Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[CH:3]=[C:4]1[N:8]=[CH:7][CH:6]=[CH:5]1.IC[CH2:12][CH3:13].O.[C:15](=O)(O)[O-:16].[Na+]>C1COCC1>[CH2:3]([C:4]1[NH:8][C:7]([CH:15]=[O:16])=[CH:6][CH:5]=1)[CH2:12][CH3:13]
Reactant: CCCI
Reactant: CN(C)C=C1C=CC=N1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1ccc(C=O)[nH]1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
To an anhydrous solution of 6-dimethylamino-1-azafulvene dimer (125; 12.0 g, 49.1 mmol) in THF (500 ml) at -15° C. was added dropwise a solution of 5-butyllithium pentane (1.7M; 87 ml, 174 mmol) over 5 minutes. The yellow cloudy solution was slowly warmed to 0° C. over 10 minutes and stirred at this temperature for a further 20 minutes. The resulting deep violet colored solution was treated with 1-iodopropane (19.2 ml, 196 mmol) and allowed to warm to room temperature over 2 hours. The mixture was treated with water (20 ml) and saturated aqueous sodium bicarbonate (20 ml) and refluxed for 15 hours. The mixture was extracted into methylene chloride and the organic phase was washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered and concentrated to a dark liquid residue (15.2 g) by rotary evaporation. Flash chromatography (silica gel, 500 g; EtOAc/hexanes, 5/95) gave 7.85 g (60%) of the title compound as a pale brown liquid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([O:22]CC)=O)=[CH:14][CH:13]=2)=[CH:10][S:9][C:8]=1[NH2:25])=[O:6])[CH3:3].[CH2:26]([Mg]Cl)[CH:27]=[CH2:28].[CH2:31]1[CH2:35]OC[CH2:32]1>>[CH2:2]([O:4][C:5]([C:7]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:20]([CH2:35][CH:31]=[CH2:32])([OH:22])[CH2:26][CH:27]=[CH2:28])=[CH:16][CH:17]=2)=[CH:10][S:9][C:8]=1[NH2:25])=[O:6])[CH3:3]
Reactant: C=CC[Mg]Cl
Reactant: C1CCOC1
Reactant: CCOC(=O)COc1ccc(-c2csc(N)c2C(=O)OCC)cc1
Agent: Cl
Product: C=CCC(O)(CC=C)COc1ccc(-c2csc(N)c2C(=O)OCC)cc1
Reaction time: 0.5 h

