Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.Cl.[CH3:12][NH:13][CH:14]1[C:19]2=[C:20]([CH3:27])[C:21]3[C:26]([N:18]2[CH2:17][CH2:16][CH2:15]1)=[CH:25][CH:24]=[CH:23][CH:22]=3>O1CCCC1>[CH3:27][C:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:18]2[CH2:17][CH2:16][CH2:15][CH:14]([N:13]([CH3:12])[CH:1]=[O:3])[C:19]=12
Reactant: CNC1CCCn2c1c(C)c1ccccc12
Reactant: O=CO
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: Cc1c2n(c3ccccc13)CCCC2N(C)C=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Formic acid (7 mL) and acetic anhydride (14 mL) were mixed and heated at 60° C. for 4 hours. A solution of 6,7,8,9-tetrahydro-N,10-dimethylpyrido[1,2-a]indol-9-amine hydrochloride (7.49 g, 35 mmol) in tetrahydrofuran (40 mL) was added, and the mixture was stirred at room temperature overnight. The resultant solution was poured onto ice, and products were extracted with ether. The combined extracts were washed with 5% hydrochloric acid, 5% bicarbonate, and water. After drying (MgSO4) and filtration, the solvent was removed, and the residual oil was rapidly filtered through a silica gel column packed in chloroform/methanol 50:1. The title formamide was obtained as a yellowish oil 6.3 g (74%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CO.C(Cl)Cl.Cl[Pd]Cl>[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[C:18]([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccnc(Br)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: COC(=O)c1ccnc(-c2cccc(C(F)(F)F)c2)c1
Temperature: 100 °C
Yield: 73.5 %

Procedure:
Methyl 2-bromoisonicotinate (2.71 g, 12.57 mmol), 3-(trifluoromethyl)phenylboronic acid (3.58 g, 18.85 mmol), potassium carbonate (2.61 g, 18.85 mmol) and PdCl2 (dppf) (0.162 g, 0.25 mmol) were mixed in methanol (30 mL) in two 20 mL microwave vials. The vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. DCM and water were added and the phases separated. The water phase (pH 9) was extracted with DCM and the combined organic phase washed with brine, passed through a phase separator and evaporated to yield a brown solid. The residue was dissolved in DCM and added onto an SCX-2 cation exchange column. The column was washed with DCM, MeOH and then eluted with NH3/MeOH (1 CV each). The NH3/MeOH layer was evaporated yielding methyl 2-(3-(trifluoromethyl)phenyl)isonicotinate (2.6 g, 73%). MS m/z 282 (M+H)+
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[NH2:11][C@@H:12]([CH2:14][OH:15])[CH3:13].[BH4-].[Na+].O>CO>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][NH:11][C@H:12]([CH3:13])[CH2:14][OH:15])=[CH:3][CH:4]=1
Reactant: C[C@@H](N)CO
Reactant: COc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(CN[C@H](C)CO)cc1
Temperature: 0 °C
Yield: 100 %

Procedure:
4-Anisaldehyde (18.1 g, 133 mmol) was added to a solution of D-alaninol (10 g, 133 mmol) in methanol (100 ml) with vigorous stirring and the mixture was stirred for 30 minutes. Sodium borohydride (5.0 g, 132 mmol) was added to the ice-cooled solution and stirred for one hour at room temperature. When the reaction was complete (checked by thin layer chromatography), excess reagent was decomposed by the addition of water. The solution was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate. Removal of the solvent under reduced pressure afforded (2R)-2-(4-Methoxybenzylamino)-propan-1-ol (26 g, 133 mmol, 100%) as white crystals.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH3:24])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]2[CH:15]=[N:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:5]1>C(O)C>[CH3:3][C:4]1([CH3:24])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([C:14]2[CH:15]=[N:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[NH:5]1
Reactant: CC1(C)Cc2ccccc2C(c2cnc3ccccc3c2)=N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1(C)Cc2ccccc2C(c2cnc3ccccc3c2)N1
Temperature: 0 °C
Yield: 53.9 %

