Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:17])[CH2:11][C:10]2[C:5](=[C:6]([CH3:15])[C:7]([CH:13]=[CH2:14])=[C:8]([CH3:12])[CH:9]=2)[CH:4]1[OH:16].N1C=CN=C1.[Si:23](Cl)([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:24][CH3:25]>C(Cl)Cl.O>[CH3:17][C:3]1([CH2:2][O:1][Si:23]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:24][CH3:25])[CH2:11][C:10]2[C:5](=[C:6]([CH3:15])[C:7]([CH:13]=[CH2:14])=[C:8]([CH3:12])[CH:9]=2)[CH:4]1[OH:16]
Reactant: C=Cc1c(C)cc2c(c1C)C(O)C(C)(CO)C2
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: C=Cc1c(C)cc2c(c1C)C(O)C(C)(CO[Si](CC)(CC)CC)C2
Reaction time: 6 h
Yield: 67 %

Procedure:
To the stirred solution of starting material 7 (0.85 g, 3.66 mmol) in dry CH2Cl2 added Imidazole (0.5 g, 7.32 mmol) and TESCl (0.6 mL, 3.66 mmol) sequentially at 0° C. under argon atmosphere and stirred the reaction mixture at same temperature for 6 h. Then reaction mixture was diluted with H2O (10 mL) followed by extraction with CH2Cl2 (50 mL), brine (25 mL), dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography (SiO2, 5 to 10% EtOAc in petroleum ether eluant) gave pure compound 8 (0.85 g, 88%) as syrup.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:8][CH2:7][C:6]1=[O:15].[CH:17](=[C:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]>CC#N>[CH:17](=[C:21]1[CH2:26][CH2:25][N:24]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:8][CH2:7][C:6]2=[O:15])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: C[C@H](CI)CN1C(=O)CSc2ccccc21
Reactant: CCCC=C1CCNCC1
Solvent: CC#N
Product: CCCC=C1CCN(C[C@@H](C)CN2C(=O)CSc3ccccc32)CC1
Temperature: 60 °C
Reaction time: 96 h
Yield: 59.6 %

Procedure:
The compound (S)-4-(3-Iodo-2-methyl-propyl]-4H-benzo[1,4]thiazin-3-one (108LM37-34) (0.432 g, 1.25 mmol) and 4-butylidenepiperidine (111MF05) (0.208 g, 1.49 mmol) in MeCN (½ mL) were reacted according to GP10 shaking at 60° C. for 4 days. Purified by cation exchange CC and flash CC (SiO2; MeOH/DCM 1:20) to give the title compound (108LM50-47) (0.267 g, 60%). 1H NMR (CDCl3) δ 7.35 (d, J=7.5 Hz, 1H), 7.26-7.18 (m, 2H), 6.98 (t, J=7.5 Hz, 1H), 5.10 (t, J=7.4 Hz, CH), 4.17-4.03 (m, 2H), 3.36 (s, CH2), 2.43-2.33 (m, 2H), 2.30-2.08 (m, 8H), 2.00-1.90 (m, 3H), 1.28-1.38 (m, 2H), 0.90-0.80 (m, 6H); 13C NMR (CDCl3) δ 166.0, 139.2, 136.4, 128.8, 127.1, 124.8, 123.5, 122.7, 118.8, 63.4, 56.4, 55.6, 47.7, 36.4, 32.1, 29.5, 29.4, 28.6, 23.4, 16.7, 14.0; HPLC-MS (ammonium acetate) [M+H]+=359.3.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])=[CH:4][N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:30](OC)(OC)([O:33]C)[O:31][CH3:32].C(=O)(O)[O-].[Na+]>O1CCCC1.O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH2:16][OH:17])[CH2:14][O:15][C:30]([O:31][CH3:32])=[O:33])=[CH:4][N:3]=1
Reactant: Nc1ncc2ncn(CCC(CO)CO)c2n1
Reactant: COC(OC)(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)OCC(CO)CCn1cnc2cnc(N)nc21
Reaction time: 1.67 h