Procedure:
To a cold (0 C) solution of 2-amino-4-(4-ethoxycarbonylmethoxy-phenyl)-thiophene-3-carboxylic acid ethyl ester hydrochloride salt (1.5 g, 3.90 mmol) in THF (20 mL) was added allylmagnesium chloride (11.7 mL, 23.4 mmol, 2 M solution in THF). The thick slurry was stirred for 0.5 h and was then quenched by the slow addition of saturated NH4Cl (20 mL). The layers were separated, and the aqueous was extracted with EtOAc (3×20 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure to a dark oil. The residue was purified by MPLC (SiO2 gel, 3:1 to 2:1 Hz EtOAc) to give the title compound. MS (ESI) m/e 388 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.94 (m, 3H), 2.29 (d, J=7.12 Hz, 4H), 3.70 (m, 2H), 3.96 (q, J=7.12 Hz, 2H), 4.78 (s, 1H), 5.03 (m, 4H), 5.88 (m, 2H), 6.09 (1H), 6.84 (m, 2H), 7.14 (m, 2H), 7.33 (s, 2H).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]([O:10][C:11]([NH:13][C@H:14]1[CH2:18][C:17](C(O)=O)=[CH:16][C@H:15]1[OH:22])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.C[O-].[Na+]>CO>[CH3:5][O:4][C:2]([C:17]1[CH2:18][C@H:14]([NH:13][C:11]([O:10][C:6]([CH3:8])([CH3:7])[CH3:9])=[O:12])[C@H:15]([OH:22])[CH:16]=1)=[O:3]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC(C(=O)O)=C[C@H]1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)C1=C[C@@H](O)[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
Methyl chloroformate (29 /ml, 0.37 mol) was added dropwise to a cooled solution (0° C.) of (3R,4S)-4-tert-butoxycarbonylamino-3-hydroxycyclopent-1-enecarboxylic acid (83 g, 0.34 mol) and triethylamine (52 ml, 0.37 mol) in methanol (600 ml). The reaction was stirred for 1 h at 0° C. and then allowed to warm to room temperature. After stirring for 14 h, it was apparent that the reaction was incomplete. After cooling to 0° C., triethylamine (30 ml, 0.22 mol) was added, and then methyl chloroformate (15 ml, 0.19 mol) was added dropwise. The reaction was complete after a further 2 h. The reaction mixture was concentrated under vacuum and the residue redissolved in dichloromethane (400 ml). The organic solution was washed sequentially with 1M potassium hydrogen sulfate (aq) (2×200 ml), saturated hydrogen carbonate (2×200 ml) and brine (200 ml) before drying over magnesium sulfate. Following filtration, the solvent was removed to yield an orange oil which was redissolved in methanol (300 ml) and cooled to 5° C. Sodium methoxide (0.25 ml, 25% wt solution in methanol, 3 mol %) was then added and the reaction mixture cooled and stirred for 4 h. The reaction was quenched with glacial acetic acid and concentrated under vacuum, and the residue was redissolved in dichlormethane (300 ml). The organic solution was washed with saturated sodium hydrogen carbonate (100 ml) then brine (100 ml) and dried over magnesium sulfate. Following filtration, the solvent was removed under vacuum to yield the title compound as an orange oil (76 g, 87%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([NH:13]C(=O)C(C)(C)C)=[CH:9][CH:8]=1.[OH-].[Na+]>Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2ncccn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(-c2ncccn2)cc1
Yield: 88.5 %

Procedure:
N-(4-(2-pyrimidinyl)phenyl)-2,2-dimethylpropanamide (1.41 g, 5.48 mmol) was boiled in 6 M hydrochloric acid (40 ml) for 2 h. The mixture was cooled and made strongly basic with NaOH (s) and extracted with CH2Cl2 (2×50 ml), dried (Na2SO4) and the solvent was removed in vacuo. Trituration with n-hexane gave 0.83 g (88%) of 4-(2-pyrimidinyl)aniline as a light-yellow powder. The product was further transformed by Method B and Method G (using cyclohexanecarboxaldehyde). M.p. 236–238° C.
Reaction SMILES: B.C1COCC1.[CH2:7]([N:14]([C:19]1[CH:24]=[C:23]([C:25](=[O:28])[CH2:26][Br:27])[CH:22]=[CH:21][C:20]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[S:15]([CH3:18])(=[O:17])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CO>C1(C)C=CC=CC=1.C1COCC1>[CH2:7]([N:14]([C:19]1[CH:24]=[C:23]([C@@H:25]([OH:28])[CH2:26][Br:27])[CH:22]=[CH:21][C:20]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[S:15]([CH3:18])(=[O:17])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CS(=O)(=O)N(Cc1ccccc1)c1cc(C(=O)CBr)ccc1OCc1ccccc1
Agent: B
Solvent: CO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CS(=O)(=O)N(Cc1ccccc1)c1cc([C@@H](O)CBr)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.1 %

