Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([C:11]2[CH:26]=[CH:25][C:14]([CH2:15][N:16]3[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=O)[CH2:18][CH2:17]3)=[CH:13][CH:12]=2)[CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][CH2:52][C:53]([CH3:56])([OH:55])[CH3:54].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[OH:55][C:53]([CH3:56])([CH3:54])[CH2:52][NH:51][C:22]([CH:19]1[CH2:20][CH2:21][N:16]([CH2:15][C:14]2[CH:25]=[CH:26][C:11]([C@@H:3]3[O:4][C:5]4=[N:6][CH:7]=[CH:8][CH:9]=[C:10]4[O:1][CH2:2]3)=[CH:12][CH:13]=2)[CH2:17][CH2:18]1)=[O:24]
Reactant: CC(C)(O)CN
Reactant: O=C(O)C1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)CNC(=O)C1CCN(Cc2ccc([C@H]3COc4cccnc4O3)cc2)CC1

Procedure:
To a solution of Intermediate K (50 mg, 0.14 mmol) in DMA (1 mL) is added HATU (59 mg, 0.16 mmol) followed by 1-amino-2-methyl-propan-2-ol (14 mg, 0.16 mmol) as a solution in DMA (1 mL) and DIEA (0.10 mL, 0.56 mmol) and the mixture stirred at rt overnight. Add water (0.1 mL) and purify by reversed phase HPLC eluting with 10-90% MeCN in water (+0.1% TFA). The concentrated pooled fractions are dissolved in 1:1 methanol/DCE and passed through a carbonate resin cartridge to provide the title compound 255 as a free base. (LC/MS method 16: ES+ m/z 426.5 [M+H]+, Rt=1.48 min)
Reaction SMILES: [CH2:1]([C@H:8]([NH:39][C:40](=[O:47])[C@H:41]([CH2:43][CH:44]([CH3:46])[CH3:45])[NH2:42])[C@@H:9]([OH:38])[CH2:10][C@@H:11]([NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:49]([O:51][CH3:52])=[O:50].C(N(CC)CC)C>ClCCl>[CH3:52][O:51][C:49](=[O:50])[NH:42][C@@H:41]([CH2:43][CH:44]([CH3:45])[CH3:46])[C:40](=[O:47])[NH:39][C@@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([OH:38])[CH2:10][C@H:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[NH:25][C:26](=[O:37])[C@H:27]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH:28][C:29](=[O:30])[O:31][CH3:32]
Reactant: COC(=O)Cl
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(C)C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C
Yield: 58.5 %

Procedure:
A solution of Example 167B (11.2 mg, 0.017 mmol) in dichloromethane (0.25 mL) was treated with methyl chloroformate (2 μL, 0.026 mmol), and triethylamine (4.8 μL, 0.034 mmol) at 25° C. for 1 h. The solvents were evaporated, and the crude residue was purified by silica gel chromatography eluting with a gradient of dichloromethane, 100% ethyl acetate, and 95% ethyl acetate/7% methanol to give the title compound (7 mg, 57%). 1H NMR (300 MHz, CDCl3)δ ppm 0.87-0.84(s, 15H), 1.34-1.29(m, 2H), 1.65-1.51(m, 3H), 2.67-2.60(m, 2H), 2.86-2.83(d, J=7.72 Hz, 2H), 2.95-2.87(m, 1H), 3.52(s, 3H), 3.65(s, 3H), 3.78-3.73(m, 1H), 3.81(s, 1H), 4.08-4.03(m, 1H), 4.24-4.19(m, 1H), 4.33(m, 1H), 7.17-7.12(m, 1H), 7.26-7.20(m, H), 7.29-7.26(d, J=8.46 Hz, 2H), 7.35-7.30(m, 1H), 7.81-7.77(m, 3H), 7.90-7.84(m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][CH:8]=[CH:7]3)[N:4]=[C:3]1[CH:15]([CH3:21])[CH2:16][C:17]([O:19]C)=[O:18].O.[OH-].[Li+]>C(#N)C.O>[CH3:1][N:2]1[C:14]2[C:5](=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[CH:9][CH:8]=[CH:7]3)[N:4]=[C:3]1[CH:15]([CH3:21])[CH2:16][C:17]([OH:19])=[O:18]
Reactant: COC(=O)CC(C)c1nc2c3cccnc3ccc2n1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CC(CC(=O)O)c1nc2c3cccnc3ccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of methyl 3-(3-methyl-3H-imidazo[4,5-f]quinolin-2-yl)butanoate (560 mg, 1.97 mmol) in acetonitrile (20 mL) and water (8 mL) was added lithium hydroxide hydrate (249 mg, 5.94 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated to about 8 mL. The pH of the solution was adjusted to ˜4 with 1N HCl aqueous solution. The mixture was concentrated to dryness and to the residue was added 50 mL of DCM/MeOH v/v 10:1. The precipitate was removed by filtration and the filtrate was concentrated to dryness to give the product as a yellow solid (480 mg, 90% yield). ESI MS: m/z 270.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[CH2:12][CH:13]1[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:12][CH:13]1[CH2:15][CH2:14]1
Reactant: CCc1ccc(O)c(Br)c1
Reactant: BrCC1CC1
Product: CCc1ccc(OCC2CC2)c(Br)c1

