Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:39])=[C:8]([N:10]2[CH2:15][CH2:14][C@@H:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@@H:27]([CH2:28][C:29]([O:31]C)=[O:30])[C@H:26]([CH3:33])[C:25]([C:34]([F:37])([F:36])[F:35])=[N:24]4)=[CH:19][CH:18]=3)[C@H:12]([CH3:38])[CH2:11]2)[CH:9]=1)[CH3:2].[Li+].[OH-]>C1COCC1.O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([F:39])=[C:8]([N:10]2[CH2:15][CH2:14][C@@H:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@@H:27]([CH2:28][C:29]([OH:31])=[O:30])[C@H:26]([CH3:33])[C:25]([C:34]([F:36])([F:37])[F:35])=[N:24]4)=[CH:19][CH:18]=3)[C@H:12]([CH3:38])[CH2:11]2)[CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(F)c(N2CC[C@@H](Oc3ccc(N4N=C(C(F)(F)F)[C@@H](C)[C@@H]4CC(=O)OC)cc3)[C@H](C)C2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(F)c(N2CC[C@@H](Oc3ccc(N4N=C(C(F)(F)F)[C@@H](C)[C@@H]4CC(=O)O)cc3)[C@H](C)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a solution of methyl 2-((4S,5S)-1-(4-(((3R,4R)-1-(5-ethoxy-2-fluorophenyl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate (2.57 g, 4.66 mmol) in THF (85 mL) and water (8.5 mL) was added a 1 M aqueous solution of LiOH (58.2 mL, 23.3 mmol) and the reaction mixture was stirred at rt until complete for 1 h. The reaction mixture was concentrated to remove the THF and hexanes were added. An emulsion formed. The layers were separated as much as possible. Brine was added to the emulsion and the layers separated completely. The combined aqueous layer and brine aqueous layer was acidified to pH 2 with 1 M aqueous HCl. The product was extracted with CH2Cl2 (3×) and the combined organic layers were dried (MgSO4) and concentrated to provide 2-((4S,5S)-1-(4-(((3R,4R)-1-(5-ethoxy-2-fluorophenyl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetic acid (2.4720 g, 4.60 mmol, 99% yield) as a white foam. To a solution of 2-((4S,5S)-1-(4-(((3R,4R)-1-(5-ethoxy-2-fluorophenyl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetic acid (7.72 g, 14.4 mmol) in acetonitrile (50 mL) was added 3 N aqueous HCl (9.57 mL, 28.7 mmol). The solution was concentrated. 2-((4S,5S)-1-(4-(((3R,4R)-1-(5-ethoxy-2-fluorophenyl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetic acid, HCl (8.08 g, 14.0 mmol, 97% yield) was isolated as an off-white solid. LC-MS Anal. Calc'd for C27H31F4N3O4: 537.55. found [M+H] 538.3. 1H NMR (400 MHz, CD3CN) δ 7.99 (br. s., 1H), 7.24 (ddd, J=12.0, 9.3, 1.2 Hz, 1H), 7.12-7.04 (m, 2H), 7.02-6.93 (m, 3H), 4.47-4.38 (m, 1H), 4.18 (td, J=10.0, 4.1 Hz, 1H), 4.04 (q, J=6.9 Hz, 2H), 3.78-3.65 (m, 2H), 3.62 (dd, J=12.4, 4.1 Hz, 1H), 3.42 (td, J=11.8, 4.4 Hz, 1H), 3.37-3.27 (m, 1H), 2.83 (br. s., 1H), 2.73 (dd, J=16.5, 3.0 Hz, 1H), 2.54-2.38 (m, 2H), 2.36-2.28 (m, 1H), 1.37 (t, J=7.0 Hz, 3H), 1.30 (d, J=7.2 Hz, 3H), 1.11 (d, J=6.9 Hz, 3H). Analytical HPLC (Orthogonal method) RT=13.3 min, HI: 97%. hGPR40 EC50=154 nM. hGPR40 IP1 EC50=11 nM. Acute oral glucose tolerance: −52% @ 0.3 mg/kg (average of two experiments).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:13][C@@H:14]([OH:17])[CH2:15]Cl)([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH:26]([NH2:28])[CH3:27])[CH:22]=[CH:23][C:24]=1[Cl:25].CCN(C(C)C)C(C)C>C(O)C>[CH2:1]([O:3][P:4]([CH2:13][C@@H:14]([OH:17])[CH2:15][NH:28][CH:26]([C:21]1[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=1)[CH3:27])([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOP(=O)(CC1CCCCC1)C[C@@H](O)CCl
Reactant: CC(N)c1ccc(Cl)c(Cl)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(CC1CCCCC1)C[C@@H](O)CNC(C)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
A mixture of 4.24 g of 3-chloro-2(R)-hydroxy-propyl-(cyclohexylmethyl)-phosphinic acid ethyl ester, 2.85 g of 1-(3,4-dichlorophenyl)ethylamine, 1.95 g of Hunig base and 15 ml of ethanol is heated at reflux for 4 days. After cooling to room temperature and removal of the solvent under reduced pressure, the reaction mixture is partitioned between dichloro-methane and water, dried over sodium sulfate and again concentrated to dryness by evaporation. Chromatography on silica gel yields 3-{N-[1-(3,4-dichlorophenyl)ethyl]amino}-2(S)-hydroxy-propyl(cyclohexylmethyl)phosphinic acid ethyl ester, [α]20D =-1.8°±0.9° (c=1.079 in chloroform).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1([C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=O.[NH:19]1[CH2:23][CH2:22][NH:21][C:20]1=[S:24].C(O)C>C(O)(=O)C>[BrH:1].[CH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[C:5]1([C:3]2[N:21]3[CH2:22][CH2:23][N:19]=[C:20]3[S:24][CH:2]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: O=C(CBr)C1(c2ccc3ccccc3c2)CCC1
Reactant: S=C1NCCN1
Solvent: CCO
Solvent: CC(=O)O
Product: Br
Product: C1=C(C2(c3ccc4ccccc4c3)CCC2)N2CCN=C2S1
Temperature: 25 °C

