Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[C:3]#[N:4].[CH2:7]([S:11](Cl)(=[O:13])=[O:12])[CH2:8][CH2:9][CH3:10]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH3:5][C:2]([NH:1][S:11]([CH2:7][CH2:8][CH2:9][CH3:10])(=[O:13])=[O:12])([CH3:6])[C:3]#[N:4]
Reactant: CCCCS(=O)(=O)Cl
Reactant: CC(C)(N)C#N
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCS(=O)(=O)NC(C)(C)C#N
Temperature: 25 °C
Yield: 39.2 %

Procedure:
To a stirred mixture of 8.4 g (0.1 mole) 2-amino-2-methyl-propionitrile and 12.2 g (0.1 mole) 4-dimethylaminopyridine in 125 ml chloroform, 15.7 g (0.1 mole) 1-butanesulfonyl chloride in 25 ml chloroform were added dropwise over 20 minutes, with evolution of heat and separation of solids. The reaction mixture was refluxed 2.5 hours. After cooling to room temperature, the reaction mixture was washed with 25 ml concentrated hydrochloric acid which had been diluted with 25 ml water. The layers were phase separated. The organic layer was washed twice with 50 ml ice water, dried over magnesium sulfate and stripped to give 8.0 g of the above-identified product, as a dark red oil.
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:31])[C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([NH:28]C=O)[CH:19]=2)[C@H:13]([CH2:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[NH:35][CH:34]=2)[CH2:12]1)(=[O:10])/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:42]>CO>[ClH:42].[NH2:28][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=1)[C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:1](=[O:10])/[CH:2]=[CH:3]/[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:12][C@H:13]1[CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH:34]=1)=[O:31]
Reactant: O=CNc1cc(C(=O)N2CCN(C(=O)/C=C/c3ccccc3)C[C@H]2Cc2c[nH]c3ccccc23)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CO
Product: Nc1cc(C(=O)N2CCN(C(=O)/C=C/c3ccccc3)C[C@H]2Cc2c[nH]c3ccccc23)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of (2R)-4-(trans-cinnamoyl)-1-[3-formylamino-5-(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (280 mg) and aqueous 10% hydrochloric acid (1 ml) in methanol (10 ml) was stirred at room temperature for 6 hours. The mixture was evaporated under reduced pressure. The resulting powder was collected by filtration and dried to give (2R)-1-[3-amino-5-(trifluoromethyl)benzoyl]-4-(trans-cinnamoyl)-2-(1H-indol-3-yl-methyl)piperazine hydrochloride (280 mg).
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][C:43]([CH:46]5[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]5)=[CH:42][CH:41]=4)[C:38]([CH3:52])=[C:37]([OH:53])[C:36]3=[O:54])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][C:43]([CH:46]5[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]5)=[CH:42][CH:41]=4)[C:38]([CH3:52])=[C:37]([O:53][CH3:3])[C:36]3=[O:54])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: CC1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1c1ccc(C2CCCCC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CO
Solvent: CCOCC
Product: COC1=C(C)C(c2ccc(C3CCCCC3)cc2)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (9 eq), ethylene glycol/Et2O (1/2 v/v, 30 ml), 1-(1H-Benzo[d]imidazol-6-yl)-5-(4-cyclohexylphenyl)-3-hydroxy-4-methyl-1H-pyrrol-2(5H)-one (0.900 g, 2.32 mmol, 1 eq) and MeOH (10 ml); yield: 0.200 g (21.4%); MS m/z: 402.1 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 12.4 (b, 1H), 8.32 (s, 1H), 7.71 (s, 1H), 7.46-7.44 (m, 1H), 7.34 (m, 1H), 7.16-7.11 (m, 4H), 5.77 (s, 1H), 3.93 (s, 3H), 2.39 (m, 1H), 1.79-1.60 (m, 8H), 1.40-1.20 (m, 6H); HPLC (METHOD [A]): rt 15.68 min (96.92%)
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[C:8]2[C:4]=1[C:5]([NH:22][C:23](=[O:33])[CH2:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH3:32])[CH2:27][CH2:26]1)([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:6](=[O:14])[NH:7]2.[OH-:36].[K+]>CC(O)(C)C>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:5]2([NH:22][C:23](=[O:33])[CH2:24][N:25]3[CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH2:30]3)[C:4]3[C:8](=[CH:9][C:10]([C:12]([NH2:13])=[O:36])=[CH:11][C:3]=3[C:2]([F:1])([F:34])[F:35])[NH:7][C:6]2=[O:14])=[CH:20][CH:19]=1
Reactant: [OH-]
Reactant: CCN1CCN(CC(=O)NC2(c3ccc(Cl)cc3)C(=O)Nc3cc(C#N)cc(C(F)(F)F)c32)CC1
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCN1CCN(CC(=O)NC2(c3ccc(Cl)cc3)C(=O)Nc3cc(C(N)=O)cc(C(F)(F)F)c32)CC1
Yield: 60.4 %

