Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[O:28][CH2:29][CH2:30][CH2:31][CH2:32]Br>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:27]3[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: COc1ccc(OCCCCBr)cc1OC
Agent: Cl
Product: COc1ccc(OCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)cc1OC

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 4-(3,4-dimethoxyphenoxy)butyl bromide are reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-N-((1-(4-(3,4-dimethoxyphenoxy)-butyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[N:3]=[CH:2]1.Cl[C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(CC)CC>CN(C=O)C>[C:13]1([C:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:1]2[CH:5]=[C:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])[N:3]=[CH:2]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)Cc1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 104 %

Procedure:
A solution of the product from Step 4.a. (3.2 g, 17.5 mmol) in DMF (50 ml) was treated with chlorotriphenylmethane (4.88 g, 17.5 mmol) and Et3N (5.4 ml, 38.5 mmol) and the reaction was stirred at room temperature for about 6 hours. The DMF was evaporated under reduced pressure and the residue was distributed between EtOAc and saturated NaCl solution. The EtOAc layer was dried over Na2SO4, filtered and concentrated under reduced pressure to yield product as a viscous oil (6.96 g, 104%) which crystallized on standing. Mass spec. 383.3 MH+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([O:20]CC3C=CC([N+]([O-])=O)=CC=3)=[O:19])=[C:14](O)[CH2:15][S:16][C@H:11]12)=[O:8].ClC(F)C(N(CC)CC)(F)[F:36]>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:31](=[O:32])[N:12]2[C:13]([C:18]([OH:20])=[O:19])=[C:14]([F:36])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: CCN(CC)C(F)(F)C(F)Cl
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(O)CS[C@H]12
Solvent: ClCCl
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)=C(F)CS[C@H]12

Procedure:
To a solution of 325 mg. (0.7 mmole) of p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-hydroxy-3-cephem-4-carboxylate in 10 ml. of methylene chloride was slowly added an equivalent amount of N-(2-chloro-1,1,2-trifluoroethyl)diethylamine. The reaction mixture was heated for 30 minutes under gentle reflux and was then evaporated to dryness in vacuo. The residue was dissolved in a mixture of ethyl acetate-water and the organic layer was separated. The organic layer was washed with 5% hydrochloric acid, water and brine and was then dried. The dried reaction product solution was concentrated to a small volume and n-hexane was added to precipitate, p-nitrobenzyl 7-[2-(2-thienyl)acetamido]-3-fluoro-3-cephem-4-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].Cl.[CH3:40]OC(=O)CNC>CCCCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:38])[CH2:4][N:5]([C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:34][CH2:35]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36])[CH3:40]
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Reactant: CNCC(=O)OC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)CN(C)C(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl

Procedure:
The title compound was prepared in analogy to Example 29, from 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) and sarcosine methylester hydrochloride (commercially available, CAS RN 945218-53-1) and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) as eluant. Light brown foam (33%). MS (ESI): m/z=569.135 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[OH-].[K+].[CH:13](=[O:16])[CH2:14][CH3:15]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[C:14]([CH3:15])[CH:13]=[O:16]
Reactant: CCC=O
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C=O)=Cc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
2,4-dichlorobenzaldehyde (26.26 g, 0.15 mol) was dissolved in toluene (200 mL), and then KOH (8.4 g, 1 eq) in water (183 mL) was added followed by BnEt3NCl. The mixture was cooled to 0° C. and n-propanal (26.15 g, 0.45 mol, 3 eq) in toluene (50 mL) was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. The organic layer was separated and washed successively with water, brine, dried (MgSO4), and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (0-1-2-3% EtOAc in hexanes) to give 17.56 g of 3-(2,4-dichlorophenyl)-2-methylpropenal.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.C[Al](C)C.[C:22](OCC)(=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>C1(C)C=CC=CC=1>[C:23]1([C:22]2[N:4]([CH:5]3[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]3)[CH2:3][CH2:2][N:1]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NCCN)CC1
Reactant: CCOC(=O)c1ccccc1
Agent: C[Al](C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(N2CCN=C2c2ccccc2)CC1
Temperature: -10 °C

