Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[N:11]=[C:12]=[O:13].[CH2:14]([OH:20])[C:15]1[O:19][CH:18]=[CH:17][CH:16]=1>C1C=CC=CC=1>[C:2]1([CH3:1])[C:3]([NH:11][C:12]([O:20][CH2:14][C:15]2[O:19][CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:4][C:5]([NH:8][C:9]([O:20][CH2:14][C:15]2[O:19][CH:18]=[CH:17][CH:16]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: OCc1ccco1
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Solvent: c1ccccc1
Product: Cc1ccc(NC(=O)OCc2ccco2)cc1NC(=O)OCc1ccco1
Reaction time: 8 h

Procedure:
To a solution of 522 g. (3 moles) of 2,4-toluenediisocyanate in 500 ml. of benzene under a nitrogen atmosphere is added a solution of 588 g. (6 moles) of furfuryl alcohol in 500 ml. of benzene at such a rate as to maintain the temperature below 50°C. The reaction is completed by refluxing for 3 hours (about 80°-90°C.) The reaction mixture is allowed to stand at room temperature overnight, during which time the product diurethane crystallizes. The material is collected by filtration, dried, and pulverized. The yield is 916 g of material (82.5% of theoretical) having a melting point of 154°-156°C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([F:11])[CH:7]=[CH:8][CH:9]=2)[C:4]([S:12](Cl)(=[O:14])=[O:13])=[N:3]1.[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17].O>C1COCC1>[C:16]([NH:20][S:12]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[F:11])[N:2]([CH3:1])[N:3]=1)(=[O:14])=[O:13])([CH3:19])([CH3:18])[CH3:17]
Reactant: Cn1nc(S(=O)(=O)Cl)c2c(F)cccc21
Reactant: CC(C)(C)N
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc(S(=O)(=O)NC(C)(C)C)c2c(F)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
Further, 13.9 g (56 mmol) of 1-methyl-4-fluoro-1H-indazole-3-sulfonylchloride in 50 ml of THF, was added to 12.9 g (177 mmol) of t-butylamine in 100 ml of THF, and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was poured into a large excess amount of water, whereupon the crystals were collected by filtration and dried in air to obtain 15.9 g (yield: 99.6%) of 3-(N-t-butylsulfamoyl)-1-methyl-4-fluoro-1H-indazole (compound represented by the formula [I-d]) (slightly purple crystals).
Reaction SMILES: FC(F)(F)C([NH:5][CH2:6][CH2:7][CH:8]([C:10]1[CH:15]=[C:14](/[CH:16]=[CH:17]/[C:18]2([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:13]=[CH:12][C:11]=1[F:25])[OH:9])=O.Cl>>[NH2:5][CH2:6][CH2:7][CH:8]([C:10]1[CH:15]=[C:14]([CH:13]=[CH:12][C:11]=1[F:25])/[CH:16]=[CH:17]/[C:18]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[OH:9]
Reactant: O=C(NCCC(O)c1cc(/C=C/C2(O)CCCCC2)ccc1F)C(F)(F)F
Agent: Cl
Product: NCCC(O)c1cc(/C=C/C2(O)CCCCC2)ccc1F

