Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:37][CH2:38][C@H:39]1[CH2:43][CH2:42][CH2:41][N:40]1C(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.ClCCl>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([NH:37][CH2:38][C@@H:39]3[CH2:43][CH2:42][CH2:41][NH:40]3)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(NC[C@@H]2CCCN2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 138 °C
Yield: 24.5 %

Procedure:
A suspension of 2-[3,5-bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methylphenyl)-3-pyridinyl]-N,2-dimethylpropanamide [WO 2005/002577] (1.5 g, 2.81 mmol) 1,1-dimethylethyl (2R)-2-(aminomethyl)-1-pyrrolidinecarboxylate (N-Boc prolinamine) (1.41 g, 7.025 mmol) and potassium carbonate (777 mg, 5.62 mmol) in 6 mL of DMSO was heated for 18 h at 150° C. (temperature detected 138° C.). A HPLC/MS check showed a 50% conversion with partial loss of the Boc protecting group. The reaction was heated under microwave irradiation to 160° C. for 1 h and to 180° C. for two cycles of 1 h and 1.5 h, respectively. The suspension was diluted with dichloromethane and extracted with sat. NaHCO3 and the organics were dried (Na2SO4) and the solution was loaded on a SCX cartridge, washed with dichloromethane (100 mL) and methanol (200 mL, this wash allowed the recovery of the unreacted chloropyridine) and eluted with 2M NH3 in MeOH. The crude thus obtained, which contained both the Boc-protected and unprotected compounds, was purified by flash chromatography (silica, cyclohexane: EtOAc 80:20 to EtOAc). Isolated 350 mg of Boc-protected amine and 410 mg of the title compound. This last compound was purified further by a boc-protection, flash chromatography, TFA deprotection and SCX isolation procedure. Final yield: 165 mg. O.A. HPLC, peak @ 5.20 min, >99% purity (UV).
Reaction SMILES: [F:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1>>[CH:19]1([NH:22][CH:15]2[CH2:16][CH2:17][N:12]([C:3]3[C:2]([F:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=3)[CH2:13][CH2:14]2)[CH2:21][CH2:20]1
Reactant: NC1CC1
Reactant: O=C1CCN(c2ncc(C(F)(F)F)cc2F)CC1
Product: Fc1cc(C(F)(F)F)cnc1N1CCC(NC2CC2)CC1

Procedure:
The title compound is prepared from 1-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperidin-4-one and cyclopropylamine following a procedure analogous to that described for Intermediate 66.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C:5](=[O:7])[NH:4][C:3]1=[N:8][C:9](=[O:11])O.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([NH2:20])[CH:14]=1.O>CN(C=O)C>[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([NH:20][C:9]([N:8]=[C:3]2[NH:4][C:5](=[O:7])[CH2:6][N:2]2[CH3:1])=[O:11])[CH:14]=1
Reactant: CN1CC(=O)NC1=NC(=O)O
Reactant: Cc1cc(C)nc(N)c1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)nc(NC(=O)N=C2NC(=O)CN2C)c1
Temperature: 55 °C
Yield: 38 %

Procedure:
A mixture of 3.0 g (12.8 mM) of the phenyl carbamate 8, and 1.6 g (12.8 mM) of 4,6-dimethyl-2-aminopyridine in 50 ml of anhydrous DMF was heated at 55° C. for 8 hrs., cooled, and poured into 200 ml water. The resulting precipitate was collected and recrystallized from ethyl acetate to give 1.3 g of the above urea as a light yellow solid, m.p. 192°-193° C.
Reaction SMILES: [OH-].[K+].[CH2:3]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1)[CH:4]([CH3:6])[CH3:5].[N+:15]([CH2:18][CH2:19][CH3:20])([O-:17])=[O:16]>C(O)C>[N+:15]([CH:18]([CH2:19][CH3:20])[CH:11]([C:10]1[CH:9]=[CH:8][C:7]([CH2:3][CH:4]([CH3:6])[CH3:5])=[CH:14][CH:13]=1)[OH:12])([O-:17])=[O:16]
Reactant: CCC[N+](=O)[O-]
Reactant: CC(C)Cc1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCC(C(O)c1ccc(CC(C)C)cc1)[N+](=O)[O-]

