Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])[CH3:2].C([O-])(=O)C.[Na+].[Br:18]Br>C(O)(=O)C.O>[Br:18][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4](=[O:12])[CH:3]2[CH2:1][CH3:2]
Reactant: BrBr
Reactant: CCC1C(=O)Nc2ccccc21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCC1C(=O)Nc2ccc(Br)cc21

Procedure:
A solution of 3-ethyloxindole (6.0 g, 40 mmol) and sodium acetate (4 g, 48 mmol) in acetic acid (100 ml) was treated with bromine (6.4 g, 40 mmol). After 30 min. the mixture was diluted with water and extracted with EtOAc (2×); the combined organic layers were washed with water, sat. sodium hydrogen carbonate solution, and brine, dried (MgSO4) and evaporated to afford the crude product (9.2 g, 96%). A sample was recrystallized from EtOAc/hexane to obtain the subtitled compound, mp. 130-132° C.; 1H-NMR (DMSO-d6) δ0.74 (t, 3H, J=7.5 Hz), 1.8-2.0 (m, 2H), 3.45 (t, 1H, J=5.5 Hz,), 6.76 (d, 1H, J=8.35 Hz), 7.42 (m, 1H), 10.43 (s, 1H; MS (−ESI) m/z 238/240 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[C:19]([N:26]1[CH2:31][CH2:30][CH:29]([CH2:32]O)[CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:32][CH:29]1[CH2:30][CH2:31][N:26]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)c(F)c2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)cc2F)CC1
Yield: 87.4 %

Procedure:
The title compound (0.32 g, 88%) was prepared as a white solid from 3-fluoro-4′-(methylsulfonyl)-4-biphenylol (0.21 g, 0.79 mmol), N-Boc-4-piperidinemethanol (0.18 g, 0.79 mmol) and Ph3P (0.21 g, 0.79 mmol) in THF (5 mL) followed by diisopropyl azodicarboxylate (0.17 g, 94%, 0.79 mmol) in THF (1.5 mL) in a manner similar to Example 1, Step 2. 1H NMR (400 MHz, CDCl3): δ 7.98 (d, 2H, J=8.6 Hz), 7.70 (d, 2H, J=8.6 Hz), 7.40-7.30 (m, 2H), 7.06 (t, 1H, J=8.5 Hz), 4.25-4.15 (m, 2H), 3.92 (d, 2H, J=6.3 Hz), 3.08 (s, 3H), 2.80-2.70 (m, 2H), 2.10-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.46 (s, 9H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 464 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[O:12][CH2:13][O:14][C:9]2=[CH:8][C:3]=1[C:4]([O:6]C)=O.Cl[C:16]1[N:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].CO>CN(C=O)C>[CH2:13]1[O:12][C:10]2[CH:11]=[C:2]3[C:3]([C:4](=[O:6])[N:24]4[CH:23]=[CH:22][CH:21]=[C:17]([C:18]([OH:20])=[O:19])[C:16]4=[N:1]3)=[CH:8][C:9]=2[O:14]1
Reactant: O=C(O)c1cccnc1Cl
Reactant: COC(=O)c1cc2c(cc1N)OCO2
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(O)c1cccn2c(=O)c3cc4c(cc3nc12)OCO4

Procedure:
A mixture of 2.00g (10.4 mmol) of methyl 2-amino-4,5-methylenedioxybenzoate, 1.67g (10.4 mmol) of 2-chloronicotinic acid and 50mg of KI was heated at 170° for 1 hour. The fusion or melt gradually solidified to an orange cake. The solid material was heated in boiling methanol (250 ml) and then filtered to yield 1.60g of crude product, mp. 273°-280° dec. The analytical sample was obtained by recrystallization from DMF, mp. 300°-304° dec.
Reaction SMILES: [ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([O:24]CC2C=CC=CC=2)=[O:23])=[O:14])[CH2:7][CH2:6]1)(=[NH:4])[NH2:3].[H][H]>C(O)(C)(C)C.O>[ClH:1].[C:2]([N:5]1[CH2:6][CH2:7][CH:8]([CH2:11][CH2:12][C:13]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([OH:24])=[O:23])=[O:14])[CH2:9][CH2:10]1)(=[NH:3])[NH2:4]
Reactant: [H][H]
Reactant: N=C(N)N1CCC(CCC(=O)Oc2ccccc2C(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: O
Product: N=C(N)N1CCC(CCC(=O)Oc2ccccc2C(=O)O)CC1
Yield: 79.8 %

