Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([C:16](O)=[O:17])=[CH:14][N:13]=[C:12]2[N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[N:20]=[CH:21][C:11]=12.[CH:31]([O:33][CH2:34][CH2:35][O:36][NH2:37])=[CH2:32].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:31]([O:33][CH2:34][CH2:35][O:36][NH:37][C:16]([C:15]1[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[C:11]2[CH:21]=[N:20][N:19]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[C:12]2=[N:13][CH:14]=1)=[O:17])=[CH2:32]
Reactant: C=COCCON
Reactant: COc1ccc(Cn2ncc3c(Nc4ccc(I)cc4F)c(C(=O)O)cnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
4-(2-Fluoro-4-iodophenylamino)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (360 mg, 0.71 mmol), O-(2-vinyloxyethyl)-hydroxylamine (79 mg, 0.77 mmol), HOBt (103 mg, 0.77 mmol), EDCI (147 mg, 0.77 mmol) and DIPEA (130 μL, 0.77 mmol) were dissolved in DMF (10 mL). The reaction mixture was stirred at room temperature for 16 hours then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—SPE, gradient 0-100% ethyl acetate in cyclohexane) to yield the title compound as a yellow solid (346 mg, 81%). LCMS (Method B): RT=4.08 min, [M+H]+=604.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([OH:22])=[O:21]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20]([OH:22])=[O:21])=[O:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Product: CC(C)(C)OC(=O)NCCCCC(=O)Nc1cccc(C(=O)O)c1

Procedure:
5-[1-(t-Butoxy)formamido]valeric acid is coupled with m-aminobenzoic acid to give m-[5-(1-t-butoxyformamido)valeramido]benzoic acid, m.p. 188° C., and the latter is reacted with 3-amino-3-phenylpropionic acid benzyl ester p-toluenesulphonate to give DL-N-[m-[5-(1-t-butoxyformamido)valeramido]benzoyl]-3-phenyl-β-alanine benzyl ester, MS: 574 (17, M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2.[I:18]I>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[I:18]
Reactant: Fc1cccc(Cl)c1-c1ccc2[nH]ccc2c1
Reactant: II
Product: Fc1cccc(Cl)c1-c1ccc2[nH]cc(I)c2c1
Yield: 103.2 %

Procedure:
This title compound was prepared analogously to compound 25c using 5-(2-chloro-6-fluorophenyl)-1H-indole (15 g, 0.06 mol) and I2 (17.1 g, 0.15 mol) to obtain the crude title compound (23 g). MS (ESI, m/z): 370.8 (M+1).
Reaction SMILES: [Na].[N+:2]([O-:5])([O-:4])=[O:3].[Rh:6]>[Pt].[Pd].[Ru].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Ru](Cl)(Cl)Cl>[N+:2]([O-:5])([O-:4])=[O:3].[Rh+3:6].[N+:2]([O-:5])([O-:4])=[O:3].[N+:2]([O-:5])([O-:4])=[O:3]
Reactant: [Rh]
Agent: Cl[Ru](Cl)Cl
Agent: [Pd+2]
Agent: [Pd]
Product: [Rh+3]

Procedure:
The zeolites were prepared as described in Example 2. The precious metal was added as follows. Sodium ZSM-5 (Si/Al=14) was slurried in about 0.01M solutions of the precious metal compounds of platinum, palladium and ruthenium proportioned to achieve 1% loadings. The compounds utilized for these exchanges were tetraamineplatinium nitrate, palladium(II) acetate and ruthenium(III) chloride. The rhodium loaded ZSM-5 was prepared by slurrying in an approximately 0.033M solution proportioned to give a 4% weight loading of rhodium(III) nitrate. Each was stirred at least 18 hours then filtered and calcined at 450° C. for 3 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH2:9][CH2:10][CH:11]=[O:12])[CH:3]=1.[BH4-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH2:9][CH2:10][CH2:11][OH:12])[CH:3]=1
Reactant: Cc1ccc(Cl)cc1CCC=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(Cl)cc1CCCO

