Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1.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>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[OH:12])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(Br)c(O)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc(F)cc2)c(O)c1

Procedure:
Methyl 4-bromo-3-hydroxybenzoate (2.1 g, 9.0 mmol), 4-fluorophenyl-boronic acid (2.52 g, 18 mmol), tetrakis(triphenylphosphine)palladium (0.52 g, 0.45 mmol), and 2M aqueous sodium carbonate solution (11 ml) in ethanol/toluene (1:5, 30 ml) were heated at reflux overnight. After cooling the solvent was removed in vacuo and the residue dissolved in EtOAc then washed with sat. aq. sodium bicarbonate and dried over MgSO4. The crude product was purified by column chromatography eluting with 1% MeOH/DCM giving the title compound as a solid (1.9 g). MS(ES): MH+ 247, M-H+ 245.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][OH:29])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:39][C:40]#[C:41][C:42]([O:45][Si:46]([CH2:51][CH3:52])([CH2:49][CH3:50])[CH2:47][CH3:48])([CH3:44])[CH3:43].[H-].[Na+].C1OCCOCCOCCOCCOC1>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29][CH2:39][C:40]#[C:41][C:42]([O:45][Si:46]([CH2:47][CH3:48])([CH2:49][CH3:50])[CH2:51][CH3:52])([CH3:43])[CH3:44])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@H](CC[C@]4(C)C(CO)=CC[C@@H]34)[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: CC[Si](CC)(CC)OC(C)(C)C#CCBr
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C)(C)C#CCOCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 66 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene (200 mg, 0.367 mmol), 1-bromo-4-triethylsilyloxy-4-methyl-2-pentyne (216 mg, 0.741 mmol), sodium hydride (60% in oil, 44 mg, 1.10 mmol) 15-crown-5 (81 mg, 0.368 mmol) and tetrahydrofuran (1 ml) were subjected to reaction using a procedure similar to that of Example 5(1) (at room temperature 17 hours), worked up and purified by column chromatography (hexane:toluene=3:2) to give the titled compound (183 mg, 66%) as a pale yellow oil.
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:10][C:11](=[O:34])[N:12]([C:14]1[CH:15]=[CH:16][C:17]([CH3:33])=[C:18]([C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=2)[CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>O1CCCC1.CO>[CH2:3]([NH:10][C:11](=[O:34])[N:12]([C:14]1[CH:15]=[CH:16][C:17]([CH3:33])=[C:18]([C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=2)[CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCNC(=O)N(C)c1ccc(C)c(-c2ccc(/C=C/C(=O)OCC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCNC(=O)N(C)c1ccc(C)c(-c2ccc(/C=C/C(=O)O)cc2)c1
Yield: 37 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 200 mg (5.0 mmol, 4.7 eq) of sodium hydroxide and 460 mg (1.05 mmol, 1 eq) of ethyl (E)-3-[5′-(3-heptyl-1-methylureido)-2′-methylbiphenyl-4-yl]acrylate in 6 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from a dichloromethane/pentane mixture, 160 mg of (E)-3-[5′-(3-heptyl-1-methylureido)-2′-methylbiphenyl-4-yl]acrylic acid are obtained in the form of a white powder. (m.p.=159° C.). Yield=37%
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]=[C:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+]>O.C(O)(=O)C>[C:1]([O:5][C:6]([NH:8][NH:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NN=C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)OC(=O)NNC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
To tert-butyl 4-[(tert-butoxycarbonyl)hydrazono]piperidine-1-carboxylate (15.7 g; 50.1 mmol; 1 eq.) in water (78.5 mL) and glacial acetic acid (78.5 mL) is added sodium cyanoborohydride (3.15 g; 50.1 mmol; 1 eq.) and the reaction mixture is stirred at rt overnight. The solvents are removed to near dryness and the product is extracted with AcOEt. The combined organic phase is washed with NaOH (1 M), dried over MgSO4, filtered and concentrated to afford: 14.1 g (89%) of the title compound. 1H NMR (300 MHz, DMSO): δ 8.22 (s, 1H), 4.61-4.14 (m, 1H), 3.81-3.55 (m, 2H), 3.08-2.67 (m, 2H), 1.73-1.50 (m, 2H), 1.38 (s, 18H), 1.22-0.98 (m, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.[CH3:29][O:30][CH2:31][CH2:32][N:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38](B3OC(C)(C)C(C)(C)O3)[CH:39]=2)[C:34]1=[O:51]>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:38]3[CH:39]=[C:40]4[C:35](=[CH:36][CH:37]=3)[C:34](=[O:51])[N:33]([CH2:32][CH2:31][O:30][CH3:29])[CH2:41]4)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COCCN1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Product: COCCN1Cc2cc(-c3n[nH]c4cc(-c5c(F)c(OC)cc(OC)c5F)ncc34)ccc2C1=O

