Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH:3]([OH:5])[CH3:4].C(N(CC)CC)C.[F:14][C:15]([F:27])([F:26])[C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:27][C:15]([F:14])([F:26])[C:16]1[CH:17]=[CH:18][C:19]([S:22]([O:6][CH2:1][CH2:2][CH:3]([OH:5])[CH3:4])(=[O:24])=[O:23])=[CH:20][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(O)CCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(O)CCOS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
A solution of 1,3-butanediol (2.00 g, 22.193 mmol) and triethylamine (2.695 g, 26.631 mmol) in 10 mL of methylene chloride was stirred at −20° C. under nitrogen. (4-trifluoromethyl)benzene sulfonyl chloride (5.429 g, 22.193 mmol) in 10 mL of methylene chloride was added drop wise to the solution, over 1 hr. The reaction was kept at −20° C. for an additional 3 hours and then stirred at room temperature for 24 hours. The reaction was quenched with water and then washed with 10% aqueous HCl (5×30 mL), sat. NaHCO3 (3×20 mL), H2O (2×20 mL) and brine (1×20 mL). The organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure. The product obtained was purified by column chromatography to get a white solid. (1.541 g, 23% yield). 1H NMR (400 MHz, CDCl3) δ1.19 (d, J=6.29, 3H, CH3), 1.66-1.76 (m, 1H, CH2), 1.80-1.91 (m, 1H, CH2), 3.93 (br. s, 1H, CH—OH), 4.14-4.23 (m, 1H, CH2O—SO2), 4.25-4.36 (m, 1H, CH2O—SO2), 7.81 (d, J=8.08, 2H, aromatic), 8.04 (d, J=8.71, 2H, aromatic). Repeat synthesis: To a solution of 1,3-butane diol (4.34 g, 48 mmol) and TEA (3.19 g, 31.5 mmol) in CH2Cl2 (20 mL) at 0° C. was added p-(trifluoromethyl)benzene-sulfonyl chloride (3.97 g, 16.2 mmol) dissolved in CH2Cl2 (20 mL). The solution was stirred at 0° C. for 2 h. Saturated aqueous NaHCO3 (15 mL) was added to the solution and mixture was stirred at rt for 40 min. The organics were extracted with CH2Cl2 (50 mL) and washed with 1 M HCl (3×25 mL) and saturated aqueous NaCl (1×25 mL). The organics were dried over Na2SO4 and concentrated to give the desired product (3.28 g, 65%). 1H NMR (400 MHz CDCl3) δ 8.02 (d, 2H, J=8.2 Hz), 7.80 (d, 2H, J=8.3), 4.29 (m, 1H), 4.17 (m, 1H), 3.91 (m, 1H), 1.83 (m, 1H), 1.70 (m, 1H), 1.17 (d, 3H, J=6.2 Hz); Anal. Calcd. For C11H13F3O4S: C, 44.29; H, 4.39. Found: C, 44.16; H, 4.17.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:17]=[C:18]3[C:24]4[CH:25]=[CH:26][C:27]([N:29]5[CH2:33][CH2:32][CH2:31][C@H:30]5[C:34]([O:36]C(C)(C)C)=[O:35])=[CH:28][C:23]=4[O:22][CH2:21][CH2:20][N:19]3[CH:41]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].C([SiH](CC)CC)C>ClCCl>[CH:8]([N:11]1[C:15]([C:16]2[N:17]=[C:18]3[C:24]4[CH:25]=[CH:26][C:27]([N:29]5[CH2:33][CH2:32][CH2:31][C@H:30]5[C:34]([OH:36])=[O:35])=[CH:28][C:23]=4[O:22][CH2:21][CH2:20][N:19]3[CH:41]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCC[C@H]3C(=O)OC(C)(C)C)cc1OCC2
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCC[C@H]3C(=O)O)cc1OCC2
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (3 ml) was added to a mixture of 153 mg of (S)-tert-butyl 1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxylate and 0.2 ml of triethylsilane in 5 ml of dichloromethane. The reaction mixture was stirred for 3 hours. The mixture was concentrated, the residue partitioned between 1 M aq. Na2CO3 and ethyl ether. The aqueous layer was extracted with ethyl acetate two more times. The organic layers were discarded, the aqueous solution neutralized to pH 6. A precipitate was collected, washed with water, dried in high vacuum for 36 hours to give (S)-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxylic acid. Yield 55 mg. M/z 409.3, calc. 408.19
Reaction SMILES: [CH:1]([N+:4]1[CH2:8][CH2:7][CH2:6][C:5]=1OC)([CH3:3])[CH3:2].[CH3:11][O:12][S:13]([O-:16])(=[O:15])=[O:14].[CH3:17][NH:18][CH3:19]>C1C=CC=CC=1>[CH:1]([N+:4]1[CH2:8][CH2:7][CH2:6][C:5]=1[N:18]([CH3:19])[CH3:17])([CH3:3])[CH3:2].[CH3:11][O:12][S:13]([O-:16])(=[O:15])=[O:14]
Reactant: COC1=[N+](C(C)C)CCC1
Reactant: CNC
Agent: COS(=O)(=O)[O-]
Solvent: c1ccccc1
Product: CC(C)[N+]1=C(N(C)C)CCC1

Procedure:
Add dropwise, with stirring, 161 g of 1-isopropyl-2-methoxy-1-pyrrolinium-methylsulfate to a solution of 43.8 g of dimethylamine in 283 ml of benzene. Subsequently, boil the resulting reaction mixture under reflux for 1.5 hours; separate off the heavy phase and wash it 4 times with, in each case, 50 ml of diethyl ether. Dry the washed product under a high vacuum to obtain 154 g (91% of theory) of the title compound as reddish oil.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:9]([OH:10])[CH2:8]1.C(C1C=C(C(C)C)C=C(C(C)C)C=1S(Cl)(=O)=O)(C)C.C1([NH3+])CCCCC1.[C:44]1([S-:50]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[P:51](=[S:54])([O-])[O-:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C1([NH3+])CCCCC1.C1([NH3+])CCCCC1.O>N1C=CC=CC=1>[C:44]1([SH:50]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[P:51]([O:13][CH2:12][C@H:11]2[O:14][C@@H:7]([N:6]3[CH:15]=[C:2]([F:1])[C:3](=[O:17])[NH:4][C:5]3=[O:16])[CH2:8][C@@H:9]2[OH:10])(=[S:54])[OH:52])[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: [O-]P([O-])(=S)[S-](c1ccccc1)c1ccccc1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1F
Agent: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: [NH3+]C1CCCCC1
Solvent: O
Solvent: c1ccncc1
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COP(O)(=S)[SH](c3ccccc3)c3ccccc3)O2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
A solution of 500 mg (2.03 mmol) of 2'-deoxy-5-fluorouridine in 5 ml of pyridine was cooled to -10° C. to 0° C. in an ice-water bath. To this solution was added dropwise a mixture of 1.00 g (3.30 mmol) of 2,4,6-triisopropylbenzenesulfonylchloride, 1.36 g (3.56 mmol) of S,S-diphenylphosphorodithioate monocyclohexylammonium and 5 ml of pyridine over the period of 10 minutes. After the completion of the dropwise addition, the mixture was stirred at room temperature overnight. To this reaction mixture was added 100 ml of water. The mixture was extracted with 10 ml of chloroform repeatedly three times. The extract was washed with an aqueous solution of dilute hydrochloric acid and water in order, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure The obtained residue was subjected to silica gel column chromatography with the use of a mixture of chloroform and methanol (9:1 v/v) as the eluent to give 599 mg of 2'-deoxy-5-fluorouridine 5'-(S,S-diphenylphosphorodithioate) in a glassy form (Yield 55%).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.OC(C(F)(F)F)=O.[NH2:33][CH2:34][C:35]([CH3:40])([CH3:39])[C:36]([OH:38])=[O:37].C[O-].[Na+]>CCO>[OH:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([S:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9][C:8]=1[C:6]([NH:33][CH2:34][C:35]([CH3:40])([CH3:39])[C:36]([OH:38])=[O:37])=[O:7]
Reactant: CC(C)(CN)C(=O)O
Reactant: CCCCOC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC(C)(CNC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O)C(=O)O
Temperature: 150 °C
Yield: 26.7 %

Procedure:
A mixture of 4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (60 mg, 0.17 mmol) (prepared according to WO 2004108681), 3-amino-2,2-dimethyl-propionic acid TFA salt (157 mg, 0.68 mmol) and NaOMe (73 mg, 1.36 mmol) in EtOH (2 mL) was heated at 150° C. in a microwave reactor for 6 h. The solvent was evaporated, and the residue was partitioned between water and EtOAc. 1 M HCl was added with vigorous stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-30% EtOAc/hexanes+2% AcOH) to give 18 mg of the title compound as a yellow solid. MS: (+) m/z 397.11 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[C:11]([F:17])=[N:12][CH:13]=[CH:14][C:15]=2[I:16])[OH:9])=[CH:4][CH:3]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[C:11]([F:17])=[N:12][CH:13]=[CH:14][C:15]=2[I:16])=[O:9])=[CH:6][CH:7]=1
Reactant: OC(c1ccc(Cl)cc1)c1c(I)ccnc1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)c1c(I)ccnc1F
Temperature: 45 °C

Procedure:
To a solution of (4-chlorophenyl)(2-fluoro-4-iodopyridin-3-yl)methanol (2.17 g, 5.98 mmol) in CH2Cl2 (100 mL) was added manganese dioxide (10.40 g, 120 mmol) at room temperature. The reaction was heated to 45° C. for 3 h before the heterogeneous mixture was filtered through a pad of silica gel. The cake was rinsed with EtOAc, and the filtrate was concentrated to dryness under vacuum. The residue was used in the next step without any additional purification. LC/MS m/z 362 