Procedure:
To a solution of 4-chloro-2-(3-oxopropyl)toluene in MeOH was added excess NaBH4 at room temperature and the mixture was diluted with water, treated with 1N HCl, and extracted with AcOEt. The extracts was dried and concentrated to give quantitatively the title compound: 1H NMR (CDCl3) δ7.14 (bd, 1H, J=9 Hz), 7.06 (d, 1H, J=9 Hz), 7.05 (bs, 1H), 3.66~3.77 (m, 2H), 2.68 (t, 2H, J=7.2 Hz), 2.30 (s, 3H), 1.83 (5et, 2H, J=7.2 Hz), 1.35~1.44 (br, 1H).
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([C@@H:22]([F:24])[CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:25])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)(=O)C.CO.C(=O)([O-])[O-].[K+].[K+]>O>[F:24][C@H:22]1[CH2:23][C@@:6]2([CH3:7])[C@@H:8]([CH2:9][CH2:10][C@@H:5]2[OH:4])[C@H:11]2[C@H:21]1[C@:19]1([CH3:20])[C:14]([CH2:13][CH2:12]2)=[CH:15][C:16](=[O:25])[CH2:17][CH2:18]1
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](F)C[C@]12C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C[C@]12C[C@H](F)[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2O

Procedure:
1.2 g. of 17β-acetoxy-11β-fluoro-4-androsten-3-one is stirred in a mixture of 30 ml. of methanol and 5 ml. of water for 10 hours at room temperature with 1 g. of potassium carbonate. The reaction mixture is filtered off from the insoluble matter, the solution is neutralized with glacial acetic acid, concentrated under vacuum, the residue taken up in methylene chloride, and dried. After recrystallization from acetone/hexane, 800 mg. of 11β-fluoro-17β-hydroxy-4-androsten-3-one is obtained; m.p. 161°-162°. UV: ε239 = 16,600 (methanol).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([NH2:12])=[C:5]([C:7]([CH2:9][CH2:10][NH2:11])=[O:8])[CH:6]=1.[N+:13]([C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1F)([O-:15])=[O:14].C([O-])(O)=O.[Na+]>C(O)C>[NH2:12][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][C:5]=1[C:7]([CH:9]([C:17]1[CH:18]=[CH:19][C:20]([N+:22]([O-:24])=[O:23])=[CH:21][C:16]=1[N+:13]([O-:15])=[O:14])[CH2:10][NH2:11])=[O:8]
Reactant: NCCC(=O)c1ccccc1N
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: NCC(C(=O)c1ccccc1N)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 0.08 h
Yield: 63 %

Procedure:
Kynuramine 2HBr (125 mg) is dissolved in 5 cc of absolute ethanol in a 50 cc flask. A solution of 2,4-dinitrofluorobenzene, 71 mg in EtOH 5 cc is then added (a clear yellow solution is formed). After five minutes, 2 cc of a 10% NaHCO3 solution are introduced drop-wise in the flask. The reaction is left at room temperature overnight. The following morning the formed light yellow precipitate is filtered, washed with water and ethanol and dried in UHV obtaining 80 mg of product (approx. yield 63%).
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[CH:21]1([Mg]Cl)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.O>O1CCCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH:21]1([C:2]2[C:3](=[O:20])[N:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[CH:7]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=c1c(Br)cc(-c2ccccn2)cn1-c1ccccc1
Reactant: Cl[Mg]C1CCCCC1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=c1c(C2CCCCC2)cc(-c2ccccn2)cn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
34 mg of 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one was dissolved in 10 ml of tetrahydrofuran, followed by adding 1 mg of [1,3-bis (diphenylphosphino)propane]nickel(II) chloride. Under stirring in nitrogen atmosphere, 0.1 ml of cyclohexyl magnesium chloride (2.0M ether solution) was added dropwise thereinto. The mixture was stirred at room temperature in nitrogen atmosphere for 1 hour, followed by heating under reflux for 72 hours. After cooling to room temperature, water was added thereto, followed by extracting with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (chloroform/methanol system), to give 5 mg of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.S(OC)(O[CH3:18])(=O)=O>[OH-].[K+].O>[CH3:18][O:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(-c2ccccc2)c1
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(-c2ccccc2)c1
Reaction time: 0.25 h

