Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.Cl[CH2:25][C:26]1[C:27]([CH2:36][CH3:37])=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(N(C(C)C)CC)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]3[C:14](=[O:17])[N:15]([CH2:25][C:26]4[C:27]([CH2:36][CH3:37])=[N:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=4)[N:16]=[C:10]3[C:9]=2[C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:4][CH:3]=1
Reactant: CCc1nc(C(F)(F)F)ccc1CCl
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Temperature: 80 °C
Yield: 95 %

Procedure:
To a solution of 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (65 mg, 0.20 mmol) and 3-(chloromethyl)-2-ethyl-6-(trifluoromethyl)pyridine (60 mg, 0.24 mmol) in anhydrous DMF (1.0 mL) at room temperature was added anhydrous K2CO3 (66 mg, 0.48 mmol). The resulting suspension was stirred at 80° C. The reaction progressed slowly, and additional 3-(chloromethyl)-2-ethyl-6-(trifluoromethyl)pyridine (60 mg, 0.24 mmol) and K2CO3 (66 mg, 0.48 mmol) were added after 1.5 h. After stirring for additional 5 h, the same amounts of 3-(chloromethyl)-2-ethyl-6-(trifluoromethyl)pyridine and K2CO3 were again added. The reaction mixture was stirred at 80° C. for 1 h more before a few drops of diisopropylethylamine were added. The resulting black reaction mixture was stirred at 80° C. overnight. The reaction mixture was cooled to room temperature, then partitioned between EtOAc and water. The EtOAc layer was washed with water twice, then saturated aqueous NaCl, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluted with a gradient of ethyl acetate (0-70%) in hexanes to afford the title compound (95% pure) as a yellow foam. This was further purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 90% B over 10 min (A=0.1% trifluoroacetic acid, 90% water, 10% methanol and B=0.1% trifluoroacetic acid, 90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated aqueous Na2CO3 once, water twice, then saturated aqueous NaCl, dried over Na2SO4 and evaporated. The residue was dissolved in acetonitrile, frozen and lyophilized to afford 35 mg (34%) of the title compound as a light yellow powder. HPLC/MS: retention time=3.07 min, [M+H]+=510.2. 1H NMR (CDCl3, 400 MHz): δ 8.55 (dd, J=1.8, 6.2 Hz, 2H), 7.87 (d, J=7.5 Hz, 1H), 7.70 (d, J=7.9 Hz, 1H), 7.47 (d, J=7.9 Hz, 1H), 7.27 (d, J=8.8 Hz, 2H), 7.16 (d, J=1.8, 6.2 Hz, 2H), 7.05 (d, J=8.8 Hz, 2H), 6.66 (d, J=7.5 Hz, 1H), 5.26 (s, 2H), 3.04 (q, J=7.5 Hz, 2H), 1.32 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH3:1][C:2](=[C:4]([CH3:6])[CH3:5])[CH3:3].[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15](=[O:22])[CH2:16][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1>>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]1([CH2:16][N:17]2[CH:21]=[N:20][CH:19]=[N:18]2)[C:4]([CH3:6])([CH3:5])[C:2]([CH3:3])([CH3:1])[O:22]1
Reactant: O=C(Cn1cncn1)c1ccc(F)cc1F
Reactant: CC(C)=C(C)C
Product: CC1(C)OC(Cn2cncn2)(c2ccc(F)cc2F)C1(C)C
Yield: 15 %

Procedure:
Following a procedure similar to that described in Example 39, but using 2,3-dimethyl-2-butene and 2',4'-difluoro-2-(1H-1,2,4-triazol-1-yl)acetophenone, 85 mg (yield 15%) of the title compound, melting at 100°-101° C., were obtained.