Procedure:
0.16 g of the product obtained in Example 4, 0.47 g of potassium hydroxide and 7 ml of t-BuOH are placed in a round-bottomed flask equipped with a magnetic stirrer. The mixture is left to react at 50° C. for 5 hours. The resulting mixture is filtered through Celite and washed with THF. The filtrate is evaporated under vacuum and the residue is taken up in ethyl acetate and washed with water. The organic phase is dried over Na2SO4, filtered and evaporated under vacuum. 100 mg of an oil are obtained, which oil is purified by flash chromatography, eluting with 8/2 ethyl acetate/methanol. 10 mg of white solid are isolated.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@:10]([C:15]#[C:16][CH2:17][OH:18])([OH:14])[C@@H:9]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@:10](/[CH:15]=[CH:16]\[CH2:17][OH:18])([OH:14])[C@@H:9]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](O)(C#CCO)[C@@H]1c1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@](O)(/C=C\CO)[C@@H]1c1ccccc1
Reaction time: 4 h
Yield: 99.4 %

Procedure:
Palladium on calcium carbonate, poisoned with lead (Lindlar catalyst, 2 g) was added to a solution of (2S,3R)-1-tert-butoxycarbonyl-3-(3-hydroxypropyn-1yl)-2-phenylpiperidin-3-ol (Preparation 7; 32 g, 96.6 mmol) in ethyl acetate (300 ml) and the mixture was stirred under hydrogen (1 atmosphere) for 4 hours. The mixture was filtered and the solvent was evaporated under reduced pressure to give the title compound as an oil (32 g, 100%). 1H NMR (360 MHz, CDCl3) 8 7.42 (2H, d, J=7.6 Hz), 7.35-7.25 (3H, m), 5.83 (1H, d, J12.3 Hz), 5.68 (1H, dt, J=12.3, 6.0 Hz), 5.06 (1H, s), 4.27 (1H, m), 4.12 (2H, m), 3.32 (1H, m), 3.13 (1H, s), 2.28 (1H, t, J=5.9 Hz), 2.02 (1H, m), 1.92-1.78 (3H, m), and 1.32 (9H, s). m/z (ES+) 334 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]([CH2:17][C:18]#[N:19])([CH:11]1[C:15](=[O:16])[O:14][CH2:13][CH2:12]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H][H]>C(O)(=O)C.[Pt](=O)=O>[CH2:1]([O:3][C:4]([C:5]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:17][CH2:18][NH:19][C:15](=[O:16])[CH:11]1[CH2:12][CH2:13][OH:14])=[O:20])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(CC#N)(C(=O)OCC)C1CCOC1=O
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CCOC(=O)C1(C(=O)OCC)CCNC(=O)C1CCO
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.1 %

