Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C([O-])(O)=O.[Na+].[CH2:19]([O:26][C:27](ON1C(=O)CCC1=O)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCOCC1.O.C(OCC)(=O)C>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][C:27]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:28])[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 2.05 g 3-amino-1-N-Boc-pyrrolidine, 1.85 g NaHCO3 and 3.17 g N-(Benzyloxycarbonyloxy)succinimide in 10 ml dioxane/water 1:1 was stirred for 12 h at RT. The reaction mixture was diluted with ethyl acetate, the phases separated and the organic phase washed with saturated NaHCO3 and brine. The crude product obtained after evaporation of the solvent was used in the next reaction step without further purification.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].C=O.CN.[CH3:21][N:22]1[CH2:27]COC[CH2:23]1>CCO.O>[CH2:1]([N:3]1[CH2:23][N:22]([CH3:27])[CH2:21][N:6]([C:7]2[S:8][C:9]3[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:10]=3[N:11]=2)[C:4]1=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2c(s1)C(=O)CCC2
Reactant: CN1CCOCC1
Agent: C=O
Agent: CN
Solvent: O
Solvent: CCO
Product: CCN1CN(C)CN(c2nc3c(s2)C(=O)CCC3)C1=O
Temperature: 60 °C
Yield: 100.9 %

Procedure:
To a suspension of N-ethyl-N′-(7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)urea (10.0 g, 41.79 mmol) in EtOH/H2O (1/1, 300 mL) were added formaldehyde (37 wt % in H2O, 20.4 g, 417.87 mmol), methylamine (40 wt % in H2O, 10.8 mL, 125.37 mmol) and N-methylmorpholine (11.8 mL, 83.6 mmol). The suspension was heated to about 60° C. for about 5 hrs, then a solution had been formed. The reaction mixture was pumped down in vacuo to give 12.41 g (quantitative yield) pure product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[C:6]([N+]([O-])=O)[CH:5]=1.[CH2:16]([O:18][C:19](=[O:22])[CH2:20][SH:21])[CH3:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[CH:10]=[C:20]([C:19]([O:18][CH2:16][CH3:17])=[O:22])[S:21][C:6]=2[CH:5]=1)=[O:15]
Reactant: CCOC(=O)CS
Reactant: COC(=O)c1ccc(C=O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2ccc(C(=O)OC)cc2s1
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
A mixture of 4-formyl-3-nitro-benzoic acid methyl ester (15.22 g, 72.78 mmol), mercapto-acetic acid ethyl ester (8.70 mL, 79.3 mmol) and K2CO3 (12.87 g, 93.12 mmol) in 140 mL of anhydrous DMF was heated at 50° C. overnight. After cooling to rt, the mixture was poured into 1 L of ice-water and the resulting mixture was stirred for 40 min. The solid formed was filtered and washed with 4×70 mL of water. After drying, benzo[b]thiophene-2,6-dicarboxylic acid 2-ethyl ester 6-methyl ester was obtained as a pale solid. 1H NMR (CDCl3, 200 MHz) δ 8.56 (s, 1H), 8.09-7.97 (m, 2H), 7.88 (d, J=8.0 Hz, 1H), 4.40 (q, J=7.2 Hz, 2H), 3.95 (s, 3H), 1.40 (t, J=6.8 Hz, 3H). MS (EI): cal'd 265.0 (MH+), exp 265.0 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][NH:6][C:7](=[O:27])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:19][C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[F:35][C:36]([F:48])([F:47])[O:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1>>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][NH:6][C:7](=[O:27])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:19][C:20]2[CH:25]=[CH:24][C:23]([C:41]3[CH:40]=[CH:39][C:38]([O:37][C:36]([F:35])([F:47])[F:48])=[CH:43][CH:42]=3)=[CH:22][CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Sc2ccc(Br)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Sc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)cc1
Yield: 71.8 %