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 2-(2-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=481.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[NH2:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>C(O)CCC>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=[C:2]([NH:19][C:20]2[NH:21][N:22]=[C:23]([CH3:25])[CH:24]=2)[CH:7]=1
Reactant: COc1ccc(CSc2nc(Cl)cc(Cl)n2)cc1
Reactant: Cc1cc(N)n[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CSc2nc(Cl)cc(Nc3cc(C)n[nH]3)n2)cc1
Temperature: 120 °C
Reaction time: 15 h

Procedure:
To a solution of above-prepared 4,6-dichloro-2-(4-methoxy-benzylsulfanyl)-pyrimidine (915 mg, 3.04 mmol) and 3-amino-5-methylpyrazole (310 mg, 3.19 mmol) in BuOH (20 mL) is added diisopropylethylamine (0.56 mL, 3.19 mmol) followed by sodium iodide (455 mg, 3.04 mmol). The reaction mixture is stirred for 15 hours at 120° C. The solvent is removed in vacuo and the residue is purified by flash chromatography (SiO2, hexane/AcOEt gardient) to give [6-chloro-2-(4-methoxy-benzylsulfanyl)-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[NH2:20][C:21]1[CH:22]=[C:23]([C:27]#[CH:28])[CH:24]=[CH:25][CH:26]=1>CCOCC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]([F:12])([F:11])[F:10])=[CH:3][C:2]=1[C:28]#[C:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[NH2:20]
Reactant: Fc1ccc(C(F)(F)F)cc1Br
Reactant: C#Cc1cccc(N)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Nc1cccc(C#Cc2cc(C(F)(F)F)ccc2F)c1
Temperature: 70 °C
Yield: 70 %

Procedure:
A multinecked flash as described in Example 1 was charged with 4.93 g (0.020 mol) of 3-bromo-4-fluorobenzotrifluoride, 75 ml of dried, degassed triethylamine, 2.34 g (0.020 mol) of 3-aminophenylacetylene, 0.06 g (0.08 mmol) of bis(triphenylphosphine) palladium II chloride, 0.118 g (0.45 mmol) of triphenylphosphine, and 0.06 g (0.31 mmol) of cuprous iodide. The reaction mixture was heated at 70° C. for 40 hours at which point gas chromatography showed the reaction to be complete. The product mixture was cooled to room temperature and diluted with 75 ml of ether. Filtration of the insoluble hydrobromide salt followed by concentration of the filtrate gave the crude product (5.5 g, 89%) as an orange liquid. Short path distillation of the crude product under reduced pressure gave 4.05 g (0.014 mol, 70% yield) of the product as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[OH:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K].[Mn]([O-])(=O)(=O)=O.[K+]>O>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:14]([O:15][CH3:16])[CH:13]=2)=[O:18])[CH:20]=1
Reactant: COc1cc(C(O)c2cccnc2)ccc1OCc1ccccc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [K]
Solvent: O
Product: COc1cc(C(=O)c2cccnc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
ba) 3.2 g of alpha-[4-(benzyloxy)-5-methoxyphenyl]-3-pyridinemethanol suspended in 50 ml of water are treated with 2.5 g of potassium permananate, whereupon the mixture is stirred at 90° for 30 minutes After adding a further 1.0 g of potassium permanganate and stirring for a further 30 minutes at 90° the mixture is cooled to room temperature and extracted twice with 150 ml of ethyl acetate each time. The combined ethyl acetate phases are washed with sodium chloride solution, dried over sodium sulfate and evaporated. The thus-obtained residue is chromatographed on 50 g of silica gel with ethyl acetate. After recrystallization from methylene chloride/hexane there is obtained 4-(benzyloxy)-3-methoxyphenyl 3-pyridyl ketone of m.p. 76°.
Reaction SMILES: [C:1]([C:3]1([O:13][Si](C)(C)C)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)#[N:2].Cl>C(O)C>[C:1]([C:3]1([OH:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1)#[N:2]
Reactant: C[Si](C)(C)OC1(C#N)CCCc2ccccc21
Agent: Cl
Solvent: CCO
Product: N#CC1(O)CCCc2ccccc21

