Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:12][NH:13][C:14](=S)[OH:15].[Na]>C1C=CC=CC=1>[CH3:12][NH:13][C:14](=[O:15])[O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CNC(O)=S
Reactant: Oc1cccc2ccccc12
Agent: [Na]
Solvent: c1ccccc1
Product: CNC(=O)Oc1cccc2ccccc12

Procedure:
To a solution of 1-naphthol (1.44 g, 0.01 mole) and S-methyl ester of N-methylcarbamothioic acid (1.575 g, 0.015 mole) in benzene (6 ml) there was added sodium (0.15 g) and the mixture was refluxed for 20 hrs. The reaction mixture was cooled and washed with water and a cold 5% NaOH solution followed by water and brine and then dried. The removal of solvent afforded the solid which was further purified by crystallization to furnish 1-naphthyl N-methylcarbamate of the formula VII, m.p. 140-141° C., IR: 3305 (N-H), 1715 (-COO-), 1600, 1540, 770 (aromatic): PMR (CdCl3, 90 MHz), 2.86 (3H, d, J=1Hz, NH-CH3, 5.14 (1H, br s, N-H) and 7.17 to 8 (7H, m, aromatic).
Reaction SMILES: [NH2:1][C:2](=[O:17])[CH:3]([NH:6][C:7](=[O:16])[C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([CH3:15])[CH:9]=1)[C:4]#[N:5].[H-].[SH2:19].[Na+].Cl.C(NCC)C.O>O.O1CCOCC1>[NH2:1][C:2](=[O:17])[CH:3]([NH:6][C:7](=[O:16])[C:8]1[CH:9]=[C:10]([CH3:15])[N:11]=[C:12]([CH3:14])[CH:13]=1)[C:4]([NH2:5])=[S:19]
Reactant: S
Reactant: Cc1cc(C(=O)NC(C#N)C(N)=O)cc(C)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCNCC
Solvent: C1COCCO1
Product: Cc1cc(C(=O)NC(C(N)=O)C(N)=S)cc(C)n1
Temperature: 60 °C
Reaction time: 14 h
Yield: 58.1 %

Procedure:
A mixture of N-(2-amino-1-cyano-2-oxoethyl)-2,6-dimethylisonicotinamide (1.5 g, 0.00646 mol, 1 eq), sodium hydrogen sulfide hydride (1.05 g, 0.00646 mol, 3 eq) in water/1,4-dioxane, diethyl amine hydrochloride (1.0 g, 0.01939 mol, 3 eq) is stirred for 14 h at 60° C. After the completion of the reaction, the reaction mass is allowed to cool, water is added and extracted with ethyl acetate and dried over sodium sulfate. The solvent is evaporated and the crude is recrystallised in diethyl ether to afford 1.0 g of N-(1,3-diamino-1-oxo-3-thioxopropan-2-yl)-2,6-dimethylisonicotinamide; yield: 64%; MS (ESI+): 267;
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1.[OH:14][C:15]1([CH3:31])[CH:20]2[CH2:21][NH:22][CH2:23][CH:16]1[CH2:17][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]2>C(#N)C.O>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:22]2[CH2:21][CH:20]3[C:15]([OH:14])([CH3:31])[CH:16]([CH2:17][N:18]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)[CH2:23]2)=[CH:7][CH:8]=1)#[N:11]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C1)C2(C)O
Reactant: N#Cc1ccc(OC[C@@H]2CO2)cc1
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2CN(C[C@H](O)COc3ccc(C#N)cc3)CC(C1)C2(C)O
Temperature: 60 °C
Reaction time: 48 h