Procedure:
A solution of BH3.THF in THF (1 M, 2.80 mL, 2.80 mmol) was added to a mixture of N-benzyl-N-[2-benzyloxy-5-(2-bromoacetyl)phenyl]methanesulfonamide (33) (1.09 g, 2.23 mmol) and R-methyl-CBS-oxazoborolidine (1 M in toluene, 0.45 mL, 0.45 mmol) in anhydrous THF (10 mL). The reaction mixture was stirred at 0° C. for 15 min and then at rt for 16 h. Methanol (5 mL) was slowly added to quench the reaction. After removal of solvent by rotary evaporation, the resulting residue was purified by Biotage silica gel column chromatography eluting with a mixture of ethyl acetate (0-3%) in dichloromethane to give the desired bromo alcohol 34 as a white solid (0.92 g, 84%): 1H NMR (500 MHz, CDCl3) δ 2.60 (s, 1H), 2.85 (s, 3H), 3.30 (m, 1H), 3.38 (m, 1H), 4.70 (m, 3H), 5.11 (s, 2H), 7.00 (m, 2H), 7.21 (m, 5H), 7.28 (d, 1H), 7.42 (m, 5H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30].[OH-].[Na+].C(O)(=O)C>C(O)C.O>[C:1]([C:5]1[CH:10]=[C:9]([S:11][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: O=C(O)CCCCCCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(SCCCCCCCCCCCC(=O)O)cc(C(C)(C)C)c1O
Reaction time: 20 h

Procedure:
To a solution of 2,6-di-tert-butyl-4-mercaptophenol (II) (477 mg; 2 mmol) in dry ethanol (20 ml), water containing 12-bromododecanoic acid (558 mg; 2 mmol) and 97 % sodium hydroxide (250 mg; 6 mmol) was added, and the resultant mixture was allowed to stand at room temperature for 20 hours. The reaction mixture was made acidic with 10 aqueous acetic acid and extracted with ethyl acetate. The extract was washed two times with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product thus obtained was chromatographed on silica gel and eluted with ethyl acetate. The collected fractions were concentrated under reduced pressure. The residue was recrystallized from a mixture of water and methanol (1 : 1 by volume) to give the objective compound (Ie) (680 mg). Yield, 78 %. m.p., 41°-42° C.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][N:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[NH:31][CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[CH:24][N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(C(=O)O)cn3)c2CC1
Reactant: NCC1CCCCC1
Product: Cl
Product: O=C(NCC1CCCCC1)c1ccc(CSc2c(Cl)ccc3c2CCNCC3)nc1

Procedure:
Use a method similar to the Example 375, using 3-tert-butoxycarbonyl-6-(5-carboxy-pyridin-2-ylmethylthio)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine and aminomethylcyclohexane to give, after deprotection by the General Procedure 1-4, the title compound as a white solid. MS (APCI+) m/z: 444 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=[CH:9]1)(N1C=CN=C1)=[O:2].[CH3:13][CH:14]([CH3:17])[CH2:15][NH2:16].C(O)(=O)C(O)=O.[F:24][C:25]([F:38])([F:37])[C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[O:29]C1CNC1.C(N(CC)CC)C>C(Cl)Cl>[CH3:13][CH:14]([CH3:17])[CH2:15][NH:16][C:1]([N:8]1[CH2:9][CH:11]([O:29][C:28]2[CH:34]=[CH:35][CH:36]=[C:26]([C:25]([F:24])([F:37])[F:38])[CH:27]=2)[CH2:12]1)=[O:2]
Reactant: CC(C)CN
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)CNC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reaction time: 1 h
Yield: 93.3 %