Reaction SMILES: Cl/C(/C(F)(F)F)=C\[C@@H]1[C@H](C(OCC2C(F)=C(F)C(CC=CBr)=C(F)C=2F)=O)C1(C)C.[Cl:31]/[C:32](/[C:58]([F:61])([F:60])[F:59])=[CH:33]\[C@@H:34]1[C@H:36]([C:37]([O:39][CH2:40][C:41]2[C:46]([F:47])=[C:45]([F:48])[C:44]([CH2:49][C:50](C)=[CH:51][Cl:52])=[C:43]([F:54])[C:42]=2[F:55])=[O:38])[C:35]1([CH3:57])[CH3:56]>>[Cl:31]/[C:32](/[C:58]([F:59])([F:60])[F:61])=[CH:33]\[C@@H:34]1[C@H:36]([C:37]([O:39][CH2:40][C:41]2[C:42]([F:55])=[C:43]([F:54])[C:44]([CH2:49]/[CH:50]=[CH:51]/[Cl:52])=[C:45]([F:48])[C:46]=2[F:47])=[O:38])[C:35]1([CH3:57])[CH3:56]
Reactant: CC(=CCl)Cc1c(F)c(F)c(COC(=O)[C@H]2[C@@H](/C=C(\Cl)C(F)(F)F)C2(C)C)c(F)c1F
Agent: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)OCc1c(F)c(F)c(CC=CBr)c(F)c1F
Product: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)OCc1c(F)c(F)c(C/C=C/Cl)c(F)c1F

Procedure:
4-(EZ-3-bromoprop-2-en-1-yl)-2,3,5,6-tetrafluorobenzyl (±)-cis-3-(Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropanecarboxylate (E:Z ratio of alcohol moiety 3:1, Product VII) 4-(EZ-3-chloro-2-methylprop-2-en-1-yl)-2,3,5,6-tetrafluorobenzyl (±)-cis-3-(Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropanecarboxylate (E:Z ratio of alcohol moiety 1:4, Product VIII)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.C(#N)C>O>[Cl:22][C:16]1[N:15]=[C:14]2[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)=[N:13]2)=[CH:18][CH:17]=1
Reactant: O=C(O)c1cccc(F)c1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: CC#N
Solvent: O
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1cccc(F)c1
Temperature: 4 °C
Yield: 75.4 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 3-fluorobenzoic acid (20 g), N,N'-carbonyldiimidazole (23 g) and 2-amino-7-chloro-1,8-naphthyridine (16.9 g). The product produced by precipitation in water (25 g; m.p. 201° C.) is dissolved in boiling acetonitrile (230 cc). After 4 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with acetonitrile (2×20 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-chloro-1,8-naphthyridin-2-yl)-3-fluorobenzamide (21.4 g) is produced, m.p. 202° C. EXAMPLE 15
Reaction SMILES: C([O:4][C:5]1[CH:15]=[CH:14][C:8]2[O:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)(=O)C.[OH-].[K+].Cl>CO.O>[CH3:12][C:10]1([CH3:13])[O:9][C:8]2[CH:14]=[CH:15][C:5]([OH:4])=[CH:6][C:7]=2[O:11]1
Reactant: CC(=O)Oc1ccc2c(c1)OC(C)(C)O2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)Oc2ccc(O)cc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
A solution of 0.6 gram (0.003 mole) of 2,2-dimethylbenzo[3,4-d]1,3-dioxolan-5-yl acetate in 5 mL of methanol was stirred and a solution of 1.1 grams (0.02 mole) of potassium hydroxide in 5 mL of water was added in one portion. Upon completion of addition the reaction mixture was stirred at ambient temperature during a two hour period. After this time the reaction mixture was diluted with 50 mL of water and acidified with concentrated hydrochloric acid. The mixture was then extracted with two 100 mL portions of ethyl acetate. The combined extracts were dried with sodium sulfate, filtered and concentrated under reduced pressure, yielding 0.36 gram of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl.[CH2:2]1[C:5]2([CH2:9][CH2:8][CH2:7][O:6]2)[CH2:4][NH:3]1.[CH3:10][C:11]1[CH:18]=[C:17]([O:19][CH:20]2[CH2:23][N:22]([C:24]([C:26]3[O:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:29][N:30]=3)=[O:25])[CH2:21]2)[CH:16]=[CH:15][C:12]=1[CH:13]=O.[Na].C([O-])(O)=O.[Na+]>ClCCl>[CH2:4]1[C:5]2([CH2:9][CH2:8][CH2:7][O:6]2)[CH2:2][N:3]1[CH2:13][C:12]1[CH:15]=[CH:16][C:17]([O:19][CH:20]2[CH2:23][N:22]([C:24]([C:26]3[O:27][C:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:29][N:30]=3)=[O:25])[CH2:21]2)=[CH:18][C:11]=1[CH3:10]
Reactant: C1COC2(C1)CNC2
Reactant: Cc1cc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)ccc1C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(OC2CN(C(=O)c3nnc(-c4ccccc4)o3)C2)ccc1CN1CC2(CCCO2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