Procedure:
5.5 g of o-benzyloxycarbonylphenyl 1-amidino-4-piperidinepropionate hydrochloride was dissolved in a solution of 60 ml of t-butyl alcohol and 60 ml of water. 225 mg of 10% paradium-carbon was added to the solution, and the mixture was stirred at room temperature for 1 hour in the presence of hydrogen (starting pressure: 2.4 kg/cm2). The catalyst was removed by filtration, and the solvent was removed. The residue was washed with t-butyl alcohol to obtain 3.5 g (yield: 79.7%) of o-hydroxycarbonylphenyl 1-amidino-4-piperidinepropionate hydrochloride as colorless needles having a melting point of 192° to 194° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:13][O:14][CH:15]3[CH:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=5[O:39][CH3:40])=[CH:23][CH:22]=4)[CH2:19][CH2:18][N:17]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:16]3)[CH:11]=2)[C:6]([CH3:49])([CH3:48])[CH2:5]1.C(N(CC)CC)C.[C:57]1([CH3:67])[CH:62]=[CH:61][C:60]([S:63](Cl)(=[O:65])=[O:64])=[CH:59][CH:58]=1.O>CN(C)C1C=CN=CC=1.ClCCl>[CH3:48][C:6]1([CH3:49])[C:7]2[C:12](=[CH:11][C:10]([CH2:13][O:14][CH:15]3[CH:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH2:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=5[O:39][CH3:40])=[CH:23][CH:22]=4)[CH2:19][CH2:18][N:17]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:16]3)=[CH:9][CH:8]=2)[N:4]([CH2:3][CH2:2][O:1][S:63]([C:60]2[CH:61]=[CH:62][C:57]([CH3:67])=[CH:58][CH:59]=2)(=[O:65])=[O:64])[CH2:5]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3c(c2)N(CCO)CC3(C)C)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3c(c2)N(CCOS(=O)(=O)c2ccc(C)cc2)CC3(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The solution of 0.457 g of tert-butyl 3-[1-(2-hydroxyethyl)-3,3-dimethyl-2,3-dihydro-1H-indol-6-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate, 0.274 ml of triethylamine and 0.008 g of 4-dimethylaminopyridine in 10 ml of dichloromethane is admixed with stirring at 0° C. with 0.301 g of p-toluenesulphonyl chloride and stirred at room temperature over 18 hours. The reaction mixture is admixed with water (40 ml) and extracted with tert-butyl methyl ether (2×40 ml). The organic phases are washed successively with water (40 ml) and brine (40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.42 (1:1 EtOAc-heptane); Rt=6.46.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH2:23])[S:11][C:12]=2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[C:29](Cl)=[O:30]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([NH:23][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:26]([O:25][CH3:24])[CH:27]=3)[S:11][C:12]=2[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: Nc1nc(-c2ccc(F)cc2)c(Cc2ccc([N+](=O)[O-])cc2)s1
Product: COc1ccc(C(=O)Nc2nc(-c3ccc(F)cc3)c(Cc3ccc([N+](=O)[O-])cc3)s2)cc1OC
Yield: 24 %