Procedure:
To a solution of 4.35 g (0.015 mol) of the cyanodiester from Example 5 in 100 mL of glacial acetic acid was added 150 mg of platinum (IV) oxide, and the mixture was agitated under hydrogen (60 psi) until hydrogen uptake had ceased. The mixture was filtered and the acetic acid was removed under reduced pressure (Ca. 0.5 mm) at 30°-35° C. To the oily residue (containing a trace amount of acetic acid) was added 300 mL of chloroform and the mixture was stirred at room temperature for 48 h. The solvent was removed in vacuo and the residue was triturated in pet ether and filtered. The resultant solid was subjected to flash chromatography (silica, 9:1 EtOAc/MeOH). The major isolated compound was recrystallized in CHCl3 /hexane to give 3.54 g (80%) of white solid: mp 120°-121° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].Cl.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[N:34][CH:33]=1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:31]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[O:38])=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(N)cc2CN2CCOC2=O)c1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(NC(=O)c3cccnc3)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 100, Step 1, using the following starting materials: {3-[4-amino-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and nicotinoyl chloride hydrochloride.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)[C:15]([F:25])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1.ClC1C=C2C(C3N=C(N[C@H]4CCCNC4)C(F)=CN=3)=CNC2=NC=1.C(N(C(C)C)CC)(C)C.Cl[C:60]([O:62][CH3:63])=[O:61]>C(Cl)Cl.CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:11]([C:12]3[N:17]=[C:16]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][N:21]([C:60]([O:62][CH3:63])=[O:61])[CH2:20]4)[C:15]([F:25])=[CH:14][N:13]=3)=[CH:10][NH:9][C:6]2=[N:7][CH:8]=1
Reactant: COC(=O)Cl
Reactant: Fc1cnc(-c2c[nH]c3ncc(Cl)cc23)nc1N[C@H]1CCCNC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of (S)-2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoro-N-(piperidin-3-yl)pyrimidin-4-amine hydrochloride, 5b, (0.042 g, 0.100 mmol) in CH2Cl2 (1.4 mL) and DMF (0.3 mL) was added N,N-diisopropyl-N-ethylamine (0.300 mL, 1.720 mmol) followed by methyl chloroformate (0.009 g, 0.120 mmol). The reaction mixture was stirred at room temperature for 17 hours. The mixture was concentrated in vacuo, dissolved in 1 mL of DMSO and purified by preparatory HPLC (0.1% ammonium formate-H2O/acetonitrile) to afford the desired product, 440.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([O:22]CC)=[O:21])[CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[CH2:8][CH2:7]2.[OH-].[Na+].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([OH:22])=[O:21])[CH:5]=[C:6]2[C:11]=1[NH:10][CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[CH2:8][CH2:7]2
Reactant: CCOC(=O)Cc1cc(Cl)c2c(c1)CCC(c1ccccc1F)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1cc(Cl)c2c(c1)CCC(c1ccccc1F)N2
Temperature: 80 °C
Yield: 93.2 %

Procedure:
The compound (1.4 g) of Example 4 was dissolved into 10% aqueous solution of sodium hydroxide (30 ml) and small quantity of ethanol and the solution was refluxed at 80° C. for 2 hours under heat. After cooling, this was acidified with concentrated hydrochloric acid. The crystals deposited were collected by filtration and recrystallized from ethanol-hexane to obtain aimed product (1.2 g) as pale yellow prismatic crystals. Melting point: 127°-129° C.
Reaction SMILES: Cl[CH:2]1[C:6](=[O:7])[C:5]([C:8]2[C:13]([CH2:14][CH3:15])=[CH:12][C:11]([CH3:16])=[CH:10][C:9]=2[CH2:17][CH3:18])=[C:4]([O:19][CH3:20])[CH2:3]1.N12CCCN=C1CCCCC2.[O:32]1[CH:36]=[CH:35][CH:34]=[CH:33]1>>[CH2:14]([C:13]1[CH:12]=[C:11]([CH3:16])[CH:10]=[C:9]([CH2:17][CH3:18])[C:8]=1[C:5]1[C:6](=[O:7])[CH:2]2[CH:3]([C:4]=1[O:19][CH3:20])[CH:36]1[O:32][CH:33]2[CH:34]=[CH:35]1)[CH3:15]
Reactant: CCc1cc(C)cc(CC)c1C1=C(OC)CC(Cl)C1=O
Reactant: c1ccoc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1cc(C)cc(CC)c1C1=C(OC)C2C3C=CC(O3)C2C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-chloro-2-(2,6-diethyl-4-methylphenyl)-3-methoxycyclopent-2-enone (0.530 g, 1.81 mmol) in furan (40 ml) at room temperature is added by syringe pump over two hours a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (0.540 ml, 3.62 mmol) in furan (10 ml). The reaction is stirred at room temperature for a further 30 minutes and then evaporated to dryness under reduced pressure. The residue is diluted with water (50 ml), 2 M aqueous hydrochloric acid (25 ml) is added and the mixture is extracted with ethyl acetate (3×50 ml). The combined organic extracts are washed with brine (20 ml), dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated to dryness under reduced pressure. The residue is purified by column chromatography on silica gel to give (1RS,2RS,6SR,7SR)-4-(2,6-diethyl-4-methylphenyl)-5-methoxy-10-oxa-tricyclo[5.2.1.02,6]deca-4,8-dien-3-one.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)([OH:20])[CH3:19])[N:14]3[CH3:17])=[C:10]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[CH:36][C:5]=2[N:4]=1)[CH3:2].CCN(CC)CC.[CH:44]1([C:47](Cl)=[O:48])[CH2:46][CH2:45]1>C(Cl)Cl>[CH:44]1([C:47]([N:24]2[CH2:25][CH2:26][CH:21]([C:18]([C:13]3[N:14]([CH3:17])[C:15]4[C:11]([N:12]=3)=[C:10]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:9]=[C:8]([N:7]3[C:6]5[CH:33]=[CH:34][CH:35]=[CH:36][C:5]=5[N:4]=[C:3]3[CH2:1][CH3:2])[N:16]=4)([OH:20])[CH3:19])[CH2:22][CH2:23]2)=[O:48])[CH2:46][CH2:45]1
Reactant: O=C(Cl)C1CC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(C)(O)C3CCNCC3)n(C)c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(C)(O)C3CCN(C(=O)C4CC4)CC3)n(C)c2n1
Reaction time: 0.25 h
Yield: 44 %

