Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[P:8]([O-:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11].[C:16]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=1)(=[O:18])[CH3:17]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[C:16]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([P:8]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])=[O:15])=[CH:23][CH:22]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OCc1ccc(Br)cc1
Reactant: CCOP([O-])OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)c1ccc(COC(C)=O)cc1
Temperature: 100 °C
Yield: 68 %

Procedure:
A mixture of 9.7 mL (0.057 mole) of triethylamine and 2.4 grams (0.002 mole) of tetrakis(triphenylphosphine)palladium(0) was stirred, and 7.3 mL (0.057 mole) of diethyl phosphite was added. To this was added 13.2 grams (0.057 mole) of 4-bromophenylmethyl acetate. The reaction mixture was warmed to about 100° C., where it stirred for 30 minutes. The reaction mixture was cooled, and 200 mL of ethyl acetate was added. The resultant solid was collected by filtration, and washed with 50 mL of ethyl acetate. The combined wash and filtrate were concentrated under reduced pressure to a residual oil, which was subjected to column chromatography on silica gel, with 3:7 heptane:ethyl acetate as eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 11.1 grams of 4-(diethylphosphono)phenylmethyl acetate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]1([CH3:27])[CH:6]=[CH:5][C:4]([S:7]([CH:10]([C:14]2[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[C:17]([O:23][CH3:24])=[C:16]([O:25][CH3:26])[CH:15]=2)[NH:11][CH:12]=O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.O=P(Cl)(Cl)Cl.CCN(CC)CC>COCCOC>[CH3:26][O:25][C:16]1[CH:15]=[C:14]([CH:10]([N+:11]#[C-:12])[S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:27])=[CH:6][CH:5]=2)(=[O:8])=[O:9])[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[C:17]=1[O:23][CH3:24]
Reactant: COc1cc(C(NC=O)S(=O)(=O)c2ccc(C)cc2)cc([N+](=O)[O-])c1OC
Solvent: COCCOC
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: [C-]#[N+]C(c1cc(OC)c(OC)c([N+](=O)[O-])c1)S(=O)(=O)c1ccc(C)cc1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Compound 3c (2.63 g, 6.68 mmol) was suspended in dry DME (100 mL) and cooled to −10° C. POCl3 (3.78 mL, 40.4 mol) was added and a mixture of Et3N (7.5 mL, 66.6 mmol) in DME (10 mL) was dropped slowly to the reaction mixture. After stirring for 2 h at −5° C., the reaction mixture was poured into ice water. The water phase was extracted with ethyl acetate, the organic phase was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuum. By refrigeration over night a yellow solid crystallized from the residue, which was collected and dried in vacuum. Yield: 520 mg (1.51 mmol, 23%); yellow solid of mp 134° C. (dec.); νmax (ATR)/cm−1 2949, 2140, 1593, 1538, 1494, 1453, 1360, 1337, 1315, 1285, 1248, 1184, 1156, 1145, 1082, 1065, 988, 921, 819, 784, 701, 667; 1H NMR (300 MHz, CDCl3) δ 2.48 (3H, s), 3.91 (3H, s), 4.00 (3H, s), 5.53 (1H, s), 7.12 (1H, d, J=2.2 Hz), 7.18 (1H, d, J=2.2 Hz), 7.38 (2H, d, J=8.4 Hz), 7.67 (2H, d, J=8.4 Hz); 13C NMR (75.5 MHz, CDCl3) 821.9, 56.7, 62.3, 75.3, 115.3, 116.3, 122.3, 129.7, 129.8, 130.4, 144.6, 144.8, 147.4, 154.4, 167.5; m/z (EI) 375 (6) [M+-1], 344 (12), 278 (23), 262 (22), 221 (100), 211 (47), 155 (32), 139 (38).
Reaction SMILES: [CH:1]1([C:4](=[C:6]2[C:11](=[O:12])[O:10][C:9]([CH3:14])([CH3:13])[O:8][C:7]2=[O:15])[CH3:5])[CH2:3][CH2:2]1.[C-:16]#[N:17].[K+]>>[CH:1]1([C:4]([CH:6]2[C:11](=[O:12])[O:10][C:9]([CH3:14])([CH3:13])[O:8][C:7]2=[O:15])([CH3:5])[C:16]#[N:17])[CH2:3][CH2:2]1
Reactant: CC(=C1C(=O)OC(C)(C)OC1=O)C1CC1
Reactant: [C-]#N
Agent: [K+]
Product: CC1(C)OC(=O)C(C(C)(C#N)C2CC2)C(=O)O1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 120, Step 2 starting from 5-(1-cyclopropylethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione and potassium cyanide.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[N:4][C:5]([NH:8][C:9]2[C:10](=[O:15])[NH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.Br[C:24]1[NH:28][CH:27]=[N:26][N:25]=1.C(OCC)C>CO>[N:25]1[N:26]=[C:27]([N:19]2[CH2:20][CH2:21][CH2:22][C@@H:17]([NH:16][C:3]3[C:2]([F:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]4[C:10](=[O:15])[NH:11][CH:12]=[CH:13][CH:14]=4)[N:4]=3)[CH2:18]2)[NH:28][CH:24]=1
Reactant: O=c1[nH]cccc1Nc1ncc(F)c(N[C@@H]2CCCNC2)n1
Reactant: Brc1nnc[nH]1
Solvent: CCOCC
Solvent: CO
Product: O=c1[nH]cccc1Nc1ncc(F)c(N[C@@H]2CCCN(c3nnc[nH]3)C2)n1
Temperature: 150 °C
Yield: 40.4 %