Procedure:
To a suspension of 2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine (237 mg, 1.0 mmol) in dry tetrahydrofuran (3 ml) were added p-toluene-sulphonic acid monohydrate (0.21 g, 1.1 mmol) and tetramethyl orthocarbonate (0.53 ml, 4.0 mmol) and the mixture was stirred for 100 minutes. Water (0.8 ml) was added and after a further 15 minutes the solution was neutralised by addition of aqueous sodium bicarbonate. The solvent was removed and the residue was extracted with chloroform-methanol (3:1). The solvent was removed and the residue was purified by column chromatography on silica gel eluting with chloroform-methanol (10:1) to afford 2-amino-9-(3-hydroxymethyl-4-methoxycarbonyloxybut-1-yl)purine which was obtained as a white crystalline solid after trituration with ethyl acetate (65 mg, 22%), m.p. 129°-132°; νmax (KBr) 3440, 3220, 1745, 1650, 1615, and 1580 cm-1 ; &H [(CD3)2SO] 1.73 (1 H, m, 3'-H), 1.81 (2H, m, 2'-H), 3.41 (2H, t, J 5.1Hz, D2O exchange gives d, CH2OH) 3.68 (3H, s, CH3), 4.0-4.2 (4H, m, CH2OCO and 1'-H), 4.65 (1H, t, J 5.2Hz, D2O exchangeable, OH), 6.44 (2H, s, D2O exchangeable, 2-NH2), 8.06 (1H, s, 8-H), and 8.55 (1H, s, 6-H); (Observed M+, 295.1286, C12H17N5O4 requires 295.1280).
Reaction SMILES: FC(F)(F)S(O[CH:7]([CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:8]([F:11])([F:10])[F:9])(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>CS(C)=O.O>[N:26]([CH:7]([C:8]([F:11])([F:10])[F:9])[CH2:12][NH:13][C:14](=[O:15])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(NCC(OS(=O)(=O)C(F)(F)F)C(F)(F)F)OCc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: [N-]=[N+]=NC(CNC(=O)OCc1ccccc1)C(F)(F)F
Temperature: 40 °C
Reaction time: 5 h

Procedure:
To a solution of 3-{[(benzyloxy)carbonyl]amino}-1,1,1-trifluoropropan-2-yl trifluoromethanesulfonate (150 g, 380 mmol) in DMSO (1200 mL) was added sodium azide (36.5 g, 562 mmol). The reaction mixture was heated to 40° C. After 5 hours, the reaction mixture was diluted with water (1000 mL) and extracted with diethyl ether (3×1200 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford benzyl (2-azido-3,3,3-trifluoropropyl)carbamate. The material was used without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[S:13][C:14]([C:16]([O:18]C)=[O:17])=[CH:15][C:4]=2[NH:3]1.[OH-].[Na+]>C(O)C.C1COCC1>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][C:5]2[S:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:4]=2[NH:3]1
Reactant: COC(=O)c1cc2c(s1)Oc1ccccc1C(=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cc2c(s1)Oc1ccccc1C(=O)N2
Temperature: 55 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a stirring solution of compound 119 (0.856 g, 3.11 mmol) in ethanol (16 mL) and THF (8 mL) was added an aqueous solution of sodium hydroxide (5 mL, 31.3 mmol) and the resulting mixture was stirred at 55° C. for 2 h. The reaction mixture was solvent evaporated to one third volume, acidified with 3N HCl to pH 2 and the resulting white precipitate was filtered to afford 120 (0.801 g, 99%) as a beige solid. LRMS (ESI): (calc) 261.01. (found) 262.1 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[C:5]([CH3:13])=[C:4]([Cl:14])[CH:3]=1.CO[CH2:17][Cl:18].OS(O)(=O)=O>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:11])([F:10])[F:12])[C:5]([CH3:13])=[C:4]([Cl:14])[C:3]=1[CH2:17][Cl:18]
Reactant: Cc1c(Cl)cc(Cl)cc1OC(F)(F)F
Reactant: COCCl
Agent: O=S(=O)(O)O
Product: Cc1c(OC(F)(F)F)cc(Cl)c(CCl)c1Cl
Temperature: 20 °C
Yield: 92.9 %

