Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[C:15]3[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=3[CH:13]=[C:12]([C:21](O)=[O:22])[CH:11]=2)=[CH:7][C:6]=1[F:26])=[O:4].[NH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[O:34])=[CH:31][N:30]=1>>[CH3:1][N:2]([CH3:27])[C:3]([C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[C:15]3[CH2:16][C:17]([CH3:19])([CH3:20])[O:18][C:14]=3[CH:13]=[C:12]([C:21]([NH:28][C:29]3[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[O:34])=[CH:31][N:30]=3)=[O:22])[CH:11]=2)=[CH:7][C:6]=1[F:26])=[O:4]
Reactant: NC(=O)c1ccc(N)nc1
Reactant: CN(C)C(=O)c1ccc(Oc2cc(C(=O)O)cc3c2CC(C)(C)O3)cc1F
Product: CN(C)C(=O)c1ccc(Oc2cc(C(=O)Nc3ccc(C(N)=O)cn3)cc3c2CC(C)(C)O3)cc1F

Procedure:
The title compound was prepared in a similar manner as described for Example 144, from 4-(4-dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (143a) (80 mg, 0.21 mmol) and 6-aminonicotinamide (58.8 mg, 0.429 mmol) to give a brown solid (5 mg, 5% yield). 1H NMR (400 MHz, MeOD.) δ 8.82 (d, J=1.52 Hz, 1 H) 8.14-8.32 (m, 2 H) 7.31-7.44 (m, 1 H) 7.18 (dd, J=8.34, 1.26 Hz, 2 H) 6.80-6.97 (m, 2 H) 3.10 (s, 3 H) 2.98 (s, 3 H) 2.93 (s, 2 H) 1.47 (s, 6 H); LCMS for C26H25FN4O5 m/z 493.20 (M+H+).
Reaction SMILES: Cl[C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:10][C@:11]1([CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:13][O:12]1.C(=O)([O-])O.[Na+]>C(O)C>[CH3:13][C@@:11]1([CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19][CH2:20]2)[O:12][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Reactant: CCOC(=O)C1CCN(C[C@@]2(C)CO2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1CCN(C[C@@]2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Yield: 19.6 %

Procedure:
2-Chloro-4-nitro-1H-imidazole (3.7 g, 25.1 mmol), ethyl (S)-1-(2-methyloxiran-2-ylmethyl)piperidine-4-carboxylate (4.8 g, 21.1 mmol) and sodium hydrogencarbonate (2.2 g, 25.1 mmol) in ethanol (25 ml) were stirred under reflux overnight. The reaction mixture was concentrated under reduced pressure. To the residue, water was added, and the solution was extracted with methylene chloride. The organic phase was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1) and crystallized from diethyl ether to afford ethyl (S)-1-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperidine-4-carboxylate (1.4 g, yield 20%) as a white powder.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([OH:8])[CH:3]=1.[H-].[Na+].CI.[C:13]([O-])(O)=O.[Na+]>CN(C)C=O>[I:1][C:2]1[CH:7]=[CH:6][N:5]([CH3:13])[C:4](=[O:8])[CH:3]=1
Reactant: Oc1cc(I)ccn1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccc(I)cc1=O
Reaction time: 0.08 h

Procedure:
To a solution of 4-iodopyridin-2-ol (450 mg, 2.0 mmol, Maybridge, Cat. No. MO07919) in N,N-dimethylformamide (7 mL) was added sodium hydride (120 mg, 3.0 mmol, 60% dispersion in mineral oil) at 0° C., the solution was stirred 5 min., then methyl iodide (250 uL, 4.1 mmol) was added. The reaction mixture was stirred at r.t. for 2 h., and then poured into aqueous NaHCO3 solution, extracted with AcOEt. The organic layer was washed by water and brine, dried over MgSO4, filtered, and concentrated to afford the desired compound which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=235.9.
Reaction SMILES: [CH3:1][Si:2]([CH3:23])([CH3:22])[CH2:3][CH2:4][O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7].[ClH:24]>C(O)C.[Pd]>[ClH:24].[CH3:1][Si:2]([CH3:23])([CH3:22])[CH2:3][CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH2:21])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7]
Reactant: C[Si](C)(C)CCOC(=O)N1CC=C(c2cccc(C#N)c2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: C[Si](C)(C)CCOC(=O)N1CCC(c2cccc(CN)c2)CC1
Reaction time: 4 h