Procedure:
Sodium borohydride (370 mg, 1.0 mmol) was added to an ethanol (30 mL) solution of 3-(3,3-dimethyl-3,4-dihydroisoquinolin-1-yl)quinoline (650 mg, 2.7 mmol) followed by heating and refluxing for 3 hours, pouring this reaction solution into ice water, extracting with ethyl acetate, and applying the resulting residue to chromatography to obtain 420 mg of the target compound (yield: 54%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[CH3:19][C:20]1[S:21][C:22]([C:28]2[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[S:21][C:22]=3[C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)=[O:26])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)c3nc(C)sc3-c3cccc(C)c3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:28])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)=[C:14]([O:26][CH3:27])[CH:13]=2)[CH2:4][CH2:3]1>[C].[Pd].CO>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:28])[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)=[C:14]([O:26][CH3:27])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCn1ccnc1
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCn1ccnc1

Procedure:
Using 1 g of N-(trans-4-methylcyclohexyl)-4-[2-(1-imidazolyl)ethoxy]-3-methoxycinnamamide (Example 146), 0.05 g of 10% palladium-carbon, and 100 ml of methanol, a reaction similar to that conducted in Example 147 was carried out. The product obtained was recrystallized from methylene chloride/ether, yielding 0.93 g of N-(trans-4-methylcyclohexyl)-3-{4-[2-(1-imidazolyl)ethoxy]-3-methoxyphenyl}propionamide (a compound of the present invention) as light-brownish white crystal, which had the following physiochemical properties:
Reaction SMILES: O[CH:2]1[CH2:6][O:5][CH2:4][CH:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:5]1[CH2:6][CH:2]=[C:3]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1
Reactant: CC(C)(C)OC(=O)C1COCC1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1=CCOC1
Temperature: 2.5 °C
Reaction time: 12 h
Yield: 51.34 %

Procedure:
The product of Step B, t-butyl 4-hydroxytetrahydrofuran-3-carboxylate (0.83 g, 4.41 mmol) and PPh3 (1.74 g, 6.63 mmol) were placed in THF (5 mL), the solution was cooled to 0-5° C., and DIAD (1.13 mL, 5.74 mmol) was added dropwise. After reacting at rt for 12 h, the reaction mixture was filtered, washed with a solution of EtOAc/Hex=1/4, and the filtrate concentrated in vacuo The residue was purified by column chromatography (eluent, EtOAc/Hex=1/7) to give the title compound (0.39 g, 51.34%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:7]([O:14][NH:15][CH:16]1[CH2:21][NH:20][CH:19]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:18][CH2:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)(O)[O-].[K+].O.O.C(O)(=O)C(O)=O>C(OCC)(=O)C.O.CO>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH2:7]([O:14][NH:15][C@H:16]1[CH2:21][NH:20][C@H:19]([C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[CH2:18][CH2:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(OCc1ccccc1)C1CCC(NOCc2ccccc2)CN1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(OCc1ccccc1)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Temperature: 45 °C

Procedure:
To a slurry of benzyl 5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) (10 g, 23.3 mmol, 3:1, SR:SS) in ethyl acetate (70 ml) was added a solution of potassium bicarbonate (9.3 g, 93 mmol, 4 eq) in water (90 ml). The mixture was stirred until all the solids had dissolved. The layers were separated and the aqueous layer was extracted with ethyl acetate (30 ml). The combined organic layers were washed with water (50 ml) and concentrated under vacuum below 40° C. to a final volume of 40 ml. The solution was passed through a filter and warmed to 45° C. Methanol (20 ml) at 40° C. was added, followed by a freshly prepared solution of oxalic acid dihydrate (3.67 g, 29.1 mmol) in methanol (10 ml). The mixture was cooled and the product was isolated by filtration. The solid was washed with an ethyl acetate/methanol mixture, then with ethyl acetate. The solid was dried to give benzyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate ethanedioate (1:1) as a single isomer (7.0 g, 16.3 mmol, 70%).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[CH:13]=[O:14].C(=O)([O-])[O-].[K+].[K+]>O>[CH2:1]([O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[CH:13]=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of benzyl bromide (6.9 g, 40.3 mmol) and 3-hydroxy-4-nitrobenzaldehyde (9.7 g, 58.0 mmol) is added potassium carbonate (8.9 g, 64.4 mmol). The mixture is stirred at RT for 18 h, diluted with water and extracted with EtOAc. The organic phase is washed with aqueous potassium carbonate and brine, dried over MgSO4, filtered and concentrated to afford the title compound as a yellow solid: (M+1)+=258.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]([CH3:10])[CH:8]=O.Cl.[NH:12]1[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH2:14][C:13]1=[O:21]>ClCCl.N1C=CC=CC=1>[CH3:6][N:7]([CH:10]=[C:14]1[C:15]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[NH:12][C:13]1=[O:21])[CH3:8]
Reactant: CN(C)C=O
Reactant: O=C1Cc2cccnc2N1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=C1C(=O)Nc2ncccc21
Temperature: 2.5 °C
Reaction time: 0.17 h

