Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[CH:12]1.CN1CCOCC1.Cl.[CH3:35][N:36]([CH3:53])[C:37]1([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH2:42][CH2:41][CH:40]([CH2:43][C:44](O)=[O:45])[CH2:39][CH2:38]1.C1(N=C=NC2CCCCC2)CCCCC1.C(NC1CCCCC1)(NC1CCCCC1)=O.[OH-].[Na+]>CN(C)C=O.O>[CH3:53][N:36]([CH3:35])[C:37]1([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH2:42][CH2:41][CH:40]([CH2:43][C:44]([NH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][CH:12]=2)=[O:45])[CH2:39][CH2:38]1
Reactant: CN(C)C1(c2ccccc2)CCC(CC(=O)O)CC1
Reactant: NCCCCCCc1c[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C(NC1CCCCC1)NC1CCCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CN(C)C1(c2ccccc2)CCC(CC(=O)NCCCCCCc2c[nH]c3ccccc23)CC1
Reaction time: 72 h
Yield: 58.1 %

Procedure:
1-Hydroxybenzotriazole (540 mg, 4.0 mmol), 6-(1H-indol-3-yl)hexylamine (432 mg, 2.0 mmol) and N-methylmorpholine (0.444 ml, 4.0 mmol) were added to a solution of 4-dimethylamino-4-phenylcyclohexyl-acetic acid hydrochloride (595 mg, 2.0 mmol) in dry dimethylformamide (10 ml) under argon. The clear solution was cooled in an ice-bath, dicyclohexylcarbodiimide (825 mg, 4.0 mmol) was added and the mixture was stirred at RT for 5 d, during which dicyclohexylurea precipitated out. Working up of the mixture was carried out by separating off the urea which had precipitated out and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). Still further urea thereby precipitated out and was separated off. After 10 min the crude product precipitated out of the filtrate and was filtered off. The aqueous phase was diluted with water (300 ml), 5 M sodium hydroxide solution (7 ml, 35 mmol) was added and the mixture was stored at 5° C. for 3 d. Further product thereby precipitated out as a beige-coloured solid in a yield of 9% (82 mg) with an m.p. of 152-156° C. The crude product was purified by chromatography on silica gel (40 g) with EA/methanol (4:1) and (1:1). The product was thereby isolated as a beige-coloured compound (534 mg) in a yield of 58%.
Reaction SMILES: [CH:1]([CH:3]([O:6][CH:7]([C:10]1[S:11][CH:12]=[C:13]([C:15](=[O:17])[NH2:16])[N:14]=1)[CH:8]=[O:9])[CH2:4][OH:5])=[O:2].[NH2:18][C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1>O>[OH:9][CH:8]1[C@H:7]([C:10]2[S:11][CH:12]=[C:13]([C:15](=[O:17])[NH2:16])[N:14]=2)[O:6][C@H:3]([CH2:4][OH:5])[CH:1]([OH:2])[N:18]1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: NC(=O)c1csc(C(C=O)OC(C=O)CO)n1
Reactant: Nc1ncccn1
Solvent: O
Product: NC(=O)c1csc([C@@H]2O[C@H](CO)C(O)N(c3ncccn3)C2O)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.7 %

Procedure:
[R-(R*, R*)]-α-(1-Formyl-2-hydroxyethoxy)-4-carbamoyl-2-1,3-thiazoleacetaldehyde (1.10 g) was dissolved in water (30 ml). To the solution was added 2-aminopyrimidine (0.41 g). The mixture was stirred at ambient temperature for five hours to give a clear solution. The solution was lyophilized to give 2-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-pyrimidinyl)morpholin-2-yl]-4-carbamoylthiazole (1.50 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1.C([Li])CCC.[C:15]1(=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C1COCC1>[CH3:9][O:8][C:4]1[N:5]=[CH:6][C:7]([C:15]2([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:2][CH:3]=1
Reactant: O=C1CCCCC1
Reactant: COc1cc(Br)ccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCCCC2)cn1
Temperature: -78 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
According to Scheme 26 Step 1: To a stirred solution of 4-bromo-2-methoxypyridine (1 eq, 5.30 mmol, 1.00 g) in anhydrous THF (30 mL) at −78° C. under nitrogen was added dropwise a solution of butyl lithium (1.3 eq, 2.5M solution in hexane, 6.90 mmol, 2.8 mL). The reaction was then stirred at −78° C. for 2 hours. Cyclohexanone (5 eq, 27.0 mmol, 2.8 mL) was then added dropwise over 5 minutes. The reaction was stirred at −78° C. for two hours then allowed to warm to room temperature. The reaction was stirred for a further 16 hours then quenched with water. The reaction was evaporated in vacuo, redissolved in CH2Cl2 (100 mL) and washed with brine (100 mL). The organic phase was extracted, dried over MgSO4, filtered and evaporated to leave a yellow oil. The oil was purified by column chromatography (AIT Flashsmart prepacked column 25 g SiO2, pure AcOEt), yielding the title compound (4.10 mmol, 0.86 g, 78%) as a colorless oil which solidified on standing.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][C:28]=1[O:35][CH3:36]>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[C:28]([O:35][CH3:36])[CH:29]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cc([Mg]Br)ccc1Cl
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)ccc1Cl

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 92 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 2.01 mL 0.25M 4-chloro-3-methoxyphenylmagnesium bromide. Yield: 40 mg of a white solid. LC-MSD, m/z for C23H16BrClN2O3 [M+H]+=483.0, 485.0; HPLC retention time: 2.5 min.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][C:22]=1[NH:29][C:30](=[O:48])[CH2:31][CH:32]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[C:39]=1[O:46][CH3:47])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O.C(OCC)(=O)C>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:23][C:22]=1[NH:29][C:30](=[O:48])[CH2:31][CH:32]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[C:39]=1[O:46][CH3:47])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH3:18])([CH3:19])[CH3:20]
Reactant: CCCCCC(CC(=O)Nc1cc(C=O)ccc1C(C)(C)C)c1cccc(OC)c1OC
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCC(CC(=O)Nc1cc(CCC(=O)OCC)ccc1C(C)(C)C)c1cccc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
1.23 ml (6.22 mmol) of ethyl diethylphosphonoacetate were added dropwise, whilst ice-cooling, over a period of 3 minutes to a suspension of 271 mg (6.22 mmol) of sodium hydride (as a 55% w/w dispersion in mineral oil) in 7 ml of dimethylformamide, and the resulting mixture was then stirred at room temperature for 30 minutes. A solution of 1.37 g (3.11 mmol) of N-(2-t-butyl-5-formylphenyl)-3-(2,3-dimethoxyphenyl)octanamide (prepared as described in Preparation 24), in 6 ml of dimethylformamide was ice-cooled and then added dropwise to the mixture over a period of 3 minutes. The resulting mixture was stirred at room temperature for 1.5 hours. At the end of this time, the reaction mixture was diluted with ethyl acetate, and the diluted solution was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. A solution of the residue in 20 ml of ethanol was stirred at room temperature for 8 hours in an atmosphere of hydrogen and in the presence of 400 mg of 10% palladiun-on-charcoal. At the end of this time, the reaction mixture was filtered using a Celite (trade mark) filter aid to remove the catalyst, and the filtrate was freed from the solvent by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.56 g (yield 98%) of the title compound as an oily substance.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:8]([NH:10][CH:11]2[C:31](=[O:32])[N:13]3[C:14]([C:18]([O:20]CC4C=CC([N+]([O-])=O)=CC=4)=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(O)(=O)C.O.CO>[C].[Pd].O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:8]([NH:10][CH:11]2[C:31](=[O:32])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(C(=NOCc2ccccc2)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)=CCS[C@H]23)cs1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(C(=NOCc2ccccc2)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Reaction time: 6 h
Yield: 52.7 %

Procedure:
A mixture of 4-nitrobenzyl 7-[2-(2-aminothiazol-4-yl)-2-benzyloxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 2.7 g.), 10% palladium carbon (1 g.), acetic acid (1 ml.), water (4 ml.), methanol (20 ml.) and tetrahydrofuran (30 ml.) was subjected to catalytic reduction at room temperature under ordinary pressure for 6 hours. After removing the insoluble substance from the resultant mixture by filtration, the filtrate was concentrated in vacuo. Water was added to the residue and adjusted to pH 7 to 8 with sodium bicarbonate, and the insoluble substance was filtered out. The filtrate was washed with ethyl acetate and adjusted to pH 3.0 with conc. hydrochloric acid under ice cooling. The precipitates were collected by filtration, washed with water and dried over phosphorus pentoxide to give 7-[2-(2-aminothiazol-4-yl)-2-benzyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 1.1 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][C:36]2[N:39]([CH3:43])[N:40]=[C:41]([CH3:42])[C:35]=2[CH2:34]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:30][CH2:31][CH2:32][N:33]4[CH2:38][CH2:37][C:36]5[N:39]([CH3:43])[N:40]=[C:41]([CH3:42])[C:35]=5[CH2:34]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Reactant: Cc1nn(C)c2c1CN(CCCCl)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCc2c(c(C)nn2C)C1
Temperature: 80 °C
Yield: 244.6 %

Procedure:
To a mixture of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (0.50 g, 0.16 mmol, 1.0 eq) and K2CO3 (0.05 g, 0.32 mmol, 2.0 eq) in 20 mL of DMF was added 5-(3-chloropropyl)-1,3-dimethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (0.05 g, 0.19 mmol, 1.2 eq) at room temperature. The reaction mixture was heated at 80° C. for 8.0 h and concentrated in vacuo. The residue was poured into a mixture of water (100 mL) and CH2Cl2 (150 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 30:1 (v/v) DCM/MeOH) to give the title compound as a yellow solid (0.20 g, 24.98%), HPLC: 95.21%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 513.02 (M+1); 1H NMR (400 MHz, d6-DMSO) δ: 1.91-2.08 (m, J=4.0 Hz 2H), 2.51 (s, 3H), 2.78 (s, 3H), 2.79-2.89 (m, 6H), 2.90-2.96 (m, 2H), 3.95 (s, 3H), 4.19 (m, 2H), 7.25 (s, 1H), 7.47 (t, J=8.12 Hz, 1H), 7.54 (s, 2H), 8.11 (t, J=5.16 Hz, 1H), 8.50 (s, 1H) ppm.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[S:22][C:16]2[N:17]=[CH:18][NH:19][C:20](=[O:21])[C:15]=2[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[C:31]1([CH2:34][N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)[CH2:33][O:32]1>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[S:22][C:16]2[N:17]=[CH:18][N:19]([CH2:33][C:31]([C:25]3[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=3[F:23])([OH:32])[CH2:34][N:35]3[CH:39]=[N:38][CH:37]=[N:36]3)[C:20](=[O:21])[C:15]=2[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]cnc2sc(CCCCOCc3ccccc3)cc12
Reactant: Fc1ccc(C2(Cn3cncn3)CO2)c(F)c1
Product: O=c1c2cc(CCCCOCc3ccccc3)sc2ncn1CC(O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
This compound was prepared by procedure B using 6-(4-benzyloxybutyl)-thieno[2,3-d]pyrimidin-4(3H)-one and 1[[2-(2,4-difluorophenyl)oxiranyl]methyl]-1H-1,2,4-triazole of the Formula (5). 1HNMR (CDCl3, 200 MHz): 1.61-1.86 (m, 4H), 2.84 (t, J=6 Hz, 2H), 3.49 (t, J=6 Hz, 2H), 4.23 (d, J=16 Hz, 1H), 4.49 (s, 2H), 4.53 (d, J=16 Hz, 1H), 4.72 (d, J=16 Hz, 1H), 4.80 (d, J=16 Hz, 1H), 6.22 (s, 1H), 6.72-6.90 (m, 2H), 7.08 (s, 1H), 7.32 (bs, 5H), 7.50-7.62 (m, 1H), 7.84 (s, 1H), 7.92 (s, 1H), 8.10 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][N:7]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:6][CH2:5][N:4]1C(OC(C)(C)C)=O.[ClH:26]>C(#N)C>[ClH:26].[OH:1][CH2:2][C@H:3]1[NH:4][CH2:5][CH2:6][N:7]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1CO
Agent: Cl
Solvent: CC#N
Product: O=C(OCc1ccccc1)N1CCN[C@H](CO)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
4-Benzyl 1-tert-butyl (2S)-2-(hydroxymethyl)piperazine-1,4-dicarboxylate (see WO 02/000631; 1.6 g, 4.6 mmol was dissolved in acetonitrile (25 mL) and to the resultant solution was added concentrated HCl (1 mL). The mixture was stirred at RT overnight and then the solvent was removed by evaporation. There was obtained 1.3 g (100%) of benzyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate hydrochloride as a colorless oil. 1H NMR (500 MHz, CD3OD): 3.1-3.4 (m, 5H), 3.7 (m, 1H), 3.8 (m, 1H), 4.2 (m, 2H), 5.2 (m, 2H), 7.2-7.4 (m, 5H); LCMS: m/z 251 (M+1)+.
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C@@H:8]([CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[C:9]([OH:11])=[O:10])[CH:2]=1.N[C@H](CC1C=C(OC)C(OC)=C(OC)C=1)C(O)=O>>[C:1]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C@H:8]([CH2:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[C:9]([OH:11])=[O:10])[CH:2]=1
Reactant: COc1cc(C[C@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc(OC)c1OC
Agent: COc1cc(C[C@@H](N)C(=O)O)cc(OC)c1OC
Product: COc1cc(C[C@@H](Nc2cccc(-c3ccccc3)c2)C(=O)O)cc(OC)c1OC

Procedure:
The title compound is prepared as described for (S)-2-(Biphenyl-3-ylamino)-3-(3,4,5-trimethoxy-phenyl)-propionic acid (example 1) but using (R)-2-amino-3-(3,4,5-trimethoxy-phenyl)-propionic acid (3,4,5-OCH3-phe-OH).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[CH2:6][CH:7]([CH2:11][CH3:12])[C:8](O)=[O:9].S(Cl)([Cl:20])=O>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[CH2:6][CH:7]([CH2:11][CH3:12])[C:8]([Cl:20])=[O:9]
Reactant: CCC(Cc1cccc(C(F)(F)F)c1)C(=O)O
Reactant: O=S(Cl)Cl
Product: CCC(Cc1cccc(C(F)(F)F)c1)C(=O)Cl
Yield: 92.2 %

Procedure:
To 1.0 g (4.1 mmol) of 2-(m-trifluoromethylbenzyl)butanoic acid was added 0.98 g (8.2 mol) of thionyl chloride, and the resulting mixture was refluxed for 3 hours. Thionyl chloride was removed by an evaporator to obtain 1.0 g of 2-(m-trifluoromethylbenzyl)butanoic acid chloride as a colorless liquid.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=O)[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[NH2:48][CH2:49][CH:50]([OH:53])[CH2:51][OH:52]>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([NH:48][CH2:49][CH:50]([OH:53])[CH2:51][OH:52])=[O:44])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:4])([CH3:3])[CH3:5]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: NCC(O)CO
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NCC(O)CO)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(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]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with 3-amino-propane-1,2-diol (Aldrich) to give the title compound as a mixture of diastereomers. HR-MS (ES, m/z) calculated for C38H49Cl2N6O5 [(M+H)+] 739.3136, observed 739.3139.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH:9]2[CH2:10][CH2:11][CH:5]1[CH2:6][NH:7][CH2:8]2.Cl[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)C(N1CC2N(C)C(CC2)C1)=O)C>>[C:13]([N:7]1[CH2:6][CH:5]2[N:4]([CH3:3])[CH:9]([CH2:10][CH2:11]2)[CH2:8]1)([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)Cl
Reactant: CN1C2CCC1CNC2
Agent: CCN(CC)C(=O)N1CC2CCC(C1)N2C
Agent: Cl
Product: CCOC(=O)N1CC2CCC(C1)N2C
Yield: 73 %

Procedure:
8-Methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (2.5 g, 0.0126 mole), prepared as described in Example 1, was reacted with 1.51 ml (0.0189 mole) ethyl chloroformate according to the procedure described above for 3-(N,N-diethylcarbamyl)-8-methyl-3,8-diazabicyclo[3.2.1]octane in Example 1. A white monohydrochloride, melting point 200°-205° C, was obtained in 73% yield: 2.16 g.
Reaction SMILES: C[O:2][C:3](=[O:38])[C:4]([CH3:37])([CH3:36])[CH2:5][C:6]1[N:7](C2C=CC([N+]([O-])=O)=CC=2)[C:8]2[C:13]([C:14]=1[S:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16])=[CH:12][C:11]([CH:24]([CH3:26])[CH3:25])=[CH:10][CH:9]=2.[OH-].[Na+].Cl>C(OCC)(=O)C.CO.C1COCC1.[Pd]>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:24][N:7]2[C:8]3[C:13](=[CH:12][C:11]([CH:24]([CH3:26])[CH3:25])=[CH:10][CH:9]=3)[C:14]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[C:6]2[CH2:5][C:4]([CH3:36])([CH3:37])[C:3]([OH:2])=[O:38])=[CH:10][CH:9]=1
Reactant: COC(=O)C(C)(C)Cc1c(S(=O)(=O)c2ccccc2)c2cc(C(C)C)ccc2n1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)c1ccc2c(c1)c(S(=O)(=O)c1ccccc1)c(CC(C)(C)C(=O)O)n2Cc1ccc(N)cc1
Reaction time: 16 h

Procedure:
A solution of 480 mg methyl[1-(4-nitrophenyl)-α,α-dimethyl-5-isopropyl-3-phenylsulfonylindole-2-propanoate] in 45 ml ethyl acetate was heated with 100 mg Pd/C (5%) catalyst and the solution hydrogenated a 45 psi for 16h. A further 50 mg catalyst was added and the hydrogenation continued for another 16h. The catalyst was removed by filtration through celite and the product isolated (480 mg) after removal of solvent. Hydrolysis was achieved by treatment of the ester with 2N NaOH in 3 ml MeOH/THF 1:1. The solution was neutralized with 0.5N HCl and the product extracted with ethyl acetate 3×10 ml. The solution was dried (Na2SO4) and stripped to yield the title product, m.p. 290° decomposition.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[C:12]2=[O:22])=[CH:7][CH:6]=1.[I-].[CH3:26][S+](C)(C)=O>>[F:24][C:2]([F:1])([F:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:16][CH2:17][C:18]4([O:21][CH2:26]4)[CH2:19][CH2:20]3)[C:12]2=[O:22])=[CH:7][CH:6]=1
Reactant: O=C1CCC2(CC1)CCN(c1ccc(OCC(F)(F)F)cc1)C2=O
Reactant: C[S+](C)(C)=O
Agent: [I-]
Product: O=C1N(c2ccc(OCC(F)(F)F)cc2)CCC12CCC1(CC2)CO1

Procedure:
The title compound was prepared in analogy to example 346 step 1 from 2-[4.5]decane-1,8-dione (described in example 86 step 1) and trimethylsulfoxonium iodide. White solid (87%). MS (m/e): 356.1 [MH+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH3:24])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=[CH:32][C:31]=1[N:45]1[CH2:57][CH2:56][N:48]2[C:49]3[CH2:50][CH2:51][CH2:52][CH2:53][C:54]=3[CH:55]=[C:47]2[C:46]1=[O:58])(=[O:27])[CH3:26].C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.C(Cl)Cl>[C:25]([O:28][CH2:29][C:30]1[C:31]([N:45]2[CH2:57][CH2:56][N:48]3[C:49]4[CH2:50][CH2:51][CH2:52][CH2:53][C:54]=4[CH:55]=[C:47]3[C:46]2=[O:58])=[CH:32][CH:33]=[CH:34][C:35]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH3:24])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:27])[CH3:26]
Reactant: CCN1CCN(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CCN1CCN(c2ccc(Nc3cc(-c4cccc(N5CCn6c(cc7c6CCCC7)C5=O)c4COC(C)=O)cn(C)c3=O)nc2)CC1

Procedure:
To a microwave tube equipped with a stirring bar, 138c (250 mg, 0.637 mmol), 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a (325.5 mg, 0.701 mmol), Pd(PPh3)4 (36.8 mg, 0.0319 mmol), Na2CO3 aqueous solution (1.0 N, 2.10 mL, 2.10 mmol), DME (2.0 mL) were added. The mixture was reacted in microwave at 135° C. for 15 min. CH2Cl2 (200 mL) was added and the resulting mixture was washed with water (30 mL×3), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (MeOH:CH2Cl2=5:95) gave 2-(5-(5-(4-ethylpiperazin-1-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-6-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzyl acetate 138d.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([O:17][CH3:18])=[O:16]>C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:14]1[O:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccco1
Reactant: Cc1ccccc1CBr
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(Cc2ccccc2C)o1
Yield: 33.5 %

Procedure:
A mixture of 2-methylbenzyl bromide [prepared as described by Radziszewaki and Wispek, Ber, 15, 1747 (1882); 18.5 g.], methyl 2-furoate (15.3 g.) and anhydrous ferric chloride (0.3 g.) in dry carbon tetrachloride (25 ml.) was heated on a steam bath under reflux for 18 hours and then distilled to give crude methyl 5-(2-methylbenzyl)-2-furoate (7.7 g.) in the form of a pale brown coloured oil, b.p. 120°-145° C./0.1 mm.Hg, suitable for use as a starting material in procedures hereinafter described.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[CH:12]1([C:15](=O)[CH2:16][C:17](OCC)=[O:18])[CH2:14][CH2:13]1>>[CH:12]1([C:15]2[CH:16]=[C:17]([OH:18])[N:1]([C:3]3[CH:8]=[C:7]([CH:6]=[CH:5][N:4]=3)[C:9]([OH:11])=[O:10])[N:2]=2)[CH2:14][CH2:13]1
Reactant: NNc1cc(C(=O)O)ccn1
Reactant: CCOC(=O)CC(=O)C1CC1
Product: O=C(O)c1ccnc(-n2nc(C3CC3)cc2O)c1
Yield: 24 %

Procedure:
The title compound was prepared in 24% yield from 2-hydrazinylpyridine-4-carboxylic acid and ethyl 3-cyclopropyl-3-oxopropanoate according to the procedure for the preparation of Example 1. 1H NMR (400 MHz, CD3OD): δ 0.83-0.88 (2H, m), 1.05-1.09 (2H, m), 1.88-1.91 (1H, m), 4.86 (1H, s), 7.70 (1H, dd, J=5.2, 1.2 Hz), 8.54 (1H, d, J=5.2 Hz), 8.75 (1H, s). [M+H] Calc'd for C12H11N3O3, 246. Found, 246.