Procedure:
Starting from 2-bromo-4-ethyl-phenol (example B.a5) and commercially available bromomethyl-cyclopropane the title compound is obtained as colorless oil after distillation at 10 mbar.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11].[CH:30]1([CH2:33]O)[CH2:32][CH2:31]1>>[CH3:1][C:2]1([CH3:29])[C@@H:4]([C:5]#[C:6][C:7]([O:9][CH2:33][CH:30]2[CH2:32][CH2:31]2)=[O:8])[C@H:3]1[C:10]([O:12][C@H:13]([C:27]#[N:28])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:15]=1)=[O:11]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)O
Reactant: OCC1CC1
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)OCC1CC1

Procedure:
Using the procedure of Step A of Example 7, 1.4 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-(2-carboxyethynyl)-cyclopropane-carboxylate and 0.3 ml of cyclopropylcarbinol were reacted and the product was chromatographed over silica gel. Elution with an 8-2 cyclohexane-ethyl acetate mixture yielded 1.5 g of (S)α-cyano-3-phenoxybenzyl(1R,cis)2,2-dimethyl-3-(cyclopropylmethoxycarbonylethynyl)-cyclopropane-carboxylate melting at 72° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](Cl)[C:5]2[C:6](=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:9]([CH3:11])[N:10]=2)[N:7]=1.[C:21]1([CH3:31])[CH:26]=CC(S(O)(=O)=O)=CC=1>C(NCCC)CC>[CH3:1][C:2]1[CH:3]=[C:4]([N:7]([CH2:26][CH2:21][CH3:31])[CH2:2][CH2:3][CH3:4])[C:5]2[C:6](=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:9]([CH3:11])[N:10]=2)[N:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1cc(Cl)c2nn(C)c(-c3ccc(Cl)cc3Cl)c2n1
Solvent: CCCNCCC
Product: CCCN(CCC)c1cc(C)nc2c(-c3ccc(Cl)cc3Cl)n(C)nc12

