Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:13][NH2:14].C(N(C(C)C)CC)(C)C.O>C(O)CO.C(OCC)(=O)C>[F:11][C:7]1[CH:6]=[C:3]2[C:4]([NH2:5])=[N:14][NH:13][C:2]2=[N:9][C:8]=1[CH3:10]
Reactant: Cc1nc(Cl)c(C#N)cc1F
Reactant: NN
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc2[nH]nc(N)c2cc1F

Procedure:
58 g (340.027 mmol) of 2-chloro-5-fluoro-6-methylnicotinonitrile (preparation described in WO2007/41052, example U-2, page 80) was put in 1,2-ethanediol (580 ml) and then hydrazine hydrate (24.813 ml) and 56.091 ml (340.027 mmol) of diisopropyl ethylamine were added. The reaction mixture was heated with stirring for 16 h to 80° C. and then for 66 h to 120° C. After cooling, water (2.5 l) and ethyl acetate (2.5 l) were added and it was filtered with suction. The solid obtained was dried. 28.4 g (47% of theor.) of the target compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10](F)[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(#N)C.C(N(CC)CC)C.[O:26]1[CH2:31][CH2:30][CH:29]([C:32]2[NH:33][CH:34]=[CH:35][N:36]=2)[CH2:28][CH2:27]1>C(OCC)(=O)C.O>[F:1][C:2]1[CH:11]=[C:10]([N:33]2[CH:34]=[CH:35][N:36]=[C:32]2[CH:29]2[CH2:30][CH2:31][O:26][CH2:27][CH2:28]2)[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Reactant: c1c[nH]c(C2CCOCC2)n1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1cc([N+](=O)[O-])c(-n2ccnc2C2CCOCC2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.3 %

Procedure:
To a mixture of 4.10 g of methyl 2,4-difluoro-5-nitrobenzoate and 40 mL of acetonitrile was added 4.76 mL of triethylamine, and 2.60 g of 2-(tetrahydro-2H-pyran-4-yl)-1H-imidazole was gradually added thereto under ice-cooling, followed by stirring at room temperature for 4 hours. To the reaction mixture were added water and ethyl acetate, followed by extraction with ethyl acetate, the organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 3.84 g of methyl 2-fluoro-5-nitro-4-[2-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-1-yl]benzoate as a yellow solid.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[C:14]([NH2:22])[CH:13]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1.C(=O)(O)[O-].[K+]>CO>[C:1]1([S:7]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:21])[CH3:20])=[C:14]([NH:22][CH2:30][C:29]3[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:34])[F:35])=[CH:33][CH:32]=3)[CH:13]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CC(=O)Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1N
Agent: O=C([O-])O
Agent: [K+]
Solvent: CO
Product: CC(=O)Nc1ccc(C(=O)NS(=O)(=O)c2ccccc2)cc1NCc1ccc(C(F)(F)F)cc1
Yield: 40.7 %

Procedure:
A methanol (7 ml) solution of N-benzenesulfonyl-4-acetylamino-3-aminobenzamide (0.50 g), 4-(trifluoromethyl)benzyl bromide (0.418 g) and potassium bicarbonate (0.423 g) is stirred for 1 hour at 60° C. to give preliminarily purified N-benzenesulfonyl-4-acetylamino-3-[4-(trifluoromethyl)benzylamino]benzamide (0.30 g). This is dissolved in methanol. When it is left undisturbed crystals precipitated. The crystals are separated through filtration, dried and thus, 6-benzenesulfonylcarbamoyl-2-methyl-1-[4-(trifluoromethyl)benzyl]benzimidazole (0.160 g)is obtained.
Reaction SMILES: [C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[C:21]([O-:24])(C)C.[K+].C(OCC)=O.Cl>C(O)(C)(C)C.O.C(OCC)(=O)C>[C:1]1([C:7]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:8][CH2:9][C:10](=[O:13])[CH:11]([CH:21]=[O:24])[CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)CC1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=CC1CC(c2ccccc2)(c2ccccc2)CCC1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 107.9 %