Procedure:
4-(3-Cyanophenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid 2-trimethylsilanyl-ethyl ester (10.40 g, 32 mmol) was dissolved in ethanol (250 ml), concentrated hydrochloric acid (3 ml, 35 mmol) and 10% palladium on carbon (50% wet, 5.0 g) was added. The mixture was hydrogenated at 50 psi for 4 hours then filtered through celite and concentrated. The oily solid obtained was triturated with ether/pentane and 4-(3-aminomethyl-phenyl)-piperidine-1-carboxylic acid 2-trimethylsilanyl-ethyl ester hydrochloride was obtained as a white solid (7.10 g). 1H NMR [(CD3)2SO, 300 MHz]: δ 8.38 (br s, 2H), 7.20-7.40 (m, 4H), 4.10 (t, 4H), 3.98 (s, 2H), 2.63-3.00 (m, 3H), 1.75 (m, 2H), 1.50 (m, 2H), 0.94 (t, 2H), 0.02 (s, 9H). LC-MS (ES) 335 (M++H), 93% TIC.
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.[CH2:11]([Mg]Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[O:9]=[C:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH2:7][CH:8]1[NH:4][C:3](=[O:10])[CH2:2][CH2:1]1
Reactant: O=C1CCC2CCC(=O)N12
Reactant: Cl[Mg]Cc1ccccc1
Solvent: ClCCl
Product: O=C(CCC1CCC(=O)N1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
To a solution of tetrahydro-pyrrolizine-3,5-dione (5 g, 36 mmol) in CH2Cl2 (320 mL) at 0° C. was added benzyl magnesium chloride (1 M solution in THF, 39 mL, 39 mmol) dropwise. The solution was stirred at 0° C. for 3 h and was quenched with saturated aqueous ammonium chloride. After warming to room temperature, the aqueous solution was extracted with CH2Cl2 (3×). The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography eluting with a solvent gradient (1% MeOH in CH2Cl2to 2% MeOH in CH2Cl2) to yield 5.9021 g of 5-(3-oxo-4-phenyl-butyl)-pyrrolidin-2-one. 1H NMR (CDCl3) δ7.35-7.18 (m, 5H), 3.69 (s, 2H), 3.56 (m, 1H), 2.50 (t, 2H), 2.27 (m, 2H), 2.15 (m, 1H), 1.73 (m, 2H), 1.61 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:29])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:26]([NH2:28])=[O:27])=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([CH:40]=O)=[C:35]([CH:39]=1)[C:36]([OH:38])=[O:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.O1CCCC1>[C:26]([C:11]1[C:12]2[NH:13][C:14]3[C:19]([C:20]=2[C:8]([C:4]2[C:3]([CH3:29])=[C:2]([NH:1][CH2:40][C:34]4[CH:33]=[CH:32][C:31]([Cl:30])=[CH:39][C:35]=4[C:36]([OH:38])=[O:37])[CH:7]=[CH:6][CH:5]=2)=[CH:9][N:10]=1)=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][O:24][CH3:25])[CH:15]=3)(=[O:27])[NH2:28]
Reactant: O=Cc1ccc(Cl)cc1C(=O)O
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(N)c3C)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COCCOc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3cccc(NCc4ccc(Cl)cc4C(=O)O)c3C)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.4 %