Procedure:
Deprotection of (E)-2,2,2-trifluoro-N-(3-(2-fluoro-5-(2-(1-hydroxycyclohexyl)vinyl)phenyl)-3-hydroxypropyl)acetamide followed by HCL salt formation following the methods used in Example 123 gave. Example 128 hydrochloride as a light color solid. Yield (0.08 g, 49%): 1H NMR (400 MHz, MeOD) δ 7.59 (dd, J=6.4, 2.4 Hz, 1H), 7.32-7.36 (m, 1H), 6.99 (dd, J=10.4, 8.8 Hz, 1H), 6.74 (d, J=16.0 Hz, 1H), 6.43 (d, J=16.4 Hz, 1H), 5.89 (t, J=2.4 Hz, 1H), 5.11 (dd, J=8.4, 4.4 Hz, 1H), 3.02-3.16 (m, 2H), 2.14-2.38 (m, 4H), 1.95-2.08 (m, 3H), 1.54-1.78 (m, 5H).
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[CH3:5][C:6]1([CH3:21])[CH2:15][CH2:14][CH2:13][C:12]2[CH:11]=[C:10]([O:16][CH2:17][C@@H:18]3[CH2:20][O:19]3)[CH:9]=[CH:8][C:7]1=2>CO>[CH3:21][C:6]1([CH3:5])[CH2:15][CH2:14][CH2:13][C:12]2[CH:11]=[C:10]([O:16][CH2:17][CH:18]3[O:19][C:2]([NH2:3])=[N:1][CH2:20]3)[CH:9]=[CH:8][C:7]1=2
Reactant: CC1(C)CCCc2cc(OC[C@@H]3CO3)ccc21
Reactant: N#CN
Agent: [Na]
Solvent: CO
Product: CC1(C)CCCc2cc(OCC3CN=C(N)O3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
To a vigorously stirred solution of sodium hydrogen cyanamide (0.52 g, 7.9 mmol) in methanol (20 mL) was added slowly (S)-2-(5,5-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yloxymethyl)-oxirane (1.8 g, 7.9 mmol). The reaction mixture was stirred at room temperature overnight after which it was concentrated. Anhydrous diethyl ether (100 mL) was added. The resulting white precipitate was filtered and the filtrate concentrated. The residue was purified by flash chromatography (silica, 7N NH3 in methanol/methylene chloride) to give 1.0 g (46%) of 5-(5,5-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yloxymethyl)-4,5-dihydro-oxazol-2-ylamine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8]([C:10]2([OH:21])[CH2:16][CH2:15][C:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=3[CH2:12][CH2:11]2)=[O:9])[CH:7]=1.[H-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:21][C:10]3([CH2:16][CH2:15][C:14]4[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=4[CH2:12][CH2:11]3)[C:8](=[O:9])[C:6]=2[CH:7]=1
Reactant: O=C(c1cc(Br)ccc1F)C1(O)CCc2ccccc2CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1c2cc(Br)ccc2OC12CCc1ccccc1CC2
Temperature: 100 °C
Yield: 70.7 %

Procedure:
A mixture of (5-bromo-2-fluorophenyl)(7-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)methanone (1.3739 g, 3.78 mmol) and 60% NaH (0.5900 g, 14.75 mmol) in THF (20 mL) was heated at 100° C. for 1 h. The reaction mixture was then cooled with an ice bath and quenched with 2 N HCl (5 mL), extracted with ethyl acetate, dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to afford 0.9170 g (71%) of 5′-bromo-5,6,8,9-tetrahydro-3′H-spiro[benzo[7]annulene-7,2′-benzofuran]-3′-one as a solid. LC-MS tR=2.31 min in 3 min chromatography, m/z 343, 345 (MH+); 1H NMR (400 MHz, CDCl3) δ 7.79-7.78 (m, 1H), 7.73-7.71 (m, 1H), 7.17 (m, 4H), 7.11-7.09 (m, 1H), 3.41-3.35 (m, 2H), 2.78-2.75 (m, 2H), 1.95-1.85 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 201.53, 169.46, 141.50, 140.56, 128.93, 127.47, 126.62, 121.63, 115.61, 114.15, 92.58, 32.98, 29.67.
Reaction SMILES: C(OC(=O)C1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[N:7][CH:6]=1)C.C[Mg]Cl.Cl.[Cl-].[Na+].C[O:23][C:24]([CH3:27])([CH3:26])[CH3:25]>O.O1CCCC1>[F:12][C:11]([F:14])([F:13])[C:8]1[N:7]=[CH:6][C:25]([C:24]([OH:23])([CH3:27])[CH3:26])=[CH:10][CH:9]=1
Reactant: COC(C)(C)C
Reactant: CCOC(=O)c1ccc(C(F)(F)F)nc1
Agent: C[Mg]Cl
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(C(F)(F)F)nc1
Temperature: 8.5 °C