Procedure:
4,4-Diphenylcyclohexanone (40 g) is added to a solution of potassium tert-butylate (66.5 g) in tert-butanol (500 cc), and a solution of ethyl formate (47.6 cc) in tert-butanol (500 cc) is then added dropwise. The reaction mixture is stirred at 50° C. for 8 hours, then cooled and diluted with water (3000 cc) and ethyl acetate (750 cc) and acidified to pH 2 with 4N hydrochloric acid. The aqueous phase is extracted with ethyl acetate (2×250 cc) and the combined organic phases are washed with water (250 cc) and saturated sodium chloride solution (250 cc), then dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). 4,4-Diphenyl-2-formylcyclohexanone (48 g) is obtained, and is used without purification for the next step of the synthesis.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1.[H-].[Na+].F[C:19]1[C:24]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:23][CH:22]=[CH:21][N:20]=1>CN(C=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[N:11]1[CH2:12][CH:13]([O:15][C:19]2[C:24]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:14]1
Reactant: OC1CN(c2ccc3ccccc3n2)C1
Reactant: Fc1ncccc1N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cnc(OC2CN(c3ccc4ccccc4n3)C2)c(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.5 %

Procedure:
To a solution of 1-(quinolin-2-yl)azetidin-3-ol (see PREPARATION P1.2; 237 mg, 1.186 mmol) in DMF (1.6 mL) was added sodium hydride, 60% in oil (49.4 mg, 1.235 mmol). The reaction mixture was stirred at RT for 15 min and 4-(2-fluoropyridin-3-yl)morpholine (see PREPARATION P17.1; 150 mg, 0.823 mmol) was added. The reaction mixture was heated at 60° C. for 3 hours. The reaction mixture was partitioned between EtOAc and brine. The aqueous layer was back extracted with EtOAc (3×) and the combined organic layers were dried (Na2SO4) and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 80% EtOAc in hexane, to provide 4-(2-(1-(quinolin-2-yl)azetidin-3-yloxy)pyridin-3-yl)morpholine (273 mg, 0.753 mmol, 91% yield) as off-white solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)[C:12]2=[O:24])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.[NH:29]1[CH2:32][CH:31]([C:33]([OH:35])=[O:34])[CH2:30]1.C([BH3-])#N.[Na+]>ClCCl.CO.CS(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:20][N:29]4[CH2:32][CH:31]([C:33]([OH:35])=[O:34])[CH2:30]4)=[CH:22][CH:23]=3)[C:12]2=[O:24])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(N2CCN(c3ccc(C=O)cc3)C2=O)cc1
Reactant: O=C(O)C1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)c1ccc(N2CCN(c3ccc(CN4CC(C(=O)O)C4)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.8 %

Procedure:
A mixture of 4-(3-(4-tert-butylphenyl)-2-oxoimidazolidin-1-yl)benzaldehyde (32 mg, 0.1 mmol), acetic acid (50 μl) and azetidine-3-carboxylic acid (13 mg, 0.13 mmol) in dichloromethane/MeOH (1:1, 5 mL) was stirred at room temperature for 1 hour. Sodium cyanoborohydride (3.5 mg, 0.05 mmol) was added and the reaction mixture was stirred for 6 hour at room temperature. After concentration of solvent under reduced pressure, the resulting residue was dissolved in dimethylsulfoxide, filtered and purified by reverse phase preparative HPLC (Phenomenex reverse phase Luna 5u C18(2) column, 60×21.2 mm ID, mobile phase: A=0.05% TFA in water; B=0.05% TFA in acetonitrile. The flow rate was 10-12 mL/min) to yield the title product 4 mg (10%): 1H NMR (400 MHz, CDOD3) δ 7.72 (d, 2H), 7.51-7.40 (m, 6H), 4.33 (s, 2H), 4.28 (m, 4H), 4.02 (s, 4H), 3.64 (m, 1H), 1.32 (s, 9H). MS (ESI) m/z: Calculated: 407.22; Observed: 408.00 (M++1).
Reaction SMILES: C([N:9]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:36])[C:15](=[O:35])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:10]1)(=O)C1C=CC=CC=1>CO.[Pd]>[CH3:36][N:14]([C@@H:11]1[CH2:12][CH2:13][NH:9][CH2:10]1)[C:15](=[O:35])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[C:28]1[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=1
Reactant: CN(C(=O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1)C1CCN(C(=O)c2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)CCCCC(c1ccc(F)cc1)c1ccc(F)cc1)[C@@H]1CCNC1
Reaction time: 24 h