Procedure:
A mixture of 4-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide (60.0 mg, 0.154 mmol), 5-chloro-2-formylbenzoic acid (70.9 mg, 0.384 mmol), sodium triacetoxyborohydride (98 mg, 0.461 mmol), and acetic acid (0.018 mL, 0.307 mmol) in dichloroethane (3 mL) and tetrahydrofuran (2 mL) was stirred at room temperature for 16 hr and then quenched with water (3 mL). The resulting mixture was diluted with ethyl acetate (50 mL) and washed with water (25 mL). The aqueous solution was extracted with ethyl acetate (2×30 mL). The combined extract was washed with brine (25 mL) and dried over anhydrous MgSO4. The organic solution was concentrated under vacuum to dryness. The residue was dissolved with minimum amount of DMF, diluted with MeOH (3 mL), divided into 2 portions, and purified by prep. reverse phase HPLC. The correct fractions were combined, concentrated under vacuum, and lyophilized to afford the desired product (TFA salt) (38 mg, 0.056 mmol, 36.7% yield) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][CH:8]2[NH:12]C(=O)N[C:9]2=[O:14])=[CH:5][CH:4]=1.[OH-:17].[Na+].Cl>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]([C:9]([OH:14])=[O:17])[NH2:12])=[CH:15][CH:16]=1
Reactant: COc1ccc(CC2NC(=O)NC2=O)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc(CC(N)C(=O)O)cc1

Procedure:
A solution of 148 g. of 5-p-methoxybenzyl hydantoin and 188 g. of sodium hydroxide in one liter of water is heated at reflux for 25 hours. The solution is cooled and made acid to pH 1 with concentrated hydrochloric acid. The formed solid is separated by filtration, washed with water and dried to give the above named compound, mp. 255° C. dec.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][C:7]1[C:8]([OH:15])=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11].C(=O)([O-])[O-].[Na+].[Na+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CC(C)=O>[CH3:1][O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][C:7]1[C:8]([O:15][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11]
Reactant: COc1c(C)c(Cc2cccc(C=O)c2O)c(OC)c(OC)c1OC
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1c(C)c(Cc2cccc(C=O)c2OCc2ccccc2)c(OC)c(OC)c1OC
Yield: 82.6 %

Procedure:
3-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzaldehyde (1.16 g, 3.35 mol) was dissolved in acetone (5.0 ml) and, after addition of anhydrous sodium carbonate (1.02 g, 7.38 mmol) and benzyl bromide (0.69 g, 4.02 mmol), the mixture was heated to reflux for 3 hours. The reaction solution was filtered and the residue obtained by concentration of the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the title compound (1.45 g, 3.32 mmol, 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][C:36](O)=[O:37])[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O.CO.CCCCCC>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH:32]([CH2:35][C:36](=[O:37])[NH:1][C:2]2[CH:3]=[C:4]3[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]4=[C:7]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[NH:8][C:9]([CH:10]=2)=[C:5]34)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)Nc2cc3c4c(c(-c5ccccc5)[nH]c4c2)C=NNC3=O)CC1
Yield: 100 %

Procedure:
Preparation of example 30 from the title compound of Example 7 (hydrochloride) (22 mg, 0.07 mmol), 4-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (20 mg, 0.084 mmol), triethylamine (0.015 mL, 0.105 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (32 mg, 0.084 mmol) in CH2Cl2 (0.3 mL) and N,N-dimethylformamide (0.3 mL) was carried out analogously to Example 11. Silica gel chromatography (8:5:2 CH2Cl2:hexane:methanol), also in an analogous manner, afforded the title compound (35 mg, 0.070 mmol) as a yellow powder in 100% yield.
Reaction SMILES: C(OC(=O)[N:7]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1)[C:8]1[N:13]=[C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:11]=[N:10][CH:9]=1)(C)(C)C.[ClH:29].CCOCC>CO>[ClH:29].[F:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][NH:7][C:8]1[N:13]=[C:12]([N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[CH:11]=[N:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(F)c1)c1cncc(N2CCNCC2)n1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Fc1cccc(CNc2cncc(N3CCNCC3)n2)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 81.6 %

Procedure:
To a solution of (3-fluoro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-6′-yl)-carbamic acid tert-butyl ester I-4c (1.09 g, 2.82 mmol) in Methanol (6 mL) was treated with 1.0 M HCl/ether (28.2 mL, 28.2 mmol). The reaction mixture was stirred at ambient temperature for 19 h and concentrated in vacuo. The residue was repulped overnight in a mixture of Methanol (5 mL) and Ether (40 mL). The resulting tan solid was filtered and dried under high vacuum to afford the title compound 4-L (745 mg).
Reaction SMILES: [N+:1]([C:4]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].Br[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:11][C:10]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH:6][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1
Reactant: OCCc1ccc(Br)cc1
Reactant: Cc1cccc(N)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cccc(Nc2ccc(CCO)cc2)c1[N+](=O)[O-]
Temperature: 200 °C
Yield: 20.7 %