Procedure:
3-{4-[1-(4-bromo-phenylsulfanyl)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester (350 mg, 0.75 mmol), potassium carbonate (311 mg, 2.25 mmol), 4-triflouromethoxylphenyl boronic acid (311 mg, 1.5 mmol) and tetrakis-(triphenylphosphine)palladium (87 mg, 0.075 mmol) are place in a flask. After the reaction is purged with N2 for several times, THF/H2O (20 ml/5 ml) is added. The resulting solution is refluxed overnight, loaded on silica gel, eluted with hexane and ethyl acetate to give 3-{4-[3-Methyl-1-(4′-trifluoromethoxy-biphenyl-4-ylsulfanyl)-butyl]-benzoylamino}-propionic acid methyl ester (294 mg) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]([C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1)([CH3:9])[C:6](O)=[O:7].[NH2:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]([C:10]1[CH:11]=[CH:12][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][CH:15]=1)([CH3:9])[C:6]([NH:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1)=[O:7]
Reactant: CC(Oc1ccc(F)cc1F)(C(=O)O)c1ccc(S(C)(=O)=O)cc1
Reactant: Nc1nccs1
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1ccc(F)cc1F)(C(=O)Nc1nccs1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
To a mixture of 2-(2,4-Difluoro-phenoxy)-2-(4-methanesulfonyl-phenyl)-propionic acid (0.184 g, 0.52 mmol), 2-aminothiazole (0.59 g, 0.60 mmol) HOBt (0.070 g, 0.52 mmol), and EDCI 0.10 g, 0.52 mmol) in methylene dichloride (10 ml) was added triethyl amine (0.06 g, 0.59 mmol). The resulting mixture was stirred at room temperature for overnight followed by dilution with 10 ml methylene dichloride. The reaction mixture was poured onto water (20 ml), and organic layer separated, washed with water (2×20 ml), brine (20 ml), dried over sodium sulfate and solvent evaporated to get residue which was purified by preparative TLC using 50% ethyl acetate in hexane as mobile phase to give the desired compound (0.12 g). 1H NMR (400 MHz, CDCl3): δ 1.90 (s, 3H), 3.08 (s, 3H), 6.64-6.71 (m, 2H), 6.94 (m, 1H), 7.05 (d, J=3.6 Hz, 1H), 7.51 (d, J=3.6 Hz, 1H), 7.86 (d, J=8.4 Hz, 2H), 8.01 (d, J=8.4 Hz, 2H), 10.20 (s, 1H); MS (EI) m/z: 439.00 (M+1); mp: 89-90° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:14][C@@H:15]2[CH2:19][CH2:18][O:17][CH2:16]2)=[C:7]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:8]=1.C([O-])([O-])=O.[K+].[K+].F[C:27]1[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[N:31][CH:32]=1>CN(C=O)C>[F:2][C:3]1[CH:4]=[CH:5][C:6]([O:14][C@@H:15]2[CH2:19][CH2:18][O:17][CH2:16]2)=[C:7]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:27]2[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[N:31][CH:32]=2)[CH:8]=1
Reactant: O=[N+]([O-])c1ccc(F)cn1
Reactant: Fc1ccc(O[C@@H]2CCOC2)c(C2CCCN2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCCC2c2cc(F)ccc2O[C@@H]2CCOC2)cn1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.3 %