Procedure:
A stirred solution of 3.6 g (0.022 mole) of 1,1'-carbonyldiimidazole in 100 ml of methylene chloride under nitrogen was treated with 1.6 g (0.022 mole) of 2-methylpropylamine (added via a syringe and needle through a septum placed in one neck of the reaction flask). After stirring for 1 hr, 6.2 g (0.02 mole) of 3-[3-(trifluoromethyl)phenoxy]azetidine oxalate was added all at once followed in 30 min with 5 ml of triethylamine and stirring continued for 18 hr. The reaction mixture was washed with water (2×25 ml), dried over magnesium sulfate and concentrated in vacuo, yielding 13 g of crude solid residue. Recrystallization from ethanol/water yielded 5.9 g of product having a pink cast. A second recrystallization from cyclohexane yielded 4.8 g of fine white crystals, m.p. 124°-125° C. Rework of the filtrates yielded 1.2 g additional beige crystals. Total yield of product was 75.6% of theory.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:29])=[C:7]([C:21]([NH:23][CH2:24][CH:25]([OH:28])[CH2:26][OH:27])=[O:22])[C:8]([I:20])=[C:9]([C:18]=1[I:19])[C:10]([NH:12][CH2:13][CH:14]([OH:17])[CH2:15][OH:16])=[O:11])(=[O:3])[CH3:2].C[O-].[Na+].Cl[CH2:34][CH:35]([OH:38])[CH2:36][OH:37].NC1C(I)=C(C(NCC(O)CO)=O)C(I)=C(C=1I)C(NCC(O)CO)=O>C(O)C(O)C>[OH:38][CH:35]([CH2:36][OH:37])[CH2:34][N:4]([C:5]1[C:18]([I:19])=[C:9]([C:10]([NH:12][CH2:13][CH:14]([OH:17])[CH2:15][OH:16])=[O:11])[C:8]([I:20])=[C:7]([C:6]=1[I:29])[C:21]([NH:23][CH2:24][CH:25]([OH:28])[CH2:26][OH:27])=[O:22])[C:1](=[O:3])[CH3:2]
Reactant: OCC(O)CCl
Reactant: CC(=O)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Agent: C[O-]
Agent: Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Agent: [Na+]
Solvent: CC(O)CO
Product: CC(=O)N(CC(O)CO)c1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Temperature: 50 °C
Reaction time: 48 h

Procedure:
5-Acetamido-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)isophthalamide (37.4 g; 50 mmole) was dissolved in propylene glycol (110 ml) by adding 5.3 M sodium methoxide (14.2 ml; 75 mmole) and heating in an oil bath at 50° C. When all or nearly all of the starting material was dissolved, the excess of methanol was evaporated in vacuo. After cooling to room temperature 3-chloropropane-1,2-diol (6.3 ml; 75 mmole) was added. When the reaction mixture was applied to TLC in system (B) after stirring for two days, two new spots with Rf values 0.26 and 0.33 in a ratio of about 1:9 and less than 0.5% of the starting material with Rf 0.42 were observed. The new spots were assumed to represent endo/exo isomers. The reaction mixture was evaporated in vacuo and the residue dissolved in methanol (125 ml). A small amount of undissolved material was filtered off and water (30 ml) added. This solution was treated with a mixture of Amberlite cation exchange resin IR 120H (27.5 g) and Dowex anion exchange resin 1×4 (50 g) for two hours. After filtration, the pH of the solution was adjusted to 4.9, and then evaporated in vacuo. The oily residue was triturated in butanol (125 ml). The product crystallized out following this treatment. After storing at -20° C., the product was filtered off. Then the product was dissolved in water, and the solution evaporated in vacuo. Yield 38 g.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([CH:21]([O:23][C:24]2[CH:29]=[CH:28][C:27](Br)=[CH:26][N:25]=2)[CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:50]([Si:52]([CH3:55])([CH3:54])[CH3:53])#[CH:51]>C1COCC1.C(NCC)C.C(OCC)(=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([CH:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:51]#[C:50][Si:52]([CH3:55])([CH3:54])[CH3:53])=[CH:26][N:25]=2)[CH3:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: CC(Oc1ccc(Br)cn1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(Oc1ccc(C#C[Si](C)(C)C)cn1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 85 °C
Yield: 67.6 %