Procedure:
A mixture of the crude 2-bromo-1-[1-(2-naphthyl)cyclobutyl]ethanone described above, imidazolidine-2-thione (5.1 g), ethanol (60 ml) and acetic acid (40 ml) was heated under reflux for 18 hours then allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue was triturated with a hot mixture of ethyl acetate (100 ml) and acetone (20 ml). The resulting solid was collected by filtration, washed with ethyl acetate (50 ml), dried in vacuo at 60° C., then crystallised from ethanol. The resulting solid was collected by filtration, washed with ethanol (30 ml), and dried in vacuo at 60° C. to give 3-[1-(2-naphthyl)cyclobutyl]-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide as pale yellow prisms (10 g), m.p. 239-241° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][C:19]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:13]([F:34])[CH:12]=1)[C:2]1C=CC=CC=1.C([Li])CCC.C1OC1>O1CCCC1>[CH2:27]([O:26][C:19]1[CH:20]=[C:21]([CH2:24][CH3:25])[CH:22]=[CH:23][C:18]=1[O:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]2[CH2:2][CH2:1][O:8][C:9]2=[O:35])=[CH:12][C:13]=1[F:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CCc1ccc(Oc2ccc(NC(=O)OCc3ccccc3)cc2F)c(OCc2ccccc2)c1
Agent: [Li]CCCC
Solvent: C1CO1
Solvent: C1CCOC1
Product: CCc1ccc(Oc2ccc(N3CCOC3=O)cc2F)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
A solution of [4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]-carbamic acid-benzyl ester (500 mg, 1.06 mmol) in 5 ml tetrahydrofuran under nitrogen atmosphere was cooled to −78° C. To this added 2.8M n-butyl lithium (0.075 g, 1.16 mmol) dropwise and the stirring at −78° C. for 1 h. Condensed ethylene oxide (0.5 ml, 9.9 mmol) was then added dropwise to the reaction mixture and warmed slowly to rt. The reaction was stirred at rt overnight and then quenched with saturated ammonium chloride solution. The aqueous phase was extracted with dichloromethane and the combined organic phase was dried over anhydrous Na2SO4 and concentrated. The crude obtained was purified by column chromatography on silica gel using 25% ethyl acetate in petroleum ether as eluant to obtain 350 mg, 81% of the title compound as a brown oil.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[C:28]([F:34])[C:27]=1[O:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1.[Cl:46][C:47]1[N:48]=[C:49]([CH:55]2[CH2:57][CH2:56]2)[NH:50][C:51]=1[C:52](O)=[O:53].C(N(C(C)C)CC)(C)C>CN(C=O)C>[Cl:46][C:47]1[N:48]=[C:49]([CH:55]2[CH2:56][CH2:57]2)[NH:50][C:51]=1[C:52]([NH:33][CH2:32][C:29]1[CH:30]=[CH:31][C:26]([Cl:25])=[C:27]([O:35][C:36]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=[CH:38][CH:37]=2)[C:28]=1[F:34])=[O:53]
Reactant: O=C(O)c1[nH]c(C2CC2)nc1Cl
Reactant: NCc1ccc(Cl)c(Oc2cccc3ccccc23)c1F
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
Product: O=C(NCc1ccc(Cl)c(Oc2cccc3ccccc23)c1F)c1[nH]c(C2CC2)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.1 %

