Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Sn](CCCC)(CCCC)CCCC)[N:3]=1.I[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]3[O:35][C:34]([NH:36][CH2:37][C:38]4[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=4)=[N:33][N:32]=3)[CH:29]=2)[N:24]([S:46]([C:49]2[CH:55]=[CH:54][C:52]([CH3:53])=[CH:51][CH:50]=2)(=[O:48])=[O:47])[CH:23]=1.CN(C=O)C>C(Cl)Cl.[Cu]I.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:1][C:2]1[N:3]=[C:4]([C:22]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31]4[O:35][C:34]([NH:36][CH2:37][C:38]5[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=5)=[N:33][N:32]=4)[CH:29]=3)[N:24]([S:46]([C:49]3[CH:50]=[CH:51][C:52]([CH3:53])=[CH:54][CH:55]=3)(=[O:48])=[O:47])[CH:23]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(Cl)n1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(Cl)n3)cn4S(=O)(=O)c3ccc(C)cc3)o2)cc1
Temperature: 100 °C
Yield: 49.1 %

Procedure:
In a 20 mL glass microwave tube, 2-chloro-6-(tributylstannyl)pyrazine (0.807 g, 1.999 mmol), 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (1.00 g, 1.665 mmol), CuI (0.381 g, 1.999 mmol), Pd(PPh3)4 (0.096 g, 0.083 mmol) was purged with argon and treated with DMF (15 mL). The tube was heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 1 h. The crude mixture was then diluted with DCM and washed with water. The organic layer was dried, filtered and concentrated and the residue was purified with flash chromatography to give 5-(3-(6-chloropyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-oxadiazol-2-amine (0.48 g, 0.818 mmol, 49%) as a light yellow amorphous solid. MS (ESI, pos. ion) m/z: 586.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.44 (1H, s), 9.02 (1H, s), 8.85 (1H, s), 8.71 (1H, s), 8.28-8.36 (1H, m), 8.18 (1H, d, J=8.8 Hz), 8.03 (1H, m, J=8.4 Hz), 7.95 (1H, s), 7.88-7.95 (1H, m), 7.45 (1H, m, J=8.2 Hz), 7.33 (2H, m, J=8.6 Hz), 6.90 (2H, m, J=8.6 Hz), 4.37 (2H, d, J=6.1 Hz), 3.72 (3H, s), 2.33 (3H, s).
Reaction SMILES: [F:1][C:2]1([F:42])[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[C:15]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=4)=[N:16][C:17]4[C:22]([C:23]=3[C:24]([O:26]C)=[O:25])=[CH:21][C:20]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:19][CH:18]=4)[CH2:9][CH2:8]2)[CH2:3]1.O.[OH-].[K+]>CO>[F:42][C:2]1([F:1])[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[C:15]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:39])([F:40])[F:41])[CH:33]=4)=[N:16][C:17]4[C:22]([C:23]=3[C:24]([OH:26])=[O:25])=[CH:21][C:20]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:19][CH:18]=4)[CH2:9][CH2:8]2)[CH2:3]1
Reactant: COC(=O)c1c(CN2CCC(N3CCC(F)(F)C3)CC2)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCC(F)(F)C4)CC3)c(C(=O)O)c2c1
Temperature: 65 °C
Yield: 75.8 %

Procedure:
To a solution of methyl 3-{[4-(3,3-difluoro-1-pyrrolidinyl)-1-piperidinyl]methyl}-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (0.970 g, 1.586 mmol) in methanol (15.86 mL) was added water (5.29 mL) and potassium hydroxide (0.445 g, 7.93 mmol). The mixture was heated to 65° C. for 15 h. The mixture was cooled to room temperature and concentrated. The residue was acidified to pH 4-5 with 2N HCl. The resulting precipitate was collected by filtration, washed with water (2×1 mL), and dried in the vacuum oven (35° C.) overnight to provide 3-{[4-(3,3-difluoro-1-pyrrolidinyl)-1-piperidinyl]methyl}-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.718 g, 72% yield) as a yellow solid. MS (m/z) 598.1 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][C@H:12]1[C:18]([NH2:21])=[N:19][OH:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]([C:26]#[C:27][C:28]([O:30][CH3:31])=[O:29])=[O:25]>C(Cl)(Cl)Cl>[CH3:22][O:23][C:24](=[O:25])[C:26]([O:20][N:19]=[C:18]([NH2:21])[C@@H:12]1[CH2:13][C:14]([F:17])([F:16])[CH2:15][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[CH:27][C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)C#CC(=O)OC
Reactant: NC(=NO)[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)C=C(ON=C(N)[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1)C(=O)OC