Procedure:
The procedure of Example 3 was followed for the reaction of 5 ml of 3.7N potassium hydroxide with 16.2 g of p-isobutylbenzaldehyde and 26.7 g of 1-nitropropane in 7.5 ml of ethanol. Obtained was 20.0 g of a yellow viscous liquid which did not crystallize: ir (film) 2.8 (s), 3.4 (s), 6.4 (s), 7.3 (m), 9.7 (m), 12.4 (m) microns; nmr (CCl4) 7.11 (4H, q), 4.84 (1H, d), 4.42 (1H, sextet), 3.15 (1H, s), 2.44 (2H, d), 1.75 (2H, m), 0.86 (6H, d), 0.83 (3H, t) ppm.
Reaction SMILES: [CH2:1]([CH:3]([C:9](O)([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]>C(Cl)(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([C:3](=[C:9]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOC(=O)C(CC)C(O)(c1ccccc1)c1ccc(OC)cc1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(CC)=C(c1ccccc1)c1ccc(OC)cc1
Yield: 107.9 %

Procedure:
7.3 g (0.02 mol) of ethyl 2-ethyl-3-hydroxy-3-(p-methoxyphenyl)-3-phenylpropionate were dehydrated in 150 ml of chloroform by using trifluoroacetic acid as catalyst (see example 10) to give 6.7 g (93%) of product, which was a mixture of E- and Z-isomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[S:7][C:8]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16](O)=[O:17])[C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1.S(Cl)([Cl:23])=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[S:7][C:8]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([Cl:23])=[O:17])[C:9]=3[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2c(c1)CCc1c(cccc1C(=O)O)S2
Solvent: c1ccccc1
Product: COc1ccc2c(c1)CCc1c(cccc1C(=O)Cl)S2

Procedure:
An amount of 572 mg of 2-methoxy-9-carboxy-10,11-dihydrodibenzo[b,f]thiepin was dissolved in 10 ml of anhydrous benzene and to the mixture was added 1 ml of thionyl chloride. The resulting mixture was refluxed for 3 hours and freed of solvent under reduced pressure to obtain 614 mg of 2-methoxy-10,11-dihydrodibenzo[b,f]thiepin-9-carbonyl chloride.
Reaction SMILES: O=P(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)[Cl:7].[CH3:12][C:13]([C:15]([CH3:23])([CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[OH-].[NH4+]>C(OCC)C>[CH3:22][C:15]([C:13]([Cl:7])=[CH2:12])([CH3:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(=O)C(C)(C)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: C=C(Cl)C(C)(C)c1ccccc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
Into a 250 ml round bottomed flask equipped with magnetic stirring and a reflux condenser was placed 15 g (98 mmol) of POCl3, 30 g (145 mmol) of PCl5, and 19.9 g (123 mmol) of α,α-dimethylbenzyl methyl ketone. The reaction was heated in an oil bath to an external temperature of 110° C. Gas evolution ceased after one hour. The reaction was cooled and carefully poured onto ice and aqueous ammonium hydroxide. Extractive workup with diethyl ether gave a mixture of 1-(α,α-dimethylbenzyl)-1-chloroethylene and 1-(α,α-dimethylbenzyl)-1,1-dichloroethane. Vacuum distillation gave purified 1-(α,α-dimethylbenzyl)-1-chloroethylene bp (23 torr) 110-120° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])[O:12][CH2:11][C:10]1[N:5]2[C@H:6]([CH3:24])[C:7](=[O:23])[NH:8][N:9]=1.CC1(C)C(C)(C)OB([C:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH:34]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:42]([O:41][C:39]([N:36]1[CH2:35][CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[O:12][CH2:11][C:10]2[N:5]3[C@H:6]([CH3:24])[C:7](=[O:23])[NH:8][N:9]=2)[CH2:38][CH2:37]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c(Br)cc3N21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c(C4=CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Temperature: 90 °C
Yield: 63.3 %

Procedure:
A mixture of (R)-6-bromo-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (2.0 g, 5.13 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (2.38 g, 7.69 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.84 g, 1.03 mmol) and K2CO3 (1.42 g, 10.25 mmol) in dioxane (21 mL) and water (7 mL) was heated at 90° C. overnight. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 10-50% EtOAc in petroleum ether) to give 4-[(R)-7-(2-fluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.6 g, 61%) as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ 8.64 (brs, 1H), 7.36-7.20 (m, 3H), 7.19-7.05 (m, 2H), 6.99 (s, 1H), 6.81 (s, 1H), 5.49 (brs, 1H), 4.79 (q, J=6.4 Hz, 1H), 4.72-4.57 (m, 2H), 3.88 (brs, 2H), 3.35 (m, 2H), 2.06 (brs, 2H), 1.60-1.57 (m, 3H), 1.47 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:23]2[CH2:26][CH:25]([C:27](=O)[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)[CH2:24]2)=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].Cl.[CH3:37][O:38][NH2:39]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:23]2[CH2:26][CH:25]([C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=3)=[N:39][O:38][CH3:37])[CH2:24]2)=[C:6]([CH:22]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:20][CH:21]=2)[CH2:11][CH2:12]1)=[O:8]
Reactant: O=C(O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(C(=O)c4cccc(F)c4)C3)CC2)cc1
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C(c1cccc(F)c1)C1CN(c2ncc(Cl)cc2C(=O)NC2(c3ccc(C(=O)O)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 60 h
Yield: 22.9 %