Procedure:
102 g of 3-hydroxy biphenyl are dissolved in a solution of 67.8 g of potassium hydroxide in 650 cc of water. 86.6 cc of dimethyl sulphate are added dropwise within 30 minutes while stirring, whereby the reaction mixture warms itself. The reaction mixture is then kept at 75° for a further 15 minutes. After 1 hour a further 33.6 g of potassium hydroxide in 45 cc of water are added dropwise, and subsequently 37.8 g of dimethyl sulphate are added dropwise at 65° within 15 minutes. The mixture is again kept at 75° for 1 hour. After cooling, the oily layer is separated and taken up in methylene chloride. Washing is effected once with 2 N sodium hydroxide and once with water. Extraction is again effected twice with methylene chloride. The organic phases are combined, dried over anhydrous sodium sulphate and concentrated. 3-methoxy biphenyl is obtained and is used for the next reaction step without purification.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([Br:7])[N:6]=1.[CH3:11]N(C)CCCN=C=NCC>CO>[CH3:11][O:9][C:8]([C:4]1[S:3][C:2]([Br:1])=[N:6][C:5]=1[Br:7])=[O:10]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1sc(Br)nc1Br
Solvent: CO
Product: COC(=O)c1sc(Br)nc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
A solution of 2,4-dibromo-thiazole-5-carboxylic acid (1.7 g, 5.92 mmol) in methanol (20 ml) was treated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (920 mg, 5.92 mmol). The mixture was stirred at ambient temperature overnight. The solvent was evaporated and water (30 ml) was added. The mixture was then extracted with 3×30 ml of EtOAc. The combined organics were washed with brine, dried with MgSO4 and concentrated in vacuo. The crude was purified by flash chromatography (0 to 5% EtOAc/Hexanes) to afford 2,4-Dibromo-thiazole-5-carboxylic acid methyl ester (1.4 g, 78%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 3.91 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)Cc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1cccc(N)c1
Yield: 105.9 %

Procedure:
A solution of 10.3 g (49 mmol) of ethyl 3-nitrophenylacetate in 120 ml of ethanol was hydrogenated over 1 g of 10% palladium on charcoal for 6 hours. The mixture was filtered and the filtrate evaporated to give 9.3 g (100%) of ethyl 3-aminophenylacetate as a yellow oil. [NMR spectrum (250 MHz) δ1.19(t) (3H), δ3.48(s) (2H), δ4.16(q) (2H), δ7.48(dd) (1H), δ7.62(d) (1H), δ8.12(m) (2H)].
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[CH:16]=3)[N:11]=2)=[CH:2]1.[OH-].[Na+].Cl>O1CCCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=3)[N:11]=2)=[CH:2]1
Reactant: COC(=O)c1ccc2nc(-c3coc4ccccc34)c(N(C)C(C)C)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1coc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.6 %

Procedure:
To a solution of methyl 2-(benzofuran-3-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (100 mg, 0.27 mmol) in tetrahydrofuran (20 mL) and water (1 mL) was added sodium hydroxide (105 mg, 2.62 mmol). After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 mL), the pH was adjusted to 6 with HCl (3N) and filtered to give 2-(benzofuran-3-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (35.7 mg, 37%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:23]#[CH:24])[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.Cl[C:26](=[N:48][OH:49])[C:27]1[CH:47]=[CH:46][C:30]([CH2:31][N:32]([CH:40]2CCOCC2)[C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[CH:29][CH:28]=1.C(N(CC)CC)C>C(Cl)Cl.O>[Br:1][C:2]1[N:3]=[C:4]([C:23]2[O:49][N:48]=[C:26]([C:27]3[CH:28]=[CH:29][C:30]([CH2:31][N:32]([C:33]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:39])[CH3:40])=[CH:46][CH:47]=3)[CH:24]=2)[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(Cl)=NO)cc1)C1CCOCC1
Reactant: C#Cc1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(Cc1ccc(-c2cc(-c3nc(Br)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)on2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 92 %