Procedure:
To a solution of 2-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)pyrrolidine hydrochloride (3.15 g, 10.98 mmol) in dry DMF (10 ml) was added K2CO3 (3.15 g, 22.88 mmol) and stirred for 5 min at room temperature then added 5-fluoro-2-nitropyridine (1.3 g, 91.54 mmol) under N2 atmosphere and stirred for 16 h at 80° C. After completion of reaction, reaction mixture was poured in to ice and stirred for 10 min then solid was collected by filtration. Solid was dried under high vacuum to afford 5-(2-(5-fluoro-2-(((R)-tetrahydrofuran-3-yl)oxy)phenyl)pyrrolidin-1-yl)-2-nitropyridine as yellow solid (2.8 g, Yield: 82.11%) MS (ESI): 374.3 (M+H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:47]=[CH:46][C:12]([O:13][CH2:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:20][C:19]=3[N:37](C)[C:38](=O)OC(C)(C)C)=O)=[CH:11][CH:10]=2)[S:3]1.[ClH:48].O1CCOCC1>>[ClH:48].[CH3:38][N:37]1[C:19]2[CH:20]=[C:21]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:22]=[CH:23][C:18]=2[N:17]=[C:15]1[CH2:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH:4]2[S:3][C:2](=[O:1])[NH:6][C:5]2=[O:7])=[CH:47][CH:46]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2-c2ccccc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccccc3-c3ccccc3)cc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of t-butyl N-{2-[4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetylamino]-5-(2-phenylphenoxy)phenyl}-N-methylcarbamate (2.33 g) and 4N hydrogen chloride/dioxane (20 ml) was stirred at ambient temperature for 20 hours. The solvent of the reaction mixture was evaporated to dryness. To the residue was added ethyl acetate and insoluble product was collected by filtration and washed with ethyl acetate to give the title compound (1.87 g).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([OH:21])[CH:14]=2)[C:8]2[C:4]=1[N:5]=[C:6]([CH:22]([CH3:24])[CH3:23])[N:7]=2.C(=O)([O-])[O-].[K+].[K+].Br[C@H:32]1[CH2:36][CH2:35][C@H:34]([OH:37])[CH2:33]1.BrC1CCC(O)C1>CN(C=O)C>[ClH:1].[NH2:2][C:3]1[N:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH:32]3[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33]3)[CH:14]=2)[C:8]2[C:4]=1[N:5]=[C:6]([CH:22]([CH3:24])[CH3:23])[N:7]=2
Reactant: O[C@H]1CC[C@H](Br)C1
Reactant: COc1ccc(Cn2cnc(N)c3nc(C(C)C)nc2-3)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: OC1CCC(Br)C1
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cnc(N)c3nc(C(C)C)nc2-3)cc1OC1CCC(O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.1 %

Procedure:
A solution of 6-amino-3-(3-hydroxy-4-methoxy-benzyl)-8-isopropyl-3H-purine hydrochloride (2.45 g, 7.0 mmole) in DMF (25 ml) was treated with potassium carbonate (5.80 g, 42 mmol), the mixture stirred at room temperature for 1 hour, then crude cis/trans-3-bromocyclopentanol (3.47 g, 21 mmole) was added. After 21 hours a second batch of potassium carbonate (2.90 g, 21 mmole) and 3-bromocyclopentanol (3.47 g, 21 mmole) were added. After stirring for 6 days the solid was filtered off and the solvent evaporated to dryness in vacuo. The residue was dissolved in chloroform (50 ml), extracted with IM NaOH solution and again evaporated in vacuo. The residue (5.84 g) was dissolved in dichloromethane:methanol, 98:2 (50 ml) and purified by column chromatography on silicagel, eluting with a gradient of 2-10% of methanol in dichloromethane. The fractions were collected (0.78 g; 28.0%), converted to the HCl salt and crystallized from acetone to give the title compound, (0.55 g, 18.1%), mp 185-187° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](B)[CH:7]=[CH:8][CH:9]=1)([OH:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([C:19]([C:37]1[CH:42]=[CH:41][C:40](OS(C(F)(F)F)(=O)=O)=[C:39]([CH3:51])[CH:38]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([CH2:34][CH3:35])([OH:33])[CH2:31][CH3:32])=[C:24]([CH3:36])[CH:23]=1)[CH2:20][CH3:21])[CH3:18].O>CN(C)C=O.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>[CH2:17]([C:19]([C:37]1[CH:42]=[CH:41][C:40]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([C:1]([OH:3])=[O:2])[CH:5]=2)=[C:39]([CH3:51])[CH:38]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([CH2:31][CH3:32])([OH:33])[CH2:34][CH3:35])=[C:24]([CH3:36])[CH:23]=1)[CH2:20][CH3:21])[CH3:18]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(OS(=O)(=O)C(F)(F)F)c(C)c2)cc1C)CC
Reactant: Bc1cccc(C(=O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3cccc(C(=O)O)c3)c(C)c2)cc1C)CC
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 59.3 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (6.8 mg, 0.0059 mmol), 3-carboxyphenylborane acid (6.8 mg, 0.0195 mmol) and potassium carbonate (13.4 mg, 97.5 μmol) were added to a solution of trifluoromethanesulfonic acid 4-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl ester (Example 1-(6); 10 mg, 0.0195 mmol) in N,N-dimethylformamide (0.5 mL) at room temperature, and then the mixture was stirred at 80° C. for five minutes. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (chloroform/methanol=8/3, saturated with water) to give the title compound (5.6 mg, 60%).
Reaction SMILES: [CH3:1][N:2]([CH2:9][C:10]#[CH:11])[C:3]1[S:4][C:5]([CH3:8])=[CH:6][N:7]=1.CCCCCC.C([Li])CCC.[I:23]I>O1CCCC1.C(Cl)(Cl)Cl>[CH3:1][N:2]([CH2:9][C:10]#[C:11][I:23])[C:3]1[S:4][C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: II
Reactant: C#CCN(C)c1ncc(C)s1
Agent: [Li]CCCC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cnc(N(C)CC#CI)s1
Yield: 82.7 %