Procedure:
1,3-Dichloro-5-(trifluoromethoxy)-4-methylbenzene (8.0 g, 33 mmol) and 5.0 g (78 mmol) of chloromethyl methyl ether were added to 50 ml of H2SO4 (98%) with stirring at 20° C. The temperature rose slowly to 30° C. The mixture was stirred for 15 hours, then poured into 200 ml of ice water and extracted with 2×100 ml portions of hexane. The hexane extracts were combined, washed with 100 ml of water, dried (MgSO4), filtered, and concentrated. The residue was dissolved in 50 ml of hexane, filtered and concentrated. The resulting white solid was dried (25° C./0.001 mm) to give 9.0 g of 1,3-dichloro-2-chloromethyl-4-methyl-5-(trifluoromethoxy)benzene.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[C:21]([F:29])[CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:33]O.Cl>CO.O>[F:29][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[C:25]([F:28])([F:27])[F:26])[CH2:18][C@H:10]1[CH2:9][C@@H:8]([C:6]2[O:7][NH:33][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2ccc(C(F)(F)F)c(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(C(F)(F)F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 70 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluoro-4-(trifluoromethyl)benzyl)piperidine-1-carboxylate (2.033 g, 4.69 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. Sodium hydroxide (0.188 g, 4.69 mmol) dissolved in water (2.4 mL) was added over 1 min and the resulting solution was stirred at −40° C. for 20 min. Then hydroxylamine (50% by weight in water, 0.3 mL, 4.90 mmol) was added over 1 min and stirring continued at −40° C. for 2 h 20 min. The reaction mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (40 mL, 240.00 mmol) and the mixture was continued to be stirred at 80° C. for 1 h. Then cooled to room temperature. Methanol was evaporated, then water was added. Extracted three times with DCM. Combined organic layers dried over MgSO4 and evaporated. Product was pale yellow oil. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-35% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. Cis-methyl 2-(3-fluoro-4-(trifluoromethyl)benzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate (1.32 g, 70%) was isolated as a colorless foam. 1H NMR (600 MHz, cdcl3) δ 1.84-1.99 (m, 3H), 1.99-2.10 (m, 1H), 2.62 (dd, 1H), 2.82 (dd, 1H), 2.92-3.06 (m, 1H), 3.10-3.19 (m, 1H), 3.59 (s, 3H), 3.93-4.03 (m, 1H), 4.19-4.34 (m, 1H), 5.73 (s, 1H), 6.91-6.99 (m, 2H), 7.46 (t, 1H). MS m/z 403 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].N1C=CC=CC=1.[CH3:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>C1COCC1>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:8]([C:7]2[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[O:9])[CH2:22][CH2:21]1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CN1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Yield: 47.3 %

Procedure:
A 1-liter-3-neck flask was loaded with 4-nitrobenzoyl chloride (50.5 g, 267 mmol) and THF (500 ml) and cooled to 0° C. Pyridine (44 ml, 544 mmol), then 1-methyl-piperazine (35 ml, 316 mmol) were added while mechanically stirring at 0° C. After the addition was completed the ice bath was removed and the mixture stirred for 1 hour, while warming to room temperature. A voluminous precipitate forms. The slurry was diluted with dichloromethane and 1 M aq. KOH and the layers separated. The organic layer was washed one more time with 1 M aq. KOH, then with brine and dried over MgSO4, filtered and concentrated in vacuum. 31.5 g yellow solid (4-methylpiperazin-1-yl)(4-nitrophenyl)methanone were isolated. MS (ESI) m/z 250 (M+H). 1H NMR (CDCl3) δ ppm 8.27 (d, 2H, J=7.9), 7.56 (d, 2H, J=7.9), 3.81 (bs, 2H), 3.37 (bs, 2H), 2.50 (bs, 2H), 2.34 (bs, 2H), 2.32 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(N)cccc1Cl
Product: CC(=O)Nc1cccc(Cl)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a solution of 3-chloro-2-methylaniline (27 g, 0.19 mol) in 270 mL of ETOH at rt was added acetic anhydride (22 mL, 0.23 mol), and the solution was stirred at rt for 2 h. The mixture was concentrated under reduced pressure to give 35 g (100%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([NH2:18])=[N:14][CH:15]=[C:16]([I:17])[C:11]=3[O:10][CH:9]=2)=[CH:4][C:3]=1[O:19][CH3:20].[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[C:31](Cl)=[O:32]>N1C=CC=CC=1>[NH2:18][C:13]1[C:12]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:31]([C:23]4[N:22]([CH3:21])[C:30]5[C:25]([CH:24]=4)=[CH:26][CH:27]=[CH:28][CH:29]=5)=[O:32])=[C:3]([O:19][CH3:20])[CH:4]=3)=[CH:9][O:10][C:11]=2[C:16]([I:17])=[CH:15][N:14]=1
Reactant: COc1cc(-c2coc3c(I)cnc(N)c23)ccc1N
Reactant: Cn1c(C(=O)Cl)cc2ccccc21
Solvent: c1ccncc1
Product: COc1cc(-c2coc3c(I)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.7 %