Procedure:
A suspension of tert-butyl N-(5-bromo-3-ethynylpyrazin-2-yl)-N-tert-butoxycarbonylcarbamate (Compound 4-iii) (1.59 kg, 3.99 mol) and tert-butyl 4-(chloro(hydroxyimino)methyl)benzyl(tetrahydro-2H-pyran-4-yl)carbamate (1.31 kg, 4.39 mol; 1.10 equiv.) in CH2Cl2 (12.7 L) is stirred at ambient temperature. Triethylamine (444 g, 611 mL, 4.39 mol) is added to the suspension and the reaction temperature is maintained between 20-30° C. for 20-48 h to ensure complete reaction. The reaction mixture is diluted with water (8 L) and thoroughly mixed, then the phases are separated. The organic phase is washed with water (8 L), dried (Na2SO4), and then concentrated until about 1 L of CH2Cl2 remains. The concentrate is diluted with heptane (3.2 L) and re-concentrated at 40° C./200 torr until no distillate is observed. The concentrate is stirred and further diluted with heptane (12.7 L) to precipitate a solid. The suspension is stirred overnight. The solid is collected by filtration, washed with heptane (2×3 L) then dried to afford Compound 4-iv (2.42 kg; 92% yield, 100 area % purity by HPLC) as a light tan powder. 1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 7.82 (d, J=8.2 Hz, 2H), 7.31 (m, 3H), 4.46 (br s, 2H), 2.84 (br d, 3H), 1.57 (s, 2H), 1.44 (br s, 9H), 1.36 (s, 18H).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH2:13][N:12]([C:25](=[O:40])[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:11]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[CH2:13][N:12]([C:25](=[O:40])[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:11]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CN(C(=O)CCCCC(=O)OCc2ccccc2)C[C@@H]1c1cccc(C(F)(F)F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(CCCCC(=O)N1C[C@H](CO)[C@@H](c2cccc(C(F)(F)F)c2)C1)OCc1ccccc1

Procedure:
Benzyl 6-{(3R,4S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-[3-(trifluoromethyl)phenyl]pyrrolidin-1-yl}-6-oxohexanoate was dissolved in THF, mixed with a THF solution of TBAF at room temperature and stirred for 5Hours. Thereafter, work-up and purification were carried out in the standard method to obtain benzyl 6-{(3R,4S)-3-(hydroxymethyl)-4-[3-(trifluoromethyl)phenyl]pyrrolidin-1-yl}-6-oxohexanoate.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=1)\[CH2:4][C@H:5]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].Cl.[NH2:30][C@H:31]1[CH2:36][CH2:35][C@H:34]([C:37]([O:39][CH3:40])=[O:38])[CH2:33][CH2:32]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[CH3:40][O:39][C:37]([CH:34]1[CH2:33][CH2:32][CH:31]([NH:30][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([C@H:5]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[CH3:12])[CH2:4]/[C:3](=[N:2]\[OH:1])/[C:22]3[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=3)=[CH:14][CH:15]=2)[CH2:36][CH2:35]1)=[O:38]
Reactant: Cc1cc(/C(C[C@H](c2ccc(C(=O)O)cc2)c2ccccc2C)=N/O)ccn1
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: COC(=O)C1CCC(NC(=O)c2ccc([C@@H](C/C(=N\O)c3ccnc(C)c3)c3ccccc3C)cc2)CC1

Procedure:
In analogy to example 207, step 2, 4-[(R)-3-[(E)-hydroxyimino]-3-(2-methyl-pyridin-4-yl)-1-o-tolyl-propyl]-benzoic acid (example 272) was coupled with trans-methyl 4-amino-cyclohexanecarboxylate hydrochloride using benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as a light yellow viscous oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]([CH:13]3[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]3)=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.[Br:26]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1>[NH2:1][C:2]1[C:7]2=[C:8]([Br:26])[CH:9]=[C:10]([C:11]([CH:13]3[O:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]3)=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)c2ccc3c(N)ncnn23)C1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(C(=O)c2cc(Br)c3c(N)ncnn23)C1
Reaction time: 1 h