Procedure:
HATU (0.113 g, 0.298 mmol) was added to a solution of {[4-chloro-2-fluoro-3-(1-naphthalenyloxy)phenyl]methyl}amine (0.060 g, 0.199 mmol) and 4-chloro-2-cyclopropyl-1H-imidazole-5-carboxylic acid (0.037 g, 0.199 mmol) and diisopropylethylamine (0.052 mL, 0.298 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 1 hr. The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue was purified by reverse phase HPLC (acetonitrile:water with 0.1% TFA) to give the title compound (0.016 g, 14%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.284-8.37 (m, 1H), 8.00-8.13 (m, 1H), 7.95 (dd, 1H), 7.54-7.66 (m, 3H), 7.48 (dd, 1H), 7.25-7.37 (m, 2H), 6.49 (d, 1H), 4.33-4.62 (d, 2H), 1.75-2.03 (m, 1H), 0.85-0.93 (m, 2H), 0.77-0.84 (m, 2H). ES MS: m/z 470 (M+1).
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:8]([C:24]([O:26][CH3:27])=[O:25])=[CH:7][CH:6]=1)=[O:2].[Cl:28]N1C(=O)CCC1=O>O1CCCC1>[Cl:28][C:6]1[CH:7]=[C:8]([C:24]([O:26][CH3:27])=[O:25])[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH2:12]2)=[N:10][C:5]=1[CH2:4][NH:3][CH:1]=[O:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(CNC=O)nc1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)c(CNC=O)nc1N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 106 %

Procedure:
tert-Butyl 4-{6-[(formylamino)methyl]-3-(methoxycarbonyl)pyridin-2-yl}piperazine-1-carboxylate (4.85 g, 0.0128 mol) and N-chlorosuccinimide (2.1 g, 15 mmol) was stirred in tetrahydrofuran (85 mL) at 50° C. for 16 hours. Evaporation and purification on silica gel using ethyl acetate in hexanes (0-80%) gave the desired compound (5.6 g, 100%). LCMS calculated for C18H26ClN4O5 (M+H)+: m/z=413.2. found: 412.9.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([CH:9]([CH2:13][CH2:14][CH2:15][C@H:16]1[C@@H:24]2[C@@H:19]([NH:20][C:21]([NH:23]2)=[O:22])[CH2:18][S:17]1)[C:10](=[O:12])[OH:11])=[O:8])C(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][CH2:2][C:7]([CH:9]([CH2:13][CH2:14][CH2:15][C@H:16]1[C@@H:24]2[C@@H:19]([NH:20][C:21]([NH:23]2)=[O:22])[CH2:18][S:17]1)[C:10](=[O:11])[OH:12])=[O:8]
Reactant: CC(C)(C)[C@H](N)C(=O)C(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)C(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a solution of tert-butylglycylbiotin (0.271 g, 0.758 mmol) in CH2Cl2 (0.5 mL) was added 0.5 mL trifluoroacetic acid. The reaction mixture was stirred at room temperature for 2 h, concentrated, and triturated with anhydrous diethyl ether. The off-white precipitate was collected to yield 0.209 g (0.694 mmol, 92%)of the title compound. Mass spec M+H!+ at m/z 302.
Reaction SMILES: Cl[C:2]1[CH:3]2[CH2:13][CH2:12][CH:6]([C:7](Cl)(Cl)[C:8]=1[Cl:9])[CH:5]=[CH:4]2.C(O)(=[O:16])C.[OH2:18]>FC(F)(F)C(O)=O.C(OCC)C>[Cl:9][CH:8]1[C:7](=[O:18])[CH:6]2[CH2:12][CH2:13][CH:3]([CH:4]=[CH:5]2)[C:2]1=[O:16]
Reactant: ClC1=C(Cl)C(Cl)(Cl)C2C=CC1CC2
Reactant: O
Reactant: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: O=C1C2C=CC(CC2)C(=O)C1Cl