Procedure:
Cool the contents of an inerted reaction vessel containing technical grade 6-trifluoromethyl-nicotinic acid ethyl ester (45.6 moles; 10.00 kg) and tert-butyl methyl ether (71.6 L; 53.0 kg) to 10-15° C., and add the solution into a separate inerted reaction vessel cooled to 5-12° C. containing 3 M methylmagnesium chloride (136.8 moles; 45.6 L; 46.2 kg) and tetrahydrofuran (76.5 L; 68.0 kg). Observe a moderate exotherm during the addition, and maintain the internal reaction temperature between 15-25° C. Confirm that the starting ester is completely consumed by HPLC, and cool the reactor contents to 0-3° C. Add the contents from the reaction vessel slowly to a separate reactor cooled to 0-5° C. containing hydrochloric acid (203 moles; 16.67 L; 20.0 kg) and water (81.0 L, 81.0 kg), and observe gas evolution. Separate the layers and extract the aqueous phase once with tert-butyl methyl ether (59.5 L; 44.0 kg). Combine the organic layers and wash with a 20% sodium chloride solution (189.3 moles; 46.5 L; 55.3 kg). Filter the organic solution, concentrate to approximately 1 volume, and dilute with acetonitrile (31.8 L; 25.0 kg). Concentrate the solution to approximately 1 volume to provide the titled compound as a technical grade oil (7.9 kg; 84.4%, based on HPLC) in acetonitrile. Use the crude material as a solution in acetonitrile without further purification. A pure sample of the product can be obtained by following the procedure given below.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[NH2:8].[CH:10]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11]1>O>[Cl:9][C:6]1[C:7]([NH2:8])=[C:2]([NH:15][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:3]=[N:4][CH:5]=1
Reactant: NC1CCCC1
Reactant: Nc1c(Cl)cnnc1Cl
Solvent: O
Product: Nc1c(Cl)cnnc1NC1CCCC1
Temperature: 150 °C
Yield: 90 %

Procedure:
3,5-Dichloropyridazin-4-amine (Preparation 4, 1 g, 6.09 mmol) was added to cyclopentylamine (3.0 mL, 30.41 mmol) and water (1 mL) in a stainless steel sealed container. The mixture was heated for 16 hours at 150° C. The reaction mixture was cooled to room temperature then evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc to afford the title compound as yellow solid in 90% yield, 1.17 g.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH2:15]([NH2:18])[CH2:16][NH2:17]>>[NH2:17][CH2:16][CH2:15][NH:18][C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)nc1
Reactant: NCCN
Product: CC(C)(C)OC(=O)c1ccc(NCCN)nc1

Procedure:
The tert-butyl 6-chloropyridine-3-carboxylate was heated with ethylenediamine (20 ml) at 80° C. overnight. The solvent was removed in vacuo. The residue was partitioned between dichloromethane and 2.5 M aqueous sodium hydroxide solution. The aqueous layer was extracted a further three times with dichloromethane. The combined organic layers were washed with water, dried and concentrated in vacuo to give tert-butyl 6-[(2-aminoethyl)amino]pyridine-3-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[C:20]2[CH:21]=[CH:22][N:23]=[C:24]([O:25]CC)[C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[N:16][CH:17]=2)[N:12]=1.[NH:28]1[C:32](B(O)O)=[CH:31][CH:30]=[N:29]1.C([O-])(O)=O.[Na+].B(Br)(Br)Br>C(Cl)(Cl)Cl.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>[Cl:9][C:4]1[CH:5]=[C:6]([C:30]2[NH:29][N:28]=[CH:32][CH:31]=2)[CH:7]=[C:2]([Cl:1])[C:3]=1[NH:10][C:11]1[C:20]2[CH:21]=[CH:22][NH:23][C:24](=[O:25])[C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[N:16][CH:17]=2)[N:12]=1
Reactant: CCOc1nccc2c(Nc3c(Cl)cc(I)cc3Cl)nc3ccncc3c12
Reactant: OB(O)c1ccn[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Product: O=c1[nH]ccc2c(Nc3c(Cl)cc(-c4ccn[nH]4)cc3Cl)nc3ccncc3c12
Temperature: 80 °C

Procedure:
To a solution of N-(2,6-dichloro-4-iodophenyl)-10-ethoxypyrido[4,3-c]-1,6-naphthyridin-6-amine (200 mg, 0.40 mmol) were added 1H-pyrazol-5-ylboronic acid (48 mg, 0.43 mmol) 2.0 M solution of NaHCO3 (1 mL) and tetrakis(triphenylphosphine)palladium (0) (90 mg, 0.78 mmol) and the mixture was heated to 80° C. for 4 hr. After cooling to room temperature, the reaction mixture was extracted with EtOAc and water. Column chromatography (100% Hex to 100% EtOAc) afforded the cross-coupled product. This purified material (79 mg) was taken up in chloroform (5 mL) followed by the addition of BBr3 (1.40 mL, 1M in CH2Cl2) and heated to 85° C. for 1 hr. The solution was cooled to room temperature, extracted with 3:1 CHCl3/IPrOH and washed with saturated NaHCO3. The organic layers were dried with MgSO4, filtered, and concentrated under reduced pressure. Purification by column chromatography (100% CH2Cl2 to 35% MeOH/65% CH2Cl2) afforded the title compound as a mixture of rotamers.
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)[CH2:3][CH2:2]1.I(O)(=O)(=O)=[O:15].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.[Fe](Cl)(Cl)Cl>[CH:1]1([S:4]([C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=2)=[O:15])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(SC2CC2)cc1
Reactant: [O-][I+3]([O-])([O-])O
Agent: Cl[Fe](Cl)Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(S(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76 %