Procedure:
A solution of tert-butyl 2-[(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)carbonyl]morpholine-4-carboxylate (0.66 g, 1.90 mmol) in THF (5 mL) was cooled to −50° C. and stirred for 1 h before adding 1.3-dibromo-5,5-dimethylhydantoin (0.27 g, 0.94 mmol) in portions. The reaction was then quenched with satd. Na2SO3 solution. The product was extracted with EtOAc, dried (MgSO4) and concentrated. The crude solid was triturated with EtOAc and filtered. An off-white solid was isolated (530 mg, 65%). 1H-NMR (DMSO-d6) δ 8.10 (s, 1 H), 7.54 (s, 1 H), 5.05-4.95 (m, 1 H), 4.00-3.89 (m, 2H), 3.69-3.55 (m, 2 H), 3.10-3.00 (m, 2 H), 1.33 (bs, 9 H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2[O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2)([OH:3])=O.[CH3:26][O:27][CH2:28][CH2:29][NH2:30].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C.O>[CH3:26][O:27][CH2:28][CH2:29][NH:30][C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2[O:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2)=[O:3]
Reactant: COCCN
Reactant: COc1cc2nccc(Oc3ccc4[nH]ccc4c3)c2cc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COCCNC(=O)c1cc2c(Oc3ccc4[nH]ccc4c3)ccnc2cc1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
After dissolving 6-carboxy-7-methoxy-4-(indol-5-yloxy)quinoline (100 mg) in dimethylformamide (4.0 ml), there were added methoxyethylamine (0.04 ml), triethylamine (0.08 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (198 mg), and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, extraction was performed with ethyl acetate, and then the organic layer was washed with water and saturated brine in that order and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was used for recrystallization to obtain the title compound (86 mg).
Reaction SMILES: C[O:2][C:3](=[O:26])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)=[CH:14][C:13]1=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[CH:14][C:13]2=[O:25])[C:3]([OH:26])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(F)c2)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(F)c2)=CC1=O
Temperature: 23 °C
Reaction time: 2 h
Yield: 88279.7 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[4-(3-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (1.10 g, 0.003 mol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (382 mg, 0.016 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-[4-(3-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (920 gm, 87%) as an off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[N:15](COCC[Si](C)(C)C)[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:17][C:10]=12.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.NCCN>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH2:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[NH:15][C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:17][C:10]=12
Reactant: C[Si](C)(C)CCOCn1c(-c2cccnc2)cc2c(Oc3ccc(N)cc3F)ccnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: NCCN
Product: Nc1ccc(Oc2ccnc3[nH]c(-c4cccnc4)cc23)c(F)c1
Temperature: 65 °C
Yield: 92.1 %

Procedure:
A mixture of 3-fluoro-4-(2-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-4-yloxy)benzenamine (275 mg, 0.61 mmol), tetrabutylammonium fluoride (1 M in THF, 4 mL), and 1,2-diaminoethane (0.2 mL) in THF (4 mL) was heated at 65° C. for 24 h. The solvent was removed in vacuo. The residue was purified by flash column chromatography (silica gel, 5% MeOH/EtOAc) to afford the desired product (180 mg, 92%) as a yellow solid. LC/MS(ESI+) m/z 321 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][NH:6][C:7]([O:9][CH2:10][C@@H:11]1[C@@H:15]([O:16]C2CCCCO2)[CH2:14][C@@H:13]([O:23]C2CCCCO2)[C@H:12]1[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][C:36]([OH:38])=O)=[S:8].[CH2:42]([NH2:44])[CH3:43]>>[CH2:42]([NH:44][C:36]([CH2:35][CH2:34][CH2:33]/[CH:32]=[CH:31]\[CH2:30][C@H:12]1[C@@H:13]([OH:23])[CH2:14][C@@H:15]([OH:16])[C@@H:11]1[CH2:10][O:9][C:7](=[S:8])[NH:6][CH2:5][C:4]1[CH:39]=[CH:40][CH:41]=[C:2]([Cl:1])[CH:3]=1)=[O:38])[CH3:43]
Reactant: O=C(O)CCC/C=C\C[C@H]1[C@H](COC(=S)NCc2cccc(Cl)c2)[C@@H](OC2CCCCO2)C[C@H]1OC1CCCCO1
Reactant: CCN
Product: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](COC(=S)NCc2cccc(Cl)c2)[C@H](O)C[C@@H]1O

Procedure:
According to the procedures described above in Examples 17 and 18 acid 7 was converted with use of ethylamine to 30 mg of the above titled compound.