5-Oxa-2-azaspiro[3.4]octane HCl salt (0.064 g, 0.43 mmol) was dissolved in dichloromethane (2 ml). Triethylamime (0.064 ml, 0.47 mmol) was added, followed by 2-methyl-4-(1-(5-phenyl-1,3,4-oxadiazole-2-carbonyl)azetidin-3-yloxy)benzaldehyde (0.13 g, 0.36 mmol) and finally sodium triacetoxyhydroborate (0.152 g, 0.72 mmol). The resulting mixture was stirred at ambient temperature overnight. The reaction mixture was the diluted with dichloromethane (10 ml) and shaken with NaHCO3 (sat. 3 ml). The two phases were separated by the use of a phase separator. Evaporation of the organic phase afforded a solid residue, which again was dissolved in dichloromethane (ca. 20 ml), washed with water (20 ml), filtered through a phase separator and evaporated. The residue was purified by column chromatography (ISOLUTE SI, 20 g/70 ml), eluting with NH3 in MeOH (2M)/dichloromethane (1:99, 2:98). After evaporation of the solvent mixture, 112 mg (68%) of the desired product was obtained as a solid. 1H NMR (400 MHz, CDCl3) δ 1.91 (p, 2H), 2.14 (t, 2H), 2.33 (s, 3H), 3.15 (d, 2H), 3.39 (d, 2H), 3.59 (s, 2H), 3.82 (t, 2H), 4.35 (dd, 1H), 4.67 (dd, 1H), 4.74-4.8 (m, 1H), 5.11 (ddt, 2H), 6.57 (dd, 1H), 6.62 (d, 1H), 7.22 (d, 1H), 7.53-7.65 (m, 3H), 8.16-8.23 (m, 2H). MS (APCI+) m/z 461.3 [M+H]+, LC purity: 99%
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][C:12]([C:16]([O:18]C)=[O:17])=[CH:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:14]([CH2:13][C:12]([C:16]([OH:18])=[O:17])=[CH:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1=CC2CN(C(=O)OC(C)(C)C)CC2C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2C=C(C(=O)O)CC2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.4 %

Procedure:
To a solution of methyl 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]-oct-6-ene-7-carboxylate (0.350 g, 1.31 mmol) in THF-methanol (6.0 mL, 1:1) was added a solution of lithium hydroxide (0.100 g in 1 mL of water, 3.94 mmol), and the reaction was stirred at ambient temperature for 3 h. The solvent was evaporated, the residue was acidified to pH 4 with 1 M aqueous hydrochloric acid, and extracted with ethyl acetate (50 mL). The organic layer was washed with water (50 mL) and brine (50 mL), dried (anhydrous sodium sulfate), and concentrated to obtain 0.31 g (92% yield) of 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]-oct-6-ene-7-carboxylic acid, as a white solid (1H NMR (CDCl3, 300 MHz): δ 6.76 (bs, 1H), 3.76-3.62 (m, 1H), 3.58-3.42 (m, 2H), 3.11-2.94 (m, 2H), 2.84-2.67 (m, 1H), 2.46-2.23 (m, 1H), 1.42 (s, 9H). MS (m/z): 254 (M+1), 198 (M+1-56)).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([O:14][C:15]3[S:16][C:17]4[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=4[N:19]=3)[CH:12]=[CH:13][C:7]=2[CH:6]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].[NH4+].[Cl-]>C(Cl)Cl>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[O:14][C:11]1[CH:12]=[CH:13][C:7]2[CH:6]=[C:5]([CH2:3][OH:2])[S:9][C:8]=2[CH:10]=1
Reactant: COC(=O)c1cc2ccc(Oc3nc4ccccc4s3)cc2s1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: ClCCl
Product: OCc1cc2ccc(Oc3nc4ccccc4s3)cc2s1
Temperature: 0 °C
Reaction time: 3 h
Yield: 103.3 %

Procedure:
To a cooled (0° C.) solution 6-(benzothiazol-2-yloxy)-benzo[b]thiophene-2-carboxylic acid methyl ester (274 mg, 0.8 mmol) in DCM (8 mL) was added LAH (2 M in THF, 0.4 mL, 0.3 g, 0.8 mmol) and the reaction mixture was stirred (0° C., 3 h). The reaction mixture was treated with saturated aqueous NH4Cl (2 mL) and partitioned with DCM (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2×15 mL). The organic layer was dried, filtered and concentrated in vacuo to provide the title compound as a yellow solid (259 mg, 77%). MS (ESI): mass calcd. for C16H11O2S2, 313.0; m/z found, 314.0 [M+H]+.