Procedure:
4-[(2S)-Oxiranylmethoxy]benzonitrile (from step (v) above, 247 mg, 1.4 mmol) was added to a stirred solution of tert-butyl 9-hydroxy-9-methyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (from step (iv) above, 328 mg, 1.28 mmol) in acetonitrile:water (4:1). The reaction was heated to 60° C. for 12 h, after which stirring was continued at rt for a further 48 h.
Reaction SMILES: [Cl-].[C:2]([O:7][CH2:8][CH3:9])(=[O:6])[C:3]([O-:5])=O.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH:23]=[CH2:24])[NH:18]2)=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.C(Cl)(Cl)Cl>[F:10][C:11]1[CH:12]=[CH:13][C:14]([C@H:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH:23]=[CH2:24])[N:18]2[C:3](=[O:5])[C:2]([O:7][CH2:8][CH3:9])=[O:6])=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(=O)[O-]
Reactant: C=C[C@@H]1CCC[C@H](c2ccc(F)cc2)N1
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@@H]1CCC[C@H](c2ccc(F)cc2)N1C(=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl oxalate chloride (0.5 mL) was added to a solution of (2R*,6S*)-2-(4-fluorophenyl)-6-vinylpiperidine (520 mg) and DIEA (0.66 mL) in methylene chloride (10 mL), and the reaction solution was stirred at room temperature for one hour. Chloroform and 1 N aqueous hydrochloric acid were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with saturated sodium bicarbonate water, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane->heptane:ethyl acetate=1:1) to obtain 426 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]1[CH2:10][NH:9][CH2:8][CH2:7][NH:6]1)=[O:4].Cl[CH2:12][C:13]([NH:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([Cl:23])=[CH:18][C:17]=1[Cl:24])=[O:14].C(N(CC)CC)C>COCCO>[CH3:1][NH:2][C:3]([CH:5]1[NH:6][CH2:7][CH2:8][N:9]([CH2:12][C:13]([NH:15][C:16]2[C:17]([Cl:24])=[CH:18][C:19]([Cl:23])=[CH:20][C:21]=2[Cl:22])=[O:14])[CH2:10]1)=[O:4]
Reactant: CNC(=O)C1CNCCN1
Reactant: O=C(CCl)Nc1c(Cl)cc(Cl)cc1Cl
Solvent: COCCO
Solvent: CCN(CC)CC
Product: CNC(=O)C1CN(CC(=O)Nc2c(Cl)cc(Cl)cc2Cl)CCN1
Temperature: 60 °C
Reaction time: 3 h
Yield: 24.4 %

Procedure:
A mixture of 15.33 parts of N-methyl-2-piperazinecarboxamide, 27.2 parts of 2-chloro-N-(2,4,6-trichlorophenyl)acetamide, 9.8 parts of N,N-diethylethanamine and 300 parts of 2-methoxyethanol was stirred for 3 hours at 60° C. The reaction mixture was evaporated. The residue was taken up in a small amount of water and treated with sodium carbonate. The product was extracted three times with dichloromethane. The combined extracts were dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off (the filtrate was set aside) and dried, yielding a first fraction of 9.27 parts (24.4%) of 3-[(methylamino)carbonyl]-N-(2,4,6-trichlorophenyl)-1-piperazineacetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH:6]=[O:7])=[C:4]([F:11])[CH:3]=1.[CH:12]1([Mg]Br)[CH2:14][CH2:13]1.Cl.C(OCC)(=O)C>C(OCC)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH:6]([CH:12]2[CH2:14][CH2:13]2)[OH:7])=[C:8]([F:10])[CH:9]=1
Reactant: Br[Mg]C1CC1
Reactant: O=Cc1c(F)cc(Cl)cc1F
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(c1c(F)cc(Cl)cc1F)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.00 g (11.33 mmol) of 4-chloro-2,6-difluorobenzaldehyde were dissolved in 15 ml of diethyl ether at 0° C., and 34.0 ml (16.99 mmol) of a 0.5N solution of cyclopropylmagnesium bromide in tetrahydrofuran were slowly added dropwise. After stirring at RT for 2 h, the reaction solution was mixed with 1N hydrochloric acid and ethyl acetate, and the phases were separated. The aqueous phase was extracted three times with diethyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution, and the solvents were removed in vacuo. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 1.20 g (48% of theory) of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH:10]=[O:11])=[C:4]([I:12])[CH:3]=1.[CH2:13]([SiH](CC)CC)C.CO.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([I:12])[C:5]([CH2:10][O:11][CH3:13])=[C:6]([O:8][CH3:9])[N:7]=1
Reactant: CC[SiH](CC)CC
Reactant: COc1nc(Cl)cc(I)c1C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COCc1c(I)cc(Cl)nc1OC
Temperature: 25 °C
Reaction time: 14 h
Yield: 93 %

Procedure:
To a mixture of 6-chloro-4-iodo-2-methoxy-3-pyridinecarboxaldehyde (1.07 g, 3.60 mmol), triethylsilane (0.86 mL, 5.40 mmol) and methanol (0.43 mL, 10.6 mmol) at 0° C. was added trifluoroacetic acid (2.2 mL, 28.6 mmol), and the resulting solution was stirred at 25° C. for 14 h. After dilution with ether (30 mL), saturated NaHCO3 was added until the aqueous phase was rendered basic. The aqueous layer was extracted with ether (10 mL), and the combined ether layers were washed with water (10 mL) and brine (10 mL), and dried (Na2SO4). Concentration gave the crude product which was purified by radial PLC (silica gel, 5% ethyl acetate/hexanes) to afford 2-chloro-4-iodo-6-methoxy-5-(methoxymethyl)pyridine as a white solid (1.05 g, 93%): mp 69°-72° C. Recrystallization from hexanes provided an analytical sample: mp 74°-75° C. 1H NMR (300 MHz, CDCl3) δ 7.40 (S, 1H), 4.53 (s, 2H), 3.96 (s, 3H), 3.42 (s, 3H); IR (nujol) 1550, 1300, 1115, 1090, 1020, 940, 905, 830, 720 cm-1.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-:16])=[O:15])=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=1.[NH3:17].CO>>[N+:14]([C:5]1[CH:4]=[CH:3][C:2]([NH2:17])=[CH:7][C:6]=1[N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([O-:16])=[O:15]
Reactant: N
Reactant: O=[N+]([O-])c1ccc(F)cc1N1CCCCC1
Solvent: CO
Product: Nc1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Yield: 47 %

Procedure:
A solution of 1-(5-fluoro-2-nitro-phenyl)-piperidine (514 mg, 2.29 mmol) in 10 mL of saturated NH3-MeOH were heated in a sealed tube at 110° C. for 48 h. The result was concentrated in vacuo and purified by preparative thin layer chromatography to afford 240 mg (47%) of the title compound. Mass spectrum (ESI, m/z): Calcd. for C11H15N3O2, 222.1 (M+H), found 222.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[IH:12]>>[I:12][C:4]1[N:3]=[C:2]([NH2:1])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: I
Product: Nc1nc(I)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2-amino-6-chloro-3-nitropyridine (5-1) (5.00 g, 28.8 mmol) and 57% HI (100 mL) was stirred for 48 hours at RT. The red-orange colored suspension was filtered to collect the precipitate which was washed with a small amount of water. The resulting yellow solid was suspended in CH2Cl2 (100 mL) and water (50 mL), and triethylamine (5.0 mL) was added while stirring. The layers were separated and the aqueous phase was reextracted with 4:1 CHCl3-isopropanol. The organic layers were combined and concentrated to yield a yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[Br:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=3)=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: OB(O)c1ccc(Br)cc1
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(-c3ccc(Br)cc3)nc2c1
Yield: 11.9 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and 4-bromophenylboronic acid (67.9 mg, 0.34 mmol, 1.50 equiv) as reactants. Purification via silica gel column (dichloromethane/methanol (5:1)) yielded 14 mg (10%) of 3-(4-bromophenyl)-2-phenylquinoxaline-6-carboxylic acid as a light yellow solid.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].[Cl:7][C:8]1[N:13]=[CH:12][C:11]([CH2:14][N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=[N:21][C:22](=[N:27][OH:28])[C:23]([F:26])([F:25])[F:24])=[CH:10][CH:9]=1.CC(C)([O-])C.[K+]>C(#N)C>[Cl:7][C:8]1[N:13]=[CH:12][C:11]([CH2:14][N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=[N:21][C:22](=[N:27][O:28][C:5](=[O:6])[NH:4][CH2:1][CH2:2][CH3:3])[C:23]([F:24])([F:25])[F:26])=[CH:10][CH:9]=1
Reactant: ON=C(N=c1ccccn1Cc1ccc(Cl)nc1)C(F)(F)F
Reactant: CCCN=C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCNC(=O)ON=C(N=c1ccccn1Cc1ccc(Cl)nc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
5 ml of anhydrous acetonitrile was added to 11 mg (0.13 mmol) of normal propyl isocyanate, 40 mg (0.12 mmol) of the N-[1-((6-chloropyridin-3-yl)methyl)pyridin-2(1H)-ylidene]-2,2,2-trifluoro-N′-hydroxyacetimidamide (1-499) synthesized by the method in Synthetic Example 7 and 4 mg (0.04 mmol) of potassium-t-butoxide were added thereto, and the resulting mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and ethyl acetate and a saturated saline solution were added thereto to perform liquid separation. The ethyl acetate layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and purified by a TLC plate (one sheet of 0.5 mm plate, evolved with hexane:ethyl acetate=1:3) to obtain the subject material. Amount obtained 16 mg (yield 32%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[O:10][C:11]2[C:12]([N:18]=1)=[N:13][CH:14]=[C:15](Br)[CH:16]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1[CH:21]=[C:22]2[O:28]C(=O)N(C)C2=NC=1>>[C:22]([C:15]1[CH:16]=[C:11]2[O:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:18][C:12]2=[N:13][CH:14]=1)(=[O:28])[CH3:21]
Reactant: Brc1cnc2nc(OCc3ccccc3)oc2c1
Reactant: Cn1c(=O)oc2cc(Br)cnc21
Product: CC(=O)c1cnc2nc(OCc3ccccc3)oc2c1

Procedure:
The method of operation is the same as that used for the synthesis of the compound of Example 1 (coupling with 1-ethoxy-1-(trimethylstannyl)ethylene), 2-benzyloxy-6-bromooxazolo[4,5-b]pyridine from Preparation 4 being used instead of the 6-bromo-3-methyloxazolo[4,5-b]pyridin-2(3H)-one from Preparation 2. The yield obtained is 78%. ##STR49##
Reaction SMILES: [NH2:1][C@@H:2]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]2[N:17]=[C:16]3[N:18]([CH3:27])[C:19](=[O:26])[N:20]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]3=[CH:14][CH:13]=2)[CH:5]=1)[CH3:3].[CH:28]([S:30]([CH:33]=[CH2:34])(=[O:32])=[O:31])=[CH2:29]>C(O)C>[CH3:24][C:22]([CH3:23])([CH3:25])[CH2:21][N:20]1[C:15]2[C:16](=[N:17][C:12]([C:6]3[CH:5]=[C:4]([C@H:2]([N:1]4[CH2:34][CH2:33][S:30](=[O:32])(=[O:31])[CH2:28][CH2:29]4)[CH3:3])[CH:11]=[CH:10][C:7]=3[C:8]#[N:9])=[CH:13][CH:14]=2)[N:18]([CH3:27])[C:19]1=[O:26]
Reactant: C[C@@H](N)c1ccc(C#N)c(-c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)c1
Reactant: C=CS(=O)(=O)C=C
Solvent: CCO
Product: C[C@H](c1ccc(C#N)c(-c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)c1)N1CCS(=O)(=O)CC1
Reaction time: 1 h

Procedure:
To a solution of 38-4 (20 mg, 0.055 mmol) in ethanol (0.3 mL) at room temperature was added (ethenylsulfonyl)ethene (0.011 mL, 13 mg, 0.11 mmol). After 1 hour, the reaction was filtered and purified by reverse phase chromatography (1-100%, 0.1% TFA in H2O/Acetonitrile) to give desired product. MS (M+H)+: observed=482.2212, calculated=482.2220.
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[O:11][C:12]4[CH:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C1COCC1.O>[CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[O:11][C:12]4[CH:18]=[CH:17][C:16]([C:19]([N:22]5[CH2:26][CH2:25][CH2:24][CH2:23]5)=[O:21])=[CH:15][C:13]=4[N:14]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc2oc(N3CCN(C4CC4)CC3)nc2c1
Reactant: C1CCNC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(c1ccc2oc(N3CCN(C4CC4)CC3)nc2c1)N1CCCC1
Reaction time: 15 h
Yield: 35.1 %