Procedure:
The silyl cyanohydrin of Example 3 (40.7 g, 165 mol) was dissolved in 300 ml ethanol and perfused at 0° C. with hydrogen chloride for 30 minutes. After an additional 16 hours at 0° C. the mixture was evaporated in vacuo to an oil. This was taken up in chloroform and washed with 2×100 ml sodium bicarbonate, 1×80 ml water, 1×80 ml brine, dried over magnesium sulfate, filtered, and evaporated in vacuo to a residue which partially crystallized. This solid was triturated with 10% ethereal hexane 17.6 g (62%) mp 55°-59° C. (69°-75° C. after recrystallization from ether/hexane).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[C:4]([CH2:12]Br)[CH:3]=1.[CH3:14][NH2:15].CO>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:7])[N:15]([CH3:14])[CH2:12]2
Reactant: COC(=O)c1ccc(Br)cc1CBr
Reactant: CN
Solvent: CO
Product: CN1Cc2cc(Br)ccc2C1=O
Reaction time: 18 h

Procedure:
A solution of methyl 4-bromo-2-(bromomethyl)benzoate (410 mmol) in MeNH2/MeOH (1500 mL) was heated to reflux and stirred for 18 h. The reaction mixture was concentrated and the residue was purified by chromatography on silica eluting with petroleum ether/ethyl acetate (6:1 to 3:1) to afford the sub-titled compound (48.5 g).
Reaction SMILES: [NH2:1][CH:2]1[CH:6]([C:7]([O:9]C)=O)[S:5][C:4]2[C:11]3[C:16]([CH2:17][CH2:18][C:3]1=2)=[CH:15][CH:14]=[CH:13][CH:12]=3.[Cl:19][CH2:20][C:21]#[N:22]>Cl.O1CCOCC1>[Cl:19][CH2:20][C:21]1[NH:22][C:7](=[O:9])[CH:6]2[CH:2]([C:3]3[CH2:18][CH2:17][C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:4]=3[S:5]2)[N:1]=1
Reactant: COC(=O)C1SC2=C(CCc3ccccc32)C1N
Reactant: N#CCCl
Agent: Cl
Solvent: C1COCCO1
Product: O=C1NC(CCl)=NC2C3=C(SC12)c1ccccc1CC3
Temperature: 100 °C

Procedure:
A solution of EXAMPLE 12D (200 mg) and 2-chloroacetonitrile in 4M hydrochloric acid in dioxane (4 mL) was heated at 65° C. for 18 hours. The mixture was cooled, filtered and the solid heated in N,N-dimethylformamide (6 mL) at 100° C. for 2 hours. The solution was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to provide 145 mg of the title compound as a white solid. 1H NMR (DMSO-d6) δ 12.85 (bs, 1H), 7.55 (m, 1H), 7.31-7.38 (m, 3H), 4.60 (s, 2H), 3.01 (t, J=7.3 Hz, 2H), 2.93-2.96 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@@H:10]([OH:13])[CH2:11][OH:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23].C(N(CC)CC)C.CCCCCCC>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C@@H:10]([OH:13])[CH2:11][O:12][S:22]([CH3:21])(=[O:24])=[O:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)COS(C)(=O)=O
Reaction time: 1 h
Yield: 106.8 %