Procedure:
Intermediate (5) was suspended in dipropylamine (1 ml) and p-toluenesulfonic acid (30 mg) and heated to 200° C. for 2 hours in a sealed tube. The reaction mixture was cooled and partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated, dried and concentrated. The residue was purified over silica gel (eluens: ethyl acetate/hexanes), yielding 5-methyl-7-(dipropylamino)-2-methyl-3-(2,4-dichlorophenyl)pyrazolo[4,3-b]pyridine (compound 1).
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[CH:10][S:11][C:7]=2[C:6]2[S:12][CH:13]=[CH:14][C:5]1=2)[CH2:2][CH3:3].C([Li])CCC.CCCCCC.[CH3:26][Sn:27](Cl)([CH3:29])[CH3:28].O>C1COCC1>[CH2:1]([N:4]1[C:8]2[CH:9]=[C:10]([Sn:27]([CH3:29])([CH3:28])[CH3:26])[S:11][C:7]=2[C:6]2[S:12][C:13]([Sn:27]([CH3:29])([CH3:28])[CH3:26])=[CH:14][C:5]1=2)[CH2:2][CH3:3]
Reactant: C[Sn](C)(C)Cl
Reactant: CCCn1c2ccsc2c2sccc21
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCn1c2cc([Sn](C)(C)C)sc2c2sc([Sn](C)(C)C)cc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 1.1 g (5.0 mmol) of 4-propyl-4H-dithieno[3,2-b;2′,3′-d]pyrrole (32) in 17 ml of dry THF are added 6.9 ml (11.0 mmol) of a 1.6 M n-butyllithium/hexane solution at −78° C. After the mixture has been stirred at −78° C. for 1 h, the cooling bath is removed and the mixture is stirred at room temperature for a further hour. A precipitate forms during this time. The suspension is cooled −78° C. and a solution of 2.2 g (11.0 mmol) of trimethylstannyl chloride dissolved in 3 ml of THF is added. The mixture is stirred −78° C. for 1 h and then the cooling bath is removed to stir at room temperature for a further 3 h. 50 ml of n-hexane are added and hydrolysis is effected with water. The organic phase is washed three times with 50 ml of water and dried over sodium sulfate. After the solvents have been distilled off, the residue is dried under reduced pressure and the crude product (2.26 g, 88%) is used in the next stage without further purification. 1H NMR (CDCl3): 7.01 ppm (s, 2H), 4.16 (t, 2H), 1.94 (qa, 2H), 0.98 (t, 3H), 0.40 (s, 18H).
Reaction SMILES: C(OC([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:40]([CH3:42])[CH3:41])[C:24](=[O:39])[C:25]([F:38])([F:37])[C:26](=[O:36])[NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[O:21])[C:15]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[N:14][CH:13]=1)=O)C1C=CC=CC=1.C(Cl)(Cl)Cl.C(Cl)(Cl)Cl.CO>CO.ClCCl>[NH2:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH:40]([CH3:42])[CH3:41])[C:24](=[O:39])[C:25]([F:38])([F:37])[C:26](=[O:36])[NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[O:21])[C:15]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[N:14][CH:13]=1
Reactant: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(NC(=O)OCc2ccccc2)c1=O)C(=O)C(F)(F)C(=O)NCCc1ccncc1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2)ncc(N)c1=O)C(=O)C(F)(F)C(=O)NCCc1ccncc1

Procedure:
2-(5-Benzyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydropyrimidin-1-yl)-N-[3,3-difluoro-1-isopropyl-2-oxo-3-[N-[2-(4-pyridyl)ethyl)carbamoyl]propyl]acetamide. The compound described in part a. was subjected to conditions similar to those described in Example 1. Multiple use of chromatography (first column) with chloroform:methanol (gradient, 97:3, 94:6), (second column) chloroform:methanol (98:2), (chromatotron-2 mm plate: flow 6 mL/min) dichloromethane:methanol (gradient, 98:2, 96:4) yielded the title compound; TLC: Rf =0.21, dichloromethane:methanol (97:3); MS: m/z=661(M+1). Analysis for C34H34F2N6O6.0.7 H2O: Calculated: C, 60.65; H, 5.30; N, 12.48; Found: C, 60.62; H, 5.24; N, 12.39. This product is also a Compound of the invention.
Reaction SMILES: CS([CH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)(=O)=O.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[CH:13]=1.CC(O)([C:23]#[N:24])C.C(N(CC)CC)C>CO>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[CH:8]3[CH2:9][CH2:10][C:5]2([C:23]#[N:24])[CH2:6][CH2:7]3)[CH:13]=1
Reactant: NCc1cccnc1
Reactant: CC(C)(O)C#N
Reactant: CS(=O)(=O)C1CCC(=O)CC1
Solvent: CCN(CC)CC
Solvent: CO
Product: N#CC12CCC(CC1)N2Cc1cccnc1
Temperature: 100 °C
Yield: 50 %