Procedure:
179 mg (1.11 mmol) of iron(III) chloride was added to a mixture of 7.2 g (36.88 mmol) of 1-cyclopropylsulfanyl-4-nitrobenzene in 140 ml acetonitrile and it was stirred for 15 minutes at room temperature. Then 9.25 g (40.57 mmol) of periodic acid was added in portions at 25° C. The mixture was stirred for 30 minutes and then added, while stirring, to a cooled saturated sodium thiosulfate solution. It was then extracted with ethyl acetate (2×). The combined organic phases were dried (Na2SO4), filtered and concentrated by evaporation. The residue obtained was purified chromatographically (hexane/ethyl acetate 1:1). 5.93 g (28.07 mmol; yield: 76%) of the product was obtained.
Reaction SMILES: [NH2:1][C@@H:2]([C:22](=[O:24])[NH2:23])[CH2:3][CH2:4][C:5]([NH:7][C@@H:8]([C:19]([OH:21])=[O:20])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)=[O:6].[OH-].[NH4+]>>[NH4+:1].[NH2:1][C@@H:2]([C:22](=[O:24])[NH2:23])[CH2:3][CH2:4][C:5]([NH:7][C@@H:8]([C:19]([O-:21])=[O:20])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)=[O:6]
Reactant: NC(=O)[C@H](N)CCC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: NC(=O)[C@H](N)CCC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)[O-]
Reaction time: 2 h

Procedure:
H-D-iGlu-D-Trp-OH (1 g from Example 3) was mixed with ammonium hydroxide (0.55M, 6 mL). The mixture was stirred and the pH was measured to be around 4.5. Ammonium hydroxide (0.55M) was added dropwise until the pH of the solution reached between 7.0 to 7.5. Volatile materials were removed in vacuo, and the residual oil was mixed with isopropanol. A white precipitate appeared. After 2 h, the solid ammonium salt was collected by suction filtration. The solid was dried to constant weight (1 g) under high vacuum for 12 h to give the D-isoglutamyl-D-tryptophan, ammonium salt (1:1). The water content as determined by the Karl-Fisher test was 4.6%.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:3][CH2:2]1.C[O:17]C1C=C2C(=CC=1)C=C([C@H](C)C(O)=O)C=C2>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:10]1([NH:9][C:8]([NH:7][CH:4]2[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]2)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DCC (0.56 g, 2.7 mmol) in CH2Cl2 (20 mL) was added dropwise to a stirred solution of the product of Example 13d (0.5 g, 2.45 mmol), (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (0.56 g, 2.45 mmol), and DMAP (0.05 g) in CH2C2 (20 mL) at room temperature. The resulting suspension was stirred for 1 hour at room temperature. The precipitate was removed by filtration and washed with CH2Cl2 (25 mL). The filtrate was concentrated to give a green oil which was chromatographed on silica gel eluting with 1:9 MeOH:CH2Cl2 to afford a green solid (contaminated with dicyclohexyl urea). The solid was triturated with hexane (50 mL) and filtered. The filtrate was concentrated to give the title compound (0.7 g, 69%) as a viscous green oil. 1H NMR (300 MHz, CDCl3) δ 7.50-7.65 (mult, 3H), 7.01-7.29 (mult, 3H), 4.18 (t, J=6.5 Hz, 2H), 3.83 (s, 3H), 3.72 (q, J=7.0 Hz, 1H), 2.51 (t, J=6.6 Hz, 2H), 2.13 (s, 3H), 2.00-2.60 (mult, 8H), 1.45 (d, J=7.2 Hz, 3H), 1.47 (d, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 174.4, 157.7, 135.4, 133.7, 129.2, 128.9, 127.2, 126.1, 126.0, 119.0, 105.6, 61.1, 57.6, 55.3, 51.4, 51.3, 46.0, 45.4, 40.8, 36.5, 36.4, 18.2; mass spectrum (API-TIS) m/z 415 (M+H).
Reaction SMILES: B(Br)(Br)Br.[C:5]([CH2:8][CH:9]1[C:15]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=2[N:13]([C:21](=[O:40])[C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])=[CH:24][C:23]=2[O:38]C)[CH2:12][CH2:11][CH2:10]1)([OH:7])=[O:6].O>ClCCl>[C:5]([CH2:8][CH:9]1[C:15]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=2[N:13]([C:21](=[O:40])[C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])=[CH:24][C:23]=2[OH:38])[CH2:12][CH2:11][CH2:10]1)([OH:7])=[O:6]
Reactant: COc1cc(NC(=O)c2ccccc2Cl)ccc1C(=O)N1CCCC(CC(=O)O)c2cc(Cl)ccc21
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(O)CC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3Cl)cc2O)c2ccc(Cl)cc21
Reaction time: 8 h
Yield: 93.3 %