Procedure:
4-(1-(5-chloro-2-(3-(3-fluorobenzoyl)azetidin-1-yl)nicotinamido)cyclopropyl)benzoic acid (E25) (12.6 mg, 0.025 mmol) was dissolved in dry pyridine (1.2 ml) then O-methylhydroxylamine hydrochloride (4.3 mg, 0.051 mmol) was added and the resulting mixture was stirred at room temperature for 60 h. Solvents were evaporated in vacuo, and the residue was diluted with water (5 ml) and extracted with ethylacetate (3×20 ml). Collected organics, after solvent evaporation, afforded a residue that was washed with methanol and dried in vacuo to afford the title compound (E26) (D021/092/2) (3 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[S:6][C@@H:5]2[C@H:7](N)[C:8](=[O:9])[N:4]2[C@H:3]1[C:11]([OH:13])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1([CH3:14])[S:6][C@@H:5]2[CH2:7][C:8](=[O:9])[N:4]2[C@H:3]1[C:11]([OH:13])=[O:12]
Reactant: CC1(C)S[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)S[C@@H]2CC(=O)N2[C@H]1C(=O)O
Reaction time: 2 h

Procedure:
2.16 g 6-amino-penicillanic acid were added to 20 ml methylene chloride cooled to +5° C. Then, 2 g triethylamine were added and the mixture was stirred for 2 hours at +5° C. Then, at 0° C. 10 ml methylene chloride were added, in which 2.6 g compound of formula (III) obtained in Example 6 were dissolved. Then, the mixture was stirred for 30 minutes at +5° C., the solvent was vacuum evaporated and the residue was dissolved in 10 ml methyl-ethyl-ketone. Then, 1.9 g para-toluensulphonic acid dissolved in 10 ml methyl-ethyl-ketone were added. The solid thus formed was filtered and crystallized from a mixture acetone-water.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([Cl:20])[C:7]([CH3:19])=[C:8]([C:17]#[N:18])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO.C(#N)C>[NH2:27][CH:1]([C:4]1[CH:5]=[C:6]([Cl:20])[C:7]([CH3:19])=[C:8]([C:17]#[N:18])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[CH3:2]
Reactant: CC(=O)c1cc(Cl)c(C)c(C#N)c1-c1cccc(F)c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: Cc1c(Cl)cc(C(C)N)c(-c2cccc(F)c2)c1C#N
Temperature: 65 °C