Procedure:
A solution of 3-(4-amino-3-methoxyphenyl)-7-iodofuro[3,2-c]pyridin-4-amine (2.53 g, 6.65 mmol) in pyridine (30 mL) was cooled to 0° C. and 1-methyl-1H-2-indolecarbonyl chloride (2.57 g, 13.3 mmol) was added. The mixture was stirred for 15 minutes at 0° C. and then allowed to rise to ambient temperature over an 18 hour time period. The solvent was removed in vacuo and the residue was dissolved in water (50 mL) and brought to pH 12 with 0.1 N aqueous sodium hydroxide, at which point a precipitate formed. The suspension was extracted with dichloromethane (4×25 mL) and the combined organic layers were washed with brine (25 mL) and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo to give the title compound (3.21 g, 89%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ 9.48 (s, 1H), 8.14 (s, 1H), 8.08 (s, 1H), 8.04 (t, 1H), 7.71 (d, 1H), 7.59 (d, 1H), 7.30-7.37 (m, 2H), 7.25 (d, 1H), 7.11-7.18 (m, 2H), 5.75-5.83 (bs, 2H), 4.04 (s, 3H), 3.93 (s, 3H); RP-HPLC (Conditions d) Rt 8.73 min.; MS: MH+ 539.
Reaction SMILES: [OH-].[K+].[C:3]([OH:6])(=[S:5])[CH3:4].Cl[CH:8]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH:13]=1)[C:9]([OH:11])=[O:10]>C(O)C>[C:3]([S:5][CH:8]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[CH:13]=1)[C:9]([OH:11])=[O:10])(=[O:6])[CH3:4]
Reactant: COc1ccc2cc(C(Cl)C(=O)O)ccc2c1
Reactant: CC(O)=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2cc(C(SC(C)=O)C(=O)O)ccc2c1
Reaction time: 15 h

Procedure:
To a solution of 600 ml. of anhydrous ethanol and 21 g. (0.317 moles) of potassium hydroxide is added 45 ml. of thioacetic acid dropwise. To this mixture is then added 0.244 moles of α-chloro-6-methoxy-2-naphthylacetic acid and stirring is continued for 15 hours. The solid which forms is filtered off and washed with ethanol. The filtrate is evaporated to dryness and the residue is dissolved in 500 ml. of ether and washed several times with water. Drying the ether and evaporation to dryness results in α-acetylthio-6-methoxy-2-naphthylacetic acid.
Reaction SMILES: C[C:2]([O:4][CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.B(F)(F)F.CCOCC.FS(O)(=O)=O.B(OC)(OC)OC>S1(CCCC1)(=O)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][O:4][CH3:2])[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: COB(OC)OC
Agent: FB(F)F
Agent: O=S(=O)(O)F
Solvent: CCOCC
Solvent: O=S1(=O)CCCC1
Product: COCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Temperature: 25 °C