Procedure:
To a solution of 6,6-Bis-(4-fluoro-phenyl)-hexanoic acid(1-benzoyl-pyrrolidin-3-yl)-methyl amide(1.0 g, 2.1 mmol in CH3OH (50 ml) was added Pd/C 20% (250 mg). The resulting slurry was hydrogenated at 50 psi for 24 hours. The catalyst was filtered through Celite and filtrate evaporated under reduced pressure to give 0.78 g of desired product.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[C:10]([Cl:15])[N:9]=1.[CH3:16][O:17][C:18]1[C:26]([CH3:27])=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][C:19]=1[CH3:28].S(=O)(=O)(O)[O-].[Na+]>ClCCl>[Cl:7][C:8]1[C:13]([NH:14][C:22](=[O:23])[C:21]2[CH:25]=[C:26]([CH3:27])[C:18]([O:17][CH3:16])=[C:19]([CH3:28])[CH:20]=2)=[CH:12][CH:11]=[C:10]([Cl:15])[N:9]=1
Reactant: Nc1ccc(Cl)nc1Cl
Reactant: COc1c(C)cc(C(=O)Cl)cc1C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(C)cc(C(=O)Nc2ccc(Cl)nc2Cl)cc1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
With ice cooling, a solution of 2.7 ml of absolute pyridine in 5 ml of dry dichloromethane was initially added dropwise to a solution of 5.00 g of 2,6-dichloropyridin-3-ylamine in 50 ml of dry dichloromethane. 6.70 g of 4-methoxy-3,5-dimethylbenzoyl chloride, dissolved in 15 ml of dry dichloromethane, were then added, and the reaction was stirred at 0° C. for 1 h and then at room temperature for 16 h. 10% strength aqueous sodium bisulfate solution was then added, and the mixture was stirred for 15 minutes. The phases were then separated, and the aqueous phase was extracted twice with dichloromethane. The collected organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. This gave 10.00 g (100%) of the product, which was used for the next step without any further purification.
Reaction SMILES: OC1(C)C2CCC1CC([C:10]1[NH:18][C:17]3[C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH3:22])[C:14](=[O:23])[N:13]([CH2:24][CH2:25][CH3:26])[C:12]=3[N:11]=1)C2.[Li]CCCC.[CH:33]12[O:40][CH:37]([CH:38]=[CH:39]1)[CH2:36][C:35](=[O:41])[CH2:34]2>C1COCC1>[OH:41][C:35]1([C:10]2[NH:11][C:12]3[N:13]([CH2:24][CH2:25][CH3:26])[C:14](=[O:23])[N:15]([CH2:20][CH2:21][CH3:22])[C:16](=[O:19])[C:17]=3[N:18]=2)[CH2:34][CH:33]2[O:40][CH:37]([CH:38]=[CH:39]2)[CH2:36]1
Reactant: O=C1CC2C=CC(C1)O2
Reactant: CCCn1c(=O)c2[nH]c(C3CC4CCC(C3)C4(C)O)nc2n(CCC)c1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCn1c(=O)c2nc(C3(O)CC4C=CC(C3)O4)[nH]c2n(CCC)c1=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1,3-dipropyl-7-pyrrolidin-1-ylmethyl-3,7-dihydro-purine-2,6-dione (Example 48) (522 mg, 1.63 mmol) in THF (50 ml) at −78° C. was added n-BuLi (1.55 M in hexanes, 1.2 eq, 1.3 ml). The color of the resulting yellow mixture deepened to orange-red and was stirred at this temperature for 0.5 h. A solution of 8-oxa-bicyclo[3.2.1]oct-6-en-3-one (1.1 eq, 222 mg, 1.79 mmol) in THF (4 ml) was added via syringe over a period of 20 minutes. The mixture was held at −78° C. for 2 h and allowed to reach ambient temperature overnight (12 h). The reaction mixture was partitioned between saturated aqeuous NH4Cl (20 ml) and EtOAc (20 ml) and the aqueous phase was extracted with EtOAc (20 ml). The combined organic extracts were washed with saturated aqeuous NaCl (20 ml), dried (MgSO4), filtered and concentrated in vacuo. The resulting orange oil was purified by chromatography on silica using 5% MeOH in CH2Cl2 as eluent to give a clear oil that solidified upon standing (50 mg, 8%).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[N:14]=[C:15]([S:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)[S:16][C:17]=1[N+:18]([O-:20])=[O:19]>C(Cl)Cl>[Cl:12][C:13]1[N:14]=[C:15]([S:21]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[O:6])[S:16][C:17]=1[N+:18]([O-:20])=[O:19]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(Sc2nc(Cl)c([N+](=O)[O-])s2)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)c2nc(Cl)c([N+](=O)[O-])s2)cc1