Procedure:
Phosphorous oxychloride (1.93 mL, 3.17 mmol) is added slowly to a stirred solution of dimethylformamide (1.99 nmL) and dichloromethane (3 mL) cooled to 0-5° C. After 10 min, a solution of the above 1,3-dihydropyrrolo[2,3-b]pyridine-2-one hydrochloride (6-aza-1,3-dihydroindol-2-one) (790 mg, 4.63 mmol), pyridine (1.5 mL) and dichloromethane (5 mL) is added over 5 min and the reaction is stirred at room temperature for 18 hr. The solvents are removed to yield crude 3-dimethylaminomethylene-1,3-dihydropyrrolo[2,3-b]pyridin-2-one.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[C:3](=[CH2:6])[CH:4]=[O:5].[CH2:8]([O:10][C:11](=[O:15])[CH2:12][N+:13]#[C-:14])[CH3:9]>>[CH2:8]([O:10][C:11]([CH:12]1[CH:4]([C:3]([CH:2]([CH3:7])[CH3:1])=[CH2:6])[O:5][CH:14]=[N:13]1)=[O:15])[CH3:9]
Reactant: C=C(C=O)C(C)C
Reactant: [C-]#[N+]CC(=O)OCC
Product: C=C(C(C)C)C1OC=NC1C(=O)OCC

Procedure:
The starting material is manufactured as follows: Reaction of 3-methyl-2-methylene-butanal with isocyanoacetic acid ethyl ester analogously to Example 1 yields 5-(3-methyl-buten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester, which is hydrolysed analogously to Example 15 to 2-formylamino-3-hydroxy-4-isopropyl-4-pentenoic acid ethyl ester. Subsequent treatment with thionyl bromide followed by reaction with trimethyl phosphite analogously to Example 1 yields E-2-formylamino-4-isopropyl-5-dimethylphosphono-3-pentenoic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:15]([O-:17])=O)[C:5]([NH:8][C:9](=O)[C:10]([F:13])([F:12])[F:11])=[N:6][CH:7]=1.Cl.O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[N:15]([OH:17])[C:9]([C:10]([F:13])([F:12])[F:11])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1ncc(Cl)cc1[N+](=O)[O-])C(F)(F)F
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: On1c(C(F)(F)F)nc2ncc(Cl)cc21
Reaction time: 0.25 h

Procedure:
5-Chloro-3-nitro-2-(trifluoroacetamido)pyridine (2.7 grams), anhydrous stannous chloride (3.8 grams), and 4.0 milliliters of concentrated hydrochloric acid were mixed in 20 milliliters of acetic acid. The mixture was cooled to temperatures of 0°-10°C. and maintained thereat for 15 minutes. Water (50 milliliters) was then added to the reaction mixture, and the desired 6-chloro-1-hydroxy-2-(trifluoromethyl)imidazo(4,5-b)-pyridine product precipitated. It was separared and dried. The yield was 1.3 grams, 55 percent. The product so obtained melted at 264°-66°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N+:21]([O-])=O)(=[O:14])=[O:13])[CH:6]=[N:7][C:8]=1[O:9][CH3:10]>[Fe].C(O)(=O)C>[NH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([NH:11][C:5]1[CH:6]=[N:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:14])=[O:13]
Reactant: COc1cc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cnc1OC
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1cc(NS(=O)(=O)c2ccccc2N)cnc1OC
Yield: 104.7 %