Procedure:
9.1 ml of 98% boron tribromide was dropwise added, at -10° C. with stirring, to a solution of 10 g of 5-carboxymethyl-7-chloro-1-[2-methoxy-4-(2-chlorobenzoyl-amino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine dissolved in 400 ml of dichloromethane. The mixture was slowly returned to room temperature and stirred overnight at the same temperature. The reaction mixture was mixed with water, followed by extraction with dichloromethane. The extract was water-washed, then dried over anhydrous magnesium sulfate, and subjected to vacuum distillation to remove the solvent. The residue was purified by silica gel column chromatography to obtain 9.08 g of 5-carboxymethyl-7-chloro-1-[2-hydroxy-4-(2-chlorobenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzoazepine.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@H:14]([CH3:15])[CH2:13][N:12]([C:16]2[C:21]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]4[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=4[F:39])[N:26]=3)=[O:24])=[CH:20][N:19]=[C:18]3[O:40][CH2:41][CH2:42][C:17]=23)[CH2:11][C@H:10]1[NH:43]C(=O)OC(C)(C)C)(C(C)(C)C)(C)C.[H+].[H+].F[Si-2](F)(F)(F)(F)F.O.[NH4+].[OH-]>CC#N>[NH2:43][C@H:10]1[C@H:9]([OH:8])[C@@H:14]([CH3:15])[CH2:13][N:12]([C:16]2[C:21]([NH:22][C:23]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]4[C:33]([F:39])=[CH:34][CH:35]=[CH:36][C:37]=4[F:38])[N:26]=3)=[O:24])=[CH:20][N:19]=[C:18]3[O:40][CH2:41][CH2:42][C:17]=23)[CH2:11]1
Reactant: C[C@H]1CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [H+]
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: C[C@H]1CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCO3)C[C@@H](N)[C@@H]1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 16.1 %

Procedure:
To a solution of tert-butyl {(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-[5-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-2,3-dihydrofuro[2,3-b]pyridin-4-yl]-5-methylpiperidin-3-yl}carbamate (24.9 mg, 0.0349 mmol) in MeCN (2.0 mL) was added a 1.7 M dihydrogen hexafluorosilicate solution in water (200 μL, 0.340 mmol). The mixture was stirred at 50° C. for 2 h. After cooling to room temperature, the reaction mixture was neutralized with a 14.8 M NH4OH solution in water (200 μL, 2.96 mmol), and was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (2.8 mg, 16%). LCMS calc. for C25H25F3N5O3 (M+H)+: m/z=500.2. found 500.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:16][C:15]1[CH:17]=[CH:18][CH:19]=[C:13]([C:12]([F:11])([F:20])[F:21])[CH:14]=1)=[O:7]
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: Nc1cccc(C(F)(F)F)c1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccnc(Br)c1