Procedure:
A mixture of 6-acetyl-4-chloro-3′-fluoro-3-methylbiphenyl-2-carbonitrile (50 mg, 0.2 mmol) and ammonium acetate (130 mg, 1.7 mmol) in methanol (0.98 mL) and acetonitrile (0.99 mL) was heated at 65° C. in a sealed tube for 30 min. After the mixture was cooled, sodium cyanoborohydride (22 mg, 0.35 mmol) was added. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature and quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness. The residue was used directly in next step. LCMS calculated for C16H15ClFN2 (M+H)+: m/z=289.1. found: 289.1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:20]=[C:19]([F:21])[C:7]([CH2:8][N:9]2[C:13]3[CH2:14][CH2:15][CH2:16][C:12]=3[C:11]([C:17]#[N:18])=[N:10]2)=[C:6]([F:22])[CH:5]=1)[CH3:2].C[O-].[Na+].C(O)(=O)C.[Cl-].[NH4+:31]>CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([F:22])[C:7]([CH2:8][N:9]2[C:13]3[CH2:14][CH2:15][CH2:16][C:12]=3[C:11]([C:17](=[NH:31])[NH2:18])=[N:10]2)=[C:19]([F:21])[CH:20]=1)[CH3:2]
Reactant: CCOc1cc(F)c(Cn2nc(C#N)c3c2CCC3)c(F)c1
Reactant: [NH4+]
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOc1cc(F)c(Cn2nc(C(=N)N)c3c2CCC3)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
7.73 g of 1-(4-ethoxy-2,6-difluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]-pyrazole-3-carbonitrile 1-1-1 (25.5 mmol, 1.00 eq) were suspended in 100 mL methanol. 7.65 mL sodium methanolate in methanol (2.23 g, 41.3 mmol, 1.62 eq.) were added at rt. The reaction mixture was stirred for 4 h at rt. 2.36 mL acetic acid (2.45 g, 41.3 mmol, 1.62 eq.) and 2.05 g ammonium chloride (38.2 mmol, 1.50 eq.) were added and the reaction mixture was stirred at 50° C. for two days. The mixture was concentrated in vacuo and the residue was filtered off and washed with methanol. The filtrate was suspended in water and aqueous hydrochloric acid (4N). DCM was added, the aqueous layer was washed with DCM twice. To the aqueous layer aqueous sodiumhydroxid solution (2N) was added to reach pH 12. The aqueous layer was extracted with DCM/isopropanol (4:1) three times. The united organic layers were dried over a silicone filter, concentrated in vacuo to provide 2.67 g (7.99 mmol, 31.3%) of analytically pure target compound.
Reaction SMILES: [O:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=[CH:19][CH2:20][OH:21])[CH:16]=2)[N:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl.Cl>[O:1]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH:18]=[CH:19][CH2:20][O:21][C:28](=[O:30])[CH3:29])[CH:16]=2)[N:11]=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC=Cc1ccc2ncnc(Oc3ccccc3)c2c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCC=Cc1ccc2ncnc(Oc3ccccc3)c2c1
Reaction time: 2 h

Procedure:
To alcohol 25 (900 mg, 3.23 mmol) and pyridine (0.8 mL, 10 mmol) in dry CH2Cl2 (15 mL) at 0° C. was added acetyl chloride (0.3 mL, 4.2 mmol). The resulting mixture was stirred for 2 hours, the diluted with CH2Cl2 (10 mL) and 5% HCl (10 mL). The mixture was transferred to a separatory funnel and the organic layer washed with H2O and brine. The organic layer was dried (Na2SO4), solids filtered and the solvent removed in vacuo to provide the desired acetate 26 as a yellow waxy solid (1.04 g, 100%).1H NMR (CDCl3; 400 MHz): δ: 8.72 (s, 1H), 8.30 (d, 1H, J=1.7 Hz), 7.98 (m, 2H), 7.49 (m, 2H), 7.30 (m, 1H), 7.25 (m, 2H), 6.84 (d, 1H, J=16.0 Hz), 6.46 (m, 1H), 4.79 (dd, 2H, J=6.2 Hz, 1.2 Hz), 2.11 (s, 3H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([CH:32]([CH3:39])[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[N:30][CH:31]=1.C(N(C(C)C)CC)(C)C.[C:49]([O:52][C:53]1[CH:54]=[C:55]([CH2:62][C:63](O)=[O:64])[CH:56]=[CH:57][C:58]=1[N+:59]([O-:61])=[O:60])(=[O:51])[CH3:50]>CN(C)C=O>[C:49]([O:52][C:53]1[CH:54]=[C:55]([CH2:62][C:63]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([CH:32]([CH3:39])[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[N:30][CH:31]=2)=[O:64])[CH:56]=[CH:57][C:58]=1[N+:59]([O-:61])=[O:60])(=[O:51])[CH3:50]
Reactant: CC(=O)Oc1cc(CC(=O)O)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(C)c1ccc(N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CC(C)c1ccc(NC(=O)Cc2ccc([N+](=O)[O-])c(OC(C)=O)c2)cn1
Temperature: 30 °C
Reaction time: 24 h