Procedure:
The title compound (486 mg) was prepared from N-(5,6-dimethoxypyridin-3-yl)-2-nitrobenzenesulfonamide (509 mg, 1.5 mmol), Fe powder (559 mg, 15.0 mmol) and acetic acid (10 mL) using the methods of (IntA17), Step 2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(C)=O.C(N(CC)CC)C>C(Cl)Cl.CCOCC>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCO
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCC=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 79.6 %

Procedure:
To a solution of 700 mg (4.34 mmol) of 2-(t-butoxycarbonylamino)ethanol in 35 mL of dry methylene chloride was added 4.0 mL of dimethylsulfoxide and 4.8 mL (35 mmol) of triethylamine, followed by 2.8 g (17 mmol) of pyridine sulfur trioxide complex in three portions over 5 minutes. The reaction was stirred at room temperature for 3 hours then diluted with 500 mL of ether. The mixture was transferred to a separatory funnel and washed with 1N HCl (2×50 mL), saturated aqueous sodium bicarbonate (100 mL), and brine (100 mL). The organic layer was dried over magnesium sulfate, filtered, and the solvent removed under vacuum to afford 550 mg (80%) of product which was used without further purification. 1H NMR (200 MHz,CDCl3): 1.40 (s,9H), 4.05 (d,7 Hz,2H), 5.17 (s,1H), 9.62 (s,1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=O.[N:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)=[C:13]=[S:14].C(=O)([O-])O.[Na+].CC(O)C>O>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([N:12]2[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:3][N:2]=[C:13]2[SH:14])=[CH:20][CH:19]=1
Reactant: NCC(=O)c1ccccc1
Reactant: COc1ccc(N=C=S)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(-n2c(-c3ccccc3)cnc2S)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 17.5 parts of 2-amino-1-phenylethanone hydrochloride, 16.5 parts of 1-isothiocyanato-4-methoxybenzene, 10 parts of sodium hydrogen carbonate and 200 parts of 2-propanol is stirred first for 30 minutes at room temperature and further for 2 hours at reflux temperature. The reaction mixture is poured onto 500 parts of water. The product is filtered off and stirred and refluxed for 1 hour with 240 parts of hydrochloric acid solution 10%. After cooling, the product is filtered off, washed with water and 2-propanol, and dried, yielding 25.3 parts (90%) of 1-(4-methoxyphenyl)-5-phenyl-1H-imidazole-2-thiol; mp. 267.4° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][NH:7][C:8](=[O:17])[C:9]1[CH:14]=[C:13]([I:15])[CH:12]=[CH:11][C:10]=1[NH2:16])[CH3:2].N1C(C)=CC=CC=1C.Cl[CH:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][NH:7][C:8](=[O:17])[C:9]1[CH:14]=[C:13]([I:15])[CH:12]=[CH:11][C:10]=1[NH:16][CH:28]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH3:2]
Reactant: CCOC(=O)CCNC(=O)c1cc(I)ccc1N
Reactant: ClC(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)CCNC(=O)c1cc(I)ccc1NC(c1ccccc1)c1ccccc1
Temperature: 50 °C
Yield: 56.2 %