Procedure:
In a manner similar to that described in Preparation 17, 2-bromoisonicotinic acid and 3-trifluoromethylaniline were converted to the title compound
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[CH2:16]([N:20]1[C:25]2[N:26]=[C:27]([CH:41]([CH3:43])[CH3:42])[C:28](/[CH:37]=[CH:38]/[CH:39]=[O:40])=[C:29]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:24]=2[C:23](=[O:44])[NH:22][C:21]1=[O:45])[CH2:17][CH2:18][CH3:19].C(O)(=O)C>O1CCCC1.CCCCCC.O>[CH2:16]([N:20]1[C:25]2[N:26]=[C:27]([CH:41]([CH3:42])[CH3:43])[C:28](/[CH:37]=[CH:38]/[CH:39]([OH:40])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6])=[C:29]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:24]=2[C:23](=[O:44])[NH:22][C:21]1=[O:45])[CH2:17][CH2:18][CH3:19]
Reactant: COC(=O)CC(C)=O
Reactant: CCCCn1c(=O)[nH]c(=O)c2c(-c3ccc(F)cc3)c(/C=C/C=O)c(C(C)C)nc21
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCn1c(=O)[nH]c(=O)c2c(-c3ccc(F)cc3)c(/C=C/C(O)CC(=O)CC(=O)OC)c(C(C)C)nc21
Reaction time: 0.25 h

Procedure:
0.7 g (6 mmol) of methyl acetoacetate are added dropwise at 0°-5° C. to a suspension of 0.2 g (6.6 mmol) of 80% strength sodium hydride in 8 ml of anhydrous tetrahydrofuran. After 15 min, 4.9 ml (8 mmol) of 15% strength butyllithium in hexane are added dropwise in the course of 10 min and the mixture is kept at 0° C. for a further 15 min. 0.82 g (2 mmol) of the compound from Example 6 and 10 ml of tetrahydrofuran are then added and the mixture is stirred at 0°-5° C. for 1 h. 1.2 g (20 mmol) of acetic acid in 20 ml of water are then added cautiously, the mixture is extracted three times with ethyl acetate, and the organic phase is washed with sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. The residue is chromatographed on 40 g of 230-400 mesh silica gel (φ 3 cm) using petroleum/ethyl acetate (2:1) to (1:3).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:12])=[C:8]([CH:11]=1)[CH:9]=O)([O-:3])=[O:2].Cl.[NH2:14][CH2:15][CH2:16][SH:17].C([BH3-])#N.[Na+].C(O)(=O)C>CO>[ClH:12].[Cl:12][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]=1[CH2:9][NH:14][CH2:15][CH2:16][SH:17]
Reactant: NCCS
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(Cl)c(CNCCS)c1
Reaction time: 24 h
Yield: 78.8 %

Procedure:
T a slurry of 5-nitro-2-chloro-benzaldehyde (1.5 g, 0.0078 mol), 2-aminoethanethiol hydrochloride (2.73 g, 0.023 mol), sodium cyanoborohydride (0.49 g, 0.0078 mol) in anhydrous methanol (30 mL) was added acetic acid (5 mL) and stirred 24 hrs. The mixture was evaporated and the residue triturated with isopropanol giving 2-(2-chloro-5-nitro-benzylamino)-ethanethiol hydrochloride (0.87 g, 45%) as a white solid. MP: 228-231° C.; 1H-NMR (DMSO-d6) δ 9.76-82 (br, 2H), 8.75 (s, 1H), 8.28-31 (d, 1H), 7.85-90 (d, 1H), 4.40 (s, 2H), 3.15-25 (m, 2H), 2.80-90 (m, 2H); LC/MS (ESI+): 247 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13](Cl)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[NH2:25][C:26]1[CH:27]=[C:28]([NH:32][C:33](=[O:36])[CH:34]=[CH2:35])[CH:29]=[CH:30][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]=[CH:11][N:12]=[C:13]([NH:25][C:26]3[CH:27]=[C:28]([NH:32][C:33](=[O:36])[CH:34]=[CH2:35])[CH:29]=[CH:30][CH:31]=3)[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)Nc1cccc(N)c1
Reactant: Clc1cccc(Nc2ncnc(Cl)n2)c1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cccc(Nc2ncnc(Nc3cccc(Cl)c3)n2)c1
Temperature: 100 °C

Procedure:
To a slurry of (3-chlorophenyl)-(4-chloro-[1,3,5]triazin-2-yl)amine (Step 1) (80.0 mg, 0.332 mmol) in IpOH (2.5 ml) was added DIEA (0.087 mL, 0.50 mmol) and N-(3-aminophenyl)acrylamide (59.2 mg, 0.365 mmol). The mix was heated at 100° C. for 18 h. The solution was then cooled to RT. A precipitate fell out of solution, was filtered off and dried under reduced pressure to give N-{3-[4-(3-chlorophenylamino)-[1,3,5]triazin-2-ylamino]-phenyl}-acrylamide: MS m/z=367[M+H]. Calc'd for C18H15ClN6O: 366.10.