Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]3([CH2:25][CH3:26])[CH2:24][O:23][CH2:22]3)[C:17]([OH:19])=O)[C:10](=[O:27])[CH:9]=2)[CH:7]=1.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[NH:41][C:40](=[O:42])[O:39][N:38]=2)=[CH:33][CH:32]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]3([CH2:25][CH3:26])[CH2:22][O:23][CH2:24]3)[C:17]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([C:37]4[NH:41][C:40](=[O:42])[O:39][N:38]=4)=[CH:35][CH:36]=3)=[O:19])[C:10](=[O:27])[CH:9]=2)[CH:7]=1
Reactant: CCC1(CC(C(=O)O)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)COC1
Reactant: Nc1ccc(-c2noc(=O)[nH]2)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CCC1(CC(C(=O)Nc2ccc(-c3noc(=O)[nH]3)cc2)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)COC1
Reaction time: 0.58 h

Procedure:
37.4 mg (89.6 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(3-ethyloxetan-3-yl)propanoic acid (racemate), 15.9 mg (89.6 μmol) of 3-(4-aminophenyl)-1,2,4-oxadiazol-5(4H)-one, 12.7 mg (89.6 μmol) of Oxima and 14.0 μl (89.6 μmol) of DIC in 950 μl of dimethylformamide were reacted according to General Method 5. The crude product was purified by preparative HPLC [column: Chromatorex C18, 10 nm, 125 mm×30 mm, mobile phase: acetonitrile/0.05% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)] and then using Method 10. Yield: 2 mg (4% of theory)
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:20])=[CH:15][N:14]=3)[CH:11]=2)[N:6]([C:27](=[O:29])[CH3:28])[C@@H:5]([CH3:30])[CH2:4]1.Br[C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][N:33]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:30][C@H:5]1[CH2:4][C@@H:3]([NH:2][C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][N:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:20])=[CH:15][N:14]=3)[CH:11]=2)[N:6]1[C:27](=[O:29])[CH3:28]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)cn3)cc2[C@H](N)C[C@@H]1C
Reactant: Cc1ccc(Br)nc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)cn3)cc2[C@H](Nc2ccc(C)cn2)C[C@@H]1C
Temperature: 130 °C
Yield: 42 %

Procedure:
1-((2S,4R)-4-amino-2-methyl-6-(5-(morpholine-4-carbonyl)pyridin-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone hydrochloride (for a preparation see Intermediate 65) (80 mg, 0.186 mmol), 2-bromo-5-methylpyridine (63.9 mg, 0.371 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (14.6 mg, 0.037 mmol), tris(dibenzylideneacetone)dipalladium(0) (17 mg, 0.019 mmol) and sodium tert-butoxide (53.5 mg, 0.557 mmol) were combined in 1,4-dioxane (2 mL) and the mixture degassed over a period of 15 mins, before being heated under microwave irradiation to 130° C. for 50 mins. A further portion of 2-bromo-5-methylpyridine (63.9 mg, 0.371 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (14.6 mg, 0.037 mmol), tris(dibenzylideneacetone)dipalladium(0) (17 mg, 0.019 mmol), sodium tert-butoxide (53.5 mg, 0.557 mmol) and 1,4-dioxane (1 mL) were added and the mixture degassed over a period of 15 mins, before being heated under microwave irradiation to 130° C. for 25 mins. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate (50 mL) and DCM (3×50 mL). The organics were combined, dried by passing through a hydrophobic frit and concentrated in vacuo to give a residue which was purified by MDAP (HpH) to give 1-((2S,4R)-2-methyl-4-((5-methylpyridin-2-yl)amino)-6-(5-(morpholine-4-carbonyl)pyridin-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (38 mg, 0.078 mmol, 42% yield). LCMS: (Formate, 2 min), Rt=0.58 mins, MH+486.
Reaction SMILES: N12CCCN=[C:7]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.[C:12]12([C:22](=[O:25])[CH:23]=[CH2:24])[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2.[Cl-].[O:27]=C(C)C[N+]1C=CC=CC=1>C(O)C>[C:12]12([C:7]3[CH:6]=[C:5]([OH:27])[CH:4]=[CH:3][CH:2]=3)[CH2:21][CH:16]3[CH2:15][CH:14]([CH2:20][CH:18]([CH2:17]3)[CH2:19]1)[CH2:13]2.[C:12]12([C:22](=[O:25])[CH:23]=[CH2:24])[CH2:19][CH:18]3[CH2:17][CH:16]([CH2:15][CH:14]([CH2:20]3)[CH2:13]1)[CH2:21]2
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(=O)C[n+]1ccccc1
Agent: C=CC(=O)C12CC3CC(CC(C3)C1)C2
Agent: [Cl-]
Solvent: CCO
Product: Oc1cccc(C23CC4CC(CC(C4)C2)C3)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A THF solution (20.0 mL, 10.0 mmol) comprising 1 mol/L of vinylmagnesium bromide was slowly added dropwise to a THF (45 mL) solution comprising 2.23 g (5.00 mmol) of N-methoxy-N-methyladamantan-1-carboxamide that had been cooled in a bath containing ice and salt while keeping the THF solution at −10 to 0° C. Thereafter, the mixture was stirred at 0° C. for 1 hour, and stirred at room temperature overnight. The reaction mixture was slowly added dropwise, using a Pasteur pipette, to saturated ammonium chloride water that had been cooled in a bath containing ice and salt, while keeping it at −10 to −5° C. After the completion of the dropwise addition, the mixture was heated to 0° C. Since the mixture comprises two layers, the water layer was separated, and ethyl acetate extraction was performed three times. Subsequently, the primarily separated organic layer and the combined ethyl acetate layers were combined, and the organic layer was washed with saturated ammonium chloride water 5 times, and with brine once. Drying over sodium sulfate, filtration, condensation, and drying under reduced pressure at room temperature for 3 hours were performed, thereby giving the crude product of 1-(adamantan-1-yl)prop-2-en-1-on (containing 1.56 g of impurities such as 3-[methoxy(methyl)amino]-1-(adamantan-1-yl)propan-1-on, etc.) The crude product was used in the next reaction without purification. Under an Ar atmosphere, 1.43 g of 1,8-diazabicyclo[5.4.0]undeca-7-en (DBU) was added to an ice-cooled suspension comprising 1.18 g of the crude product of 1-(adamantan-1-yl)prop-2-en-1-on, 1.60 g of 1-(2-oxopropyl)pyridinium chloride, 1.18 g of molecular sieves 4A, and ethanol (24 mL), and the mixture was stirred at room temperature for 2 days. Under ice-cooling, 1N HClaq. was added to the reaction mixture, the pH was adjusted to 1, and ethyl acetate extraction was performed. The organic layer was separated, and washed with brine three times, followed by drying over sodium sulfate, filtration, condensation, and drying under reduced pressure at room temperature for 1 hour, thereby giving the crude product (936 mg) of 3-(adamantan-1-yl)phenol. This crude product and the crude product of 3-(adamantan-1-yl)phenol (456 mg) obtained from the crude product of 400 mg of 1-(adamantan-1-yl)propa-2-en-1-on under the same conditions were combined. Then this crude product was separated and purified by silica gel column chromatography, thereby giving 222 mg of 3-(adamantan-1-yl)phenol (yield: 9.7%).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:14][C:15]1[C:22]([CH3:23])=[C:21]([O:24][CH3:25])[CH:20]=[CH:19][C:16]=1[CH:17]=O>>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:16]([CH2:17][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=3)[CH2:2][CH2:3]2)=[C:15]([CH3:14])[C:22]=1[CH3:23]
Reactant: COc1ccc(C=O)c(C)c1C
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: COc1ccc(CN2CCN(c3cc(=O)[nH]cn3)CC2)c(C)c1C

Procedure:
6-[4-(4-Methoxy-2,3-dimethyl-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2,3-dimethylanisaldehyde. Mass spectrum (ES) MH+=329.
Reaction SMILES: C([NH:4][CH:5]([CH3:18])[CH2:6][C:7]1[CH:17]=[CH:16][C:10]([O:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:9][CH:8]=1)(=O)C.[OH-].[Na+]>O>[NH2:4][CH:5]([CH3:18])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:16][CH:17]=1
Reactant: CC(=O)NC(C)Cc1ccc(OCC(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(N)Cc1ccc(OCC(=O)O)cc1

Procedure:
The 29 g. of residual oil described in Example 3 above (ethyl ester of rac. 4-(2-acetamidopropyl)phenoxyacetic acid was refluxed with 16.4 g. of sodium hydroxide (0.41 moles) in 150 ml. of water for 15 hrs., after which the solution was cooled, a trace of flocculent matter removed by filtration and the clear filtrate passed over a column of 750 ml. (0.75 eq) of Dowex® 2-X4 in the hydrogen form. After washing the column with water until the effluent pH was 4-5, the amino acid was eluted with 2 l. of 10% aqueous pyridine. Distillation of the pyridine effluent in a rotary evaporator left a residue of 18 g., m.p. 301°-303° dec.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([F:15])[CH:3]=1.[CH3:16][S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O)(=[O:19])=[O:18].C1COCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CCOC(C)=O.[Pd+2]>[F:15][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[S:17]([CH3:16])(=[O:19])=[O:18])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1
Reactant: Nc1ccc(-c2ccc(Cl)cc2F)cn1
Reactant: CS(=O)(=O)c1ccccc1B(O)O
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccccc1-c1ccc(-c2ccc(N)nc2)c(F)c1
Temperature: 60 °C
Yield: 29.3 %

Procedure:
5-(4-Chloro-2-fluorophenyl)pyridin-2-amine (100 mg, 0.449 mmol), 2-(methylsulfonyl)phenylboronic acid (112 mg, 0.561 mmol), and chloro(2-dicyclohexyl-phosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II) (33 mg, 0.045 mmol) were placed in a sealable reaction tube under nitrogen. THF (2 mL, sparged with nitrogen) and K3PO4 (2 mL, 0.5 M sparged with nitrogen) were added, and the reaction vessel was sealed and heated at 60° Celsius for 16 hours with vigorous stirring. The mixture was cooled to rt, diluted with EtOAc, and washed with 2 M K2CO3, then dried and concentrated to dryness. The residue was subjected to FCC to provide the title compound (45 mg, 29%). MS (CI): mass calcd. for C18H15FN2O2S, 342.08; m/z found, 343.0 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.38-8.31 (s, 1H), 8.29-8.22 (m, 1H), 7.77-7.71 (m, 1H), 7.71-7.65 (m, 1H), 7.64-7.57 (m, 1H), 7.52-7.45 (m, 1H), 7.42-7.37 (m, 1H), 7.36-7.27 (m, 2H), 6.64-6.59 (m, 1H), 4.66-4.51 (s, 2H), 2.81-2.69 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([OH:16])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23]([O:30][C:31](=[O:34])[CH2:32]Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16][CH2:32][C:31]([O:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:34])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CCOC(=O)c1cc(O)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCC(=O)OCc2ccccc2)c2ccccc2n1
Reaction time: 16 h

Procedure:
To a solution of 10 g of 4-Hydroxy-quinoline-2-carboxylic acid ethyl ester in 300 ml of DMF, 10 g of potassium carbonate and 15.2 g of Bromo-acetic acid benzyl ester was added and stirred for 16 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate (3×150 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with n-heptane/ethyl acetate (2/8). The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 10.2 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:18][CH2:17][CH2:16][C@H:15]3[N:10]2[C:11](=[O:19])[CH2:12][CH:13]=[CH:14]3)[CH:5]=[CH:6][C:7]=1[F:8].[H][H]>CO.[Pt]=O>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:18][CH2:17][CH2:16][C@H:15]3[N:10]2[C:11](=[O:19])[CH2:12][CH2:13][CH2:14]3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CC=C[C@H]2CCC[C@@H](c3ccc(F)c(F)c3)N12
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: O=C1CCC[C@H]2CCC[C@@H](c3ccc(F)c(F)c3)N12
Yield: 71.1 %

Procedure:
Platinum oxide (48 mg) was added to a solution of (6S,9aR)-6-(3,4-difluorophenyl)-3,6,7,8,9,9a-hexahydroquinolizin-4-one (558 mg) in methanol (15 mL), and the reaction solution was stirred in a hydrogen stream at room temperature for three hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 400 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1O)=[C:10]([O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[CH:9]=[C:8]([O:22][CH3:23])[CH:7]=2)#[N:2].P(Cl)(Cl)([Cl:26])=O>C(#N)C>[Cl:26][C:12]1[C:11]2[C:6](=[CH:7][C:8]([O:22][CH3:23])=[CH:9][C:10]=2[O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[N:5]=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: COc1cc(OC2CCN(C)CC2)c2c(O)c(C#N)cnc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1cc(OC2CCN(C)CC2)c2c(Cl)c(C#N)cnc2c1
Reaction time: 20 h

Procedure:
A mixture of 3-cyano-4-hydroxy-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinoline (313 mg) and phosphoryl chloride (1.8 ml) in acetonitrile (10 ml) was refluxed and stirred for 20 hours. After cooling, the solution was evaporated to dryness. The flask containing the residue was filled with ice chips and excess concentrated aqueous ammonia (25 ml) was added. This mixture was allowed to warm up while stirring overnight. The product was filtered off and dried under high vacuum overnight. The title compound was obtained as a white solid (225 mg, 68%); NMR spectrum: (DMSOd6) 1.80 (m, 2H), 1.98 (m, 2H), 2.18 (s, 3H), 2.27 (m, 2H), 2.58 (m, 2H), 3.94 (s, 3H), 4.72 (m, 1H), 6.92 (d, 1H), 7.09 (d, 1H), 8.93 (s, 1H); Mass spectrum: M+H+ 332.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]([CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([N+:21]([O-:23])=[O:22])=[CH:13][CH:12]=1)[C:7]([OH:9])=[O:8])=[O:4].N1C=CC=CC=1.[CH3:30][Si:31]([CH3:36])([CH3:35])[CH2:32][CH2:33]O.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C>[CH3:30][Si:31]([CH3:36])([CH3:35])[CH2:32][CH2:33][O:8][C:7](=[O:9])[CH:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([N+:21]([O-:23])=[O:22])=[CH:13][CH:12]=1
Reactant: COC(=O)NC(Cc1ccc([N+](=O)[O-])c2ccccc12)C(=O)O
Reactant: C[Si](C)(C)CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Solvent: c1ccncc1
Product: COC(=O)NC(Cc1ccc([N+](=O)[O-])c2ccccc12)C(=O)OCC[Si](C)(C)C
Reaction time: 1 h

Procedure:
To a mixture of 2-methoxycarbonylamino-3-(4-nitro-naphthalen-1-yl)-propionic acid (0.35 g, 1.1 mmol), pyridine (0.78 mL) and 2-trimethylsilylethanol (0.18 mL, 1.25 mmol, 1.1 eq) in acetonitrile (1.1 mL) cooled in an ice bath was added dicyclohexylcarbodiimide (0.25 g, 1.21 mmol). The mixture was stirred cold for 1 hour, placed in the refrigerator for 14 hours. The reaction mixture was filtered, concentrated under reduced pressure and purified on silica gel eluting with heptane/ethyl acetate (4:1) to provide the titled compound. MS ESI(−)) m/e 417 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:29][C:30]2[CH:38]=[CH:37][C:33]3[O:34][CH2:35][O:36][C:32]=3[CH:31]=2)[S:7](=[O:28])(=[O:27])[C:8]2[CH:22]=[C:21](OC)[C:20](OC)=[CH:19][C:9]=2[C:10]=1OS(C(F)(F)F)(=O)=O)=[O:4].[O:39]1[C:43]2[CH:44]=[CH:45][C:46]([S-:48])=[CH:47][C:42]=2[O:41][CH2:40]1.[Na+].O1C2C=CC(S)=CC=2OC1.[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:29][C:30]2[CH:38]=[CH:37][C:33]3[O:34][CH2:35][O:36][C:32]=3[CH:31]=2)[S:7](=[O:28])(=[O:27])[C:8]2[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=2[C:10]=1[S:48][C:46]1[CH:45]=[CH:44][C:43]2[O:39][CH2:40][O:41][C:42]=2[CH:47]=1)=[O:4]
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)c2cc(OC)c(OC)cc2S(=O)(=O)N1Cc1ccc2c(c1)OCO2
Reactant: [S-]c1ccc2c(c1)OCO2
Agent: Sc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1=C(Sc2ccc3c(c2)OCO3)c2ccccc2S(=O)(=O)N1Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
To 2-Benzo[1,3]dioxol-5-ylmethyl-4-hydroxy-1,1-dioxo-1,2-dihydro-1λ6 -benzo[e][1,2]thiazine-3-carboxylic acid methyl ester in dichloromethane (6 mL) and pyridine (0.65 mL, 7.75 mmol) was added trifluoromethanesulfonic anhydride (0.32 mL, 1.71 mmol). This mixture was stirred at room temperature for 30 minutes. Diluted with ethyl acetate (100 mL), washed with 1N HCl (2×50 mL), brine (50 mL), dried with magnesium sulfate and then evaporated in vacuo to afford the crude 2-benzo[1,3]dioxol-5-ylmethyl-6,7-dimethoxy-1,1-dioxo-4-(trifluoro-methanesulfonyloxy)-1,2-dihydro-1λ6 -benzo[e][1,2]thiazine-3-carboxylic acid methyl ester. A solution of this ester, in DMF (3 mL), was added to sodium 1,3-benzodioxole-5-thiolate (0.31 g, 2.0 mmol) {prepared by dissolving 1,3-benzodioxole-5-thiol (0.31 g, 2.0 mmol) in DMF (3 mL) and stirring with sodium hydride (0.081 g, 2.0 mmol) for 5 minutes} in DMF (3 mL). After stirring at room temperature for 16 hours the mixture was diluted with ethyl acetate (100 mL), washed with 1N NaOH(2×50 mL), brine (50 mL), dried with magnesium sulfate, and evaporated in vacuo. Silica gel column chromatography eluting with 25% ethyl acetate in hexane afforded the title compound as a foam (0.64 g, 79%);
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1.Br.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:20][C:21]4[N:26]([CH2:39][C:40]5[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=5)[C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1cccnc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Agent: Br
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3cccnc3)C(=O)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
To a solution of tert-butyl(1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (51 mg, 0.11 mmol) in dry DMF (1 ml) was added sodium hydride (11 mg, 0.26 mmol) and 3-(bromomethyl)pyridine.HBr (33 mg, 0.13 mmol) under nitrogen. The resulting mixture was stirred for 1 hour at room temperature. A saturated solution of NaHCO3 was added and the mixture was extracted with dichloromethane (3×10 ml) using a phase separator (Isolute® SPE). The combined organic phases were concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 80% EtOAc in cyclohexane) to give the title compound (23 mg, 38%). 1H NMR (500 MHz, CDCl3): 8.60-8.50 (2H, br s), 7.60 (2H, d), 7.28 (1H, s), 7.19-7.15 (6H, m), 7.12 (1H, s), 6.97 (2H, d), 5.13 (2H, s), 4.93 (3H, s), 2.52-2.20 (4H, m), 2.00-1.95 (1H, m), 1.75-1.70 (1H, m), 1.44-1.15 (9H, br).
Reaction SMILES: C([Si](C(C)C)(C(C)C)[N:5]1C=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)[CH:15]=2)=[CH:6]1)(C)C.[NH:30]1C=C(B(O)O)C=N1>>[NH:5]1[CH:6]=[C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)[CH:15]=2)[CH:8]=[N:30]1
Reactant: OB(O)c1cn[nH]c1
Reactant: CCOC(=O)c1cn2cc(-c3ccn([Si](C(C)C)(C(C)C)C(C)C)c3)ccc2n1
Product: CCOC(=O)c1cn2cc(-c3cn[nH]c3)ccc2n1
Temperature: 90 °C

Procedure:
This product is prepared under conditions similar to those described for the preparation of Intermediate 15 (step 15.1), replacing the 1-(triisopropylsilyl)pyrrole-3-boronic acid with pyrazole-4-boronic acid and heating at 90° C. by microwave for 37 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[O:16][CH3:17].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])[C:22]([Cl:38])=[CH:21][N:20]=1>>[Cl:38][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[S:32]([N:35]([CH3:37])[CH3:36])(=[O:34])=[O:33])=[N:24][C:19]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[C:3]=2[O:16][CH3:17])=[N:20][CH:21]=1
Reactant: CCN1C(=O)CCCc2c1ccc(N)c2OC
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CCN1C(=O)CCCc2c1ccc(Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)c2OC

Procedure:
Following a procedure analogous to Example 113, 7-Amino-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (40 mgs) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide (59 mgs) were converted to the title compound (18 mgs as a white solid). 1H-NMR (CDCl3): δ 9.48 (s, 1H), 8.58 (d, J=8.3 Hz, 1H), 8.24 (d, J=8.8 Hz, 1H), 8.19 (s, 1H), 7.91 (d, J=7.8 Hz, 1H), 7.63 (t, J=7.6 Hz, 1H), 7.50 (s, 1H), 7.31-7.28 (m, 1H), 6.94 (d, J=8.9 Hz, 1H), 4.40-4.10 (broad absorption, 2H), 3.83 (s, 3H), 3.70-2.90 (broad absorption, 2H), 2.78 (s, 6H), 2.31-2.00 (broad absorptions, 4H), 1.16 (t, J=7.0 Hz, 3H). LC/MS: (M+H)+ found=545.16; MP 183° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@@H:9]([C:25]([O:27]CC1C=CC=CC=1)=[O:26])[CH2:10][CH2:11][C@@H:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[F:24])[CH2:13][N+:14]([O-])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[C:38]([O:37][C:35]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@@H:9]([C:25]([OH:27])=[O:26])[CH2:10][CH2:11][C@@H:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[F:24])[CH2:13][NH2:14])=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@H](C[N+](=O)[O-])c1cccc(F)c1F)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC[C@H](CN)c1cccc(F)c1F)C(=O)O
Reaction time: 18 h
Yield: 97.7 %

Procedure:
A solution of benzyl (5S)—N,N-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-6-nitro-D-norleucinate (15.5 g, 26.8 mmol) and 10% Pd/C (12.0 g) in EtOH (175 mL, SureSeal from Aldrich), was hydrogenated at 55 psi overnight. After 18 h, another 4 g of 10% Pd/C was added and the reaction hydrogenated at 55 psi for another 18 h. The reaction was filtered through Celite with more EtOH and concentrated to afford the title compound (12.0 g). MS 459.2 (M+1).