Procedure:
A magnetically stirred solution of 1.1 gram of N-(2-amino-5-iodobenzoyl)-b-alanine ethyl ester (3.1 mmol), prepared by the method shown in part (b) of example 1, 0.48 mL of 2,6-lutidine (4.1 mmol), 1.2 grams of chlorodiphenylmethane (4.7 mmol), and 10 mL of dimethylformamide was heated to 50° C. for 1 hour. The reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The resulting oil was dissolved in 35 mL of methylene chloride and washed with 2×50 mL 10% citric acid, 1×50 mL water, dried over sodium sulfate, decanted and concentrated in vacuo. The resulting oil was further purified by column chromatography, using silica gel, eluting with a solvent gradient of 10/90 ethyl acetate/hexane to 25/75 ethyl acetate/hexane (TLC, SiO2, 1:1 EtOAc/hexane, Rf =0.82, υν positive) to yield 0.92 gram (56%) of N-(2-diphenylmethylamino-5-iodobenzoyl)-b-alanine ethyl ester. 1H NMR (CDCl3, dTMS) 8.40 (1H, d, 3JHH =5 Hz, NHCHAr2), 7.56 (1H, d, 3JHH =2 Hz, ArH o-CON), 7.18-7.36 (1H, m, 4JHH =2 Hz, ArH Ph, ArH p-CON), 6.73 (1H, t, 3JHH =6 Hz, NHCH2), 6.29 (1H, d, 3JHH =9 Hz, ArH m-CON), 5.52 (1H, d, 3JHH =5 Hz, CHNH), 4.15 (2H, q, 3JHH =7 Hz, OCH2), 3.61 (2H, q, 3JHH =6 Hz, CH2NH), 2.58 (2H, t, 3JHH =6 Hz, CH2CO), 1.25 (3H, t, 3JHH =6 Hz, CH3CH2O).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[N:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][N:17]([CH2:20][CH2:21][C@@:22]([CH3:37])([S:33]([CH3:36])(=[O:35])=[O:34])[C:23]([NH:25][O:26]C4CCCCO4)=[O:24])[C:16](=[O:38])[CH:15]=3)=[CH:10][CH:9]=2)[N:4]=1.ClCCl.O.Cl>O1CCOCC1>[OH:26][NH:25][C:23](=[O:24])[C@:22]([CH3:37])([S:33]([CH3:36])(=[O:35])=[O:34])[CH2:21][CH2:20][N:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([N:5]3[N:4]=[C:3]([O:2][CH3:1])[CH:7]=[N:6]3)=[CH:9][CH:10]=2)=[CH:15][C:16]1=[O:38]
Reactant: COc1cnn(-c2ccc(-c3ccn(CC[C@](C)(C(=O)NOC4CCCCO4)S(C)(=O)=O)c(=O)c3)cc2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: COc1cnn(-c2ccc(-c3ccn(CC[C@](C)(C(=O)NO)S(C)(=O)=O)c(=O)c3)cc2)n1
Reaction time: 0.25 h