Procedure:
A solution of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (10.95 g) in dry dimethylformamide (20 mL) was added to a solution of (RS) ethyl 3-(5-aminopyrid-2-yl)butanoate (3.0 g, Reference Example 5), diisopropylethylamine (10 mL) and (3-acetoxy-4-nitro-phenyl)acetic acid (6.89 g, Reference Example 17) in dimethylformamide (90 mL) under a nitrogen atmosphere. After stirring at 30° C. for 24 hours the reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate. The organic phase was washed with water, then with brine, then dried over magnesium sulphate, then treated with decolourising charcoal followed by filtration and evaporation of the filtrate to give the title compound as a dark oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:5])[CH3:2].[F:32][C:33]([F:44])([F:43])[C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:37]3[CH:38]=[CH:39][C:34]([C:33]([F:44])([F:43])[F:32])=[CH:35][CH:36]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[CH:18][CH:17]=2)[C:7]=1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC(C)C)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(OC(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-isopropoxyphenyl)indole-3-carboxylic acid ethyl ester (250 mg, 0.59 mmol and 4-trifluoromethylphenylboronic acid (167 mg, 0.88 mmol) and was used in the subsequent step without purification.
Reaction SMILES: Br[CH:2]1[C:7](=[O:8])[CH2:6][CH:5]([CH3:9])[CH2:4][C:3]1=O.C([O-])(=O)C.[Na+].[NH2:16][C:17]([NH2:19])=[S:18]>C(O)(=O)C>[NH2:19][C:17]1[S:18][C:2]2[C:7](=[O:8])[CH2:6][CH:5]([CH3:9])[CH2:4][C:3]=2[N:16]=1
Reactant: CC1CC(=O)C(Br)C(=O)C1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1CC(=O)c2sc(N)nc2C1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 24 in acetic acid (540 mL) was added sodium acetate (44.3 g, 540 mmol) and thiourea (28.8 g, 378 mmol). The reaction mixture was stirred with a mechanical stirrer at 100° C. for 3 h. The reaction mixture was partially concentrated in vacuo. EtOAc was added (500 mL). The mixture was made basic with 1 M NaOH, and the layers were separated. The aqueous layer was extracted with EtOAc (2×300 mL). The combined organic layers were dried, filtered, and concentrated in vacuo to give 49.3 g of 25, which was taken on without further purification. LCMS-ESI+: calc'd for C8H1N2OS: 183.1 (M+H+); Found: 183.1 (M+H+).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].C(O)=O.S(=O)(=O)(O)O.[CH2:17]=[CH:18][CH2:19][CH3:20]>>[C:1]([O:8][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5]
Reactant: C=CCC
Reactant: CC(=O)CCC(=O)O
Agent: O=S(=O)(O)O
Solvent: O=CO
Product: CCCCOC(=O)CCC(C)=O
Temperature: 100 °C

Procedure:
A 5 cc autoclave is charged with 2 cc of an aqueous solution containing 2 mmoles of levulinic acid and 2 mmoles of formic acid. 5 wt. % sulfuric acid is added as a catalyst. The reactor is pressurized to 0.69 MPa with 1-butene and heated to 100° C. for 2 hours while maintaining a constant pressure of 1-butene. After cooling, the organic phase is separated. A mixture of butyl formate and butyl levulinate is formed as product.
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH3:10][C:11]1([CH3:36])[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21](O)=[O:22])[CH:18]=2)[NH:13][CH:12]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH2:34][CH2:33][O:32][C:31]2=[O:35])[CH:25]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:10][C:11]1([CH3:36])[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:22])[CH:18]=2)[NH:13][CH:12]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH2:34][CH2:33][O:32][C:31]2=[O:35])[CH:25]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2CCOC2=O)c1
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(C(=O)NS(=O)(=O)C3CC3)ccc2NC1c1cccc(N2CCOC2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.7 %

Procedure:
To a suspension of 60% sodium hydride (106 mg, 2.6 mmol) in N,N-dimethylformamide (2.5 mL) was added cyclopropanesulfonamide (327 mg, 2.7 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 3,3-dimethyl-2-[3-(2-oxo-oxazolidin-3-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.27 mmol) and 1,1′-carbonyldiimidazole (87 mg, 0.55 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid {3,3-dimethyl-2-[3-(2-oxo-oxazolidin-3-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-amide (25 mg, 20%) as a white solid: LC/MS m/e calcd for C24H27N3O5S (M+H)+: 470.53, observed: 470.4.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]=[N+]=[N-])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN=[N+]=[N-])CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reaction time: 3 h

Procedure:
To a solution of 1-5 (19.3 g, 0.076 moles) in THF (400 ml)/H2O (195 ml) was added triphenylphosphine (80.0 g, 0.305 moles) in one portion at room temperature. This was stirred for 3 hours and the solvent was then removed in vacuo. The residue was acidified to pH 2 with 10% KHSO4 solution and this was extracted with 4×100 ml portions of EtOAc. The organic extract was extracted with 2×100 ml portions of 10% KHSO4 and the aqueous phases were combined and the pH was adjusted to pH 10 with 2N NaOH. This solution was extracted with EtOAc and the organic phase was dried (MgSO4), and the solvent was removed to give 1-6 as a yellow liquid, Rf 0.3 (silica gel 10% CH3OH in CHCl3 /NH3),