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[N:13]([C@@H:22]([CH2:30][CH3:31])[CH2:23][NH:24][S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])[C:12](=[O:32])[C@:11]([CH2:34][C:35]([OH:37])=[O:36])([CH3:33])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].I[CH3:41]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:14]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[N:13]([C@@H:22]([CH2:30][CH3:31])[CH2:23][N:24]([CH3:41])[S:25]([CH2:28][CH3:29])(=[O:26])=[O:27])[C:12](=[O:32])[C@:11]([CH2:34][C:35]([OH:37])=[O:36])([CH3:33])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC[C@@H](CNS(=O)(=O)CC)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cc(F)cc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H](CN(C)S(=O)(=O)CC)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cc(F)cc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-((3R,5R,6S)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (Example 393, Step D, 26.6 mg, 0.046 mmol) in DMF (464 μl) at rt was added a dispersion of 60% sodium hydride in mineral oil (5.57 mg, 0.139 mmol). The grey slurry was stirred at rt for 30 min then iodomethane (5.80 μl, 0.093 mmol) was added. The mixture was stirred at rt for 1 h. The mixture was quenched with 1 M HCl and diluted with EtOAc. The aqueous layer was extracted with EtOAc 2×. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by reverse phase preparatory HPLC (column: Gemini™ Prep C18 10 um column; Phenomenex, Torrance, Calif.; eluent: 0 to 100% MeCN +0.1% TFA in water +0.1% TFA, over 20 minutes) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][OH:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([N:35]2[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36]2)(=[O:34])=[O:33])[C:22]([Cl:41])=[CH:21][N:20]=1>>[Cl:41][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([N:35]2[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36]2)(=[O:34])=[O:33])=[N:24][C:19]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][OH:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: C[C@H]1CCN(S(=O)(=O)c2ccccc2Nc2nc(Cl)ncc2Cl)C1
Reactant: COc1cc2c(cc1N)CCN(CCO)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CC[C@H](C)C3)n1)CCN(CCO)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-ethanol and (2,5-Dichloro-pyrimidin-4-yl)-[2-((S)-3-methyl-pyrrolidine-1-sulfonyl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white foam (0.035 g, 29%). MP: 65-85° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 9.37 (s, 1H), 8.49 (d, J=8.3 Hz, 1H), 8.15 (s, 1H), 8.01 (s, 1H), 7.94 (dd, J=8.0 Hz and 1.4 Hz, 1H), 7.57-7.50 (m, 2H), 7.25-7.20 (m, 1H), 6.65 (s, 1H), 3.87 (s, 3H), 3.64 (t, J=5.4 Hz, 2H), 3.43 (dd, J=9.5 Hz and 7.2 Hz, 1H), 3.40-3.34 (m, 1H), 3.30-3.22 (m, 1H), 2.90-2.86 (m, 2H), 2.80 (dd, J=9.5 Hz and 7.5 Hz, 1H), 2.24-2.11 (m, 1H), 1.96-1.87 (m, 1H), 1.43-1.33 (m, 1H), 0.86 (d, J=6.6 Hz, 3H). MS: 587.16 (MH)+.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([NH2:7])[CH2:3][CH2:2]1.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[C:25]3[C:24](=[O:26])[CH2:23][CH2:22][CH2:21][C:20]=3[N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)[C:18](=[O:37])[N:17]2[C:38](OC2C=CC([N+]([O-])=O)=CC=2)=[O:39])=[CH:12][CH:11]=1)#[N:9]>C(#N)C>[C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[C:25]3[C:24](=[O:26])[CH2:23][CH2:22][CH2:21][C:20]=3[N:19]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=3)[C:18](=[O:37])[N:17]2[C:38]([NH:7][CH:4]2[CH2:5][CH2:6][S:1][CH2:2][CH2:3]2)=[O:39])=[CH:14][CH:15]=1)#[N:9]
Reactant: NC1CCSCC1
Reactant: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: CC#N
Product: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2C(=O)NC2CCSCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Tetrahydro-2H-thiopyran-4-amine (76 mg, 0.65 mmol) is added to a solution of 4-nitrophenyl 4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)1,2,5,6,7,8-hexahydroquinazoline-3(4H)-carboxylate (intermediate 37, 220 mg, 0.32 mmol) in acetonitrile (6 mL), and the mixture is stirred at room temperature for 30 min and purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 168 mg; ESI mass spectrum [M+H]+=555; Retention time HPLC: 1.19 min (Z018_S04).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].[Cl:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:36]1[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][CH:35]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: OB(O)c1ccc(Cl)cc1
Product: COC(=O)c1c(-c2ccc(Cl)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1

Procedure:
The present compound was synthesized by a method similar to that in Example 272 and using 2-benzyl-6-chloro-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (100 mg) and 4-chlorophenylboronic acid. Colorless crystals (55 mg).