Procedure:
To a mixture of 2-(4-cyclopropylpiperazin-1-yl)benzooxazole-5-carboxylic acid (340 mg, 1.18 mmol), pyrrolidine (102 mg, 1.44 mmol) and diisopropylethylamine (372 mg, 2.88 mmol) in THF (5 mL) was added PyBop (1.25 g, 2.4 mmol) portionwise at 25° C. After stirring for 15 h, the mixture was diluted with water and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by the preparative HPLC to give 141 mg (35%) of [2-(4-cyclopropylpiperazin-1-yl)benzooxazol-5-yl]pyrrolidin-1-ylmethanone as a trifluoroacetate salt.
Reaction SMILES: Cl.N1([C:14](=[O:15])[C:13]2[N:11](C)C=N[C:8]=2N(C)C1=O)C.[CH:16]1(C)[CH2:21][CH2:20][CH:19](C(C)C)[CH:18]([OH:25])[CH2:17]1>O>[CH:18]([O:25][C:14](=[O:15])[C@H:13]([CH2:8][C:21]1[CH:16]=[CH:17][C:18]([OH:25])=[CH:19][CH:20]=1)[NH2:11])([CH3:19])[CH3:17]
Reactant: CC1CCC(C(C)C)C(O)C1
Reactant: Cn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: Cl
Solvent: O
Product: CC(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1

Procedure:
HCl (70 g) was dissolved in water (1 L). Caffeine (60 g) and menthol (10 g) were added into the mixture and the mixture was stirred for a few minutes. The mixture was filled into either spray bottles or roll-on bottles.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:23]=O)[C:8]([OH:22])=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[Cl:21])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26]>>[ClH:21].[C:1]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][C:12]=2[Cl:21])[C:8]([OH:22])=[C:7]([CH2:23][NH:29][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(C(F)(F)F)cc2Cl)c1
Product: CC(C)(C)NCc1cc(C(C)(C)C)cc(-c2ccc(C(F)(F)F)cc2Cl)c1O
Product: Cl

Procedure:
5-(tert-Butyl)-3-((tert-butylamino)methyl)-2′-chloro-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-ol hydrochloride was prepared as a white solid using the procedure described in Example 9 from 5-(tert-butyl)-2′-chloro-2-hydroxy-4′-(trifluoromethyl)-[1,1′-biphenyl]-3-carbaldehyde and tert-butylamine.
Reaction SMILES: [CH2:1]([C@@:4]1([O:30][CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])CO)[C:5]1=[O:29])[CH:2]=[CH2:3].[CH3:32][NH:33][S:34]([CH:37]1[CH2:39][CH2:38]1)(=[O:36])=[O:35].[C:40](C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH2:1]([C@@:4]1([O:30][CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:32][N:33]([CH3:40])[S:34]([CH:37]2[CH2:39][CH2:38]2)(=[O:36])=[O:35])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: CNS(=O)(=O)C1CC1
Reactant: CCCCP(=CC#N)(CCCC)CCCC
Reactant: C=CC[C@@]1(OC)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Solvent: Cc1ccccc1
Product: C=CC[C@@]1(OC)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CN(C)S(=O)(=O)C2CC2)C1=O
Temperature: 70 °C
Reaction time: 48 h