Procedure:
A total of 4.35 g (0.025 mol) of 3-chloroperoxybenzoic acid are added in portions (about 8 portions) to a solution of 5.2 g (0.018 mol) of 4-chloro-2-(4-methylphenylmercapto)-5-nitrothiazole (compound No. 57 according to the invention) in 200 ml of methylene chloride at room temperature in the course of about 50 hours. The mixture is then concentrated to dryness in vacuo at room temperature and the residue which remains is stirred intensively with excess aqueous sodium bicarbonate solution, filtered off, washed with water and dried. 4-Chloro-2-(4-methylphenylsulphinyl)-5-nitrothiazole of melting point 112° C. (from cyclohexane) is obtained.
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54]C(OC(C)(C)C)=O)[S:52][CH:53]=4)=[N:28]\[O:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[S:64][CH:65]([S:67][C:68]2[N:72]=[CH:71][NH:70][N:69]=2)[CH3:66])=[O:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.O>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:27](=[N:28]/[OH:29])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:63])[N:22]3[C:17]([C:15]([OH:16])=[O:14])=[C:18]([S:64][CH:65]([S:67][C:68]4[N:72]=[CH:71][NH:70][N:69]=4)[CH3:66])[CH2:19][S:20][C@H:21]23)=[O:62])[N:50]=1
Reactant: CC(SC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(=O)OC(C)(C)C)n3)[C@H]2SC1)Sc1nc[nH]n1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: C[N+](=O)[O-]
Solvent: O
Product: CC(SC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\O)c3csc(N)n3)[C@H]2SC1)Sc1nc[nH]n1
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetylamino]-3-(1-methyl-1,2,4-triazol-3-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (1.52 g: 1.47 mMol.) in a mixture of anisole (5 ml) and nitromethane (20 ml) at -40° C. is added a solution of aluminum chloride (1.56 g: 11.7 mMol.) in anisole (5 ml), and the mixture is stirred at -30° to -40° C. for 1 hour. The reaction mixture is mixed with 1N-hydrochloric acid (12 ml), diluted with water, washed with ethyl acetate, concentrated to remove remaining organic solvents, and passed through a column of styrene-divinylbenzene copolymer adsorbent. The adsorbed product is eluted with water-methanol (1:4). The eluate is concentrated to give powder and washed with ethyl acetate to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetylamino]-3-(1-methyl-1,2,4-triazol-3-ylthiomethylthio)-3-cephem-4-carboxylic acid (628 mg) as yellow powder. Yield: 81%.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:11])([CH3:10])[CH2:8][OH:9])[O:4][N:3]=1.C(C1C=C(N[C:21](=[O:29])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)ON=1)(C)C>>[OH:9][CH2:8][C:7]([C:5]1[O:4][N:3]=[C:2]([NH:1][C:21](=[O:29])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=1)([CH3:11])[CH3:10]
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)on1
Reactant: CC(C)(CO)c1cc(N)no1
Product: CC(C)(CO)c1cc(NC(=O)Oc2ccccc2)no1
Yield: 72 %