Procedure:
A mixture of 2-nitro-3-methylaniline (Newman, M. S.; Kannan R. J. Org. Chem., 1976, 41, 3356., 1.9 g, 12.4 mmol), 4-bromophenylethyl alcohol (2.5 g, 12.4 mmol), K2CO3 (1.7 g, 12.4 mmol) and Cul (230 mg, 1.24 mmol) was placed in a sealed tube and heated at 200° C. for 2 h. After cooling, the mixture was poured into water (100 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with 2N aqueous NaOH (100 mL) and brine (100 mL), then dried (Na2SO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 700 mg (21%) of the title compound as an orange oil: 1H-NMR (CDCl3) δ 7.77 (1H, br.s), 7.09-7.45 (6H, m), 6.69 (1H, d, J=6.3 Hz), 3.83 (2H, t, J=6.6 Hz), 2.82 (2H, t, J=6.6 Hz), 2.59 (3H, s).
Reaction SMILES: ONC([C@H]([C@@H](CC(C)C)C(NN1C(=O)C2(CCN(S(C)(=O)=O)CC2)NC1=O)=O)CCCC1C=CC=CC=1)=O.O1CCCCC1[O:45][NH:46][C:47]([C@H:49]([CH:59]([CH2:73][CH:74]([CH3:76])[CH3:75])[C:60]([NH:62][N:63]1[C:67](=[O:68])[C@H:66]([CH2:69][O:70][CH3:71])[NH:65][C:64]1=[O:72])=[O:61])[CH2:50][CH2:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:48]>>[OH:45][NH:46][C:47]([C@H:49]([C@@H:59]([CH2:73][CH:74]([CH3:76])[CH3:75])[C:60]([NH:62][N:63]1[C:67](=[O:68])[C@H:66]([CH2:69][O:70][CH3:71])[NH:65][C:64]1=[O:72])=[O:61])[CH2:50][CH2:51][CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)=[O:48]
Reactant: COC[C@@H]1NC(=O)N(NC(=O)C(CC(C)C)[C@H](CCCc2ccccc2)C(=O)NOC2CCCCO2)C1=O
Agent: CC(C)C[C@@H](C(=O)NN1C(=O)NC2(CCN(S(C)(=O)=O)CC2)C1=O)[C@H](CCCc1ccccc1)C(=O)NO
Product: COC[C@@H]1NC(=O)N(NC(=O)[C@H](CC(C)C)[C@H](CCCc2ccccc2)C(=O)NO)C1=O

Procedure:
In a manner analogous to that described in Example 3 from 0.561 g of 2(R)-[[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenylbutyl]-N-[4(S)-(methoxymethyl)-2,5-dioxo-1-imidazolidinyl]-4-methylvaleramide there was obtained 0.11 g of 2(R)-[1(S)-(hydroxycarbamoyl)-4-phenylbutyl]-N-[4(S)-(methoxymethyl)-2,5-dioxo-1-imidazolidinyl]-4-methylvaleramide in the form of an off-white solid.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:12][C@H:11](C(C)(C)C)[N:10](C)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC(=O)[C@H](CC1C=CC=CC=1)N>CN>[CH3:11][NH:10][C:9](=[O:18])[C@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[NH2:12]
Reactant: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Agent: CN
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Product: CNC(=O)[C@@H](N)Cc1ccccc1
Yield: 82 %