Procedure:
0.7 g (2.7 mmol) of 2,3,4,4-tetrachloro-bicyclo[3.2.2]nona-2,6-diene (known from U.S. Pat. No. 3,538,117) is heated in a mixture of 1 ml of trifluoroacetic acid, 4 ml of acetic acid and 1 ml of water for 18 hours at a temperature of 70° C. The cooled reaction solution is then taken up in diethyl ether and extracted first with water and then with saturated sodium chloride solution. After chromatographic purification (ethyl acetate/hexane 1:4), 0.33 g of 3-chloro-bicyclo-[3.2.2]non-6-ene-2,4-dione is obtained as a tautomeric mixture of the forms Da and Db.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[CH3:12][C:13]([CH3:20])=[CH:14][CH2:15][CH2:16][C:17](=[O:19])[CH3:18]>[OH-].[Na+]>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6]([CH:7]=[CH:18][C:17](=[O:19])[CH2:16][CH2:15][CH:14]=[C:13]([CH3:20])[CH3:12])=[CH:5][C:4]=2[O:9]1
Reactant: CC(=O)CCC=C(C)C
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Product: CC(C)=CCCC(=O)C=Cc1ccc2c(c1)OCO2

Procedure:
15 g of piperonal (0.1 mole) and 12.6 g of 6-methyl-5-heptene-2-one (0.1 mole) in an aqueous-alcoholic solution of sodium hydroxide (200 cm3 of 10% NaOH+20 cm3 of ethanol) are stirred for 15 days at ambient temperature. The product obtained is filtered off, washed with water, and recrystallised from ethanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:16][Mg]Br.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>CCN(CC)CC>[CH3:19][S:20]([O:15][CH:14]([CH:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:6]=[CH:7][C:2]([F:1])=[CH:3][N:4]=2)[CH2:9][CH2:10]1)[CH3:16])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: O=CC1CCN(c2ncc(F)cn2)CC1
Reactant: C[Mg]Br
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)C1CCN(c2ncc(F)cn2)CC1

Procedure:
(±)-1-[1-(5-Fluoro-2-pyrimidinyl)-4-piperidinyl]ethyl methanesulfonate (0.24 g) was prepared as a colorless oil from 1-(5-fluoro-2-pyrimidinyl)-4-piperidinecarbaldehyde and methylmagnesium bromide (3M in Et2O) then methanesulfonyl chloride and Et3N in a manner similar to Example 139, Steps 1-2. The crude product was purified by chromatography on an ISCO silica gel column using 0 to 40% EtOAc/hexanes to give (±)-1-[1-(5-fluoro-2-pyrimidinyl)-4-piperidinyl]ethyl methanesulfonate as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 8.17 (s, 2H), 4.80-4.70 (m, 2H), 4.70-4.60 (m, 1H), 2.99 (s, 3H), 2.90-2.75 (m, 2H), 1.95-1.70 (m, 3H), 1.40 (d, 3H, J=6.3 Hz), 1.35-1.25 (m, 2H); LRMS (ESI), m/z 304 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17]CC)=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11](=[O:31])[N:10]2[CH2:32][C:33]2[CH:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([O:43]CC)=[O:42])=[CH:35][CH:34]=2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].Cl>C(O)C>[C:41](/[CH:40]=[CH:39]/[C:36]1[CH:37]=[CH:38][C:33]([CH2:32][N:10]2[CH:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[C:14]([C:15]([OH:17])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:28])[F:30])[CH:22]=3)[C:11]2=[O:31])=[CH:34][CH:35]=1)([OH:43])=[O:42]
Reactant: CCOC(=O)/C=C/c1ccc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C(C)=C(C(=O)OCC)C2c2ccc(C#N)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1=C(C(=O)O)C(c2ccc(C#N)cc2)N(Cc2ccc(/C=C/C(=O)O)cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 16 h

Procedure:
A stirred solution of ethyl 4-(4-cyanophenyl)-3-{4-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]benzyl}-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 40) (100 mg, 0.16 mmol) in ethanol (2 ml) is treated with 10% aq. sodium hydroxide solution (1 ml). After 16 hours, the pH of the reaction solution is adjusted to 2 with 1 N hydrochloric acid, and the crude product is extracted with ethyl acetate (3×150 ml). The combined organic phases are washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue is purified by preparative HPLC (RP18 column; eluent: acetonitrile/0.1% aq. formic acid 10:90→90:10).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=3[F:24])=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:25][CH3:26].C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][S:35]([CH3:34])(=[O:37])=[O:36])=[C:7]([O:25][CH3:26])[CH:8]=3)[N:13]=[CH:12][N:11]=2)=[C:18]([F:24])[CH:19]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc2c(Oc3ccc(Br)cc3F)ncnc2cc1OCCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc(Br)cc3F)ncnc2cc1OCCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.1 %

Procedure:
A solution of 7-(3-aminopropoxy)-4-(4-bromo-2-fluorophenoxy)-6-methoxyquinazoline (2.71 g, 6.4 mmol) and triethylamine (1.1 ml, 0.80 g, 7.9 mmol) in dichloromethane (15 ml) was treated with a solution of methanesulphonyl chloride (0.53 ml, 0.79 g, 6.9 mmol) in dichloromethane (10 ml) and stirred at ambient temperature, under nitrogen for 18 hours. The dichloromethane was then removed by evaporation and THF (4 ml) added. The resulting solution was treated with saturated aqueous sodium hydrogen carbonate solution (to pH 8), stirred vigorously for 30 minutes and the precipitate filtered, washed with water and dried to give 4-(4-bromo-2-fluorophenoxy)-6-methoxy-7-(3-(N-methylsulphonylamino)propoxy)quinazoline (2.98 g, 93%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=O>C(O)C.N1CCCCC1>[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[CH:16][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[NH:12][C:11]1=[O:17]
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Reactant: Cc1cc(C)c(C=O)[nH]1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C)c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42.1 %

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3,5-dimethyl-1H-pyrrole-2-carbaldehyde (32 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-(3,5-Dimethyl-1H-pyrrol-2-ylmethylene)-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (35 mg, 45%).
Reaction SMILES: [I:1][CH3:2].[CH2:3]([O:6][C:7]([N:9]1[C@H:13]([CH2:14][C:15]2[N:16]3[CH:22]=[N:21][CH:20]=[C:17]3[S:18][CH:19]=2)[CH2:12][C@H:11]([S:23][C:24]2[C@H:25]([CH3:41])[C@@H:26]3[C@@H:36]([C@H:37]([OH:39])[CH3:38])[C:35](=[O:40])[N:27]3[C:28]=2[C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30])[CH2:10]1)=[O:8])[CH:4]=[CH2:5]>>[I-:1].[CH2:3]([O:6][C:7]([N:9]1[C@H:13]([CH2:14][C:15]2[N+:16]3[C:17](=[CH:20][N:21]([CH3:2])[CH:22]=3)[S:18][CH:19]=2)[CH2:12][C@H:11]([S:23][C:24]2[C@H:25]([CH3:41])[C@@H:26]3[C@@H:36]([C@H:37]([OH:39])[CH3:38])[C:35](=[O:40])[N:27]3[C:28]=2[C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30])[CH2:10]1)=[O:8])[CH:4]=[CH2:5]
Reactant: CI
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3csc4cncn34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3csc4cn(C)c[n+]34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: [I-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.5 %