Procedure:
Compound (b) (950 mg) was dissolved in anhydrous tetrahydrofuran (30 ml) and a hexane solution (4.5 ml) of butyllithium was added thereto at -78° C. After 30 minutes iodine (1.6 g) was added to the above mixture, which was then allowed to react for 10 minutes at room temperature and evaporated to remove the tetrahydrofuran. Water is added to the residue, which was then extracted with ether. The extract was washed with water and evaporated to remove the solvent. The residue was applied to chromatography on silica gel (25 g) to give 2-(N-methyl-3-iodo-2-propynylamino)-5-methylthiazole (No.1) (1.38 g, yield 83%) from chloroform eluate. mp. 97°-98° C. (hydrochloride: mp. 205°-213° C. (decomp.))
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24](O)=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[Cl:27][C:28]1[CH:29]=[C:30]([C:34](=[N:36][OH:37])[NH2:35])[CH:31]=[CH:32][CH:33]=1>>[Cl:27][C:28]1[CH:29]=[C:30]([C:34]2[N:35]=[C:24]([CH:11]3[CH2:10][CH:9]([C:6]4[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=4)[CH2:14][N:13]([C:15]([N:17]4[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]4)=[O:16])[CH2:12]3)[O:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1
Reactant: NC(=NO)c1cccc(Cl)c1
Product: CCc1ccc(C2CC(c3nc(-c4cccc(Cl)c4)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1

Procedure:
80 mg (0.22 mmol) of 5-(4-ethylphenyl)-1-[(4-hydroxypiperidin-1-yl)carbonyl]piperidine-3-carboxylic acid (Example 59A) and 57 mg (0.33 mmol, 1.5 eq.) of 3-chloro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 86 mg (78% of theory)
Reaction SMILES: C(=O)([O-])[O-].[Zn+2:5].[NH2:6][CH2:7][C:8]([OH:10])=[O:9].C(=O)=O>>[NH2:6][CH2:7][C:8]([O-:10])=[O:9].[Zn+2:5].[NH2:6][CH2:7][C:8]([O-:10])=[O:9]
Reactant: NCC(=O)O
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [Zn+2]
Product: NCC(=O)[O-]

Procedure:
In this method, the zinc carbonate is added to an aqueous solution of glycine. The CO2 is liberated and the solution is evaporated to dryness or spray dried to obtain white crystals of zinc glycinate. This method does not require the addition of a precipitating agent such as ethanol or sodium hydroxide as in the first two methods explained above, rendering it a more commercially viable method (less costly and more direct).
Reaction SMILES: S1C=CC=C1CC([NH:9][CH:10]1[C:39](=[O:40])[N:12]2[C:13]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[C:14]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[C@H:15]([CH3:17])[S:16][C@H:11]12)=O.P(Cl)(Cl)(Cl)(Cl)Cl.OP([O-])([O-])=O.[K+].[K+].OP(O)(O)=O>C(Cl)Cl.CO.N1C=CC=CC=1>[NH2:9][CH:10]1[C:39](=[O:40])[N:12]2[C:13]([C:23]([O:25][CH:26]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:24])=[C:14]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[C@H:15]([CH3:17])[S:16][C@H:11]12
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S[C@H]1C
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=P(O)(O)O
Agent: O=P([O-])([O-])O
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2S[C@H]1C
Reaction time: 0.75 h
Yield: 117.9 %