Procedure:
A procedure similar to that in Example 4 was used. 4-(4-fluoro-phenyl)-5-(4-nitro-benzyl)-thiazol-2-ylamine prepared in Example 9 and 3,4-dimethoxy-benzoyl chloride prepared in the step 1 of Example 12 were used as starting materials, allowed to react at room temperature overnight, followed by post-treatment to obtain a crude product, which was purified by a silica gel column chromatography eluted with a gradient of dichloromethane and ethyl acetate (20:1-10:1) to obtain a product as a white solid in a yield of 24.0%, mp: 128-129└. 1H-NMR (DMSO-d6, 400 MHz) δ: 3.91 (3H, s, OCH3), 3.95 (3H, s, OCH3), 4.31 (2H, s, CH2), 6.90 (1H, d, J=9.00 Hz, ArH), 7.08 (2H, t, J=8.68 Hz, ArH), 7.38 (2H, d, J=8.68 Hz, ArH), 7.25˜7.47 (4H, m, ArH), 8.19 (2H, d, J=8.68 Hz, ArH), 10.04 (1H, br, CONH); EI-MS m/e (%): 493.2 (M+, 17), 165.3 (100); HREI-MS Calcd. for C25H20FN3O5S: 493.1108. found: 493.1105.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[Br:30]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[C:13]([Br:30])[N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 77.6 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (600 mg, 1.55 mmol) and N-bromosuccinimide (291 mg, 1.63 mmol) in CH2Cl2 (4.2 mL) was refluxed for 3 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was purified by silica gel chromatography (0-60% EtOAc/hexanes+2% AcOH) to give 560 mg of the title compound as a yellow solid. MS: (+) m/z 464.97, 466.94 (M+H, 79/81Br)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[CH:12]=[N:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C1C(=O)N([I:39])C(=O)C1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([I:39])=[N:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: Cn1cnc(-c2ccc(S(C)(=O)=O)cc2)c1Sc1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(I)nc(-c2ccc(S(C)(=O)=O)cc2)c1Sc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To the solution of Step 2 product (200 mg, 0.528 mmol) in CH2Cl2 (0.5 ml) was added TFA (3 ml) and NIS (238 mg, 1.06 mmol) at rt, and then reaction mixture was heated to reflux overnight. Reaction mixture was cooled to rt and concentrated. To the residue was added CH2Cl2, quenched with NaHCO3 (aq), washed with aq Na2S2O3, water and brine. Dried over Na2SO4, filtered and concentrated. Separated by prep TLC (hex:EtOAc=1:1) to give 5-[(4-chlorophenyl)sulfanyl]-2-iodo-1-methyl-4-[4-(methylsulfonyl)phenyl]-1H-imidazole as light yellow solid (180 mg). LCMS: [M+1]+=505.0 Human FAAH lysate assay: IC50=15.6 nM.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1Br.C([Li])CCC.[NH:13]1[C:21](=[O:22])[C:19](=O)[C:17](=[O:18])[NH:16][C:14]1=[O:15]>CCOCC.O1CCCC1>[Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:19]1[C:17](=[O:18])[NH:16][C:14](=[O:15])[NH:13][C:21]1=[O:22]
Reactant: Clc1sccc1Br
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2ccsc2Cl)C(=O)N1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Following the method of Gronowitz et al. [Chemica Scripta 15, p. 2 (1980)], 2-chloro-3-bromothiophene is reacted with n-butyl lithium in ether at -70° C. After 15 minutes, the organolithium reagent is poured into a solution of alloxan in tetrahydrofuran at -70° C. The reaction mixture is allowed to warm to room temperature for 2 hours, and 5-(2-chloro-3-thienyl)-2,4,6(1H,3H,5H)-pyrimidinetrione isolated according to Example 5.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5](Br)=[C:4]([CH3:11])[N:3]=1.[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:16]2[CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=[C:14]([C:13]([F:12])([F:28])[F:27])[CH:15]=2)=[C:4]([CH3:11])[N:3]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1nc(N)c(C#N)nc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1nc(N)c(C#N)nc1-c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
This compound is prepared in a manner analogous to that of Step A of Example 4, using 1.7 grams (0.008 mole) of 2-amino-3-cyano-5-bromo-6-methylpyrazine, 3.2 grams (0.012 mole) of 3,5-di(trifluoromethyl)phenylboronic acid, 4.3 grams (0.031 mole) of potassium carbonate and 0.3 gram of tetrakis(triphenylphosphine)palladium(0)in 150 mL of toluene, yielding 2-amino-3-cyano-5-[3,5-di(trifluoro-methyl)phenyl]-6-methylpyrazine.
Reaction SMILES: [CH2:1]([O:6][CH2:7][C:8]#[C:9][CH2:10][OH:11])[CH2:2][CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C=O>C(OCC)C.O>[CH3:19][S:20]([O:11][CH2:10][C:9]#[C:8][CH2:7][O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCOCC#CCO
Agent: C=O
Solvent: CCOCC
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCOCC#CCOS(C)(=O)=O
Temperature: 5 °C
Yield: 9009.8 %

Procedure:
To a 300 mL 3 neck flask equipped with magnetic stirrer, addition funnel, and nitrogen inlet was charged 7.42 grams (g) of 4-(pentyloxy)but-2-yn-1-ol (0.45 mmol), 70 mL of dry ethyl ether, and 6.8 g (68 mmoles) of anhydrous triethyl amine The reaction mixture was cooled to 5° C. with stirring followed by the dropwise addition of 4.95 g (43 mmole) of methane sulfonyl chloride in 7 mls of ethyl ether. The temperature was adjusted to 0° C. and 5.4 g (180 mmole) of solid paraformaldehyde was added. The mixture was then stirred at 10-15° C. for 6 hours, then diluted with another 40 mls of ether and 70 mls of water. The organic phase was separated, and washed with water and brine, then dried over anhydrous magnesium sulfate. Filtered and concentrated under vacuum on a rotary evaporator. Isolated 9.5 g of a clear colorless liquid which was consistent with the desired structure upon analysis by 300 MHz 1H NMR.
Reaction SMILES: O[C:2]([C:8]1[S:9][CH:10]=[CH:11][C:12]=1[NH:13]C(OC(C)(C)C)=O)([CH3:7])[CH2:3][CH:4]([CH3:6])[CH3:5].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[NH2:13][C:12]1[CH:11]=[CH:10][S:9][C:8]=1[CH:2]([CH3:7])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)CC(C)(O)c1sccc1NC(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC(C)c1sccc1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.5 %