Procedure:
In a dry pressure resistant vessel of 20 ml, 1.0 g (5.20 mmole) 4-methanesulphonylcyclohexanone, 0.56 g (5.20 mmole) 3-picolylamine, 0.89 g (10.4 mmole) acetonecyanohydrin and 1.06 g (10.4 mmole) triethylamine were dissolved in 16 ml dry methanol. The vessel was closed and heated for 50 hours at 100° C. Methanol was then evaporated and the residue was redissolved in dichloromethane, washed with a saturated NaHCO3 solution, dried over MgSO4, filtered and evaporated. The residue was further purified by means of column chromatography. 7-(pyridin-3-ylmethyl)-7-aza-bicyclo[2.2.1]heptane-1-carbonitrile (structural formula below) was thus obtained in a 50% yield and characterised by proton (1H-NMR) and carbon (13C-NMR) nuclear magnetic resonance, infrared (IR) spectrophotometry and mass spectrum (MSES) as follows:
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[C:3]([OH:5])=O.O=S(Cl)Cl.[CH:20]1([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(N(C(C)C)C(C)C)C>C1(C)C=CC=CC=1>[Br:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][CH:7]=1)[C:3]([NH:34][C:31]1[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:33][CH:32]=1)=[O:5]
Reactant: Nc1ccc(OCC2CCCCC2)cc1
Reactant: CC(C)(C)c1ccc(C(Br)C(=O)O)cc1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C(Br)C(=O)Nc2ccc(OCC3CCCCC3)cc2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
To a stirring solution of bromo-(4-tert-butyl-phenyl)-acetic acid (1.2 g, 4.43 mmol) in toluene (20 mL) was added SOCl2 (0.8 mL, 11.1 mmol). The mixture was stirred at 90° C. for 1 hr and concentrated under reduced pressure. This crude product was dissolved into toluene (20 ml), and 4-cyclohexylmethoxy-phenylamine (0.91 g, 4.43 mmol) and ethyl-diisopropyl-amine (0.85 mL, 4.87 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was quenched with water and diluted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with ethyl acetate-hexanes (3:7) to afford 2-bromo-2-(4-tert-butyl-phenyl)-N-(4-cyclohexylmethoxy-phenyl)-acetamide as a brown oil (1.2 g, 59%): 1H NMR (300 MHz, DMSO-d6): δ 10.35 (s, 1H) 7.49 (m, 6H), 6.87 (d, J=9.3 Hz, 2H), 5.74 (s, 1H), 3.75 (d, J=6.3 Hz, 2H), 1.69 (m, 6H), 1.27 (m, 12H), 1.09 (m, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:13][C@@H:12]([C:14]([O:16]C(C)(C)C)=[O:15])[N:11]([C:21](=[O:34])[C@H:22]([CH3:33])[CH2:23][S:24][C:25](=[O:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]1=[O:35]>C1(C)C=CC=CC=1>[CH3:8][N:9]1[CH2:13][C@@H:12]([C:14]([OH:16])=[O:15])[N:11]([C:21](=[O:34])[C@H:22]([CH3:33])[CH2:23][S:24][C:25](=[O:32])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:10]1=[O:35]
Reactant: C[C@H](CSC(=O)c1ccccc1)C(=O)N1C(=O)N(C)C[C@H]1C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](CSC(=O)c1ccccc1)C(=O)N1C(=O)N(C)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
15 ml of trifluoroacetic acid are added to 4.0 g of tert.-butyl (4S)-1-methyl-3-[(2S)-3-benzoylthio-2-methylpropionyl]-2-oxo-imidazolidine-4-carboxylate, and the mixture is stirred at room temperature for 2 hours. The reaction mixture is condensed under reduced pressure. Toluene is added to the residue, and said mixture is again condensed under reduced pressure. The residue thus obtained is recrystallized from a mixture of ethyl acetate and n-hexane. 3.2 g of (4S)-1-methyl-3-[(2S)-3-benzoylthio-2-methylpropionyl]-2-oxo-imidazolidine-4-carboxylic acid is thereby obtained as colorless syrup. The physico-chemical properties of this product are identical with those of the sample obtained in Example 1-(5).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CCN(C(C)C)C(C)C.[NH2:46][CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52]([NH:55][C:56]2[N:61]=[C:60]([NH2:62])[CH:59]=[CH:58][N:57]=2)=[CH:51][CH:50]=1>ClCCCl>[NH2:62][C:60]1[CH:59]=[CH:58][N:57]=[C:56]([NH:55][C:52]2[CH:53]=[CH:54][C:49]([CH2:48][CH2:47][NH:46][C:21]([C:18]3[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:5]([CH3:24])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=4[CH3:9])(=[O:11])=[O:12])[CH3:14])[O:20][CH:19]=3)=[O:22])=[CH:50][CH:51]=2)[N:61]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: NCCc1ccc(Nc2nccc(N)n2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCCc3ccc(Nc4nccc(N)n4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AE using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (60 mg, 0.15 mmol), CDI (51 mg, 0.31 mmol), DIPEA (0.134 mL, 0.76 mmol) and N2-[4-(2-aminoethyl)phenyl]pyrimidine-2,4-diamine (49 mg, 0.15 mmol) in DCE (1 mL). A portion of the crude product was purified using prep method A.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@@H:4]([NH:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[NH2:26][CH2:27][C@@H:28]([C:30]1[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=1)[OH:29]>>[CH3:1][O:2][C:3](=[O:25])[C@@H:4]([NH:9][C:10](=[O:24])[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([NH:26][CH2:27][CH:28]([OH:29])[C:30]3[CH:31]=[CH:32][C:33]([OH:41])=[C:34]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=3)[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N2CCC(NCC(O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from methyl 4-methyl-2-[(2S)-4-(4-oxo-piperidine-1-yl)-benzoylamino]-pentanoic acid methyl ester(which was obtained in Example 166) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 180 as a white solid; mp >90° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 0.86 (d, J=6.4 Hz, 3H), 0.92 (d, J=6.4 Hz, 3H), 1.20-1.40 (m, 2H), 1.50-1.95 (m, 5H), 2.55-2.92 (m, 5H), 2.91 (s, 3H), 3.62 (s, 3H), 3.70-3.85 (m, 2H), 4.40-4.55 (m, 2H), 6.82 (d, J=8.2 Hz, 1H), 6.93 (d, J=8.9 Hz, 2H), 7.00 (dd, J=8.2, 2.0 Hz, 2H), 7.18 (d, J=2.0 Hz, 1H), 7.75 (d, J=8.9 Hz, 2H), 8.34 (d, J=7.7 Hz, 1H); MS (ES) m/z: 577.3 (MH+); HRMS Calcd. for C28H41N4O7S(MH+): 577.2690. Found: 577.2682.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C@H:17]2[CH2:19][O:18]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([CH:30]([O:33][NH:34][S:35]([C:38]1[CH:46]=[CH:45][C:41]2[O:42][CH2:43][O:44][C:40]=2[CH:39]=1)(=[O:37])=[O:36])[CH2:31][CH3:32])[CH3:29]>O1CCCC1>[O:42]1[C:41]2[CH:45]=[CH:46][C:38]([S:35]([N:34]([O:33][CH:30]([CH2:31][CH3:32])[CH2:28][CH3:29])[CH2:19][C@@H:17]([OH:18])[C@@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:14][CH:13]=3)(=[O:36])=[O:37])=[CH:39][C:40]=2[O:44][CH2:43]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@H]1CO1
Reactant: CCC(CC)ONS(=O)(=O)c1ccc2c(c1)OCO2
Solvent: C1CCOC1
Product: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.9 %