Procedure:
A 6.8 ml portion of pyridine was added to a solution of 4 g of diphenylmethyl 7-(2-thienylacetamido)-2β-methyl-3-acetoxymethylceph-3-em-4-carboxylate in 170 ml of CH2Cl2, and 4.35 g of PCl5 was then added to the mixture at -12° C., followed by stirring at the same temperature for 45 minutes. 45 ml of MeOH was added in once to the mixture, followed by stirring at -10° C. for 30 minutes and further at room temperature for 1 hour. 100 ml of 0.5M K2HPO4 solution and further 25% H3PO4 were added to the reaction solution to adjust to pH 1.5, followed by stirring for 45 minutes and separating out the CH2Cl2 layer. The layer was washed with saturated aqueous NaCl solution and dried over MgSO4, and the CH2Cl2 was distilled off under reduced pressure. The residue was added on a column of silica gel, and the fractions eluted with CH2Cl2.AcOEt (10:1) were collected to distill off the solvent under reduced pressure. Petroleum ether was added to the residue, thus yielding 3.7 g (87%) of crystals of diphenylmethyl 7-amino-2β-methyl-3-acetoxymethylceph-3-em-4-carboxylate,
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[C:12]([Br:13])=[CH:11][S:10][C:9]=1[C:14]([O:16]C)=O)[CH3:5].O>C1COCC1>[CH3:3][N:4]([N:6]=[N:7][C:8]1[C:12]([Br:13])=[CH:11][S:10][C:9]=1[C:14]([NH2:2])=[O:16])[CH3:5]
Reactant: [NH4+]
Reactant: COC(=O)c1scc(Br)c1N=NN(C)C
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)N=Nc1c(Br)csc1C(N)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 53 %

Procedure:
To an ice cold (0-5° C.) solution of ammonium hydroxide (10 mL) was added a solution of methyl 3-[(dimethylamino)diazenyl]-4-bromothiophene-2-carboxylate (500 mg) in THF (5 mL) for 5 min and stirred at rt for 20 h. The solution was poured into ice cooled water and extracted with ethyl acetate (3×50 mL). The combined EtOAc layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (98:2) as eluents to give the product as an off-white solid (250 mg, 53%), mp 194-196° C. 1H NMR (400 MHz, DMSO-d6): δ 7.85 (1H, s), 7.75 (1H, br s), 7.56 (1H, br s), 3.56 (3H, br s), 3.21 (3H, br s); LC-MS (positive ion mode): m/z 277, 279 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12]C)[CH:6]=2.B(Br)(Br)Br.CO>ClCCl>[F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([OH:12])[CH:6]=2
Reactant: COc1ccc2cc(F)cnc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Oc1ccc2cc(F)cnc2c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Fluoro-7-methoxyquinoline (130 mg, 0.74 mmol) was taken up in dichloromethane (2 ml) under nitrogen and treated with boron tribromide (4 ml of a 11.0M solution of in dichloromethane). The reaction mixture was stirred for 24 hours at ambient temperature followed by quenching the reaction by the slow addition of excess methanol. The solution was stirred for a further 2 hours and evaporated to dryness to give 3-fluoro-7-hydroxyquinoline which was used without further purification.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:20](=O)([O:24]CC)[O:21][CH2:22][CH3:23]>>[C:20](=[O:24])([O:21][CH2:22][CH3:23])[O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCOC(=O)OCC
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Product: CCCCCCCC/C=C\CCCCCCCCOC(=O)OCC