Procedure:
A solution of 1-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-1-piperidin-4-ylethanol and NEt3 (74 μL, 0.53 mmol) in DCM (5 mL) was cooled to −78° before the addition of cyclopropane carbonyl chloride (18 μL, 0.20 mmol). The resulting mixture was stirred for 15 min then quenched with H2O and extracted with DCM. The combined organics were dried (phase separator) and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% NH4OH in water on a gradient acetonitrile 10-70%) affording 865 as a white solid (44 mg, 44%). LCMS (method I): RT 3.51 min, [M+H]+ 559.4. 1H NMR (CDCl3, 400 MHz): δ 8.01-8.00 (1 H, m), 7.80 (1 H, d, J=7.13 Hz), 7.33-7.28 (2 H, m), 4.71 (1 H, brd s), 4.32 (4 H, brd s), 3.98 (3 H, s), 3.87 (4 H, t, J=4.69 Hz), 3.40 (2 H, q, J=7.47 Hz), 3.14-2.98 (1 H, m), 2.60-2.43 (1 H, m), 2.20-2.09 (1 H, m), 1.86-1.65 (6 H, m), 1.62-1.36 (3 H, m), 1.47 (3 H, t, J=7.47 Hz), 1.00-0.93 (2 H, m), 0.75-0.74 (2 H, m)
Reaction SMILES: [Cl:1][C:2]1[C:18]([Cl:19])=[C:17]([CH2:20][CH2:21][C:22](=[O:39])[C:23]2[S:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=3)=[CH:26][CH:27]=2)[CH:16]=[CH:15][C:3]=1[O:4][C:5]([CH3:14])([CH3:13])[C:6]([O:8]C(C)(C)C)=[O:7].FC(F)(F)C(O)=O>>[Cl:1][C:2]1[C:18]([Cl:19])=[C:17]([CH2:20][CH2:21][C:22](=[O:39])[C:23]2[S:24][C:25]([C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35]([F:36])([F:37])[F:38])=[CH:32][CH:33]=3)=[CH:26][CH:27]=2)[CH:16]=[CH:15][C:3]=1[O:4][C:5]([CH3:14])([CH3:13])[C:6]([OH:8])=[O:7]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(=O)c2ccc(-c3ccc(OC(F)(F)F)cc3)s2)c(Cl)c1Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Oc1ccc(CCC(=O)c2ccc(-c3ccc(OC(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)O

Procedure:
2-(2,3-Dichloro-4-(3-oxo-3-(5-(4-(trifluoromethoxy)phenyl)thien-2-yl)propyl)-phenoxy)-2-methylpropanoic acid is prepared from tert-butyl 2-(2,3-dichloro-4-(3-oxo-3-(5-(4-(trifluoromethoxy)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoate according to general procedure E using 10 equivalents of trifluoroacetic acid.
Reaction SMILES: [C:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[C:21]#[CH:22]>CC(C)=O>[C:1]([N:3]([CH2:22][C:21]#[CH:20])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=1)#[N:2]
Reactant: N#CNc1cccc(C(F)(F)F)c1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCN(C#N)c1cccc(C(F)(F)F)c1
Yield: 63.1 %