Procedure:
To 20 ml of sulfolane were added 1.41 g of 7-ACA, 8.2 ml of boron trifluoride ethyl ether, 1.9 ml of fluorosulfonic acid and 6.12 ml of trimethyl borate. The mixture was heated at 25° C. for 20 minutes to advance a reaction. After completion of the reaction, substantially the same procedure as in Example 1 was repeated, to thereby obtain the desired product, namely 7-amino-3-methoxymethyl-3-cephem-4-carboxylic acid. The amount of the desired product was 0.76 g. The yield of the desired product was 60%.
Reaction SMILES: [Br:1]Br.[O:3]=[C:4]1[C:9]([C:10]#[N:11])=[CH:8][CH:7]=[CH:6][NH:5]1>C(O)(=O)C>[Br:1][C:7]1[CH:8]=[C:9]([C:10]#[N:11])[C:4](=[O:3])[NH:5][CH:6]=1
Reactant: BrBr
Reactant: N#Cc1ccc[nH]c1=O
Solvent: CC(=O)O
Product: N#Cc1cc(Br)c[nH]c1=O

Procedure:
Bromine (29 ml, 560 mmol) was added to a stirred solution of 2-oxo-1,2-dihydro-pyridine-3-carbonitrile (34 g, 280 mmol) in acetic acid (180 ml) at room temperature. After 14 hours the reaction mixture was concentrated in vacuo and the resulting oil was trituated with ethanol to afford the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:15])([C:12]([O-:14])=[O:13])[C:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:15])([C:12]([OH:14])=[O:13])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C(=O)[O-])(C(=O)[O-])c1ccc(-c2ccccc2)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Yield: 93 %

Procedure:
To a stirred solution of 7.58 g (22.0 mmol) of diethyl 2-(2-fluoro-4-biphenylyl)-2-methylmalonate VI in 50 ml of absolute ethanol, maintained under nitrogen gas at ~15° C. (ice bath) is added 8.72 g (109.0 mmol, 5.0 mol -equiv.) of 50% aqueous sodium hydroxide. The temperature is maintained at <25° C. for 6 hours. The resulting suspension is diluted with 150 ml water and the pH is adjusted to ~8.0 with dilute hydrochloric acid. The solution is transferred to a separatory funnel and is extracted with 3×60 ml of methylene chloride. The aqueous layer is acidified to pH <1 with concentrated hydrochloric acid and is then extracted with 200 ml of ethyl acetate in three portions. The combined extracts are dried over anhydrous sodium sulfate and concentrated in vacuo to give 5.9 g 2-(2-fluoro-4-biphenylyl)-2-methyl malonic acid. This material is dissolved in 15 ml of glacial acetic acid and the solution is heated to reflux for ~17 hours. Water (15 ml) is added and the solution is allowed to cool slowly with stirring and seeding. After 1 hour stirring at room temperature, the mixture is cooled with stirring to 0°-5° C., then let stand for ~15 hours. The product is isolated and washed with a few ml of cold 50% aqueous acetic acid then dried to give 4.67 g flurbiprofen Ib of melting point 113°-115° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.[N:15]1([CH2:20][CH2:21][CH2:22][NH2:23])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([NH:23][CH2:22][CH2:21][CH2:20][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:13]
Reactant: NCCCN1CCCC1
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Product: Cc1[nH]c2c(c1C(=O)NCCCN1CCCC1)CCCC2=O
Yield: 82.4 %

Procedure:
Similar procedure as Example 2, 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol) and 3-(pyrrolidin-1-yl)propan-1-amine 0.27 g (2.1 mmol) was reacted to give 0.25 g (82%) of the titled compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19]C)=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[S:8][C:7]=2[CH:29]=1.C([S-])C.[Na+].O>CN(C)C=O>[OH:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]([C:10]2[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:29][C:7]=3[S:8][C:9]=2[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[O:12])=[CH:14][CH:15]=1
Reactant: COc1ccc(C(=O)c2c(-c3ccc(OC)cc3)sc3cc(OC)ccc23)cc1
Agent: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.1 %

Procedure:
[6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl](4-methoxyphenyl)methanone (410 mg, 1.02 mmol) was dissolved in anhydrous dimethylformamide (15 ml), and sodium ethanethiolate (170 mg, 2.04 mmol) was added to the resulting solution followed by stirring for 1.5 hours at a temperature of 90° C. to 100° C. under argon atmosphere. The reaction mixture was cooled to room temperature and, after addition of water, was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/1) to give (4-hydroxyphenyl)[6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl]methanone (323 mg, Yield 81.6%) as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]([CH:7]([CH3:9])[CH3:8])[C:3](=[CH2:6])[CH:4]=[O:5].[CH2:10]=[CH:11][C:12](=[CH2:14])[CH3:13]>>[CH3:1][CH:2]([C:3]1([CH:4]=[O:5])[CH2:10][CH2:11][C:12]([CH3:14])=[CH:13][CH2:6]1)[CH:7]([CH3:9])[CH3:8]
Reactant: C=CC(=C)C
Reactant: C=C(C=O)C(C)C(C)C
Product: CC1=CCC(C=O)(C(C)C(C)C)CC1
Temperature: 160 °C
Reaction time: 12 h
Yield: 49 %

Procedure:
3,4-Dimethyl-2-methylene-pentanal (550 g, obtained as detailed above) and 393 g of isoprene were charged to a Parr Bomb, heated to 160° C., and aged for 12 hours. The rushed over material provided ˜32% recovery of 1-(1,2-dimethyl-propyl)-4-methyl-cyclohex-3-enecarbaldehyde (415 g).
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:9][C@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:13]=2)[OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.C[O:43][B:44](OC)OC>C1(C)C=CC=CC=1.CCCCCC>[C:31]1([CH2:30][N:8]([CH2:9][C@@H:10]2[C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:13]=3[B:44]([OH:43])[O:11]2)[CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O[C@H](CN(Cc1ccccc1)Cc1ccccc1)c1cccc(OCCCOCc2ccccc2)c1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: OB1O[C@H](CN(Cc2ccccc2)Cc2ccccc2)c2cccc(OCCCOCc3ccccc3)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1S)-2-[bis(phenylmethyl)amino]-1-[3-({3-[(phenylmethyl)oxy]propyl}oxy)phenyl]ethanol (240 mg, 0.50 mmol) in 5 mL of toluene at −20° C. was added 1.75 mmol of nBuLi in hexane (2.59 M, 0.67 mL) over about 5 minutes. The mixture was then stirred for 2 h and then quenched with freshly distilled trimethylborate (0.28 mL, 259 mg, 2.5 mmol). The cold bath was removed and the mixture warmed to room temperature. The reaction was then diluted with 10 mL of TBME, then 5 mL of saturated NaHCO3 solution was added. After vigorously stirring for about 30 min, the organic layer was washed with 5 mL of 0.1 M NaH2PO4, then 5 mL of saturated NaHCO3. The organic layer was then dried over Na2SO4 and concentrated.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:21])([C:17]([F:20])([F:19])[F:18])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[CH:6]=[C:5]([CH3:22])[C:4]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[C:26]=1F)[CH3:2].[C:36](=O)([O-])[O-:37].[K+].[K+]>CO>[CH2:1]([C:3]1[CH:8]=[C:7]([C:9]([F:21])([C:17]([F:20])([F:19])[F:18])[C:10]([F:16])([F:15])[C:11]([F:12])([F:13])[F:14])[CH:6]=[C:5]([CH3:22])[C:4]=1[NH:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[C:26]=1[O:37][CH3:36])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1NC(=O)c1cccc([N+](=O)[O-])c1F
Agent: [K+]
Solvent: CO
Product: CCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1NC(=O)c1cccc([N+](=O)[O-])c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a suspension of N-[2-ethyl-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)-6-methylphenyl]-2-fluoro-3-nitrobenzamide (Example 12) (5 g, 9.6 mmol) in methanol (195 ml) was added potassium carbonate (2.6 g, 16.2 mmol) at ambient temperature. The reaction mixture was stirred for 16 hours at ambient temperature. The reaction mixture was concentrated and the residue was dissolved in dichloromethane. The organic phase was washed with water, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 3:1) to give N-[2-ethyl-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)-6-methylphenyl]-2-methoxy-3-nitrobenzamide (5.1 g, 99% yield). 1H NMR (400 MHz, CDCl3): 8.90 (bs, 1H), 8.32 (d, 1H), 7.97 (d, 1H), 7.38 (m, 3H), 4.19 (s, 3H), 2.70 (q, 2H), 2.24 (s, 3H), 1.20 (t, 3H) ppm.