Procedure:
To a suspension of 2-{(SR)-1-[(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethoxy}-5-bromo-pyridine (128 mg, 0.253 mmol) and bis(triphenylphosphine) palladium(II) chloride (53 mg, 0.076 mmol) and triphenylphosphine (16.6 mg, 0.0632 mmol) and CuI (11 mg, 0.0578 mmol) in THF (3 mL) and diethylamine (1.5 mL) was added ethynyltrimethylsilane (0.108 mL, 0.759 mmol) under Ar. The mixture was heated at 85° C. over night. The reaction mixture was diluted with ethyl acetate and washed with aq.ammonium chloride solution two times. The separated organic phase was dried over anhydrous sodium sulfate and concentrated in vaccuo after filtration. The residue was purified by silica gel column chromatography (DCM) yielding 89.5 mg (68%) of the titled compound as a light yellow oil. ES-MS m/e: 523.3 (M+H+).
Reaction SMILES: [CH2:1]([C:3]1[S:19][C:6]2[NH:7][C:8](=[O:18])[N:9]([C:12]3[CH:16]=[C:15]([CH3:17])[O:14][N:13]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]2[N:38]=[C:37](C(Cl)(Cl)Cl)[O:36][N:35]=2)=[CH:24][CH:23]=1.C(=O)([O-])[O-:44].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:3]1[S:19][C:6]2[N:7]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[NH:38][C:37](=[O:44])[O:36][N:35]=4)=[CH:24][CH:23]=3)[C:8](=[O:18])[N:9]([C:12]3[CH:16]=[C:15]([CH3:17])[O:14][N:13]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Reactant: CCc1cc2c(=O)n(-c3cc(C)on3)c(=O)[nH]c2s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(-c3cc(C)on3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.9 %

Procedure:
A mixture of 6-ethyl-3-(5-methylisoxazol-3-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.6 g), 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (1.1 g), potassium carbonate (0.6 g) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (5 mL) and acetone (5 mL). 1N Aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was adjusted to pH 7 with water and 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained ethyl s acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.25 g, 22%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:29]([O:31][C:32](=[O:47])[CH2:33][CH:34]1[CH2:39][CH2:38][N:37]([C:40](N2C=CN=C2)=[O:41])[CH2:36][CH2:35]1)[CH3:30]>C(Cl)Cl>[CH2:29]([O:31][C:32](=[O:47])[CH2:33][CH:34]1[CH2:35][CH2:36][N:37]([C:40]([N:9]2[CH2:10][C@@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C@@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:41])[CH2:38][CH2:39]1)[CH3:30]
Reactant: CCOC(=O)CC1CCN(C(=O)n2ccnc2)CC1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Product: CCOC(=O)CC1CCN(C(=O)N2C[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)CC1
Reaction time: 1 h
Yield: 53.4 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (51.6 mg, 0.122 mmol) and [1-(imidazole-1-carbonyl)-piperidin-4-yl]-acetic acid ethyl ester (293.3 mg, 1.10 mmol) in CH2Cl2 (8 mL) was stirred at reflux for 16 hrs then 1 h at 140° C. in a microwave tube and finally at 160° C. for 1 hr. The reaction mixture was then purified by flash column to give rac-{1-[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-piperidin-4-yl}-acetic acid ethyl ester (40.4 mg, 53.4%). HRMS (ES+) m/z Calcd for C32H37Cl2F2N3O3+H [(M+H)+]: 620.2253; Found: 620.2254.
Reaction SMILES: [F:1][C:2]1([F:20])[C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:10]([O:12]C)=[O:11])=[CH:4][C:3]1=[CH2:19].C(=O)([O-])[O-].[K+].[K+]>CO.O>[F:1][C:2]1([F:20])[C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:10]([OH:12])=[O:11])=[CH:4][C:3]1=[CH2:19]
Reactant: C=C1C=C(Oc2cc(C(=O)OC)ccc2OC)C1(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C=C1C=C(Oc2cc(C(=O)O)ccc2OC)C1(F)F