Procedure:
Iodomethane (2.13 g) is added to 85.0 mg of allyl(1R,5S,6S)-2-[(3S,5R)-1-allyloxycarbonyl-5-(imidazo[5,1-b]thiazol-3-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate described in Example 20-b), and the mixture is stirred in an argon atmosphere in a light-shielded state at room temperature for 16 hr. The excess reagent is removed by evaporation under reduced pressure, and the residue is purified by column chromatography on Sephadex LH-20 (dichloromethane:methanol=1:1) to give 91.7 mg of allyl(1R,5S,6S)-2-[(3S,5R)-1-allyloxycarbonyl-5-(6-methylimidazo[5,1-b]thiazolium-3-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate iodide as a slightly yellow solid.
Reaction SMILES: C1C([N+]([O-])=[O:8])=CC=C(O)C=1.CC(CC(CCC(O)=O)=O)=O.N1CCC[C@H]1C(O)=O.[CH:30]1([N:36]=[C:37]=[N:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C(Cl)(Cl)Cl>[C:37]([NH:36][CH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1)([NH:38][CH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)=[O:8]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(=O)CC(=O)CCC(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: ClC(Cl)Cl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.17 h

Procedure:
Succinylacetonyl-proline was converted to succinylacetonyl-proline-NH-PEG by adding succinylacetonyl-proline to a condensing agent in the presence of p-nitrophenol in chloroform. The reaction was carried out in 10 ml of chloroform by adding 0.55 g (4.0 mmole) of p-nitrophenol to 0.64 g (3.9 mmole) of succinylacetone-proline. Next, 0.80 g (3.3 mmole) of the condensing agent, dicyclohexylcarbodiimide was added. The latter was dissolved in 2 ml chloroform, and added slowly to the mixture with stirring. Within 10 minutes, a white precipitate of dicyclohexylurea formed, and a spectrophotometric determination [L. Aldwin and D. E. Nitecki, 1987, Anal. Biochem., 164:494-501] of the amount of ester present at that time indicated that there was approximately 61.5% ester present. A similar determination two hours later revealed no change in the amount of ester formed. Dicyclohexylurea was removed by filtering the solution, followed by the addition of 0.45 g (1.1 mmole) PEG-4000-NH2 to the filtrate. The reaction mixture was allowed to stir at room temperature overnight. The product, succinylacetonyl-proline-NH-PEG was purified as follows.
Reaction SMILES: [CH:1]1([N:4]([CH3:21])[CH:5]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]3[C:10](OC)=[C:9]([C:19]#[CH:20])[CH:8]=[CH:7][C:6]2=3)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][C:27]=1[F:33].C(N(CC)CC)C.[C:42](OCC)(=[O:44])C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:22][O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:20]#[C:19][C:9]2[CH:8]=[C:7]([O:44][CH3:42])[C:6]3[CH:5]([N:4]([CH:1]4[CH2:2][CH2:3]4)[CH3:21])[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]=3[CH:10]=2)=[CH:28][C:27]=1[F:33]
Reactant: C#Cc1ccc2c(c1OC)C(C)(C)CCC2N(C)C1CC1
Reactant: COC(=O)Cc1ccc(I)cc1F
Reactant: CCOC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1F

Procedure:
Following General Procedure B and using 5-(cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene (Intermediate 81, 0.085 g, 0.3 mmol), methyl-2-fluoro-4-iodophenylacetate (0.088 g, 0.3 mmol), triethyl amine (8 mL), copper(I)iodide (0.019 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230–400 mesh) using 5–20% ethyl acetate in hexane as the eluent, the title compound was obtained as a yellow solid (0.12 g, 89%).