Procedure:
A mixture of (R)-3-(5-fluoro-4-(piperidin-3-ylamino)pyrimidin-2-ylamino)pyridin-2(1H)-one (Preparation 22c, 50 mg, 0.16 mmol) and 3-bromo-4H-1,2,4-triazole (prepared as described in J. Med. Chem. 2004, 47(19), 4645, 12.2 mg, 0.08 mmol) was stirred and heated overnight at 150° C. The reaction mixture was cooled to ambient temperature and diluted with methanol. Diethyl ether was then added and the precipitate that formed was filtered. The filtrate was concentrated under reduced pressure and the resulting semisolid was suspended in diethyl ether and filtered to yield the title compound (12 mg, 40%) as a yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)=[N:8][O:9][CH:10]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][O:17][C:14]2[CH:13]=[CH:12][C:11]([C:7]3[C:6]([C:4]([OH:5])=[O:3])=[CH:10][O:9][N:8]=3)=[CH:16][CH:15]=2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1conc1-c1ccc(OCc2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1conc1-c1ccc(OCc2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 14 h
Yield: 91 %

Procedure:
A solution of 3-[4-(4-fluoro-benzyloxy)-phenyl]-isoxazole-4-carboxylic acid ethyl ester (19.6 g, 57.5 mmol) in ethanol (65 mL) at 60° C. was treated with 2N aqueous NaOH (65 mL). After stirring for 14 h, the resulting yellow suspension was poured onto 500 mL of ice water and the mixture was adjusted to pH 2 with 4N HCl. The white suspension was removed by filtration and washed with water. The wet filter cake was dissolved in ethyl acetate and dried over Na2SO4. Filtration followed by removal of volatiles under reduced pressure gave crude material from which 3-[4-(4-fluoro-benzyloxy)-phenyl]-isoxazole-4-carboxylic acid (16.4 g, 91%) was isolated in pure form after washing twice with heptane, once with diethyl ether and dried in vacuo.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18](Cl)[C:17]([CH2:21][C:22]([O:24]CC)=O)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH2:29])[CH3:28].C(O)(C)C>O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][C:17]3[CH2:21][C:22](=[O:24])[N:29]([CH2:27][CH3:28])[C:18]=3[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cnc(N2CCN(Cc3ccccc3)CC2)nc1Cl
Reactant: CCN
Solvent: O
Solvent: CC(C)O
Product: CCN1C(=O)Cc2cnc(N3CCN(Cc4ccccc4)CC3)nc21
Temperature: 120 °C
Yield: 46 %