Procedure:
A solution of methyl 3-(4,4-difluoro-3-methylenecyclobut-1-enyloxy)-4-methoxybenzoate (1.39 g) in methanol (22 mL) is treated with a solution of potassium carbonate (0.83 g) in water (8 mL) and the solution is heated at 60°-70° C. for 8 hours, cooled and evaporated. The residue is dissolved in water (30 mL), extracted with diethyl ether (50 mL) and acidified to pH 4 by treatment with glacial acetic acid. The precipitated solid is extracted with ethyl acetate (2×75 mL). The combined organic extracts are dried over magnesium sulfate and concentrated, to give 3-(4,4-difluoro-3-methylene-cyclobut-1-enyloxy)-4-methoxybenzoic acid, in the form of a white solid, m.p. 163°-165° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:14](=[O:15])[NH:13][C:12]2[N:11]=[CH:10][C:9](/[CH:16]=[CH:17]/[C:18]([OH:20])=O)=[CH:8][C:7]=2[CH2:6]1)=[O:4].Cl.[F:22][C:23]1[CH:36]=[CH:35][C:26]([O:27][CH2:28][CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:22][C:23]1[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH:29]2[CH2:30][CH2:31][N:32]([C:18](=[O:20])/[CH:17]=[CH:16]/[C:9]3[CH:8]=[C:7]4[C:12](=[N:11][CH:10]=3)[NH:13][C:14](=[O:15])[CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]4)[CH2:33][CH2:34]2)=[CH:35][CH:36]=1
Reactant: Fc1ccc(OCC2CCNCC2)cc1
Reactant: COC(=O)C1Cc2cc(/C=C/C(=O)O)cnc2NC1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1Cc2cc(/C=C/C(=O)N3CCC(COc4ccc(F)cc4)CC3)cnc2NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.2 %

Procedure:
To a solution of (2E)-3-[6-(methoxycarbonyl)-7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl]acrylic acid (96 mg, 0.35 mmol; which may be prepared as described in Step 4) in DMF (8 mL) were added 4-[(4-fluorophenoxy)methyl]piperidine hydrochloride (102 mg, 0.42 mmol; which may be prepared as described in Step 2), DIPEA (144 μL, 0.83 mmol), 4-DMAP (17 mg, 0.14 mmol) and EDAC (80 mg, 0.42 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified by flash chromatography on silica gel (eluent: dichloromethane/MeOH from 100/0 to 80/20) to give a first solid which is purified again on preparative TLC (eluent: dichloromethane/MeOH 95/5) to give the title compound (15 mg, 8%) as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([N:15]1[CH2:24][C:23]([CH3:26])([CH3:25])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]1[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[O:34][CH2:35][C:36]([O:38]CC)=[O:37])=[O:14])(C)(C)C.C(N(CC)CC)C.ClC(O[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=O>C(Cl)Cl>[CH2:52]([O:12][C:13]([N:15]1[CH2:24][C:23]([CH3:26])([CH3:25])[C:18]2[C:17](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]1[C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[O:34][CH2:35][C:36]([OH:38])=[O:37])=[O:14])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1c2ccccc2C(C)(C)CN1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CN(C(=O)OCc2ccccc2)C(c2cc(Cl)ccc2OCC(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Trifluoroacetic acid (0.92 mL, 11.8 mmol, 20.0 eq.) was added to a solution of (±)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (280 mg, 0.59 mmol, 1.0 eq.) in DCM (1 mL). The resulting mixture was stirred at r.t. during 5 hours. The mixture was concentrated in vacuo. To an-ice cooled suspension of the residue and triethylamine (0.41 mL, 2.95 mmol, 5.0 eq.) in DCM (1 mL), benzyl chloroformate (0.18 mL, 1.18 mmol, 2.0 eq.) was added dropwise. Upon completion of the addition, the cooling bath was removed and the suspension was stirred at r.t. for 18 hours. The reaction was quenched with 1M aq. citric acid soln. (5 mL). The layers were separated. The aq. phase was extracted with DCM (3×2 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was dissolved in DMF (1 mL), 1M aq. NaOH soln. (1 mL) was added. The resulting solution was stirred at r.t. for 18 hours. The solution was neutralized with formic acid (1 mL), filtered, and then purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid.