vacuo to give the title compound (1.89 g, 72%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][CH:8]2[CH2:25][CH2:24][C:11]3([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.[ClH:26]>CO>[ClH:26].[ClH:26].[N:1]1[CH:2]=[CH:3][C:4]([O:7][CH:8]2[CH2:25][CH2:24][C:11]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][CH2:9]2)=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(Oc3ccncc3)CC2)CC1
Agent: Cl
Solvent: CO
Product: c1cc(OC2CCC3(CCNCC3)CC2)ccn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 9-(pyridin-4-yloxy)-3-azaspiro[5.5]undecane-3-carboxylate (1 g, 2.886 mmol) was dissolved in methanol (2 ml), hydrogen chloride in methanol (1.25 mol/l, 11.5 ml) was added and the mixture was refluxed for 30 min. The solvent was removed in vacuo and the residue was dissolved in a small amount of ethanol. Acetone (approx. 25 ml) was subsequently added, the mixture was stirred at 0° C. for 30 min and the solid formed was finally filtered out with suction. Yield: 0.96 g (>99%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccc(C)c(Nc2c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc3c(C(=O)O)cnn23)c1
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 67.4 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2,5-dimethylphenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.05 g, 0.10 mmol) obtained in step 2 and ethanesulfonamide (0.067 g, 0.62 mmol), the title compound (0.039 g, 65%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=[O:18])[C:8]3[C:13]4[CH2:14][CH2:15][CH2:16][CH2:17][C:12]=4[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1C=CC=CC=1>[CH3:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=[O:18])[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)Oc1sc3c(c1C(=O)N2)CCCC3
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)Oc1sc3ccccc3c1C(=O)N2
Yield: 81.4 %

Procedure:
In the same manner as in Example 77 and using 1,2,3,4-tetrahydro-8-methyl-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one (1.87 g), dichlorodicyano-p-benzoquinone (3.1 g) and benzene (55 ml), 8-methyl-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one (1.5 g) was obtained.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[CH:12]([O-])([O-])OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:12][O:11][C:2]1[CH2:3][CH2:4][C:5]2[C:10]([CH:1]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=C1CCc2ccccc2C1
Reactant: COC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COC1=Cc2ccccc2CC1
Yield: 75 %

Procedure:
A mixture of 1.4 g of 2-tetralone, 1.5 mL of methyl orthoformate, and a few crystals of para-toluenesulfonic acid monohydrate in 75 mL of benzene was stirred for 22 hours and then evaporated in vacuo. The residue was chromatographed on Florisil® eluting with hexane/ethyl ether to provide 1.15 g (75%) of the desired title intermediate. NMR.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[F:10])#[N:2].[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][Br:11])=[CH:5][C:4]=1[F:10])#[N:2]
Reactant: Cc1ccc(C#N)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)cc1F
Temperature: 25 °C

Procedure:
To a solution of the product from Step C (22.2 g, 165 mmol) in 220 mL of carbontetrachloride was added N-bromosuccinimide (29.2 g, 164 mmol) and benzoylperoxide (1.1 g). The reaction was heated to reflux for 30 minutes, then cooled to room temperature. The solution was concentrated in vacuo to one-third the original volume, poured into EtOAc, washed with water, sat. aq. NaHCO3, and brine, then dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. Analysis by 1H NMR indicated only partial conversion, so the crude material was resubjected to the same reaction conditions for 2.5 hours, using 18 g (102 mmol) of N-bromosuccinimide. After workup, the crude material was purified by silica gel chromatography (0-10% EtOAc/hexane) to provide the desired product.
Reaction SMILES: [CH3:1][P:2]([CH3:23])([CH2:4][CH2:5][N:6]([CH2:11][C:12]([S:15]CC1C=CC=CC=1)([CH3:14])[CH3:13])[CH2:7][CH2:8][O:9][CH3:10])=S.[Na].[Cl-].[NH4+]>O1CCCC1.C(Cl)(Cl)Cl>[CH3:23][P:2]([CH3:1])[CH2:4][CH2:5][N:6]([CH2:7][CH2:8][O:9][CH3:10])[CH2:11][C:12]([CH3:14])([CH3:13])[SH:15]
Reactant: COCCN(CCP(C)(C)=S)CC(C)(C)SCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COCCN(CCP(C)C)CC(C)(C)S
Temperature: -50 °C