Procedure:
After dissolving 1.2 g of 2-(1-hydroxy-1,3-dimethylbutyl)-3-t-butoxycarbonylaminothiophene in 10 ml of methylene chloride, 0.44 g of triethylsilane and 4.3 g of trifluoroacetic acid were added. The mixture was stirred at room temperature for 20 hours, neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.43 g of the desired product as a crystal. 1H-NMR(270 MHz, CDCl3, δppm, J:Hz):0.89(3H,d,J=6.6), 0.90(3H,d,J=6.6), 1.23(3H,d,J=6.6),1.35-1.65(3H,m), 2.95(1H, sextet, J=6.6), 3.35(2H,brs), 6.55(1H,d,J=5.1), 6.95(1H,d,J=5.1)
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:16](O)[CH3:17]>>[CH2:16]([O:9][C:8](=[O:10])[C:7]1[C:2]([CH3:1])=[CH:3][CH:4]=[N:5][CH:6]=1)[CH3:17]
Reactant: Cc1ccncc1C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cnccc1C

Procedure:
To a flask containing 4-methylnicotinic acid 1.5 hydrochloride (9.6 g, 55.3 mmol), dissolved in dry absolute ethanol (120 mL) was added concentrated sulfuric acid (6 mL) via drop-wise addition. The material was heated to reflux temperature and stirred over night. The flask was cooled to ambient and about 85% of the solvent was removed on the rotovap. Ethyl acetate (40 mL) was added and the material was basified via drop-wise addition of an aqueous saturated sodium bicarbonate solution. Ethyl acetate (40 mL) and water (20 mL) was added and the material was shaken in a separatory funnel. The ethyl acetate phase was collected and washed with brine (60 mL). The aqueous phases were back extracted with ethyl acetate (2×50 mL), the organic phases were combined, dried (MgSO4), filtered and stripped affording ethyl-4-methylnicotinoate as a brown mobile oil. MS (M+H)+=166.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][NH:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:28][O:29][C:30](=[O:63])[NH:31][CH:32]([C:36]([N:38]1[CH2:42][CH2:41][CH2:40][CH:39]1[C:43]1[NH:44][C:45]([C:48]2[CH:53]=[CH:52][C:51](B3OC(C)(C)C(C)(C)O3)=[CH:50][CH:49]=2)=[CH:46][N:47]=1)=[O:37])[CH:33]([CH3:35])[CH3:34].[O-]P([O-])([O-])=O.[K+].[K+].[K+].N#N>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:27])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][NH:17][C:18]([C:19]1[CH:24]=[CH:23][C:22]([C:51]2[CH:52]=[CH:53][C:48]([C:45]3[NH:44][C:43]([CH:39]4[CH2:40][CH2:41][CH2:42][N:38]4[C:36](=[O:37])[CH:32]([NH:31][C:30]([O:29][CH3:28])=[O:63])[CH:33]([CH3:35])[CH3:34])=[N:47][CH:46]=3)=[CH:49][CH:50]=2)=[CH:21][CH:20]=1)=[O:26])=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1CNC(=O)c1ccc(Br)cc1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CCCC1CNC(=O)c1ccc(-c2ccc(-c3cnc(C4CCCN4C(=O)C(NC(=O)OC)C(C)C)[nH]3)cc2)cc1)C(C)C
Temperature: 80 °C
Yield: 15 %