Reaction SMILES: [CH2:1]([CH2:16]/[C:17](/[CH3:36])=[CH:18]/[CH2:19][CH2:20]/[C:21](/[CH3:35])=[CH:22]/[CH2:23][CH2:24]/[C:25](/[CH3:34])=[CH:26]/[CH2:27][CH2:28]/[C:29](/[CH3:33])=[CH:30]/[CH2:31]Br)[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4].[CH2:37]([NH2:47])[C:38]1[CH:46]=[CH:45][C:44]2[O:43][CH2:42][O:41][C:40]=2[CH:39]=1.O>C1COCC1>[CH2:1]([CH2:16]/[C:17](/[CH3:36])=[CH:18]/[CH2:19][CH2:20]/[C:21](/[CH3:35])=[CH:22]/[CH2:23][CH2:24]/[C:25](/[CH3:34])=[CH:26]/[CH2:27][CH2:28]/[C:29](/[CH3:33])=[CH:30]/[CH2:31][NH:47][CH2:37][C:38]1[CH:46]=[CH:45][C:44]2[O:43][CH2:42][O:41][C:40]=2[CH:39]=1)[CH:2]=[C:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[CH3:9])[CH3:4]
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CBr
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)=CCCC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CNCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.2 %

Procedure:
In 10 ml of THF was dissolved 4.56 g of farnesylgeranylgeranyl bromide, 3.01 g of piperonylamine was added and stirred at room temperature for one hour. To the reaction mixture was added water and extracted with ethyl acetate. The extract was washed with water and then brine, dried over magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (using as a developing solvent hexane-ethyl acetate (4:1)→ethyl acetate) to give 1.14 g of N-farnesylgeranylgeranylpiperonylamine as a yellow liquid.
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:14]=[C:13]([F:15])[C:12]([F:16])=[CH:11][C:10]=1[Br:17])C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Br:17][C:10]1[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=1[NH:7][CH3:6]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(F)c(F)cc1Br
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1cc(F)c(F)cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 144B (29.5 g, 92 mmol) in dichloromethane (200 mL) was added trifluoroacetic acid (141 mL, 1831 mmol). The reaction mixture was stirred at room temperature for 2 hours and concentrated. The residue was partitioned between ethyl acetate and brine. The organic phase was washed with brine, dried with MgSO4, filtered, and concentrated. The filtrate was concentrated and the residue was separated by flash chromatography on silica gel (Teledyne CombiFlash Rf, 40% to 100% ethyl acetate in hexane) to provide the title compound. MS (ESI+) m/z 222 (M+1).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]([CH2:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[N:16][N:17]2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[CH:13][CH:12]=1)=[N+]=[N-].[OH-].[Na+].C(OCC)(=O)C>C1COCC1>[NH2:7][CH2:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[N:16][N:17]2[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[CH:13][CH:12]=1