Reaction SMILES: [C:1]([C:3](=[CH:8][CH:9]([CH3:11])[CH3:10])[CH2:4][C:5]([O-:7])=[O:6])#[N:2].C([NH3+])(C)(C)C.[OH-].[K+].C(O)(=O)C>O>[CH3:11][CH:9]([CH2:8][C@H:3]([CH2:1][NH2:2])[CH2:4][C:5]([OH:7])=[O:6])[CH3:10]
Reactant: CC(C)C=C(C#N)CC(=O)[O-]
Agent: CC(C)(C)[NH3+]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C[C@H](CN)CC(=O)O
Temperature: 65 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
An argon-purged 600 mL pressure reactor is charged tert-butyl ammonium 3-cyano-5-methylhex-3-enoate (prepared as described in Example 1A 36 g, 159.1 mmol) and [(R,R)MeDUPHOS]Rh(COD)BF4 (0.054 g, 0.0894 mmol). The reactor is pressure purged with argon (3×50 psi). To a 1000 mL reactor is charged 360 mL of methanol. The methanol is pressure purged with argon (3×50 psi). The methanol is then charged to the reactor containing the substrate and catalyst. The solution is pressure purged with argon (3×50 psi), and then the reactor is pressurized to 50 psi with hydrogen and stirred overnight at 27° C. to 33° C. The hydrogen pressure is released, and the solution purged with argon. The solution is transferred into a vessel containing a solution of potassium hydroxide (91%, 10.3 g, 167 mmol) in 90 mL of water. The solution is concentrated to about 180 mL in vacuo. The concentrated solution is transferred to a 600 mL pressure reactor containing sponge nickel A-7000 (12.0 g, 50% water wet). The solution is purged with argon (3×50 psi), and then the reactor is pressured to 50 psi with hydrogen and stirred overnight. The hydrogen pressure is released. The solution is purged with argon and filtered. The filter cake is washed with 90 mL of methanol. The filtrate is concentrated in vacuo to remove the methanol, and 72 mL of isopropyl alcohol is charged. The solution is heated to 65° C. Glacial acetic acid (9.4 mL, 171 mmol) is charged, and the solution is heated to 73° C. The solution is quickly cooled to 50° C., then slowly cooled to room temperature. The slurry is cooled to 0° C. to 5° C. for 3.5 hours. The slurry is filtered, and the cake is washed with isopropyl alcohol. The solid is dried under vacuum at 45° C. to give 18.4 g (73%) of pregabalin as a white solid (99.89% S).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[OH:19][CH2:20][CH:21]([CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([O:39][CH3:40])=[O:38])=[CH:33][CH:32]=1)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27].O>C1C=CC=CC=1.[Ag]=O>[F:18][C:14]1[CH:13]=[C:12]([C:10]2[S:11][C:7]3[CH:6]=[CH:5][CH:4]=[C:3]([CH2:2][O:19][CH2:20][CH:21]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:36]=4)[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:8]=3[N:9]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)CCCCC(CO)Cc1ccc(C(=O)OC)cc1
Reactant: Fc1cccc(-c2nc3c(CBr)cccc3s2)c1
Agent: O=[Ag]
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)CCCCC(COCc1cccc2sc(-c3cccc(F)c3)nc12)Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
Under argon, 102.8 mg (0.32 mmol) of 4-bromomethyl-2-(3-fluorophenyl)-benzothiazole and 300 mg of MS3A are dissolved in 5 ml of benzene. At room temperature, 82 mg (0.27 mmol) of methyl 6-hydroxymethyl-7-(4-methoxycarbonyl-phenyl)heptanoate (synthesis cf. EP-A-0 341 551, p. 31, Ex. 42) and 92 mg (0.40 mmol) of silver oxide are added. The mixture is stirred at room temperature for 6 days. About 0.2 ml of water is added, the mixture is filtered through Extrelut, which is washed with toluene, and the filtrate is concentrated under reduced pressure and chromatographed.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.Br.Br[CH:12]([C:14]1[CH:15]=[C:16]([C:31]([N:33]([CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])[CH3:34])=[O:32])[CH:17]=[C:18]2[C:23]=1[O:22][C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)=[CH:20][C:19]2=[O:30])[CH3:13]>>[CH3:38][N:37]([CH3:39])[CH2:36][CH2:35][N:33]([CH3:34])[C:31]([C:16]1[CH:17]=[C:18]2[C:23](=[C:14]([CH:12]([N:6]([C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[CH3:7])[CH3:13])[CH:15]=1)[O:22][C:21]([N:24]1[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1)=[CH:20][C:19]2=[O:30])=[O:32]