Procedure:
Hydrochloride salt of (2S,5S)-5-benzyl-2-tert-butyl-3-methylimidazolidin-4-one (1): To a solution of ethanolic MeNH2 (8.0 M, 50 ml) was added (S)-phenylalanine methyl ester (23.0 g, 130 mmol). The resulting solution was stirred at room temperature until the amino ester was judged to be consumed by TLC analysis. The resulting solution was then concentrated to provide (S)-phenylalanine N-methyl amide (18 g, 82% yield) as a white solid. To a flask containing (S)-phenylalanine N-methyl amide (8.9 g, 50 mmol) was added THF (100 ml), trimethylacetaldehyde (5.4 g, 50 mmol), FeCl3 (1.7 g, 10 mmol) and 4 Å MS (5.0 g). The resulting mixture was stirred at room temperature for 36 h, then washed with H2O (3×100 mL). The combined organics were concentrated and the resulting residue was treated with HCl (27 mL, 1N in ether). The resulting heterogeneous mixture was filtered to removed the undesired trans isomer.HCl salt and the resulting solution was concentrated. The residue was recrystallized (9:1 pentane/CH2Cl2) to provide the product (1) as a crystalline solid (2.88 g, 23% yield, >99% ee). IR (film) 3343, 2958, 1605, 1028 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.31-7.17 (m, 5H, ArH), 4.04 (s, 1H, NCHN), 3.72-3.65 (m, 1H, CHCH2), 3.13 (dd, J=4.1, 13.7 Hz, 1H, CH2), 2.92 (dd, J=7.7, 13.7 Hz, 1H, CH2), 2.90 (s, 3H, NCH3), 0.82 (s, 9H, C(CH3)3); 13C NMR (75 MHz, CDCl3) δ 175.3, 138.0, 129.8, 128.7, 126.8, 82.7, 77.8, 77.4, 76.9, 59.7, 38.6, 35.4, 31.0, 25.7; [α]D=−39.6 (c=1.0, CHCl3). The enantiomeric ratio was determined by HPLC using a Chiralpak OD-H and OD guard column (3.0% i-PrOH/hexanes, 1 mL/min); (5S) isomer tr=16.7 min, (5R) isomer tr=20.1 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([C@H:22]([O:24][CH3:25])[CH3:23])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26]N1C(=O)CCC1=O>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([C@H:22]([O:24][CH3:25])[CH3:23])=[C:14]([Cl:26])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CO[C@H](C)c1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Product: CO[C@H](C)c1nc2c(cc1Cl)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 5, intermediate from (4R,9aR)-6-(1-(R)-methoxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester and N-chlorosuccinimide.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[CH3:5][N:6]([CH3:15])[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[OH-].[Na+]>[Cl-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.[Cl-].[Na+].O>[CH3:5][N:6]([CH3:15])[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH:1][C:2](=[O:3])[CH:4]=[CH:11][C:10]2[CH:13]=[CH:14][C:7]([N:6]([CH3:15])[CH3:5])=[CH:8][CH:9]=2)=[CH:9][CH:8]=1
Reactant: CC(C)=O
Reactant: CN(C)c1ccc(C=O)cc1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CN(C)c1ccc(C=CC(=O)C=Cc2ccc(N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 21.9 %

Procedure:
To a solution of 1.0 g (17.22 mmol) of acetone and 5.26 g (35.30 mmol) of 4-dimethylamino benzaldehyde in 172 mL of a 0.25M solution of aqueous NaOH (43.05 mmol) was added 2.26 mL (1.72 mmol) of a 25% w/w aqueous solution of cetyltrimethylammonium chloride. The mixture was allowed to stir vigorously at room temperature for 72 hours, diluted with 100 ml of brine and extracted with two 75 mL portions of methylene chloride. The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was recrystallized from ethyl acetate to provide 1.21 g (22%) of a dark red powder.
Reaction SMILES: [C:1]([NH:11][C@@H:12]1[C:31](=[O:32])[N:14]2[C:15]([C:28]([OH:30])=[O:29])=[C:16]([CH2:19]OC(=O)CCC(O)=O)[CH2:17][S:18][C@H:13]12)(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[SH:33][C:34]1[N:38]([CH3:39])[N:37]=[N:36][N:35]=1.C(=O)([O-])O.[Na+:44]>O>[Na+:44].[C:1]([NH:11][C@@H:12]1[C:31](=[O:32])[N:14]2[C:15]([C:28]([O-:30])=[O:29])=[C:16]([CH2:19][S:33][C:34]3[N:38]([CH3:39])[N:37]=[N:36][N:35]=3)[CH2:17][S:18][C@H:13]12)(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: Cn1nnnc1S
Reactant: O=C(O)CCC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)[C@H](O)c3ccccc3)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cn1nnnc1SCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)[C@H](O)c3ccccc3)[C@H]2SC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
In water (5 ml) was dissolved 7β-(D-mandelamido)-3-(3-carboxypropionyloxy)methyl-3-cephem-4-carboxylic acid (0.46 g) together with 5-mercapto-1-methyl-1H-tetrazole (0.12 g) and sodium hydrogen carbonate (0.25 g). The solution was stirred at 60° C. for 1 hour and a half. After cooling in the air, the reaction mixture was subjected to column chromatography on Amberlite XAD-2, elution being carried out with water and, then, with a solvent mixture of water and methanol. The fractions containing the desired compound are pooled, concentrated and lyophilized. The procedure provided 7β-(D-mandelamido)-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid sodium salt (0.31 g)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:5]2=[N:6][CH:7]=1.[CH3:34][O:35][C:36]1[C:41]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][N:37]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[CH:15]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([C:39]4[CH:40]=[C:41]([NH:42][S:43]([CH3:46])(=[O:44])=[O:45])[C:36]([O:35][CH3:34])=[N:37][CH:38]=4)[CH:3]=3)[N:8]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:26])=[O:25])[CH:9]=2)[CH:12]=[N:13]1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ncc(-c2cnc3c(c2)c(-c2cnn(Cc4cccc(F)c4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Yield: 58.6 %

Procedure:
Using similar reaction conditions as described in step-ii of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (compound of step-i of example 9) (100 mg, 0.19 mmol) was coupled with N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide (Intermediate 65D) (69 mg, 0.20 mmol) using sodium carbonate (61 mg, 0.57 mmol) and Pd(PPh3)2Cl2 (7 mg, 0.009 mmol) in DME/water (5/0.5 mL). This afforded 72 mg (58.5% yield) of the titled compound.
Reaction SMILES: BrCC(C1C=CC([Cl:11])=C(S(=O)(=O)N(C)C)C=1)=O.C(NC(NCCC)=S)CC.Br.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2([OH:48])[CH2:40][S:39][C:38](=[N:41][CH2:42][CH2:43][CH3:44])[N:37]2[CH2:45][CH2:46][CH3:47])=[CH:32][C:31]=1[S:49](=[O:54])(=[O:53])[N:50]([CH3:52])[CH3:51]>C(OCC)C>[ClH:11].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2([OH:48])[CH2:40][S:39][C:38](=[N:41][CH2:42][CH2:43][CH3:44])[N:37]2[CH2:45][CH2:46][CH3:47])=[CH:32][C:31]=1[S:49](=[O:54])(=[O:53])[N:50]([CH3:52])[CH3:51]
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Agent: Br
Agent: CCCN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)N(C)C)c2)N1CCC
Agent: CCCNC(=S)NCCC
Solvent: CCOCC
Product: Cl

Procedure:
6.8 g of 2-bromo-4'-chloro-3'-dimethylsulfamoylacetophenone were reacted according to Example 23 with 3.3 g of 1,3-dipropylthiourea. After adding 200 ml of diethyl ether, 4-(4-chloro-3-dimethylsulfamoylphenyl)-3-propyl-2-propylimino-1,3-thiazolidine-4-ol-hydrobromide was separated as an oil. The solvent was decanted, the product was dissolved in 30 ml of water and extracted with 100 ml of ethyl acetate. After drying over sodium sulfate, the solvent was distilled off under reduced pressure, the amorphous residue was dissolved in 30 ml of ethanol and acidified with ethanolic hydrochloric acid. The solvent was distilled off, the residue was dissolved in 40 ml of water and the end product was obtained by lyophilization. Colorless amorphous solid body, decomposition beginning at 128° C., γ C=N 1615 cm-1.