Procedure:
Prepared from 2-(3-aminoisoxazol-5-yl)-2-methylpropan-1-ol (100 mg, 0.60 mmol) according to the method described for phenyl 3-isopropylisoxazol-5-ylcarbamate in Example 122A Step 3, to afford phenyl 5-(1-hydroxy-2-methylpropan-2-yl)isoxazol-3-ylcarbamate as a colorless solid (120 mg, 72%). 1H NMR (300 MHz, CDCl3) δ 8.30 (brs, 1H), 7.42-7.43 (m, 2H), 7.26 (m, 1H), 7.18-7.21 (m, 2H), 6.65 (s, 1H), 3.67 (s, 2H), 1.98 (brs, 1H), 1.32 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:12][C@@H:13]([C@H:15]2[CH2:19][N:18]([C@@H:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH3:21])[C:17](=[O:30])[CH2:16]2)[CH3:14])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2I)[CH:7]=1.[Br-].[CH:32]1([Zn+])[CH2:34][CH2:33]1>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([O:12][C@@H:13]([C@H:15]2[CH2:19][N:18]([C@@H:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[CH3:21])[C:17](=[O:30])[CH2:16]2)[CH3:14])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[CH:32]2[CH2:34][CH2:33]2)[CH:7]=1
Reactant: [Zn+]C1CC1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Cl)cn4ncc(I)c34)CC2=O)cc1
Agent: Cl
Agent: [Br-]
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3cc(Cl)cn4ncc(C5CC5)c34)CC2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(R)-4-((R)-1-((6-chloro-3-iodopyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one (58 mg, 0.11 mmol) and [(2-dicyclohexylphosphino-2′,6′-bis(N,N-dimethylamino)-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate (8.7 mg, 0.011 mmol) were added. After evacuating and backfilling with nitrogen, THF (1.1 mL) was added followed by cyclopropylzinc bromide (1.3 mL, 0.65 mmol, 0.5M solution in THF). The mixture was stirred at room temperature for 15 min. The reaction was diluted with 1N HCl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (30-100% EtOAc in hexanes) to afford (R)-4-((R)-1-((6-chloro-3-cyclopropylpyrazolo[1,5-a]pyridin-4-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[C:7]([O-])(=[O:10])[CH:8]=C>C(O)(=O)C>[C:7]([O:3][CH:2]([CH3:4])[C:1]([OH:6])=[O:5])(=[O:10])[CH3:8]
Reactant: C=CC(=O)[O-]
Reactant: CC(O)C(=O)O
Solvent: CC(=O)O
Product: CC(=O)OC(C)C(=O)O

Procedure:
In one aspect the invention pertains to a process of forming an acrylate without utilizing an anhydride reagent. Lactic acid or a lactic acid ester is introduced into a first vessel with an excess of acetic acid (as measured by molar value). The lactic acid or lactic acid ester is reacted with a first portion of the acetic acid in the presence of a first catalyst to produce the corresponding 2-acetoxy propionic acid or ester. A non-reacted portion of the acetic acid is recycled and can be re-used for further reaction without converting to an anhydride. The 2-acetoxy propionic acid or ester is transferred to a second vessel where, in the presence of a second catalyst, acetic acid is liberated from the 2-acetoxy propionic acid or ester to produce a corresponding acrylic acid or first acrylate ester. After removing the liberated acetic acid by distillation, the acetic acid or first acrylate ester is mixed with an alcohol and the acrylic acid is esterified, or the first acrylate ester is trans-esterified, by reaction with the alcohol to form a second acrylate ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29]C)=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[C:37]([CH3:38])=[CH:36][CH:35]=[C:34]([F:39])[C:33]=3[F:40])[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=[O:28])([CH3:25])[CH3:26])[CH2:14][C:13](=[O:31])[NH:12][CH:11]3[C:32]3[C:37]([CH3:38])=[CH:36][CH:35]=[C:34]([F:39])[C:33]=3[F:40])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2c(C)ccc(F)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(F)c(F)c1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 80 °C
Yield: 9.4 %