Procedure:
A solution of (1-{2-[(4-bromo-benzoylamino)-methyl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (104 mg, 0.24 mmol), [2-methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (117 mg, 0.24 mmol) and aq K3PO4 (480 μl of a 2M solution, 0.96 mmol) in DME (3 mL) was degassed with N2 gas for 20 minutes. To the degassed solution was added Pd(PPh3)4 (13.9 mg, 0.012 mmol) then the reaction was heated to 80° C. overnight. After cooling to room temperature, the reaction was concentrated and purified by reverse phase preparative HPLC (15-60% MeCN—H2O; 0.1% formic acid modifier) to afford [1-(2-{[(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-carbonyl)-amino]-methyl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (26 mg, 0.036 mmol, 15% yield). 1H-NMR: 400 MHz, (DMSO-d6) δ: 11.8 (s, 1H), 8.61 (m, 1H), 7.94-7.73 (m, 9H), 7.34 (d, 1H), 7.29 (d, 1H), 5.08 (m, 1H), 4.23 (t, 1H), 4.30 (m, 1H), 4.07 (t, 1H), 4.01 (t, 1H), 4.07-4.01 (m, 1H), 3.18 (m, 2H), 3.73-3.70 (m, 1H), 3.61 (m, 1H), 3.63 (s, 3H), 3.61 (s, 3H), 2.16-1.81 (m, 10H), 0.90-0.84 (m, 12H). LCMS-ESI+: calc'd for C39H52N7O7: 730.4 (M+H+); Found: 730.1 (M+H+).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH:13]=[N:14][CH:15]2[C:34](=[O:35])[N:17]3[C:18]([C:23]([O:25][CH2:26][O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:24])=[C:19]([CH3:22])[CH2:20][S:21][C@H:16]23)[CH2:9][CH2:8]1)=[N+]=[N-].O.[ClH:37]>C(OCC)(=O)C.[Pd]>[ClH:37].[ClH:37].[NH2:1][CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH:13]=[N:14][CH:15]2[C:34](=[O:35])[N:17]3[C:18]([C:23]([O:25][CH2:26][O:27][C:28](=[O:33])[C:29]([CH3:30])([CH3:31])[CH3:32])=[O:24])=[C:19]([CH3:22])[CH2:20][S:21][C@H:16]23)[CH2:9][CH2:8]1
Reactant: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(N=CN3CCC(CCCN=[N+]=[N-])CC3)[C@H]2SC1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)OCOC(=O)C(C)(C)C)N2C(=O)C(N=CN3CCC(CCCN)CC3)[C@H]2SC1

Procedure:
To a stirred solution of pivaloyloxymethyl 7-[(4-(3-azidopropyl)-1-piperidyl)-methyleneamino]-3-methyl-3-cephem-4-carboxylate (1.5 g) in ethyl acetate (25 ml) were added water (30 ml) and hydrochloric acid to pH=3. 10% palladium-on-carbon (0.5 g) was added, and hydrogen was bubbled through the stirred mixture, a pH-value of 3 being maintained by addition of 0.2 N hydrochloric acid. When the consumption of acid ceased, the catalyst was filtered off. The aqueous phase was separated and freeze-dried to yield the desired compound as an amorphous powder.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.CO[CH:17]1[CH2:21][CH2:20][CH:19](OC)O1.CO>C1(C)C=CC=CC=1.C(O)(=O)C>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)[CH:17]=[CH:21][CH:20]=[CH:19]1
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Reactant: COC1CCC(OC)O1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C=Cc1ccc(-n2cccc2)cc1

Procedure:
A solution of ethyl 4-aminocinnamate (1 g) and 2,5-dimethoxytetrahydrofuran (0.677 ml) in toluene (3 ml) and acetic acid (3 ml) was refluxed for 5 hours with removing methanol. After cooling, the mixture was washed with water twice and saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo. The residue was purified with column chromatography eluting with n-hexane -ethyl acetate to give ethyl 4-(1-pyrrolyl)cinnamate (740 mg) as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:15][CH3:16])=[C:4]([CH:8]=[C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH2:15][CH3:16])=[C:4]([CH:8]=[C:9]2[CH2:10][CH2:11][N:12]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:13][CH2:14]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1c(Br)cccc1C=C1CCNCC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CN1CCC(=Cc2cccc(Br)c2CC)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 111.2 %

Procedure:
To a solution of 4-[(3-bromo-2-ethylphenyl)methylidene]piperidine (D137) (0.53 g, 1.891 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added potassium carbonate (3.92 g, 28.4 mmol), followed by ethyl bromoacetate (0.190 mL, 1.702 mmol). The reaction solution was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate, washed with water, dried over sodium sulphate, concentrated to afford ethyl {4-[(3-bromo-2-ethylphenyl)methylidene]-1-piperidinyl}acetate (D142) (0.693 g). MS (ES): C18H24BrNO2 requires 365.1. found 366.1 (M+H+).