Procedure:
A mixture of 1.41 g (3.76 mmol, Referential Example 71) of ethyl 2-(4-benzylpiperazino)-4-chloropyrimidine-5-acetate, 5 ml of ethylamine and 20 ml of isopropanol was placed in a pressure vessel, in which they were heated at 120° C. for 2 hours. The solvent was then driven off under reduced pressure. The residue was added with water, followed by extraction with chloroform. After drying the organic layer with MgSO4, it was concentrated. The residue was purified by silica gel column chromatography to obtain 0.58 of the above-identified compound (yield: 46%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][C:10]12[C:22]3[C:18]([CH2:19][CH2:20][CH2:21]1)=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:13][CH2:12][CH2:11]2>C(=S)=S>[CH3:9][C:10]12[C:22]3[C:14](=[CH:15][CH:16]=[C:17]([C:5](=[O:7])[CH3:6])[C:18]=3[CH2:19][CH2:20][CH2:21]1)[CH2:13][CH2:12][CH2:11]2
Reactant: CC(=O)Cl
Reactant: CC12CCCc3cccc(c31)CCC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2c3c1CCCC3(C)CCC2
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 77 %

Procedure:
A suspension of aluminum chloride (1.62 g) in carbon disulfide (25 ml) was added with acetyl chloride (1.00 ml) at −10° C. The mixture was stirred at −10° C. for 20 minutes, and then slowly added with 3a-methyl-2,3,3a,4,5,6-hexahydro-1H-phenalene (1.74 g) dissolved in carbon disulfide (15 ml), and the temperature of the mixture was gradually elevated to room temperature. The reaction mixture was stirred at room temperature for 30 minutes, and then poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:500) to obtain 1-(6a-methyl-5,6,6a,7,8,9-hexahydro-4H-1-phenalenyl)ethanone (1.63 g, yield: 77%) and the title compound (0.465 g, yield: 22%). The compound was recrystallized from n-hexane to obtain colorless prisms (melting point: 100-101.5° C.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=1[C:13]([NH:15][CH:16]([CH3:18])[CH3:17])=[O:14].C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:22]=[CH:21][CH:20]=[CH:19][C:12]=2[C:13]([NH:15][CH:16]([CH3:18])[CH3:17])=[O:14])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)NC(=O)c1ccccc1N
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 0 °C
Reaction time: 18 h
Yield: 90.4 %

Procedure:
A round-bottomed flask was charged with 2,4,5-trichloropyrimidine (2.0 g, 6.8 mmol), 2-amino-N-(1-methylethyl)benzamide (1.2 g, 7.1 mmol), di-isopropyl-ethylamine (1.4 mL, 8.1 mmol) and 30 mL isopropanol. The flask was fitted with a reflux condenser and the reaction was heated to reflux and stirred for 18 h. A white solid appeared in the reaction mixture. The reaction was cooled to 0° C. and filtered and solid was washed with diethyl ether to afford 2-[(2,5-dichloro-4-pyrimidinyl)amino]-N-(1-methylethyl)benzamide (2.0 g, 90%)
Reaction SMILES: [P:1]([O:9]CC)([O:6][CH2:7][CH3:8])([O:3][CH2:4][CH3:5])=[O:2].COC(=O)[O-].[CH3:17][NH+:18]1[CH2:22][CH:21]([CH3:23])[N:20]([CH3:24])[CH:19]1[CH3:25].O>CO>[CH2:4]([O:3][P:1]([O-:9])([O:6][CH2:7][CH3:8])=[O:2])[CH3:5].[CH3:17][NH+:18]1[CH2:22][CH:21]([CH3:23])[N:20]([CH3:24])[CH:19]1[CH3:25]
Reactant: CCOP(=O)(OCC)OCC
Agent: CC1C[NH+](C)C(C)N1C
Agent: COC(=O)[O-]
Solvent: O
Solvent: CO
Product: CCOP(=O)([O-])OCC
Temperature: 100 °C
Reaction time: 20 h