Procedure:
A mixture of racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(2,3-difluoro-6-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (110 mg, 0.18 mmol), NaOH (15 mg, 0.375 mmol), H2O (2 mL) and methanol (5 mL) was heated at 80° C. for 2 h. After cooled to room temperature, the solution was acidified to “pH” 1-2 by addition of concentrated aqueous HCl solution. The aqueous phase was extracted with EtOAc. The organic layer was separated, washed with water, dried over anhydrous Na2SO4 and concentrated to give the crude product. The crude product was washed with ether twice to give the title compound as a white solid (10 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16](=[O:18])[CH3:17])=[CH:13][CH:14]=2)[C:9]([CH3:20])([CH3:19])[CH2:8][CH:7]=1.[C:21]([C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)([OH:23])=[O:22].[OH-].[Na+]>CO>[O:18]=[C:16]([C:12]1[CH:13]=[CH:14][C:15]2[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[CH:7][CH2:8][C:9]([CH3:20])([CH3:19])[C:10]=2[CH:11]=1)[CH:17]=[CH:28][C:27]1[CH:30]=[CH:31][C:24]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CC=C2c1cccs1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CC=C(c2cccs2)c2ccc(C(=O)C=Cc3ccc(C(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 62.6 mg (0.222 mmol) 3,4-dihydro-1-(2-thienyl)-4,4-dimethyl-6-acetylnaphthalene (Compound D33) in 4.0 mL of MeOH were added 33.4 mg (0.222 mmol) of 4-carboxy benzaldehyde, and 240.0 mg (6.00 mmol; 2.0 mL of 3M aqueous NaOH). The resulting solution was stirred at room temperature for 12 h, concentrated under reduced pressure, and the residual oil dissolved in EtOAc. The solution was treated with 10% HCl, and the organic layer washed with H2O, and saturated aqueous NaCI, before being dried over Na2SO4. Removal of the solvents under reduced pressure gave the title compound as a pale green solid after recrystallization from EtOH.
Reaction SMILES: [CH2:1]([NH:5][S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1Cl)[C:12](Cl)=[O:13])(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].[CH2:19]([C:21]1[O:25][C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[CH:22]=1)[CH3:20].[Cl-].[Al+3].[Cl-].[Cl-]>>[CH2:19]([C:21]1[O:25][C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[C:22]=1[C:12](=[O:13])[C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([S:6](=[O:8])(=[O:7])[NH:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:10]=1)[CH3:20]
Reactant: CCc1cc2ccccc2o1
Reactant: CCCCNS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCNS(=O)(=O)c1cccc(C(=O)c2c(CC)oc3ccccc23)c1

Procedure:
is obtained as described in Example 1 from 10 g of 3-butylsulfamoyl-4-chlorobenzoyl chloride and 5.1 g of 2-ethylbenzo[b]-furan in the presence of 9.4 g of aluminum chloride, in the form of a colorless to slightly yellow viscous oil.
Reaction SMILES: [CH2:1]([PH2:4])[CH2:2][CH3:3].[CH:5]([CH:7]=[O:8])=[O:6]>O1CCCC1>[CH2:1]([P:4]1[CH:5]([OH:6])[CH:7]([OH:8])[P:4]([CH2:1][CH2:2][CH3:3])[CH:5]([OH:6])[CH:7]1[OH:8])[CH2:2][CH3:3]
Reactant: CCCP
Reactant: O=CC=O
Solvent: C1CCOC1
Product: CCCP1C(O)C(O)P(CCC)C(O)C1O

Procedure:
Following the procedure of Example 1, mono-n-propylphosphine, in tetrahydrofuran, as solvent, is reacted with a 40% aqueous glyoxal solution, to give 1,4-di-n-propyl-2,3,5,6-tetrahydroxy-1,4-diphosphorinane, a solid melting at 131°-133° C.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]1[O:15][CH:13]1[CH3:14]>>[C:1]1([C:7]2[O:8][C:9]([CH2:12][CH:13]([OH:15])[CH3:14])=[CH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1CO1
Reactant: c1ccc(-c2ccco2)cc1
Product: CC(O)Cc1ccc(-c2ccccc2)o1

Procedure:
2-Phenylfuran(14.4g,0.1 mole) was reacted in a similar manner to Example 40 but using propylene oxide (9ml,0.13 mole). The title compound was obtained as a straw coloured oil (16.0g) b.p. 145° C./0.05 mm with decomposition.