Procedure:
To a solution of (3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methoxypiperidin-2-one (124 mg, 0.268 mmol; Example 203, Step D) in toluene (1.3 mL) was added N-methylcyclopropanesulfonamide (109 mg, 0.804 mmol). The mixture was evacuated and backfilled with argon (5×). Cyanomethylenetributylphosphorane (0.211 mL, 0.804 mmol) was added. The mixture was evacuated and backfilled with argon (5×). The mixture was heated in a 70° C. oil bath for 12 hours then cooled to room temperature and stirred for 2 days at room temperature. The mixture was loaded onto silica gel and the product was eluted with 20-60% ethyl acetate/hexanes. The residue was one more time purified by flash chromatography on silica gel (12 g column, eluent: 10 to 60% ethylacetate/hexanes) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C@@H:8]2[CH2:12][CH2:11][CH:10]([OH:13])[O:9]2)=[CH:4][CH:3]=1.N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(Cl)Cl>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH:8]2[CH2:12][CH2:11][CH:10]([O:13][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[O:9]2)=[CH:4][CH:3]=1
Reactant: OC1CC[C@@H](COc2ccc(F)cc2)O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCC(COc2ccc(F)cc2)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3.47 g of (2S)-(4-fluorophenoxymethyl)-5-hydroxytetrahydrofuran 7 in 30 mL of CH2Cl2 was taken in an100 mL round bottom flask equipped with a magnetic stir bar and nitrogen inlet. That solution was cooled in an ice-water bath and 2.18 g (0.032 mol) of imidazole was added, followed by a solution of 3.6 g (0.024 mol) of tert-butyldimethylsilylchloride (TBDMSCl) in 30 mL of CH2Cl2. The reaction mixture then was stirred at room temperature for 3 hours, and the reaction then quenched with ice water, the organic layer separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography using light petroleum ether:ethyl acetate (9:1) to yield (2S) (4-fluorophenoxymethyl)-5-(tert-butyldimethylsiloxy)-tetrahydrofuran) 8 as an oil (5.1 g, 95%). 1HNMR (200 MHz, CDCl3): γ 0.09 (s, 6 H), 0.88 (s, 9 H), 1.72-2.34 (m, 4 H), 3.76=4.08 (m, 2 H), 4.28-4.54 (m, 1 H), 5.47 (s, 1/3 H), 5.54 (d, J=4.5 Hz, 2/3 H), 6.75-7.0 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:18])=[C:6]([N:8]2[N:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[O:10][C:9]2=[O:17])[CH:7]=1.[S-:19][C:20]#[N:21].[NH4+].BrBr.O>C(O)(=O)C>[NH2:21][C:20]1[S:19][C:3]2[CH:4]=[C:5]([Cl:18])[C:6]([N:8]3[N:12]=[C:11]([C:13]([CH3:15])([CH3:14])[CH3:16])[O:10][C:9]3=[O:17])=[CH:7][C:2]=2[N:1]=1
Reactant: CC(C)(C)c1nn(-c2cc(N)ccc2Cl)c(=O)o1
Reactant: N#C[S-]
Agent: BrBr
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)c1nn(-c2cc3nc(N)sc3cc2Cl)c(=O)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
3-(5-Amino-2-chlorophenyl)-5-(1,1-dimethylethyl)-1,3,4-oxadiazol-2(3H)-one (38.28 g) was dissolved in 95% acetic acid (138.20 g), and ammonium thiocyanate (27.64 g) was added thereto, followed by stirring at room temperature for 3 hours. To the resultant mixture, a solution of bromine (27.64 g) in acetic acid (41.46 g) was added, followed by stirring at room temperature for 12 hours. The reaction mixture was combined with hot water (274.7 ml), heated to 100° C. and filtered while hot. The filtrate was neutralized with sodium carbonate and extracted with ethyl acetate. Teh extract was washed with water, dried and distilled under reduced pressure to give 3-(2-amino-6-chlorobenzothiazol-5-yl)-5-(1,1-dimethylethyl)-1,3,4-oxadiazol-2(3H)-one (39.06 g) as a resinous substance.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.CCN(C(C)C)C(C)C.[Cl:22][C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[Cl:22][C:23]([O:1][CH:2]1[CH2:3][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:5]1)=[O:25]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(OC(=O)Cl)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a stirred solution of 3-hydroxy-1-Boc azetidine (21; 350 mg, 2.023 mmol) and DIPEA (1.3 ml, 7.080 mmol) in THF (5 ml) at 0° C. was slowly added triphosgene (898 mg, 3.034 mmol). The resulting mixture was stirred for 2 hr at RT. After completion of the reaction, the reaction mixture was filtered and washed with fresh THF to get rid of inorganic salts. The filtrate was concentrated under reduced pressure to get crude product 61 in 55% yield. The crude product, thus obtained, was immediately used for the next reaction.