Procedure:
By adding 42 parts of triethyl phosphate (TEP: produced by Daihachi Chemical Industries Co., Ltd.) to the methanol solution of 46 parts of 1,2,3,4-tetramethylimidazolinium methyl carbonate salt obtained in Production Example 1, followed by addition of 5.4 parts of water and stirring at 100° C. for 20 hours, triethyl phosphate was hydrolyzed and a salt exchange reaction was carried out to obtain a methanol solution of 1,2,3,4-tetramethylimidazolinium diethyl phosphate monoanion. The above-described solution was heated under reduced pressure of 1.0 kPa or less at 50° C. to distill methanol until no distillate of methanol was observed. Thereafter, the temperature was raised from 50° C. to 100° C. and heating was continued for 30 minutes to distill and remove monomethyl carbonate (HOCO2CH3), methanol, and carbon dioxide (slight amounts of methanol and carbon dioxide are formed by thermal decomposition of monomethyl carbonate. Hereinafter, these are abbreviated as by-products). Thus, 1,2,3,4-tetramethylimidazolinium diethyl phosphate monoanion, electrolyte (C-2), was obtained. The yield was 99 parts (yield based on the weight of 46 parts of 1,2,3,4-tetramethylimidazolinium methyl carbonate salt; hereinafter the same shall apply). The molecular weight of the electrolyte (C-2) was 280.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[CH3:14][O:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH:24][C:25]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=[O:28].[Cl-].[NH4+]>CCOCC>[CH3:14][O:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:27]([C:26]1[CH:29]=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:25]=1[OH:24])[OH:28]
Reactant: COc1cccc(C=O)c1O
Reactant: COCOc1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: COCOc1ccccc1C(O)c1cccc(OC)c1O
Temperature: 0 °C

Procedure:
A 1.6 M solution of butyl lithium (90.6 ml, 0.145 mol) was placed in a flask and blanketed with nitrogen and to this was added with stirring, while maintaining the temperature at 25°-30° C., 16.85 g, (0.145 mol) of tetramethylethylenediamine. The mixture was then cooled to 0° C. and 20.0 g (0.145 mol) of methoxymethoxybenzene was added with stirring and allowed to react for 2 hours after which 10.0 g (0.066 mol) of 2-hydroxy-3-methoxybenzaldehyde was added under the same conditions. The mixture was allowed to react for a few minutes and was then poured into a mixture of ice and saturated aqueous ammonium chloride. The solid that formed, which was insoluble in ether, was collected by filtration to obtain 15.5 g (81 percent of theory) of the title compound. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [CH2:1](/[N:5]=[C:6]1\[CH2:7][CH2:8][CH2:9][CH:10]=[C:11]\1[NH:12][C:13]1[C:18]([CH:19]([CH3:21])[CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=1[CH:22]([CH3:24])[CH3:23])[CH2:2][CH2:3][CH3:4].C1(C)C=CC=CC=1.Cl>C(OCC)C>[CH:22]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([CH:19]([CH3:20])[CH3:21])[C:13]=1/[N:12]=[C:11]1/[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][CH2:8][CH2:9][CH2:10]/1)([CH3:24])[CH3:23]
Reactant: CCCC/N=C1\CCCC=C1Nc1c(C(C)C)cccc1C(C)C
Agent: Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCNC1=CCCC/C1=N\c1c(C(C)C)cccc1C(C)C
Yield: 100.2 %