Reactant: CC(Br)c1cc(C(=O)N(C)CCN(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: CNc1ccc(F)cc1
Agent: Br
Product: CC(c1cc(C(=O)N(C)CCN(C)C)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1ccc(F)cc1
Yield: 47.7 %

Procedure:
4-fluoro-N-methylaniline (82 mg, 0.66 mmol) was reacted with 8-(1-bromoethyl)-N-(2-(dimethylamino)ethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (90 mg, 0.16 mmol) using a procedure similar to the one described in example 3.00 to give N-(2-(dimethylamino)ethyl)-8-(1-((4-fluorophenyl)(methyl)amino)ethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (39.0 mg, 46.4%) as a white solid. Mass Spectrum: M+H+ 511. NMR Spectrum: (DMSOd6) at 323° K: 1.55 (d, 3H), 2.04 (bs, 6H), 2.40 (bs, 2H), 2.68 (s, 3H), 2.93 (s, 3H), 3.22-3.36 (m, 4H), 3.37 (bs, 2H), 3.44-3.58 (m, 4H), 5.45 (q, 1H), 5.50 (s, 1H), 6.82 (dd, 2H), 7.01 (dd, 2H), 7.56 (d, 1H), 7.83 (d, 1H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:5]2[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]2)=[CH:13][CH:12]=1
Reactant: BrCCCCCCCCCCCBr
Reactant: Oc1ccc(C2CCC(O)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: OC1CCC(c2ccc(OCCCCCCCCCCCBr)cc2)CC1
Yield: 85 %

Procedure:
A mixture of 2.40 g (0.012 mol) of 4-(4-Hydroxy-cyclohexyl)-phenol obtained in Step 1, 11.76 (0.037 mol) of 1,11-Dibromoundecane, 5.17 g (0.037 mol) of K2CO3 and 40 mL of dry butanone is refluxed for 24 h, then allowed to return to room temperature. The reaction mixture is filtered off and the butanone is distilled off under reduced pressure. The crude product is purified by recrystallisation from ethanol to give a pure product as a white solid (4.34 g, 85% yield).
Reaction SMILES: [CH3:1][Mg]Cl.[C:4]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([CH:21]2[O:25][N:24]=[C:23]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH2:22]2)=[O:20])=[CH:14][CH:13]=1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>C1COCC1>[OH:11][C:4]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([CH:21]2[O:25][N:24]=[C:23]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH2:22]2)=[O:20])=[CH:16][CH:17]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:1]
Reactant: C[Mg]Cl
Reactant: O=C(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(O)(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
) CH3MgCl, 22% (w/w)/THF (0.003 mol) was added dropwise to a cooled (0° C.) solution of (±)-N-(4-benzoylphenyl)-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide (0.003 mol) in THF (50 ml). The reaction mixture was stirred for 30 minutes at 0° C. More CH3MgCl, 22% w/w/THF (0.003 mol) was added and the mixture was stirred for 30 minutes at 0° C. Extra CH3MgCl, 22% (w/w)/THF (0.003 mol) was added and the reaction mixture was stirred for 30 minutes at 0° C. The mixture was allowed to warm to RT for 30 minutes, then cooled again to 0° C. Water was added. This mixture was extracted with CH2Cl2. The separated organic layer was dried (MgSO4), filtered and the solvent evaporated under reduced pressure. The crude oil was crystallized from EtOAc. The precipitate was filtered off, washed with EtOAc, and dried, yielding 0.5 g (50%) of (±)-4,5-dihydro-N-[4-(1-hydroxy-1-phenylethyl)phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide (compound 51).