Procedure:
A solution of benzyl-(2S)-2-[amino(hydroxyimino)methyl]-4,4-difluoropyrrolidine-1-carboxylate and dimethylacetylendicarboxylate (1.2 eq.) in chloroform was refluxed for 1 hour under nitrogen and the solution was concentrated. Residue was purified by flash chromatography on silica gel, (eluent: petroleum ether:ethyl acetate=7.5:2.5), to give the desired product as a 3:1 mixture of two isomers by 1H NMR.
Reaction SMILES: C[C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.N1C=CC=CC=1.[F:17][C:18]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:19]=1[CH2:20][O:21][C:22]1[CH:31]=[CH:30][C:25]([CH2:26]C(Cl)=O)=[CH:24][CH:23]=1.Cl>ClCCl>[F:17][C:18]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:19]=1[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][C:4](=[O:5])[CH2:6][C:7]([O:9][CH2:2][CH3:10])=[O:8])=[CH:30][CH:31]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(Cl)Cc1ccc(OCc2c(F)cccc2F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)CC(=O)Cc1ccc(OCc2c(F)cccc2F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of Meldrum's acid (0.846 g, 5.8 mmol) in dichloromethane (5 ml) was added pyridine (2 ml) over a period of 10 minutes at 0° C. To this solution was added 4-(2,6-Difluorobenzyloxy)benzylcarbonyl chloride (Step D, 1.71 g, 5.7 mmol) in dichloromethane (5 ml), which resulted in an orange solution. The dark orange solution was stirred for 1 hour at 0° C., allowed to warm to room temperature and stirred for an additional hour. The reaction mixture was diluted with dichloromethane and poured onto 2M HCl and ice. The phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic layers were washed twice with 2M HCl and brine, dried over Na2SO4, filtered and concentrated to a solid. The solid was suspended in abs EtOH (15 ml) and refluxed for 2.5 hours. The solvent was removed in vacuo to give a dark oil. The residue was purified by flash chromatography on silica gel column (hex:ethyl acetate, 2:1) to provide the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[C:38]([C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1)#[N:39]>>[CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[CH:26]=[C:25]([C:33]([F:34])([F:36])[F:35])[CH:24]=2)[CH:12]=[C:13]([C:44]2[CH:43]=[CH:42][CH:41]=[C:40]([C:38]#[N:39])[CH:45]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Product: COC(=O)C(CC(C)C)c1cc(-c2cccc(C#N)c2)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 48 %

Procedure:
The title compound was prepared in 48% yield from 4-methyl-2-(5-trifluoromethanesulfonyloxy-3′,5′-bis-trifluoromethyl-biphenyl-3-yl)-pentanoic acid methyl ester (prepared in Intermediate A) and 3-cyanophenylboronic acid under the conditions described in Example 26, step (d).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:33]=[CH:32][C:16]3[N:17]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:19][C:15]=3[CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[H-].[Na+].[CH3:38][O:39][C:40](=[O:47])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]Br.O>CN(C)C=O>[CH3:38][O:39][C:40](=[O:47])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][N:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:34])[F:35])=[CH:4][CH:5]=1)(=[O:10])=[O:11])[C:13]1[CH:33]=[CH:32][C:16]2[N:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:19][C:15]=2[CH:14]=1
Reactant: COC(=O)CCCCCBr
Reactant: O=S(=O)(Nc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCCCCN(c1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
150 mg of 4-(trifluoromethyl)-N-(1,2-diphenyl-1H-benzimidazol-5-yl)benzenesulfonamide was suspended in 0.5 ml of N,N-dimethylformamide, mixed with 11 mg of sodium hydride and stirred for 30 minutes at 20° C. 88 mg of 6-bromohexanoic acid methyl ester was added, it was allowed to stir for 15 hours, mixed with water, extracted three times with ethyl acetate, the extracts were dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was digested with diisopropyl ether.
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH2:11][CH2:10][CH:9]([S:12][C:13]2[CH:14]=[CH:15][C:16]3[O:25][CH2:24][CH2:23][N:22]4[C:18](=[N:19][C:20]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=5)=[CH:21]4)[C:17]=3[CH:32]=2)[CH2:8][CH2:7]1)([CH3:5])[CH2:3][OH:4].C(O)(C(F)(F)F)=[O:34].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH3:5][C:2]([N:6]1[CH2:7][CH2:8][CH:9]([S:12]([C:13]2[CH:14]=[CH:15][C:16]3[O:25][CH2:24][CH2:23][N:22]4[CH:21]=[C:20]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=5)[N:19]=[C:18]4[C:17]=3[CH:32]=2)=[O:34])[CH2:10][CH2:11]1)([CH3:1])[CH2:3][OH:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(CO)N1CCC(Sc2ccc3c(c2)-c2nc(-c4ccccn4)cn2CCO3)CC1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(CO)N1CCC(S(=O)c2ccc3c(c2)-c2nc(-c4ccccn4)cn2CCO3)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
To an ice-cooled solution of 2-methyl-2-[4-(2-pyridin-2-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl)piperidin-1-yl]propan-1-ol from Example 3 (187 mg, 0.415 mmol) in DCM (20 mL) was added TFA (160 μL, 2.075 mmol) followed by a solution of m-CPBA (79 mg, 0.456 mmol) in DCM (2 mL). The resulting mixture was stirred for 30 min at 0° C. then volatiles were removed under reduced pressure. The crude material was purified by column chromatography (C18, gradient 10-30% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 0.5M NH3 in MeOH. Further purification by column chromatography (Si-PCC, gradient 2-17% 2M NH3/MeOH in DCM) afforded 197 as a light brown foam (102 mg, 52%). LCMS: RT1.87 min [M+H]+ 467.1. 1H NMR (DMSO, 400 MHz): δ 8.71 (1H, d, J=2.27 Hz), 8.53 (1H, ddd, J=4.81, 1.82, 0.94 Hz), 8.00 (1H, dt, J=7.92, 1.08 Hz), 7.95 (1H, s), 7.83 (1H, td, J=7.70, 1.85 Hz), 7.50 (1H, dd, J=8.51, 2.30 Hz), 7.26-7.21 (2H, m), 4.58-4.52 (4H, m), 4.18 (1H, t, J=5.42 Hz), 3.21 (2H, d, J=5.19 Hz), 3.07-2.98 (2H, m), 2.72-2.62 (1H, m), 2.17-2.04 (2H, m), 1.78-1.72 (1H, m), 1.48-1.41 (3H, m), 0.89 (6H, s)
Reaction SMILES: Br[CH:2]([CH3:13])[C:3](=[O:12])[C:4](=[N:10][OH:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[SH:14][CH2:15][CH2:16][OH:17].C(N(CC)CC)C>C(Cl)(Cl)Cl>[OH:17][CH2:16][CH2:15][S:14][CH:2]([CH3:13])[C:3](=[O:12])[C:4](=[N:10][OH:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=NO)C(=O)C(C)Br
Reactant: OCCS
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=NO)C(=O)C(C)SCCO
Reaction time: 2 h
Yield: 78.5 %

Procedure:
A solution of ethyl 4-bromo-2-hydroxyimino-3-oxovalerate (50 g.) in chloroform (100 ml) was added dropwise to a stirred solution of 2-mercaptoethanol (20.5 g.) and triethylamine (26.6 g.) in chloroform (100 ml) at room temperature over 1.5 hours, and stirred at the same temperature for 2 hours. After removing chloroform from the resultant solution in vacuo, water (600 ml) and ethyl acetate (600 ml) were added to the residue and adjusted to pH 1.0 with conc.hydrochloric acid. The ethyl acetate layer was separated, washed with water (200 ml), dried over magnesium sulfate and then concentrated in vacuo to give ethyl 4-(2-hydroxyethylthio)-2-hydroxyimino-3-oxovalerate (38.8 g.).
Reaction SMILES: C(N(C=O)CC(C1C=CC=CC=1C#N)=O)=O.[CH:17]([N-:19][CH:20]=[O:21])=[O:18].[Na+].Br[CH2:24][C:25]([C:27]1[CH:37]=[CH:36][CH:35]=[CH:34][C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:26]>C(#N)C>[CH:17]([N:19]([CH:20]=[O:21])[CH2:24][C:25]([C:27]1[CH:37]=[CH:36][CH:35]=[CH:34][C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:26])=[O:18]
Reactant: O=C[N-]C=O
Reactant: CCOC(=O)c1ccccc1C(=O)CBr
Agent: N#Cc1ccccc1C(=O)CN(C=O)C=O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccccc1C(=O)CN(C=O)C=O
Temperature: 20 °C
Reaction time: 16 h
Yield: 59.9 %

Procedure:
The 2-(N,N-diformylglycyl)benzonitrile can be prepared in the following manner: 5.54 g of sodium diformylamide are added to a solution of 14.45 g of ethyl 2-bromoacetylbenzoate in 150 ml of acetonitrile and the mixture is stirred for 16 hours at boiling temperature and then, after cooling to 20° C., the insoluble matter produced is removed by filtration and the filtrate is concentrated to dryness under reduced pressure (15 mm Hg; 2 kPa) at 40° C. The residue is chromatographed on a neutral silica gel, eluting with a methylene chloride-ethyl acetate (80-20 by volume) mixture. 8.4 g of ethyl 2-(N,N-diformylglycyl)benzoate are thus obtained in the form of an orange-coloured oil [1H spectrum in DMSO-d6, T=300K, δ in ppm (300 MHz): 1.22 (3H, t, J=6 Hz, CH3), 4.23 (2H, q, J=6 Hz, OCH2), 4.90 (2H, s, NCH2CO), between 7.60 and 7.90 (4H, m, 4 arom. CH), 9.20 (2H, B, 2 CHO)].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([CH2:10][C@H:11]([NH2:24])[C:12](=[O:23])[NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:7]=[CH:6][C:5]=1[O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28].[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([CH2:10][C@H:11]([NH:24][S:38]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:40])=[O:39])[C:12](=[O:23])[NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:7]=[CH:6][C:5]=1[O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)COc1ccc(C[C@H](N)C(=O)NCc2ccc(OC)cc2)cc1C(=O)OC
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)COc1ccc(C[C@H](NS(=O)(=O)c2ccccc2)C(=O)NCc2ccc(OC)cc2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-[(2S)-2-Amino-2-(4-methoxy-benzylcarbamoyl)-ethyl]-2-methoxycarbonylmethoxy-benzoic acid methyl ester of Step G (40 mg, 0.072 mmol) is stirred in pyridine (0.5 mL) at 0° C. under N2. Benzenesulfonyl chloride (20 mg, 0.11 mmol) is added and the reaction is stirred overnight at RT. The mixture is then diluted with CH2Cl2 (20 mL), washed with 2N HCl (2×20 mL) and then with saturated NaHCO3 (2×20 mL). The organics are dried over MgSO4, filtered, concentrated and purified by flash column chromatography to provide 5-[(2S)-2-benzenesulfonylamino-2-(4-methoxy-benzylcarbamoyl)-ethyl]-2-methoxycarbonylmethoxy-benzoic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20](OC)[CH:21]=3)[NH:16][CH:15]=2)[CH:5]=[C:4]([Cl:27])[C:3]=1[NH:28]C(=O)C.[Br:32]C1C=C2C(=CC=1)NC=C2CC(O)=O.ClC1C=C(C=C(Cl)C=1N)CN>>[NH2:28][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([CH2:8][NH:9][C:10]([NH:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Br:32])[CH:21]=3)[NH:16][CH:15]=2)=[NH:26])=[CH:5][C:4]=1[Cl:27]
Reactant: COc1ccc2[nH]cc(CC(=O)N=C(N)NCc3cc(Cl)c(NC(C)=O)c(Cl)c3)c2c1
Reactant: O=C(O)Cc1c[nH]c2ccc(Br)cc12
Agent: NCc1cc(Cl)c(N)c(Cl)c1
Product: N=C(NCc1cc(Cl)c(N)c(Cl)c1)NC(=O)Cc1c[nH]c2ccc(Br)cc12

Procedure:
In a manner similar to that used in the preparation of the compound of example 2, but using 2-(5-bromo-1H-indol-3-yl)acetic acid in step 17 (A) and 3,5-Dichloro-4-aminobenzylamine (preparation A) in step 17 (B), the title compound was prepared. MS (ESI) (M+H)+=467.90/469.86/471.83 1H-NMR (500 MHz, CD3OD) δ 7.71 (s, 1 H), 7.32 (m, 2 H), 7.16-7.28 (m, 3 H), 4.35 (s, 2 H), 3.93 (s, 2 H).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH2:12]([CH:14]1[O:16][CH2:15]1)Cl.CCOC(C)=O>O>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:14]2[CH2:15][O:16]2)=[CH:7][CH:6]=1
Reactant: COc1ccc(O)cc1
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(OCC2CO2)cc1
Temperature: 100 °C
Yield: 48 %

Procedure:
A solution of NaOH (0.35 g) in 10 mL of water was added to a mixture of 4-methoxyphenol (1.10 g, 8.5 mmol) and epichlorohydrin (0.80 mL, 10.2 mmol). The mixture was heated at 100° C. for 3 h. After cooling, the mixture is taken up with AcOEt (50 mL). The organic phase was separated, washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The crude residue was chromatographed (Petroleum ether/AcOEt, 4:1, as eluent) to afford pure compound in 48% yield. 1H NMR (CDCl3): δ 2.73-2.75 (m, 1H), 2.89 (app t, 1H), 3.31-3.36 (m, 1H), 3.76 (s, 3H), 3.88-3.93 (m, 1H), 4.14-4.20 (m, 1H), 6.81-6.88 (m, 4H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([O:49][CH2:50][CH2:51][NH:52][CH2:53][CH2:54][O:55][CH2:56][CH3:57])[CH3:48]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:52]([CH2:53][CH2:54][O:55][CH2:56][CH3:57])[CH2:51][CH2:50][O:49][CH2:47][CH3:48])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOCCNCCOCC
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOCCN(CCOCC)C(=O)CC1CCN(C(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with bis-(2-ethoxy-ethyl)-amine (TCI-US) to give the title compound. HR-MS (ES, m/z) calculated for C44H60Cl2N5O5 [(M+H)+] 808.3966, observed 808.3968.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]=2[N:13]=1.I[CH2:15][CH2:16][C@H:17]1[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:22][C:19]1([CH3:23])[O:18][C@@H:17]([CH2:16][CH2:15][N:8]2[C:9](=[O:12])[CH:10]=[N:11][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:13][C:7]2=3)[CH2:21][O:20]1
Reactant: COc1ccc2ncc(=O)[nH]c2n1
Reactant: CC1(C)OC[C@H](CCI)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2ncc(=O)n(CC[C@H]3COC(C)(C)O3)c2n1
Temperature: 50 °C
Reaction time: 11 h
Yield: 90.2 %

Procedure:
In N,N-dimethylformamide (400 ml) were dissolved 6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (14.53 g, 82.00 mmol) and (4S)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane (23.10 g, 90.20 mmol). Cesium carbonate (34.7 g, 1.06.6 mmol) was added to the solution and the mixture was stirred at 50° C. for 11 hours. After cooling in the air, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 22.58 g (90%) of the title compound in the form of a yellow orange oily product.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].O[N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[O:24]=[C:15]1[C:16]2[C:17](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:19])[N:14]1[O:1][CH2:2][C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](CON1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 100.2 %

Procedure:
To a mixture of tert-butyl [(1S)-2-hydroxy-1-methylethyl]carbamate 57 (4.03 g, 23.0 mmol), N-hydroxyphthalimide (5.63 g, 34.5 mmol) and triphenylphosphine (9.05 g, 34.5 mmol) in anhydrous THF (172 mL) at 0° C. under nitrogen was added DIAD (6.69 mL, 34.5 mmol) in anhydrous THF (40 mL) over 15 minutes. The mixture was stirred at 0° C. for 30 min and at room temperature for 2.5 h. Solvent was evaporated off and the residue was subjected to chromatography to give a white solid 58 (7.38 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][C:3]1=[O:8].C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>C1(C)C=CC=CC=1>[OH:11][C:12]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[C:3](=[O:8])[C:4]=12
Reactant: CN1CCNCC1=O
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn2c(c1O)C(=O)N(C)CC2
Temperature: 100 °C

Procedure:
A mixture of 1-methylpiperazin-2-one (183 g, 1.6 mol) and diethyl ethoxymethylenemalonate (346 g, 1.6 mol) in toluene (12 L) was heated at 100° C. overnight. The resultant mixture was concentrated under vacuum. The residue was dissolved in anhydrous THF (8 L), brought to reflux under an atmosphere of nitrogen, and treated with a solution of lithium bis(trimethylsilyl)amide in THF (1 M, 1.05 eq). The reaction mixture was allowed to cool to rt and concentrated under vacuum. The residue was partitioned between methylene chloride and dilute aqueous HCl. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was triturated with ethyl acetate, cooled to −20° C., and the solid precipitated was filtered to provide the title compound.