Procedure:
Charge a vial with N-((6E)-6-(butylimino)-1-cyclohexen-1-yl)-2,6-bis(1-methylethyl)-benzenamine (B) (3.0038 g, 9.1995 mmol, Example B) and toluene (30.0 mL). Stir the resulting yellow solution and add a solution of 1.0M HCl (aqueous, 0.46 mL, 0.46 mmol) in diethyl ether. Stir the resulting reaction mixture for 3 hours. To the mixture add hexanes (5 mL) and filter (syringe filter) to remove fine solids. Wash the filtered solids with hexanes (6 mL), and concentrate the filtrate overnight under reduced pressure to give 3.0107 g of the product (L)d as a thick brown oil.
Reaction SMILES: [CH2:1]1[CH2:6][O:5][CH:4]=[CH:3][CH2:2]1.[NH2:7][C:8]1[S:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:12]=1>CC#N.C(O)(C(F)(F)F)=O>[O:5]1[CH2:6][CH2:1][CH2:2][CH2:3][CH:4]1[NH:7][C:8]1[S:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:12]=1
Reactant: C1=COCCC1
Reactant: CCOC(=O)c1cnc(N)s1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cnc(NC2CCCCO2)s1
Yield: 63.6 %

Procedure:
TFA (22 μL, 0.3 mmol) and DHP (3.9 mL, 43.5 mmol) were added to a suspension of ethyl 2-aminothiazole-5-carboxylate (5 g, 29 mmol) in CH3CN (40 mL) at RT. The resulting mixture was stirred at reflux overnight. The reaction mixture was concentrated and dissolved in AcOEt/PE and kept at 4 C overnight. The resultant white solid was filtrated and washed with PE, yielding ethyl 2-(tetrahydro-2H-pyran-2-ylamino)thiazole-5-carboxylate (4.73 g, 64%).
Reaction SMILES: C[O:2][C:3]1[S:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][N:7]=1.Cl>O1CCOCC1>[O:9]([CH2:8][C:5]1[S:4][C:3](=[O:2])[NH:7][N:6]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1nnc(COc2ccccc2)s1
Agent: Cl
Solvent: C1COCCO1
Product: O=c1[nH]nc(COc2ccccc2)s1
Reaction time: 1 h

Procedure:
44 g of crude 2-methoxy-5-phenoxymethyl-1,3,4-thiadiazole are added in portions to a solution of 15 g of hydrogen chloride in 200 ml of dioxane. After boiling for one hour under reflux, the mixture is evaporated and the resulting mass is recrystallised from a little methanol. This gives 30 g of 5-phenoxymethyl-1,3,4-thiadiazol-2(3H)-one as colourless crystals.
Reaction SMILES: [CH2:1]([C@@:4]1([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([C@@:4]1([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@H]2CCCN(C(=O)OC(C)(C)C)C2)C(=O)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@H]2CCCNC2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of (S)-tert-butyl 3-((R)-6-allyl-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)piperidine-1-carboxylate (700 mg, 1.67 mmol) in CH2Cl2 (16 mL) was added TFA (3.2 mL) at 0° C. The mixture was stirred at rt for 2 h. Then aqueous solution of NaHCO3 was added, and the mixture was extracted with CH2Cl2. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by preparative TLC to give (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-piperidin-3-yl)-1,3-oxazinan-2-one (530 mg, 100%).
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C@@:10]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:12][C@H:11]2[CH:13]=[CH2:14])=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1>[Ru]>[CH:1]1([S:4]([NH:7][C:8]([C@@:10]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:12][C@H:11]2[CH2:13][CH3:14])=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Agent: [Ru]
Product: CC[C@@H]1C[C@]1(NC(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Reaction time: 20 h

Procedure:
A hydrogenation vessel was charged with a solution of tert-butyl ((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)carbamate (prepared as described in WO 03/099274) followed by Ru/C (7.5 wt %). The vessel was placed under N2 (20 psig) and vented to atmospheric pressure three times to remove residual oxygen. The vessel was then placed under H2 (50 psig) and the reaction was complete in <5 h based on H2 consumption. After 20 h, the vessel was vented to atmospheric pressure. The reaction slurry was then transferred out of the reaction vessel, filtered and evaporated to a yellow oil which was brought to the following step without further purification. MS (ES+) C14H24BN2O5S requires 332. Found: 333 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]2=[N:6][Se:7][N:8]=[C:4]2[CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>OS(O)(=O)=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2=[N:6][Se:7][N:8]=[C:4]2[C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: Clc1ccc2n[se]nc2c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1c(Cl)ccc2n[se]nc12
Temperature: 0 °C

Procedure:
A solution of 5-chloro-2,1,3-benzoselenadiazole from Step A (800 mg, 1.80 mmol) in conc. H2SO4 (12 mL) was cooled to 0° C. and 90% HNO3 (0.8 mL) was added. After 30 min the reaction was cooled to 0° C. and diluted with H2O (10 mL). The solid was filtered off and washed with cold H2O to yield the title compound. MS: m/z=264 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([Br:10])[O:7][C:6]=1[CH2:11]Br)=[O:4].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1>CO>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([Br:10])[O:7][C:6]=1[CH2:11][NH:20][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)=[O:4]
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)c1cc(Br)oc1CBr
Solvent: CO
Product: COC(=O)c1cc(Br)oc1CNCc1ccc(OC)cc1

Procedure:
A solution of 5-bromo-2-bromomethyl-furan-3-carboxylic acid methyl ester (1.74, 5.88 mmol) and p-methoxy benzylamine (0.76 mL, 5.88 mmol) in MeOH (30 mL) is stirred at 85° C. for 1.5 hours. The reaction mixture is concentrated in vacuo and the residue purified by silica gel column chromatography eluting with 4:1 petroleum ether:ethyl acetate followed by 1:1 petroleum ether:ethylacetate. The title compound is isolated (643.8 mg).
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=CC(O)=C[CH:5]=1.N[C@H](C(O)=O)CC1C=CC=CC=1>>[NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][CH:4]([CH3:9])[CH3:5]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
3.17 (3), Tyr; 0.95 (1), Phe; 2.99 (3),
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:36][C:37]1[CH:42]=[C:41](Cl)[N:40]=[CH:39][N:38]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:36][C:37]1[N:38]=[CH:39][N:40]=[C:41]([C:20]2[CH:21]=[CH:22][C:17]([C@@H:15]([N:11]3[CH2:10][CH2:9][C@@:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)([CH2:32][CH2:33][CH2:34][OH:35])[O:13][C:12]3=[O:14])[CH3:16])=[CH:18][CH:19]=2)[CH:42]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: Clc1cc(Cl)ncn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: C[C@@H](c1ccc(-c2cc(Cl)ncn2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Yield: 68.6 %

Procedure:
To a mixture of ((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (30 mg, 0.062 mmol), 4,6-dichloropyrimidine (12 mg, 0.081 mmol), and 2 M aqueous Cs2CO3 (1.0 mL) in dry THF (2 mL) was added Pd(dppf)Cl2 (6 mg, 0.00621 mmol) under N2 atmosphere. The mixture was heated to reflux for 2 hours. Then the solvent was evaporated, and the residue was purified by preparative TLC to afford (R)-3-((S)-1-(4-(6-chloropyrimidin-4-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (20 mg, yield 68%).
Reaction SMILES: O[CH2:2][CH2:3][C:4]([NH2:6])=[O:5].[CH:7]1(N)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.N>>[CH:7]1([NH:6][C:4](=[O:5])[CH:3]=[CH2:2])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: NC1CCCCC1
Reactant: NC(=O)CCO
Agent: N
Product: C=CC(=O)NC1CCCCC1
Temperature: 164 °C

Procedure:
59 g of β-hydroxypropionamide and 69.4 g of cyclohexylamine were heated with 50 mg of 2,6-di-t-butyl-pcresol for 5 hours in a temperature range of 130°-170° C. until the evolution of ammonia was complete. After adding 2.5 g of polyphosphoric acid the reaction mixture was maintained at 164° C. for 1 hour and then distilled in a water jet vacuum. The main run was taken off between 140° and 160° C. at 11 bar and crystallized in the receiver.