Reactant: [N-]=[N+]=NCc1ccc2cnn(C3CCCCO3)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NCc1ccc2cnn(C3CCCCO3)c2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of LiAlH4 (9 mL, 9 mmol, 1.0 M) in THF was added dropwise to a yellow solution of 6-(azidomethyl)-1-(2-tetrahydropyranyl)indazole (2.4 g, 9 mmol) (8) in THF (30 mL) at 0° C. After stirring at 0° C. for 1 hour, NaOH (1.0 m, 1.5 mL) was added. The reaction mixture was allowed to warm to room temperature. Ethyl acetate (100 mL) was added, and the suspension was filtered through (Celite). The filter cake was washed with an addition portion of ethyl acetate (40 mL). Combined organic layers were evaporated under vacuum to five essentially pure amine (2.1 g, 97%). MS (electrospray) 232.5 (M+1); 1H NMR (CDCl3) δ 1.67 (m, 3H), 2.01 (m, 2H), 2.48 (m, 1H), 3.85 (m, 1H), 3.94 (m, 1H), 5.75 (d, 1H, J=9.4 Hz), 7.14 (d, 1H, J=8.4 Hz), 7.62 (s, 1H), 7.62 (d, 1H, J=8.4 Hz), 7.93 (s, 1H)
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8]([N:10]=[C:11]1[N:15](C(OC(C)(C)C)=O)[CH:14]([CH2:23][O:24]C(OC(C)(C)C)=O)[CH2:13][S:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO.O>[OH:24][CH2:23][CH:14]1[CH2:13][S:12][C:11]([NH:10][C:8](=[O:9])[O:7][C:3]([CH3:5])([CH3:4])[CH3:6])=[N:15]1
Reactant: CC(C)(C)OC(=O)N=C1SCC(COC(=O)OC(C)(C)C)N1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC1=NC(CO)CS1
Temperature: 20 °C
Reaction time: 4 h
Yield: 34.4 %

Procedure:
10 cm3 of aqueous 1N sodium hydroxide are added to a solution of 2 g of tert-butyl 2-[(tert-butoxycarbonyl)imino]-(4RS)-4-[(tert-butoxycarbonyl)oxy]methyl-1,3-thiazolidine-3-carboxylate in 20 cm3 of methanol and the mixture is then stirred at a temperature in the region of 20° C. for 4 hours. The reaction mixture is concentrated under reduced pressure (1 kPa) at a temperature in the region of 50° C. The residue obtained is taken up in 30 cm3 of water, filtered and washed with ethyl acetate and then with water. 0.37 g of tert-butyl N-[(4RS)-4-hydroxymethyl-4,5-dihydro-2-thiazolyl]-carbamate is obtained in the form of a white solid [mass spectrum: DCI m/z=233 MH+ m/z=177 (M-C4H7)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=O.[Cl:14][C:15]1[CH:24]=[CH:23][C:18]([O:19][CH2:20][CH2:21][NH2:22])=[CH:17][CH:16]=1.CCN=C=NCCCN(C)C.Cl.Cl>O1CCCC1.C(Cl)Cl>[Cl:14][C:15]1[CH:24]=[CH:23][C:18]([O:19][CH2:20][CH2:21][NH:22][C:11](=[O:13])[CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[CH:17][CH:16]=1
Reactant: NCCOc1ccc(Cl)cc1
Reactant: COc1ccccc1CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccccc1CCC(=O)NCCOc1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
3-(2-Methoxyphenyl)propionic acid (8.3 g, 46.2 mmol) was dissolved in tetrahydrofuran (20 mL), and 4-chlorophenoxyethylamine (10.3 g, 60.0 mmol) was added dropwise thereto at room temperature. Subsequently, a solution (10 mL) of WSC.HCl (11.5 g, 60.0 mmol) in methylene chloride was slowly added dropwise thereto under ice-cooling, followed by stirring overnight. Under ice cooling, diluted hydrochloric acid was added dropwise thereto, followed by extraction with chloroform. The organic layer was washed with brine, and the resultant mixture was subjected to drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (chloroform/methanol=20/1), whereby the target compound was obtained (12.8 g, 83%).