Procedure:
To a solution of N-tert-butoxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenyl-1-butanol 65.42 g(Net.63.38 g)dissolved in ethyl acetate 320 ml were added isopropyleter 320 ml, and then methane sulfonylchloride 28.3 g under ice-cooling, and triethylamine 25.0 g, successively, and the solution was stirred for 1 hr. N-heptane was added to the reaction solution and the solution was stirred for further 1 hr to deposit crystals, which were filtered and dried in vacuum to obtain the crude N-tert-butoxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenyl-1-methane sulfonyloxybutane 89.3 g (Net.55.7 g). The crude crystals. A ratio of main components in the crude crystals, which contain triethylamine hydrochloride, is the diol derivative compound: the 2-sulfonate derivative: the 1-sulfonate derivtive(the object product): the 1,2-disulfonate compound=1.3:0.1:95.4:3.2. A part of the crude crystal was dissolved in ethyl acetate, washed with water, and purified by recrystallization from ethyl acetate and isopropyl ether. The purified recrystals were used for anlysyses.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@H:5]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:6]([OH:8])=[O:7].[C:17]1(=O)[O:22][C:20](=[O:21])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12>CN(C=O)C>[C:13]([O:12][C:10]([NH:9][C@@H:5]([CH2:4][CH2:3][CH2:2][N:1]1[C:20](=[O:21])[C:19]2[C:18](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17]1=[O:22])[C:6]([OH:8])=[O:7])=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN)C(=O)O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCCN1C(=O)c2ccccc2C1=O)C(=O)O
Temperature: 120 °C

Procedure:
To a solution of (S)-5-amino-2-(tert-butoxycarbonylamino)pentanoic acid XLIX (6.64 g, 28.6 mmol) in DMF (150 mL) was added phthalic anhydride (4.3 g, 29.0 mmol). The mixture was placed in a tightly closed ampule and heated at 120° C. for 24 h. After the reaction was complete, the solvent was evaporated under vacuum and the residue was subjected to column chromatography on silica gel (100:1 DCM:MeOH→10:1 DCM:MeOH) affording (S)-2-(tert-butoxycarbonylamino)-5-(1,3-dioxoisoindolin-2-yl)pentanoic acid L (8.92 g, 24.6 mmol, 86%). ESIMS found for C18H22N2O6 m/z 361 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][CH2:13][CH2:14][CH2:15]O)[C:3]=1[NH:17][C:18](=S)[NH:19][C:20]1[C:25]([Br:26])=[CH:24][C:23]([O:27][CH3:28])=[CH:22][C:21]=1[Br:29].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C.CN(C)C=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]2[C:3]=1[N:17]=[C:18]1[N:19]([C:20]3[C:21]([Br:29])=[CH:22][C:23]([O:27][CH3:28])=[CH:24][C:25]=3[Br:26])[CH2:15][CH2:14][CH2:13][N:12]21
Reactant: COC(=O)c1ccc(Cl)c(NC(=S)Nc2c(Br)cc(OC)cc2Br)c1NCCCO
Agent: CCN=C=NCCCN(C)C
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Br)cc(OC)cc1Br
Temperature: 50 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
A mixture of methyl 4-chloro-3-{[(2,6-dibromo-4-methoxyphenyl)carbamothioyl]amino}-2-[(3-hydroxypropyl)amino]benzoate (560 mg, 0.963 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (203 mg, 1.06 mmol) and triethylamine (0.148 mL, 1.06 mmol) in tetrahydrofuran (10 mL) was stirred at 50° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. To a mixture of residue and triethylamine (0.671 mL, 4.81 mmol) in tetrahydrofuran (10 mL) was added methanesulfonyl chloride (0.304 mL, 3.85 mmol) at 0° C. The resultant mixture was stirred at room temperature for 1 h and concentrated in vacuo. After N,N-dimethylformamide (10 mL) and potassium carbonate (1.33 g, 9.62 mmol) were added to the residue, the resultant mixture was stirred at 80° C. for 4 h, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 30-60% ethyl acetate/n-hexane gradient mixture to give the title compound as a brown solid (466 mg, 0.881 mmol, 91%).
Reaction SMILES: [CH2:1]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:21]1([CH2:25][N:26]2[CH2:44][CH2:43][C@@:33]34[C:34]5[CH:35]=[C:36]([O:41][CH3:42])[CH:37]=[CH:38][C:39]=5[CH2:40][C@@H:27]2[C@@H:28]3[C@@H:29]([CH3:46])[CH2:30][C:31](=O)[CH2:32]4)[CH2:24][CH2:23][CH2:22]1.[ClH:47]>CS(C)=O>[ClH:47].[CH:21]1([CH2:25][N:26]2[CH2:44][CH2:43][C@@:33]34[C:34]5[CH:35]=[C:36]([O:41][CH3:42])[CH:37]=[CH:38][C:39]=5[CH2:40][C@@H:27]2[C@@H:28]3[C@@H:29]([CH3:46])[CH2:30][C:31](=[CH2:1])[CH2:32]4)[CH2:22][CH2:23][CH2:24]1
Reactant: COc1ccc2c(c1)[C@]13CCN(CC4CCC4)[C@H](C2)[C@@H]1[C@@H](C)CC(=O)C3
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CS(C)=O
Product: C=C1C[C@H](C)[C@H]2[C@H]3Cc4ccc(OC)cc4[C@@]2(CCN3CC2CCC2)C1
Yield: 37 %