Procedure:
To (2R)-4-{4-[4-(4-methoxy-2H-1,2,3-triazol-2-yl)phenyl]-2-oxopyridin-1(2H)-yl}-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (120 mg, 0.22 mmol) was added dioxane (2 ml), dichloromethane (2 ml), and water (1 ml). The reaction flask was cooled externally with ice then treated with a 4.0M sol of HCl in dioxane (0.55 ml). The reaction mixture was stirred for 15 minutes then concentrated under reduced pressure. IPA (10 ml) was added and concentrated to azeotrope any remaining water to furnish a tan solid (80 mg, 80% TY). MS (LC/MS) m/z 462.3 (M+1). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.74 (s, 3H) 2.34-2.51 (m, 1H) 2.55-2.81 (m, 1H) 3.13 (s, 3H) 3.96-4.06 (m, 1H) 4.07 (s, 3H) 4.26-4.45 (m, 1H) 6.84-7.00 (m, 2H) 7.49 (s, 1H) 7.75-7.93 (m, 3H) 8.09 (d, J=8.78 Hz, 2H)
Reaction SMILES: B(Br)(Br)Br.[C:5]([C:7]1[CH:8]=[C:9]([C:17](=[O:27])[C:18]([O:20][CH2:21]CCCCC)=[O:19])[CH:10]=[C:11]([O:15]C)[C:12]=1[O:13]C)#[N:6].CO>C(Cl)Cl>[C:5]([C:7]1[CH:8]=[C:9]([C:17](=[O:27])[C:18]([O:20][CH3:21])=[O:19])[CH:10]=[C:11]([OH:15])[C:12]=1[OH:13])#[N:6]
Reactant: CCCCCCOC(=O)C(=O)c1cc(C#N)c(OC)c(OC)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(=O)c1cc(O)c(O)c(C#N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4.8 ml of boron tribromide dissolved in 20 ml of methylene chloride are added dropwise while cooling with ice within 20 minutes to 4.0 g of hexyl (3-cyano-4,5-dimethoxyphenyl)glyoxylate dissolved in 100 ml of methylene chloride and the reaction mixture is stirred at room temperature for 18 hours. 40 ml of methanol are subsequently added dropwise thereto at -60°, the mixture is stirred at room temperature for 1 hour and evaporated. The residue is taken up in methanol. It is heated under reflux for 10 minutes, evaporated to dryness and dried in a high vacuum. The thus-obtained crude product is recrystallized from acetonitrile. There is obtained methyl (3-cyano-4,5-dihydroxyphenyl)glyoxylate of m.p. 252°.
Reaction SMILES: C(N(CC)CC)C.[S:8](Cl)([CH3:11])(=[O:10])=[O:9].O.[OH:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][CH:25]=[C:26]2[CH2:29][CH2:30][NH:31][C:32](=[O:34])[CH3:33])=[CH:21][CH:20]=1>ClCCl>[CH3:11][S:8]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]2[C:27](=[C:26]([CH2:29][CH2:30][NH:31][C:32](=[O:34])[CH3:33])[CH:25]=[CH:24][CH:23]=2)[CH:28]=1)(=[O:10])=[O:9]
Reactant: CC(=O)NCCc1cccc2ccc(OCCCO)cc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)NCCc1cccc2ccc(OCCCOS(C)(=O)=O)cc12
Temperature: -10 °C

Procedure:
In a 250 ml round-bottomed flask, the alcohol obtained in Step A is dissolved in 50 ml of dichloromethane, and 0.012 mol of triethylamine is added. The mixture is cooled in an ice/salt bath at −10° C., and then 0.012 mol of mesyl chloride is added dropwise with stirring with a magnetic stirrer. The reaction mixture is stirred at room temperature for 4 hours. 100 ml of water are then added, followed by extraction with CH2Cl2. The organic phase is washed with water, dried over MgSO4 and evaporated under reduced pressure. The resulting oil is purified by chromatography over silica gel (eluant: acetone/cyclohexane (2/8)).
Reaction SMILES: CS(C)=O.FC(F)(F)C(O)=O.[C:12]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=[CH:16][C:15]([CH2:18][OH:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.O>[C:12]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:13]=[CH:14][C:15]([CH:18]=[O:19])=[CH:16][CH:17]=1
Reactant: OCc1ccc(-c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Product: O=Cc1ccc(-c2ccccc2)cc1
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
To a solution of dimethylsulfoxide (3.9 ml, 54.4 mmol) in methylene chloride (70 ml) under nitrogen atmosphere is added trifluoroacetic acid (5.7 ml, 40.8 mmol) with stirring at -70° C. After 10 min., 4-biphenylmethanol (5 g, 27.2 mmol) is added, and after being stirred for 30 min., triethylamine (30 ml, 218 mmol) is added. The reaction mixture is allowed to warm up to r.t., diluted with water, and extracted with methylene chloride. The organic layer is washed successively with 1N hydrochloric acid and saturated sodium bicarbonate, dried over magnesium sulfate and concentrated to give 4-biphenylmethanal. To a cold solution (0° C.) of 4-biphenylmethanal in THF (50 ml) under nitrogen atmosphere is slowly added 3M phenylmagnesium bromide solution in diethyl ether (5.3 ml, 15.7 mmol) with stirring. The reaction mixture is allowed to warm up to r.t. and the stirring is continued for 15 hrs. The mixture is diluted with water and extracted with diethyl ether. The organic layer is washed with saturated ammonium chloride, dried over magnesium chloride, and concentrated in vacuo. The residue is purified by flash column chromatography on silica gel with 15% diethyl ether in hexane to give (4-biphenyl)-phenylmethanol.