Procedure:
To tert-butyl 4-[(2-aminoethyl)amino]piperidine-1-carboxylate (6 g) taken in dry toluene (50 ml) cooled to −10° C., trimethylaluminium was added slowly in dry toluene under nitrogen atmosphere. Reaction mixture was allowed to warm to r.t. and a second lot of solution of tert-butyl 4-[(2-aminoethyl)amino]piperidine-1-carboxylate (6 g in 50 ml of toluene) was added very slowly to it. The combined mixture was heated up to 55° C. for 30 minutes. A solution of ethyl benzoate (7.4 g in 50 ml of dry toluene) was added very-very slowly to the reaction mixture at 55° C. over a period of 40 minutes. After the completion of addition, the reaction mixture was refluxed for over night. Reaction mixture was cooled to 0° C. and water (3×50 ml) was added. The combined mixture was filtered through celite pad. The filtrate was concentrated under reduced pressure and the resulting oil was purified by column chromatography to afford tert-butyl 4-(2-phenyl-4,5-dihydro-1H-imidazol-1-yl)piperidine-1-carboxylate as a pure product.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH:10]([C:11]([CH2:13][CH3:14])=[CH2:12])[O:9][CH:8]=[N:7]1)=[O:5])[CH3:2].C([OH:17])C.O>>[CH2:1]([O:3][C:4](=[O:5])[CH:6]([NH:7][CH:8]=[O:17])[CH:10]([OH:9])[C:11]([CH2:13][CH3:14])=[CH2:12])[CH3:2]
Reactant: C=C(CC)C1OC=NC1C(=O)OCC
Reactant: CCO
Solvent: O
Product: C=C(CC)C(O)C(NC=O)C(=O)OCC

Procedure:
The starting material is manufactured as follows: Reaction of 2-methylene-butyraldehyde with isocyanoacetic acid ethyl ester in a manner analogous to that described in Example 1 yields 5-(buten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester. A solution of 16 g of 5-(buten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester in 100 ml of ethanol/water (1:1) is heated at the boil, under reflux, for 15 hours. The whole is concentrated by evaporation in vacuo, the residue is taken up in 200 ml of dichloromethane, dried over sodium sulphate and filtered, and the filtrate is concentrated by evaporation to yield 2-formylamino-3-hydroxy-4-ethyl-4-pentenoic acid ethyl ester.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)[CH2:8]1)(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+]>CC(N(C)C)=O.C(OCC)(=O)C>[N:20]([CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)[CH2:8]1)=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)cc2)C(=O)O1
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(I)cc2)C(=O)O1
Temperature: 80 °C
Yield: 81.2 %

Procedure:
[(5R)-3-(4-Iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl methanesulfonate (27 g, 68 mmol) was dissolved in dimethylacetamide (300 ml). Sodium azide (13.1 g, 202 mmol) was carefully added, and the solution was heated to 80° C. for 3 h. After cooling to room temperature, the mixture was diluted with ethyl acetate (500 ml), washed with water (2×), brine, and dried over sodium sulfate. Flash chromatography with 0-1% methanol in dichloromethane as eluent gave the desired product (19 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][C:11]=2[N:12]=[C:13](S(C)(=O)=O)[N:14]=1.[NH2:30][CH2:31][CH2:32][NH:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][N:35]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20][CH2:19][C:11]=2[N:12]=[C:13]([NH:30][CH2:31][CH2:32][NH:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][N:35]=2)[N:14]=1
Reactant: N#Cc1ccc(NCCN)nc1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(S(C)(=O)=O)nc(-c3ccc(Cl)cc3Cl)c2C1
Product: CC(C)(C)OC(=O)N1CCc2nc(NCCNc3ccc(C#N)cn3)nc(-c3ccc(Cl)cc3Cl)c2C1

Procedure:
Reaction of tert-butyl 4-(2,4-dichlorophenyl)-2-(methylsulfonyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate and 2-(2-aminoethylamino)-5-cyanopyridine gave tert-butyl 4-(2,4-dichlorophenyl)-2-({2-[(5-cyano(2-pyridyl))-amino]ethyl}amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidine-6-carboxylate.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])[C:4](=[O:9])[C:5]([Cl:8])=[CH:6][N:7]=1.[CH3:19][C@@:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1>>[NH2:26][C@:20]1([CH3:19])[CH2:25][CH2:24][CH2:23][N:22]([C:2]2[N:3]([CH2:10][C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])[C:4](=[O:9])[C:5]([Cl:8])=[CH:6][N:7]=2)[CH2:21]1
Reactant: N#Cc1ccccc1Cn1c(Cl)ncc(Cl)c1=O
Reactant: C[C@@]1(N)CCCNC1
Product: C[C@@]1(N)CCCN(c2ncc(Cl)c(=O)n2Cc2ccccc2C#N)C1
Yield: 65 %

Procedure:
The title compound was prepared in 65% yield from 2-(2,5-dichloro-6-oxo-6H-pyrimidin-1-ylmethyl)-benzonitrile (Example 15B) and (R)-3-methyl-piperidin-3-ylamine according to the general procedure outlined for Example 1 and was isolated as the HCl salt. 1H NMR (400 MHz, DMSO-d6): δ8.43 (br s, 3H), 8.09 (s, 1H), 7.80 (d, 1H, J=7.6 Hz), 7.64 (t, 1H, J=7.6 Hz), 7.45 (t, 1H, J=7.6 Hz), 7.22 (d, 1H, J=7.6 Hz), 5.39 (AB q, 2H, J=98.0, 14.8 Hz), 3.39-3.47 (m, 1H), 3.01-3.15 (m, 2H), 2.80-2.90 (m, 1H), 1.81-2.00 (m, 2H), 1.56-1.66 (m, 2H), 1.30 (m, 3H). MS (ES) [m+H] calc'd for C18H20N5OCl, 358, 360; found 358, 360.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[F:20]>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])=[CH:15][C:14]=1[F:20]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: N#Cc1cc(C=O)ccc1F
Product: N#Cc1cc(C=O)ccc1Oc1ccc(Br)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 4-bromo-3-fluorophenol.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]Cl)(=[O:3])[CH3:2].[I-:11].[Na+]>CC(C)=O>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][I:11])(=[O:3])[CH3:2]
Reactant: [I-]
Reactant: CC(=O)OCCCCCCl
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(=O)OCCCCCI
Temperature: 25 °C

Procedure:
5-Chloropentyl acetate (26.5 g, 0.16 mol) was added to a solution of sodium iodide (45 g, 0.30 mol) in dry acetone (200 ml). The resulting pale yellow solution was heated at reflux for 65 h, during which time a white solid separated (sodium chloride). The final mixture was cooled to room temperature and filtered to remove the NaCl, which was washed with acetone and diethyl ether, then dried under vacuum at 50° C. Expected yield of NaCl=9.4 g; isolated yield=9.47 g (100%).
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH2:58])[S:55][C:45]=2[C:46]([N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)=[N:47][CH:48]=1>C1COCC1>[CH3:41][O:42][C:43]1[C:44]2[N:57]=[C:56]([NH:58][C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[O:9])[S:55][C:45]=2[C:46]([N:49]2[CH2:50][CH2:51][O:52][CH2:53][CH2:54]2)=[N:47][CH:48]=1
Reactant: O=C(O)C1CCCCC1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)C3CCCCC3)nc12

Procedure:
From cyclohexanecarboxylic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 377 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:16][CH3:17])[CH:5]=[C:6]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[C:7]=1[C:8]#[N:9].[C:18]([N:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])[CH2:23][CH2:22]1)(=O)[CH3:19]>>[F:13][C:12]([F:14])([F:15])[CH2:11][O:10][C:6]1[CH:5]=[C:4]([O:16][CH3:17])[CH:3]=[C:2]([N:1]=[C:18]([N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[O:29])[CH2:23][CH2:22]2)[CH3:19])[C:7]=1[C:8]#[N:9]
Reactant: COc1cc(N)c(C#N)c(OCC(F)(F)F)c1
Reactant: CC(=O)N1CCCN(C(=O)N2CCOCC2)CC1
Product: COc1cc(N=C(C)N2CCCN(C(=O)N3CCOCC3)CC2)c(C#N)c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 95 %

Procedure:
The subtitle compound was prepared from 3-amino-4-cyano-5-(2,2,2-trifluoroethoxy)-anisole and 1-acetyl-4-(4-morpholinecarbonyl)-1,4-diazepane following a similar procedure to that described in Example 10(g) allowing the reaction to stir for 60 hours at room temperature. The crude product was purified on silica gel eluting with a solvent gradient of dichloromethane:methanol (100:0 to 95:5, v/v). The product was dissolved in a minimum volume of dichloromethane and an excess of ethereal hydrogen chloride added. The resulting precipitate was filtered off and partitioned between saturated aqueous sodium hydroxide solution (100 ml) and dichloromethane (200 ml). The organic layer was dried (MgSO4) and evaporated under reduced pressure to give the subtitle compound (1.83 g, 95%). Rf 0.58 (dichloromethane:methanol:0.880 aqueous ammonia 92:7:1, v/v). MS m/z 484 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4]([S:12]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1.[H-].[Na+].[CH3:28]I>CN(C=O)C>[CH3:1][O:2][C:3](=[O:25])[C:4]([S:12]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)(=[O:13])=[O:14])([CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1)[CH3:28]
Reactant: COC(=O)C(C1CCCC(=O)C1)S(=O)(=O)c1cccc2ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C1CCCC(=O)C1)S(=O)(=O)c1cccc2ccccc12
Yield: 16.7 %

Procedure:
In analogy to example 3.1:1.74 g (4.8 mmol) of (naphthalene-1-sulfonyl)-(3-oxo-cyclohexyl)-acetic acid methyl ester was dissolved in 10 mL of DMF at 0° C. 232 mg (5.3 mmol, 1.1 eq) of NaH (60%) were added and the reaction mixture was stirred 30 minutes before the addition of 1.03 g (7.2 mmol, 1.5 eq) of methyliodide. The reaction was stirred over night, poured on water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and evaporated. The resulting two diastereomers were separated by column chromatography on silica gel with AcOEt/heptane 2:1, yielded 0.30 g (17%) of (RS,SR)-2-(naphthalene-1-sulfonyl)-2-(3-oxocyclohexyl)-propionic acid methyl ester as a white foam MS: 375 (MH+) and 0.42 g (23%) of (RR,SS)-2-(naphthalene-1-sulfonyl)-2-(3-oxocyclohexyl)-propionic acid methyl ester as a white solid MS: 375 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.COC1C=CC(C[S:23][C@@H:24]2[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=3)=[O:30])[C@H:26]([C:42]([N:44]3[CH2:49][CH2:48][N:47]([C:50]([O:52][CH2:53][C:54]4[CH:59]=[CH:58][C:57]([N+:60]([O-:62])=[O:61])=[CH:56][CH:55]=4)=[O:51])[CH:46]([CH3:63])[CH2:45]3)=[O:43])[CH2:25]2)=CC=1>C1(OC)C=CC=CC=1>[SH:23][C@@H:24]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=2)=[O:30])[C@H:26]([C:42]([N:44]2[CH2:49][CH2:48][N:47]([C:50]([O:52][CH2:53][C:54]3[CH:55]=[CH:56][C:57]([N+:60]([O-:62])=[O:61])=[CH:58][CH:59]=3)=[O:51])[CH:46]([CH3:63])[CH2:45]2)=[O:43])[CH2:25]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C(=O)OCc4ccc([N+](=O)[O-])cc4)C(C)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC1CN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 0.83 h
Yield: 93.9 %

Procedure:
20 ml of trifluoroacetic acid and subsequently 0.50 ml of trifluoromethanesulfonic acid were added dropwise, whilst ice-cooling, to a solution of 2.0 g of (2S,4S)-4-(4-methoxybenzylthio)-2-[3-methyl-4-(4-nitrobenzyloxycarbonyl)piperazin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (i) above] in 3.08 ml of anisole, and the resulting mixture was stirred at the same temperature for 50 minutes. At the end of this time, the reaction mixture was worked up by the same procedure as described in Preparation 4(ii), to give 1.56 g of the title compound as an amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[S:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[CH:21]=1>>[S:24]1[C:20]([CH2:19][N:16]2[CH:11]([C:4]3[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]2=[O:17])=[CH:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]1=2
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: BrCc1cc2ccccc2s1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cc2ccccc2s1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with 2-(bromomethyl)benzo[b]thiophene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions F): tR=0.86 min.; [M+H]+: 382.22 g/mol.
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7]([O:14][CH2:15][CH3:16])(=[O:13])[C:8]([O:10]CC)=O.[C:17]1(=[O:32])[N:21]([CH2:22][CH2:23][C:24](=[O:26])[CH3:25])[C:20](=[O:27])[C:19]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:18]12.[Na]>C(O)C>[O:10]=[C:8]([CH2:25][C:24](=[O:26])[CH2:23][CH2:22][N:21]1[C:17](=[O:32])[C:18]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:19]2[C:20]1=[O:27])[C:7]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 54.6 %

Procedure:
4-Phthalimido-2-butanone was obtained from the literature procedure, Eriks et al, J. Med. Chem., 1992, 35, 3239-3246. Sodium tert-butoxide (20.75 g, 0.216 mol) was added over a period of 12 minutes to ethanol (160 mL) under a nitrogen atmosphere. When all solids had dissolved, diethyl oxalate (31.55 g, 0.216 mol) and a suspension of 4-phthalimido-2-butanone (46.9 g, 0.216 mol) were sequentially added. The reaction was stirred at ambient temperature for 2.5 hours. A precipitate was present and was isolated by filtration to provide 37.4 g of ethyl 2,4-dioxo-6-phthalimidohexanoate, sodium salt as a light orange solid.
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>O1CCOCC1>[O:15]1[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][NH:9][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])[CH2:13][CH2:14]1
Reactant: NCCN1CCOCC1
Reactant: O=C1CCCC(=O)O1
Solvent: C1COCCO1
Product: O=C(O)CCCC(=O)NCCN1CCOCC1
Reaction time: 0.75 h

Procedure:
There are added to 10 cm3 of dioxane, 1.517 g of glutaric anhydride and then, dropwise, 1.75 cm3 of N-(2-aminoethyl)morpholine. Stirring is continued at 20° C. for 0.75 hours. The white solid formed is filtered, washed successively with dioxane and diethyl ether, and then dried at 20° C. (90 Pa) to give 1.94 g of 5-(2-morpholinoethylamino)-5-oxopentanoic acid in the form of a white solid melting at 96° C.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]=2[N:3]=1.[CH3:19][Si:20]([CH3:34])([CH3:33])[CH2:21][CH2:22][O:23][CH2:24][N:25]1[C:29]([C:30](=[O:32])[CH3:31])=[CH:28][CH:27]=[N:26]1>>[CH2:14]([C@H:6]1[N:5]([CH:16]([CH3:18])[CH3:17])[C:4]2[N:3]=[C:2]([CH2:31][C:30](=[O:32])[C:29]3[N:25]([CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:34])([CH3:33])[CH3:19])[N:26]=[CH:27][CH:28]=3)[N:11]=[CH:10][C:9]=2[N:8]([CH3:12])[C:7]1=[O:13])[CH3:15]
Reactant: CC(=O)c1ccnn1COCC[Si](C)(C)C
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C(C)C
Product: CC[C@@H]1C(=O)N(C)c2cnc(CC(=O)c3ccnn3COCC[Si](C)(C)C)nc2N1C(C)C

Procedure:
Intermediates C-7 was prepared similarly to the synthetic methods used to prepare intermediate B-1, with Intermediate C instead of Intermediate B and with 1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)ethanone instead of acetophenone. LCMS: 473.3 m/z (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[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:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:38]([O:42][C:43](=[O:50])[NH:44][C@H:45]1[CH2:49][CH2:48][NH:47][CH2:46]1)([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43](=[O:50])[NH:44][C@H:45]1[CH2:49][CH2:48][N:47]([C:32]([N:12]2[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]=[C:11]2[C:8]2[CH:9]=[N:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][C:7]=2[O:35][CH2:36][CH3:37])=[O:33])[CH2:46]1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CC[C@H](NC(=O)OC(C)(C)C)C1

Procedure:
In a manner analogous to the method described in examples 8, (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 chloride (example 51) was coupled with (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C38H48Cl2N5O4 [(M+H)+] 708.3078, observed 708.3081.