Procedure:
A solution of N-(2-dimethylphosphinothioylethyl)-N-(2-methoxyethyl)-2-benzylthio-2-methylpropylamine (500 mg) in dry tetrahydrofuran (10 cm3) was placed in a flask fitted with a low temperature condenser (-50° C.), drying tube and gas inlet. The flask was flushed with nitrogen, the solution cooled to -50° C., and then dry ammonia (40 cm3) was condensed into the flask. Small pieces of sodium were then added to this mixture until the blue colouration persisted for at least 1 hour. The blue colouration was then discharged by the addition of ammonium chloride, and the mixture allowed to warm to room temperature. As the ammonia evaporated steps were taken to ensure that no air entered the apparatus. [The flask and its contents were then transfered to a glove box containing a nitrogen atmosphere for subsequent operations.] The reaction mixture was then filtered and the solvent removed under reduced pressure to give a yellow oil containing some solid material. The oil was dissolved in chloroform, the solid removed by filtration, and the solvent removed under reduced pressure to give 2-[N-(2-dimethylphosphinoethyl)-2-methoxyethylamino]-1,1-dimethylethanethiol as an oil.
Reaction SMILES: [CH3:1][C:2]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]2[OH:9].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][C@@:2]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]2[OH:9]
Reactant: CC12CCC(CC1O)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C[C@@]12CCC(CC1O)C2

Procedure:
Norbornanone (I) is reacted with methylmagnesium iodide to give 2-methyl-2-norbornanol (II). The compound (II) is reacted with acetic acid and a 75% solution of sulfuric acid to give 2-acetoxy-1-methylnorbornane (III) which is then converted into 1-methyl- 2-norbornanol (IV) with lithium-aluminum hydride. Then the compound (IV) is enzymatically resolved according to the method reported by Christian Triantaphylides et al., Tetrahedron Letters, 26(15), 1857 (1985) to give (1S)-1-methyl-2-norbornanol (V). This optically active alcohol (V) is then oxidized with pyridine dichromate complex to give (1S)-1-methyl-2-norbornanone (VI). The compound (VI) is reacted with methyltriphenylphosphonium bromide in the presence of n-butyllithium to give (1S)-2-methylenenorbornane (VII) which is then treated with peracetic acid to give an epoxy compound. This epoxy compound is treated with a boron trifluoride etherate complex to give (1S,2S)-1-methyl-2-norbornyl aldehyde (VIII) which is then reduced with lithium aluminum hydride to give (1S,2S)-1-methyl-2-hydroxymethylnorbornane (IX).
Reaction SMILES: [C:1]([C:5]1[CH:33]=[CH:32][C:8]([C:9]([NH:11][C:12]2[CH:27]=[CH:26][C:25]([C:28]([O:30]C)=[O:29])=[CH:24][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:11][C:12]2[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)=[O:15])=[O:10])=[CH:32][CH:33]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(NC(=O)c2ccc(C(C)(C)C)cc2)c(C(=O)Nc2ccc(Cl)cn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1ccc(C(=O)Nc2ccc(C(=O)O)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Reaction time: 16 h
Yield: 48.8 %

Procedure:
Into 5 mL MeOH was dissolved 91 mg (0.195 mmol) 2-(4-tert-butylbenzoylamino)-N-(5-chloropyridin-2-yl)-5-methoxycarbonylbenzamide, followed by 0.47 mL of 0.5 N (0.23 mmol) NaOH. The mixture was stirred 16 h, evaporated, diluted with 39.0 mL water, and extracted with 15 mL EtOAc-15 mL hexane mixture. The aquous layer was acidified with dilute HCl and extracted with 30 mL EtOH. The organic layer was dried (MgSO4) and evaporated, giving 43 mg (49%) title compound.