Procedure:
To a solution of tert-butyl (1S)-2-[4-(benzyloxy)phenyl]-1-[(2S)-oxiranyl]ethylcarbamate (2.66 g, 7.2 mmol) and the N-(1-ethylpropoxy)-1,3-benzodioxole-5-sulfonamide (2.30 g, 9.0 mmol) in tetrahydrofuran (12 mL) was added phosphazene base P4 tert-butyl solution (1.44 mL, 1.44 mmol, 1M in hexane). After stirring at ambient temperature for 18 h, the reaction was concentrated in vacuo, taken up in ethyl acetate (100 mL), washed with 0.5 N hydrochloric acid (2×40 mL) followed by water (40 mL), saturated sodium bicarbonate (40 mL) and brine (40 mL), dried (magnesium sulfate) and concentrated. The residue was purified by silica gel chromatography (20% ethyl acetate in hexane) to afford the title compound (4.25 g, 90%) as a white foam. 1H NMR (DMSO-d6): δ 0.79 (6H, dt), 1.11-1.74 (4H, m), 1.17 (9H, s), 2.37 (1H, t), 2.60-3.02 (3H, m), 3.38-3.49 (1H, m), 3.50-3.61 (1H, m), 4.03 (1H, m), 5.00 (2H, s), 5.04 (1H, d), 6.15 (2H, s), 6.60 (1H, d), 7.03 (2H, d), 7.10 (1H, d), 7.17-7.38 (9H, m)
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1Cl)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([N:38]3[CH2:41][CH2:40][CH2:39]3)[CH:35]=[CH:36][CH:37]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1COCC1>O>[N:38]1([C:34]2[CH:33]=[C:32]([C:13]3[C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:20]=[C:21]([CH3:22])[C:12]=3[C@H:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:37]=[CH:36][CH:35]=2)[CH2:41][CH2:40][CH2:39]1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2ccccc2c1Cl
Reactant: CC1(C)OB(c2cccc(N3CCC3)c2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2ccccc2c1-c1cccc(N2CCC2)c1
Temperature: 110 °C