Procedure:
To a solution of N-cyano-3-trifluoromethylaniline (5.0 g) in acetone (100 ml), potassium carbonate (7.4 g) and propargyl bromide (3.5 g) were added, and the resultant mixture was stirred at room temperature for 10 hours, followed by filtration of the reaction mixture. The solvent was removed from the filtrate by distillation under reduced pressure, and the residue was subjected to column chromatography to give N-cyano-N-propargyl-3-trifluoromethylaniline (3.8 g). The thus obtained N-cyano-N-propargyl-3-trifluoromethylaniline (1 g) and a catalytic amount of triethylamine were dissolved in methanol (30 ml), and the resultant mixture was cooled to 0° C. Hydrogen sulfide was gradually introduced into the mixture for 20 minutes while keeping the temperature at 0° C., followed by introduction of nitrogen gas to remove hydrogen sulfide. The solvent was removed by distillation, and the residue was subjected to column chromatography to give 0.2 g of 2-imino-3-(3-trifluoromethylphenyl)-5-methylenethiazolidine (Compound (ix)).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH3:20])[C:15]([OH:17])=O)[N:13]=1)=[O:7].[NH2:21][CH:22]1[C:43](=[O:44])[N:24]2[C:25]([C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=3)=[O:31])=[C:26]([OH:29])[CH2:27][S:28][C@H:23]12.C[Si](CC(N)=O)(C)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(OCC)(=O)C.O.CN(C)C=O>[CH:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[N:18][O:19][CH3:20])[C:15]([NH:21][CH:22]2[C:43](=[O:44])[N:24]3[C:25]([C:30]([O:32][CH2:33][C:34]4[CH:35]=[CH:36][C:37]([N+:40]([O-:42])=[O:41])=[CH:38][CH:39]=4)=[O:31])=[C:26]([OH:29])[CH2:27][S:28][C@H:23]23)=[O:17])[N:13]=1)=[O:7]
Reactant: CON=C(C(=O)O)c1csc(NC=O)n1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: C[Si](C)(C)CC(N)=O
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12)c1csc(NC=O)n1
Reaction time: 0.67 h
Yield: 43.7 %

Procedure:
N.M.R. δppm (DMSO-d6): 2.8-3.7 (2H, m), 4.90 (1H, t, J=4Hz), 5.29 (1H, d, J=4Hz), 5.38 (2H, s), 7.71 (2H, d, J=8Hz), 8.26 (2H, d, J=8Hz). (2) Phosphoryl chloride (2.87 g.) was dropwise added to a solution of N,N-dimethylformamide (1.37 g.) in ethyl acetate (10 ml.) at 5° to 10° C. Ethyl acetate (40 ml.) was added to the solution, and stirred under ice cooling for 40 minutes. To the solution was added 2-(2-formamido-4-thiazolyl)-2-methoxyiminoacetic acid (syn isomer, 3.58 g.), and the solution was stirred at 0° to 5° C. for 40 minutes. The resultant solution was added all at once to a mixture of 4-nitrobenzyl 7-amino-3-hydroxy-3-cephem-4-carboxylate (5 g.), ethyl acetate (50 ml.), trimethylsilylacetamide (14.3 g.) and bis(trimethylsilyl)acetamide (5.8 g.) at -15° C., and stirred at -20° to -15° C. for 1.2 hours. Water (50 ml.) was added to the resultant solution at -25° to -20° C., and stirred until the temperature rise 5° C. The aqueous layer was separated and extracted with ethyl acetate. The ethyl acetate layer and extract were combined, washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After the solution was concentrated to a volume of 50 ml. under reduced pressure, the precipitates were collected by filtration and washed with ethyl acetate to give 4-nitrobenzyl 7-[2-(2-formamido-4-thiazolyl)-2-methyoxyiminoacetamido]-3-hydroxy-3-cephem-4-carboxylate (syn isomer, 3.5 g.), mp 163° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH:12]1[CH2:14][CH2:13]1)[CH:6]=[C:5]2[CH2:15][C:16]([OH:18])=[O:17].[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC=CC=1.CCO.O>[CH:12]1([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:20]4[S:19][CH:23]=[CH:22][CH:21]=4)=[CH:10][CH:9]=3)[C:5]([CH2:15][C:16]([OH:18])=[O:17])=[CH:6]2)[CH2:14][CH2:13]1
Reactant: O=C(O)Cc1cn(CC2CC2)c2ccc(Br)cc12
Reactant: OB(O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1cn(CC2CC2)c2ccc(-c3cccs3)cc12
Temperature: 85 °C
Yield: 79.3 %

Procedure:
To a sealed tube containing 2-[5-bromo-1-(cyclopropylmethyl)-1H-indol-3-yl]acetic acid (100 mg, 0.32 mmol), 2-thiopheneboronic acid (124 mg, 0.97 mmol), (C6H5)4Pd (37 mg, 0.032 mmol), Na2CO3 (2.6 mmol) in a mixture of benzene/EtOH/H2O (5/1/3, 4.5 mL) was heated at 85° C. for 19 h. The mixture was poured onto diethyl ether and adjusted to pH 3 before extracting with diethyl ether. The mixture was washed with NaH2PO4, dried over MgSO4 and evaporated to give the crude product which was purified on silica gel column (33% EtOAc in hexane with 1% HCOOH) to give 79 mg (78% yield) of the product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Cl)=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH3:24])[C:17]=2[F:25])[N:6]=1)=[O:4].[CH3:26][Si:27]([CH3:44])([CH3:43])[C:28]#[C:29][Sn](CCCC)(CCCC)CCCC>ClCCCl.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>[CH3:1][O:2][C:3]([C:5]1[C:10]([C:29]#[C:28][Si:27]([CH3:44])([CH3:43])[CH3:26])=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH3:24])[C:17]=2[F:25])[N:6]=1)=[O:4]
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(NC(C)=O)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(NC(C)=O)c1C#C[Si](C)(C)C
Temperature: 130 °C
Yield: 21.2 %

Procedure:
4-Acetylamino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)-pyridine-2-carboxylic acid methyl ester (0.8 g, 2.061 mmol), trimethyl((tributylstannyl)ethynyl)silane (1.596 g, 4.12 mmol), and bis(triphenylphosphine)palladium(II) dichloride (0.145 g, 0.206 mmol) were combined in 1,2-dichloroethane (2 mL) and heated in a CEM microwave reactor at 130° C. for 15 min. The cooled reaction mixture was purified by flash chromatography on silica gel (hexane/ethyl acetate gradient) to yield the title compound (0.196 g, 21.1% yield). 1H NMR (CDCl3) δ 9.03 (s, 1H), 8.4 (br s, 1H), 7.67 (m, 1H), 7.24 (m, 1H), 4.0 (s, 3H), 3.99 (d, 3H), 2.29 (s, 3H), 0.36 (s, 9H).
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14](=[O:26])[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)C.[OH-].[Na+]>C(O)C>[F:13][C:11]1[CH:10]=[CH:9][C:8]([C:14](=[O:26])[NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)=[C:7]([CH:12]=1)[O:6][CH2:5][C:4]([OH:27])=[O:3]
Reactant: CCOC(=O)COc1cc(F)ccc1C(=O)NCc1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1cc(F)ccc1C(=O)NCc1cccc([N+](=O)[O-])c1
Reaction time: 4 h
Yield: 98.2 %

Procedure:
A suspension of [5-fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid ethyl ester (3.3 g, 8.77 mmol) in ethanol (40 mL) was treated with aq 2 N NaOH (24 mL, 47.8 mmol). After stirring for 4 h, the solution was concentrated in vacuo until most of the ethanol was removed, and the mixture was acidified to pH of 1 with 2 N HCl. After extracting with ethyl acetate, the organic layer was washed with saturated aq NaCl, dried over MgSO; and concentrated to give [5-fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid as an off-white solid (3.00 g, 98%): mp 148-151° C.; Rf 0.39 (20% methanol in dichloromethane); 1H NMR (DMSO-d6 300 MHz) δ 9.20 (t, J=6.3 Hz, 1H) 8.18 (s, 1H), 8.09 (dd, J1=7.2 Hz, J2=2.7 Hz, 1 H), 7.90 (dd, J1=8.7 Hz, J2=7.0 Hz, 1H), 7.79 (d, J=7.5 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.08 (dd, J1=10.8 Hz, J2=2.1 Hz, 1H), 6.91 (dt, J1=8.7 Hz, J2=2.4 Hz, 1H), 4.89 (s, 2H), 4.62 (d, J=6 Hz, 2H). ESI-LC/MS m/z calcd for C16H13FN2O6: 348.3; Found 347.0 (M−1)−. Anal. calcd for C16H13FN2O6: C, 55.18; H, 3.76; N, 8.04. Found C, 55.02; H, 3.79; N, 7.98.