Procedure:
To a solution of methylenetriphenylphosphorane (14.4 mmole) in dimethyl sulfoxide (30 ml) prepared in the usual fashion was added a solution of 17-cyclobutylmethyl-3-methoxy-8β-methyl-morphinan-6-one. The reaction was heated at 75° for 2 hours under an atmosphere of nitrogen. Workup followed by chromatography gave the free base of TR-5377 as a foam. This was converted to the HCl salt which was crystallized from toluene to give 860 mg (37%) of TR-5377, mp. 221°-224°.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1.C(N(CC)CC)C.ClCCl>C1(C)C(C)=CC=CC=1>[N:6]1[CH:7]=[CH:8][C:3]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:5]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1ccncc1
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(c2ccncc2)CC1

Procedure:
4.0 g (26.6 mmol) of 4-chloropyridine hydrochloride, 4.2 g (26.6 mmol) of ethyl piperidine-4-carboxylate and 7.4 ml (53.2 mmol) of triethylamine were stirred in 100 ml of xylene at 130° C. for 24 hours. After the treatment with dichloromethane as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23](B(O)O)[CH:22]=1>>[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:2]2[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]3[CH:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[N:16]4)=[CH:11][CH:10]=3)=[O:7])=[CH:4][CH:3]=2)[CH:22]=1
Reactant: O=C(Nc1ccc2cccnc2c1)c1ccc(Br)cc1
Reactant: OB(O)c1cccnc1
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(-c2cccnc2)cc1

Procedure:
Using the procedure outlined in Example 58, the title compound was prepared from 4-bromo-N-quinolin-7-ylbenzamide (Example 82) (50 mg, 0.15 mmol) and 3-pyridylboronic acid (20 mg, 0.16 mmol) as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.89 (d, 1H), 8.87 (dd, 1H), 8.65 (m, 1H), 8.26 (dd, 1H), 8.17 (dd, 1H), 8.14 (d, 1H), 8.09 (d, 2H), 7.96 (m, 1H), 7.88 (d, 1H), 7.74 (d, 2H), 7.45 (dd, 1H), 7.38 (dd, 1H).
Reaction SMILES: [O:1]1[C:5]2([CH2:9][CH2:8][NH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH:10]12[O:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15]2>O>[O:1]1[C:5]2([CH2:9][CH2:8][N:7]([C@H:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]3[OH:16])[CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C1CCC2OC2C1
Reactant: C1CC2(CN1)OCCO2
Solvent: O
Product: O[C@H]1CCCC[C@@H]1N1CCC2(C1)OCCO2
Temperature: 80 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
A mixture of 1,4-dioxa-7-azaspiro[4.4]nonane (23.54 g, step iv, no more than 182 mmol), cyclohexene oxide (22.6 mL, 98%, 219 mmol) and water (7.8 mL) was heated at 80° C. for 2 hours. The reaction mixture was then partitioned between 40% sodium hydroxide aqueous solution (60 mL) and diethyl ether (120 mL). The basic aqueous layer was extracted twice more with diethyl ether (2×120 mL). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. The residue was then pumped under high vacuum at 50° C. for 1 hour under stirring (to remove the excess of cyclohexene oxide) to yield 32.79 g of the crude title compound (yield 79.3%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][CH:39]=[N:40][CH:41]=2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:17])[CH3:18])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:42])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[N:40][CH:39]=[N:38][CH:37]=2)[CH:31]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cncnc2)c1
Product: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cncnc3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-isobutylamino-phenyl)-carbamic acid tert-butyl ester (Example J16) (235 mg, 0.75 mmol) and 3-oxo-3-(3-pyrimidin-5-yl-phenyl)-propionic acid tert-butyl ester (Example K13) (224 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white foam (260 mg, 64%).