Procedure:
260 g (1 mol) of a technical grade oleyl alcohol were reacted with 118 g (1 mol) of diethyl carbonate in the same way as described under A. The title compound was obtained in a yield of approximately 370 g in the form of a light yellow, clear liquid having an OH value of 8.5, an acid value of 0.1, an iodine value of 76 and a number average molecular weight of 333.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:11]=[C:10]([NH:12][C:13]([N:15]3[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)=[O:14])[S:9][C:5]=2[N:6]=[CH:7][N:8]=1.[Cl:22][C:23]1[CH:24]=[C:25]([Mg]Br)[CH:26]=[CH:27][CH:28]=1>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]2[N:11]=[C:10]([NH:12][C:13]([N:15]3[CH2:20][CH2:19][C:18]([C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([Cl:22])[CH:28]=4)([OH:21])[CH2:17][CH2:16]3)=[O:14])[S:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: COc1ncnc2sc(NC(=O)N3CCC(=O)CC3)nc12
Reactant: Clc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: COc1ncnc2sc(NC(=O)N3CCC(O)(c4cccc(Cl)c4)CC3)nc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 44 %

Procedure:
A solution of 4-oxo-piperidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (as prepared in Example 59, 100 mg, 0.33 mmol) in tetrahydrofuran (35 mL) cooled to 0° C. was treated with 3-chlorophenyl magnesium bromide (0.5 M in tetrahydrofuran, 1.6 mL, 0.8 mmol). The resulting mixture was stirred at 25° C. for 3 h. At this time, the reaction mixture was cooled to 0° C. and was treated with an additional amount of 3-chlorophenyl magnesium bromide (0.5 M in tetrahydrofuran, 6 mL, 3.0 mmol). The mixture was then allowed to warm to 25° C. and to stir at 25° C. overnight. At this time, the reaction was quenched with methanol and absorbed onto silica gel (6 g). ISCO chromatography (120 g, Silica, gradient elution 7/93 methanol/methylene chloride) afforded 4-(3-chloro-phenyl)-4-hydroxy-piperidine-1-carboxylic acid (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-amide (61 mg, 44%) as a light brown solid; LRMS for C18H18ClN5O3S (M+H)+ at m/z=420. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: C[N:2]([CH:4]=[O:5])C.F[C:7]1[CH:8]=[C:9]([CH:12]=[C:13](C#CC2C=CC=CN=2)[CH:14]=1)C#N>C(=O)(O)[O-].C([N+](CC)(CC)CC)C.C(Cl)Cl>[C:4]([NH2:2])(=[O:5])[C:7]1[CH:8]=[CH:9][CH:12]=[CH:13][CH:14]=1
Reactant: N#Cc1cc(F)cc(C#Cc2ccccn2)c1
Reactant: CN(C)C=O
Agent: CC[N+](CC)(CC)CC
Agent: O=C([O-])O
Solvent: ClCCl
Product: NC(=O)c1ccccc1

Procedure:
A DMF (1 mL) solution of 3-fluoro-5-(pyridin-2-ylethynyl)benzonitrile (50 mg, 0.22 mmol) and tetraethylammonium bicarbonate (0.44 mmol) was heated at 120° C. for 10 min. The yellow reaction mixture was cooled and diluted with DCM (10 mL) and washed with aqueous LiCl (5% w/v, 3×5 mL), water (3×5 mL), brine and dried over anhydrous MgSO4. Removal of DCM under reduced pressure yielded quantitative benzamide as a white solid; mp 175-176° C. 1H-NMR (300 MHz, DMSO-d6) δ (ppm): δ 8.63 (d, J=4.9 Hz, 1H), 8.17 (s, 1H), 7.97 (s, 1H), 7.88 (td, J=7.8, 1.7 Hz, 1H), 7.76-1.52 (m, 4H), 7.44 (m, 1H) ppm 13C-NMR (75 MHz, DMSO-d6) δ (ppm): 166.0, 162.0 (d, JCF=246.6 Hz), 150.78, 142.17, 137.68 (d, JCF=8.0 Hz), 137.41, 128.06, 127.47, 124.45, 123.85 (d, JCF=9.1 Hz), 121.34 (d, JCF=22.7 Hz), 116.17 (d, JCF=22.7 Hz), 90.56, 86.83 ppm HRMS (m/z): [M+H]+ calc. for C14H10F2O, 241.0772. found 241.0783.