Reaction SMILES: C[O:2][C:3](=[O:44])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([NH:12][C:13]([C@@H:15]2[NH:19][C@@H:18]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C@:17]3([C:32]4[C:27](=[CH:28][C:29]([Cl:33])=[CH:30][CH:31]=4)[NH:26][C:25]3=[O:34])[C@H:16]2[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=2[F:42])=[O:14])=[CH:6][C:5]=1[F:43].Cl>C1COCC1.O.C(OCC)(=O)C>[Cl:33][C:29]1[CH:28]=[C:27]2[NH:26][C:25](=[O:34])[C@:17]3([C@@H:16]([C:35]4[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=4[F:42])[C@H:15]([C:13]([NH:12][C:7]4[C:8]([O:10][CH3:11])=[CH:9][C:4]([C:3]([OH:44])=[O:2])=[C:5]([F:43])[CH:6]=4)=[O:14])[NH:19][C@H:18]3[CH2:20][C:21]([CH3:23])([CH3:22])[CH3:24])[C:32]2=[CH:31][CH:30]=1
Reactant: COC(=O)c1cc(OC)c(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)c(F)cc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a solution of rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-2-fluoro-5-methoxy-benzoic acid methyl ester (36 mg, 0.056 mmol) in THF (3 mL) was added LiOH monohydrate (11 mg, 0.26 mmol) in water (2 ml) and the reaction mixture was allowed to stir at rt overnight. The mixture was then treated with 1N HCl to slightly acidic, diluted with ethyl acetate (80 mL), washed with water (2×15 mL), dried with Na2SO4 and concentrated to give rac-4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-2-fluoro-5-methoxy-benzoic acid as a white solid (33 mg, 92%). MS (ES+) m/z [(M+H)+]: 632
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[C:27]3[C:22](=[C:23]([CH2:28][S:29][CH3:30])[CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH:9]2C(=O)O[C:12](C)([CH3:16])[O:11][C:10]2=[O:18])=[C:4]([F:31])[CH:3]=1>N1C=CC=CC=1.C(O)C.[Cu]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[C:27]3[C:22](=[C:23]([CH2:28][S:29][CH3:30])[CH:24]=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:9][C:10]([O:11][CH2:12][CH3:16])=[O:18])=[C:4]([F:31])[CH:3]=1
Reactant: CSCc1cccc2c(C(c3ccc(Cl)cc3F)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)CC(c1ccc(Cl)cc1F)c1c[nH]c2c(CSC)cccc12

Procedure:
5.0 mg (0.08 mmol) of copper powder were added to 3.60 g (7.79 mmol) of the compound from Example 15A in 56 ml of pyridine and 14 ml of ethanol. The reaction mixture was heated under reflux for 1 h. It was concentrated, and the residue was taken up in ethyl acetate, washed with 1N hydrochloric acid, dried over magnesium sulfate, filtered through silica gel and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 2.23 g (70% of theory) of the title compound.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:6][C@H:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O.[CH3:19][O:20][C:21]([NH:23][C@@H:24]([CH:28]([CH3:30])[CH3:29])[C:25](O)=[O:26])=[O:22].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.CCOC(C)=O>[CH3:19][O:20][C:21]([NH:23][C@@H:24]([CH:28]([CH3:30])[CH3:29])[C:25]([N:6]1[C@@H:2]([CH3:1])[CH2:3][CH2:4][C@H:5]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:26])=[O:22]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CCOC(=O)[C@@H]1CC[C@H](C)N1
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
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)[C@@H]1CC[C@H](C)N1C(=O)[C@@H](NC(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2S,5S)-Ethyl 5-methylpyrrolidine-2-carboxylate-TFA (10.0 g, 39.3 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (6.88 g, 39.3 mmol) and HATU (14.9 g, 39.3 mmol) were combined in DMF (100 mL) and DIPEA (15.0 mL, 86.5 mmol) was added. After stirring for 1 h at RT, the reaction mixture was diluted with EtOAc. The organic phase was washed successively with 10% HCl, saturated aqueous NaHCO3 and brine, then dried over MgSO4, filtered and concentrated under reduced pressure to afford (2S,5S)-ethyl 1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-5-methylpyrrolidine-2-carboxylate. The crude material was carried on without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(Cl)C(O)=O.[CH:26]([O:28][CH2:29][CH3:30])=[CH2:27].[OH-].[Na+]>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH:26]([O:28][CH2:29][CH3:30])[CH3:27])[C:11]=2[C:12]2[CH:13]=[CH:14][C:15]([S:18][CH3:19])=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CSc1ccc(-c2[nH]cnc2-c2ccccc2)cc1
Reactant: C=COCC
Agent: O=C(O)C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOC(C)n1cnc(-c2ccccc2)c1-c1ccc(SC)cc1
Temperature: 25 °C
Yield: 100.5 %

Procedure:
A mixture of 12.0 g (0.045 mole) of 4-phenyl-5-(4-methylthiophenyl)-1H-imidazole, 6.7 g (0.052 mole) of dichloroacetic acid and 24.6 g (0.34 mole) of ethyl vinyl ether in 485 ml of toluene was heated at reflux for 3 hours. The reaction mixture was cooled to room temperature and was then stirred overnight with 130 ml of 25% aqueous sodium hydroxide. The organic layer was separated and the aqueous layer was extracted with ether (2X). The organic fractions were combined, washed with brine and dried over anhydrous potassium carbonate. Removal of the solvent under vacuum afforded 15.3 g of an oil. The product was used in the subsequent reaction without purification.