Procedure:
A Smith process vial was charged with (S)-ethyl 2-tert-butoxy-2-(1-chloro-3-methylnaphthalen-2-yl)acetate (60.5 mg, 0.181 mmol), 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine (93.7 mg, 0.361 mmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]Pd(II)methyl-t-butyl ether adduct (12.2 mg, 0.0181 mmol) and potassium phosphate (153 mg, 0.543 mmol), THF (2 mL) and water (1 mL) was added and mixture sparged with nitrogen for 10 minutes and then heated in microwave at 110° C. for 1 hour. The reaction mixture was diluted with ethyl acetate and washed with brine, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to the desired product containing some impurities that was used in the next step without further purification.
Reaction SMILES: [CH3:1]/[C:2](/[C:5]([CH3:7])=[O:6])=[N:3]\[OH:4].[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.C(O)(=O)C.Cl>C(OCC)C>[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]2[O:6][C:5]([CH3:7])=[C:2]([CH3:1])[N+:3]=2[O-:4])=[CH:11][CH:10]=1
Reactant: CC(=O)/C(C)=N/O
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1oc(-c2ccc(Cl)cc2)[n+]([O-])c1C

Procedure:
1.00 g (9.89 mmol) of diacetyl monoxime and 1.53 g (10.88 mmol) of 4-chlorobenzaldehyde are initially charged in 2 ml (34.94 mmol) of glacial acetic acid. With ice-cooling, hydrogen chloride gas is then introduced into the reaction mixture for 30 min 10 ml of diethyl ether are then added to the reaction mixture. A precipitate is formed, which is filtered off with suction and washed twice with in each case 2 ml of diethyl ether. The precipitate is suspended in about 5 ml of water, and the suspension is made basic using aqueous ammonia. The suspension is then extracted four times with in each case 10 ml of dichloromethane. The combined organic phases are dried over magnesium sulphate, and the solvent is removed on a rotary evaporator. Without further purification, the product obtained in this manner is used for the subsequent step.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[N:6][C:5]([C:8](=[NH:10])[NH2:9])=[N:4]1.[Br:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O.O=[C:22]([CH3:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[Br:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]1[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:22]([CH3:29])[NH:9][C:8]([C:5]2[N:6]=[CH:7][N:3]([CH3:2])[N:4]=2)=[N:10]1
Reactant: Cn1cnc(C(=N)N)n1
Reactant: O=Cc1ccc(F)cc1Br
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Product: CCOC(=O)C1=C(C)NC(c2ncn(C)n2)=NC1c1ccc(F)cc1Br
Yield: 62.8 %

Procedure:
1-methyl-1H-1,2,4-triazole-3-carboximidamide hydrochloride (3.3 g, 20 mmol) was reacted with 2-bromo-4-fluorobenzaldehyde (4 g, 20 mmol) and ethyl 3-oxobutanoate (2.6 g, 20 mmol) according to the procedure as described in Example 1, Step A to give the title compound as a white solid (5.3 g, 63%). The compound was characterized by the following spectroscopic data: