Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)C.[CH:4]([C:7]1[CH:20]=[CH:19][C:10]([O:11][CH:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].O.Cl.[NH2:23][C@H:24]([C:27]([OH:29])=[O:28])[CH2:25][SH:26].C([O-])(=O)C.[Na+]>O>[CH:4]([C:7]1[CH:20]=[CH:19][C:10]([O:11][CH:12]2[CH2:17][CH2:16][C:15]3([S:26][CH2:25][C@@H:24]([C:27]([OH:29])=[O:28])[NH:23]3)[CH2:14][CH2:13]2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CC(C)c1ccc(OC2CCC(=O)CC2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)c1ccc(OC2CCC3(CC2)N[C@H](C(=O)O)CS3)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.7 %

Procedure:
In a solvent mixture consisting of 21 ml of ethanol and 9 ml of water were dissolved 3.10 g of 4-(4-isopropylphenoxy)-1-cyclohexanone, 2.35 g of L-cysteine hydrochloride monohydrate and 1.10 g of sodium acetate. The mixture was stirred at ambient temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, and water and ethyl ether were added to the concentrate. The deposited crystal was collected by filtration, and there was obtained 2.45 g of (3R)-8-(4-isopropylphenoxy)-1-thia-4-azaspiro[4.5]decan-3-carboxylic acid as a colorless crystalline product.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([OH:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[CH:26](=[O:30])/[CH:27]=[CH:28]/[CH3:29]>C(Cl)(Cl)Cl>[OH:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH:28]([CH3:29])[CH2:27][CH:26]=[O:30])=[O:13]
Reactant: C/C=C/C=O
Reactant: OP(O)CCCCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(CC=O)P(=O)(O)CCCCc1ccccc1

Procedure:
To a solution of 4-phenylbutyl phosphonous acid (0.5 g, 0.0025 mole) in chloroform (15 ml) was added triethylamine (0.77 ml, 0.005 mole), trimethyl silylchloride (0.70 ml, 0.005 mole) and crotonaldehyde (0.23 ml, 0.0025 mole). The reaction mixture was stirred at reflux temperature for 18 hours. The chloroform was removed in vacuo. The residue was diluted with ether and extracted with 5% NaHCO3 solution. The aqueous layer was acidified with concentrated HCl and extracted twice with ether and once with EtOAc. The combined organic phase was washed with water and brine, dried over anhydrous sodium sulphate and the organic solvent removed on a rotavap to produce the title compound as a solid which was dissolved in CH3OH; ether and hexane were added until turbidity. The mixture was kept in a freezer overnight, yield 0.099, m.p. 138° C.
Reaction SMILES: CCCCCC.C([Li])CCC.[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[CH:13]1.[Br:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([O:32][CH3:33])=[C:24]([CH:34]=[O:35])[CH:23]=1.[Cl-].[NH4+]>C1COCC1>[S:12]1[C:13]([CH:34]([C:24]2[CH:23]=[C:22]([Br:21])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[O:32][CH3:33])[OH:35])=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2
Reactant: c1ccc2sccc2c1
Reactant: COc1c(C=O)cc(Br)c2ccccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1c(C(O)c2cc3ccccc3s2)cc(Br)c2ccccc12
Reaction time: 0.17 h
Yield: 82.9 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.6 M, 6.2 ml, 9.90 mmol) was added dropwise to a solution of benzothiophene (1.33 g, 9.90 mmol) in THF (20 ml) at −78° C. and the reaction mixture was stirred at the same temperature for 10 minutes. To this mixture, a solution of 4-bromo-1-methoxynaphthalene-2-carbaldehyde (2.5 g, 9.43 mmol) in THF (30 ml) was added dropwise at −78° C. The reaction mixture was stirred at the same temperature for two hours, and then a saturated ammonium chloride aqueous solution was added thereto and the mixture was extracted with ether. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:4)] to obtain the title compound (3.12 g, 83%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8](Cl)(=[O:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1.[NH3:13]>O1CCOCC1>[NH2:1][C:2]1[C:7]([S:8]([NH2:13])(=[O:10])=[O:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)cc1S(=O)(=O)Cl
Reactant: N
Solvent: C1COCCO1
Product: Nc1ncc(Br)cc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
2-Amino-5-bromopyridine-3-sulfonyl chloride (reagent preparation 25) (95.5 mg, 0.35 mmol) was treated with 0.5M ammonia in dioxane solution (7 mL) and the mixture was stirred for 1 h at room temperature. Concentrated aqueous ammonia (2 mL) was then added to the mixture then stirred an additional 12 h. The mixture was then concentrated and the residue suspended in water (5 mL). The solid was collected by filtration and dried to give 2-amino-5-bromopyridine-3-sulfonamide (55.7 mg, 89%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14](Cl)=[N:15][CH:16]=2)=[O:10])[CH2:3][CH2:2]1.[CH3:22][S:23][C:24]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][C:25]=1[NH2:26]>C(#N)C>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:12]([C:18]([F:21])([F:20])[F:19])=[N:13][C:14]([NH:26][C:25]3[CH:27]=[CH:28][CH:29]=[C:30]([C:31]([F:32])([F:33])[F:34])[C:24]=3[S:23][CH3:22])=[N:15][CH:16]=2)=[O:10])[CH2:3][CH2:2]1
Reactant: CSc1c(N)cccc1C(F)(F)F
Reactant: O=C(NCC1CCOCC1)c1cnc(Cl)nc1C(F)(F)F
Solvent: CC#N
Product: CSc1c(Nc2ncc(C(=O)NCC3CCOCC3)c(C(F)(F)F)n2)cccc1C(F)(F)F
Yield: 14.4 %

Procedure:
2-Chloro-4-trifluoromethyl-pyrimidin-5-carboxylic acid (tetrahydropyran-4-ylmethyl)-amide (50 mg), 2-methylthio-3-(trifluoromethyl)aniline (125 mg, ex Maybridge) and acetonitrile (0.5 ml) were heated at 190° under microwave irradiation for 30 minutes. The solvent was evaporated in vacuo and the residue purified by mass-directed autopreparation technique, to give the title compound (11 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH:29]([C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.O.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>[CH:24]1([N:22]([CH3:23])[C:4]2[C:5]([CH3:21])=[C:6]([CH:20]=[C:2]([C:34]3[CH:35]=[N:36][C:31]([CH:29]=[O:30])=[CH:32][CH:33]=3)[CH:3]=2)[C:7]([NH:9][CH2:10][C:11]2[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=2[CH3:17])=[O:8])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=Cc1ccc(B(O)O)cn1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
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: C1COCCO1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 66.1 %

Procedure:
To a stirred solution of 5-bromo-3-(cyclopentyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (0.5 g, 1.12 mmol) and (6-formylpyridin-3-yl)boronic acid (0.39 g, 1.68 mmol) in dioxane/water mixture (15 mL+3 mL), Na2CO3 (0.42 g, 4.09 mmol) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.130 g, 0.112 mmol) was added the mixture was purged again for 10 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to afford crude material which was purified by column chromatography over silica gel to afford the title compound (0.35 g, 66% yield).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[CH:5]=1.CNCC1C=CC2C(=CC=CC=2)C=1CCC.[O:30]=[C:31]1[NH:36][C:35]2[N:37]=[CH:38][C:39](/[CH:41]=[CH:42]/[C:43]([OH:45])=O)=[CH:40][C:34]=2[C:33](=[O:46])[NH:32]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[O:30]=[C:31]1[NH:36][C:35]2[N:37]=[CH:38][C:39](/[CH:41]=[CH:42]/[C:43]([N:2]([CH3:1])[CH2:3][C:4]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[N:6]([CH3:13])[CH:5]=3)=[O:45])=[CH:40][C:34]=2[C:33](=[O:46])[NH:32]1
Reactant: CNCc1cn(C)c2ccccc12
Reactant: O=C(O)/C=C/c1cnc2[nH]c(=O)[nH]c(=O)c2c1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: CN(Cc1cn(C)c2ccccc12)C(=O)/C=C/c1cnc2[nH]c(=O)[nH]c(=O)c2c1
Yield: 34 %

Procedure:
According to the procedure of Example 1 (a), except substituting methyl-(1-methyl-1H-indol-3-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(2,4-dioxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl)acrylic acid for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.16 g, 34%) was prepared as a tan solid and as a mixture of amide rotamers; 1H NMR (300 MHz, DMSO-d6) δ 11.84 (s, 1H), 11.53 (s, 1H), 8.91 (s, 1H), 8.73-8.66 (m, 1H), 7.78-7.30 (m, 5H), 7.17-7.12 (m, 1H), 7.03-6.98 (m, 1H), 4.96-4.73 (m, 2H), 3.76 (s, 3H), 3.07-2.90 (m, 3H); MS (ESI) m/e 390 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[C:14]([CH3:34])=[C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:16]3[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:8][CH:7]=1.[OH-].[K+]>C1COCC1.CO>[CH2:21]([N:16]1[C:17]2[C:13](=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:35])=[O:2])=[CH:7][CH:8]=3)[CH:20]=[CH:19][CH:18]=2)[C:14]([CH3:34])=[C:15]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)COc1ccc(-c2cccc3c2c(C)c(-c2ccccc2)n3Cc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(-c2ccccc2)n(Cc2ccccc2)c2cccc(-c3ccc(OCC(=O)O)cc3)c12

Procedure:
The desired product was prepared using a procedure similar to step 2 of example 4. Thus, [4-(1-benzyl-3-methyl-2-phenyl-1H-indol-4-yl)-phenoxy]-acetic acid methyl ester (0.263 g, 0.570 mmol) was reacted with 1N KOH (1.1 ml) in THF/MeOH (3 ml/2 ml) to give the product (0.198 g, 0.442 mmol, 78%) as a white foam, mp 82-86° C. 1H NMR (DMSO-d6) δ 1.72 (s, 3H), 4.70 (s, 2H), 5.29 (m, 2H), 6.84 (d, J=7.2 Hz, 1H), 6.88 (d, J=7.3 Hz, 2H), 6.96 (d, J=8.6 Hz, 2H), 7.11 (t, J=7.5 Hz, 1H), 7.16 (t, J=7.0 Hz, 1H), 7.22 (t, J=7.0 Hz, 2H), 7.31-7.34 (m, 5H), 7.40 (t, J=7.0 Hz, 1H), 7.45 (t, J=6.7 Hz, 2H); IR (solid) 3030, 2910, 1730, 1605, 1520, 1480, 1430, 1210, and 1180 cm−1; [ESI(+)], m/z 448 (M+H)+; Anal. Calcd. for C30H25NO3.0.33H2O: C, 80.51; H, 5.63; N, 3.13; Found: C, 79.30; H, 5.78; N, 3.00.
Reaction SMILES: [C:1]([O:20][CH:21]1[CH2:26][CH2:25][N:24]([OH:27])[CH2:23][CH2:22]1)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[CH:35]=[CH2:36]>C(O)C>[C:1]([O:20][CH:21]1[CH2:26][CH2:25][N:24]([O:27][CH2:36][CH:35]=[CH2:34])[CH2:23][CH2:22]1)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C=CCBr
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC1CCN(O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C=CCON1CCC(OC(=O)CCCCCCCCCCCCCCCCC)CC1

Procedure:
Repeating the general procedure of Example 1 using 1-hydroxy-piperdin-4-yl stearate, potassium carbonate and allyl bromide in ethanol solvent yields the title compound.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:23])[O:9][CH:10]1[CH2:15][CH2:14][N:13](CC2C=CC=CC=2)[CH2:12][CH2:11]1.C(O)=O>CO.[Pd]>[C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:23])[O:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: O=C(Nc1ccccc1-c1ccccc1)OC1CCNCC1
Reaction time: 18 h
Yield: 69.3 %

Procedure:
1-Benzyl-4-piperidyl N-(2-biphenylyl)carbamate (12.5 g, 32.3 mmol) was dissolved in anhydrous methanol (150 mL) and formic acid (25 mL, 660 mmol) and the solution was flushed with gaseous nitrogen for 15 min. 10% Palladium on carbon (3 g) was added and the reaction mixture was stirred under nitrogen atmosphere. After 18 h, the reaction mixture was filtered through CeliteR and the filtrate was concentrated to give a yellow solid. The solid was partitioned between 0.1 N hydrochloric acid (300 mL) and diethyl ethr (300 mL). The aqueous layer was washed with diethyl ether and then basified with 1 N sodium hydroxide solution to pH 12. A white solid precipitated out which was extracted into ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate and evaporated to dryness to give 4-piperidyl N-(2-biphenylyl)carbamate as a colorless solid (6.63 g, 69%). MS=296.9 MH+.
Reaction SMILES: [NH2:1]C1C=CC=CC=1.[C:8]12[C:17](=[O:18])O[C:14](=[O:15])[C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13]2.O>C(O)(=O)C>[C:17]1(=[O:18])[NH:1][C:14](=[O:15])[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:8]1=2
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=O)C2=C1CCCC2

Procedure:
4.5 g (0.017 mole) of the above aniline and 2.7 g (0.018 mole) of cyclohexene-1,2-dicarboxylic anhydride in 70 ml of glacial acetic acid are stirred for 3 hours at 70° C. After the mixture has been cooled, 100 ml of water are added and the precipitate is filtered off, washed with water and dried. 3.5 g (52%) of N-[4-tetrahydropyran-4-ylmethyl)-3,3-dihydro-2H-1,4-benzoxazin -3-on-6-yl]-3,4,5,6-tetrahydrophthalimide (mp. 187-189° C.) are obtained.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([OH:18])=O)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.Cl.[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]2[CH2:26][C@H:27]3[NH:38][CH2:37][CH2:36][C@@:33]4([C:34]=2[CH:35]=1)[C@H:28]3[CH2:29][CH2:30][CH2:31][CH2:32]4.C(N(CC)CC)C>C1COCC1>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]2[CH2:26][C@H:27]3[N:38]([C:16]([C:12]4[CH:11]=[C:10]5[C:15](=[CH:14][CH:13]=4)[NH:7][CH:8]=[CH:9]5)=[O:18])[CH2:37][CH2:36][C@@:33]4([C:34]=2[CH:35]=1)[C@H:28]3[CH2:29][CH2:30][CH2:31][CH2:32]4
Reactant: COc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(C(=O)c1ccc2[nH]ccc2c1)CC3
Temperature: 25 °C
Reaction time: 10 h
Yield: 27 %

Procedure:
Oxalyl chloride (15 ul, 0.14 mmol) at RT was added to a solution of indole-5-carboxylic acid (0.02 g, 0.12 mmol) in THF (1 ml). After stirring at RT for 10 h, the mixture was added THF (1 ml) followed by (+)-3-methoxy-morphinan hydrochloride (0.04 g, 0.12 mmol), then triethylamine (0.1 ml, 0.7 mmol) was added and stirred for 18 h. The reaction mixture was filtered and washed with ethyl acetate. The filtrate was washed with saturated Na2CO3 (5 ml), dried (Na2SO4), filtered and concentrated at reduced pressure to give a crude pale brown oil. The crude product was purified by column chromatographed eluting with (MeOH: CH2Cl2=1:10) to give a pale yellow oil (0.013 g, 28% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:55][C:56]1([CH3:71])[CH2:61][NH:60][C:59]([C:62]2[CH:67]=[CH:66][C:65]([CH2:68][NH:69][CH3:70])=[CH:64][CH:63]=2)=[N:58][CH2:57]1>ClCCCl>[CH3:55][C:56]1([CH3:71])[CH2:61][NH:60][C:59]([C:62]2[CH:67]=[CH:66][C:65]([CH2:68][N:69]([CH3:70])[C:21]([C:18]3[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH3:24])(=[O:11])=[O:12])[CH3:14])[O:20][CH:19]=3)=[O:22])=[CH:64][CH:63]=2)=[N:58][CH2:57]1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: CNCc1ccc(C2=NCC(C)(C)CN2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)Cc3ccc(C4=NCC(C)(C)CN4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AG using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (55 mg, 0.15 mmol), EDCI (35 mg, 0.18 mmol), HOAt (25 mg, 0.18 mmol), DIPEA (0.156 mL, 0.89 mmol) and 1-[4-(5,5-dimethyl-1,4,5,6-tetrahydropyrimidin-2-yl)phenyl]-N-methylmethanamine (43 mg, 0.13 mmol) in DCE (1 mL). The crude product was purified using prep method C.
Reaction SMILES: [NH3:1].C[O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH:20]2[CH2:25][CH2:24][N:23]([C@H:26]([CH3:40])[CH2:27][CH2:28][NH:29][C:30]([C:32]3[C:33]([CH3:39])=[N:34][CH:35]=[N:36][C:37]=3[CH3:38])=[O:31])[CH2:22][CH2:21]2)[CH2:14][C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)=[CH:9][CH:8]=1>CO>[C:4]([CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]([CH2:14][C:15]2[CH:19]=[CH:18][S:17][CH:16]=2)[CH:20]2[CH2:21][CH2:22][N:23]([C@H:26]([CH3:40])[CH2:27][CH2:28][NH:29][C:30]([C:32]3[C:37]([CH3:38])=[N:36][CH:35]=[N:34][C:33]=3[CH3:39])=[O:31])[CH2:24][CH2:25]2)=[CH:11][CH:12]=1)(=[O:3])[NH2:1]
Reactant: N
Reactant: COC(=O)COc1ccc(N(Cc2ccsc2)C2CCN([C@H](C)CCNC(=O)c3c(C)ncnc3C)CC2)cc1
Solvent: CO
Product: Cc1ncnc(C)c1C(=O)NCC[C@@H](C)N1CCC(N(Cc2ccsc2)c2ccc(OCC(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
NH3 (g) was bubbled through a solution of {4-[(1-{(R)-3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-thiophen-3-ylmethyl-amino]-phenoxy}-acetic acid methyl ester (see EXAMPLE 297) (54 mg, 0.095 mmol) in MeOH (10 mL) for 10 minutes. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure to give COMPOUND 298 as a pale brown solid (52 mg, 100%). 1H NMR (CDCl3) δ 0.89-1.12 (m, 2H), 1.00 (d, 3H, J=6.3 Hz), 1.52-1.63 (m, 1H), 1.74-1.78 (m, 3H), 2.13 (t, 1H, J=11.4 Hz), 2.51 (s, 6H), 2.51-2.57 (m, 1H), 2.72-2.84 (m, 3H), 3.27-3.40 (m, 2H), 3.79 (s, 2H), 3.85-3.89 (m, 1H), 4.40 (s, 2H), 5.59 (br s, 1H), 6.59-6.76 (m, 5H), 6.99 (s, 2H), 8.78 (br s, 1H), 8.86 (s, 1H). ES-MS m/z 551 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH:3]=1.[CH3:24][O:25][CH2:26][CH2:27][NH:28][CH3:29].O>CN(C=O)C>[CH3:24][O:25][CH2:26][CH2:27][N:28]([CH3:29])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCCc1cccc(C(F)(F)F)c1
Reactant: CNCCOC
Solvent: O
Solvent: CN(C)C=O
Product: COCCN(C)c1ccc([N+](=O)[O-])c(OCCc2cccc(C(F)(F)F)c2)c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
Dissolved 4-fluoro-1-nitro-2-[2-(3-trifluoromethylphenyl)ethoxy]benzene (200 mg, 0.61 mmol) in DMF (1 mL) and added N-(2-methoxyethyl)methylamine (270 mg, 3.04 mmol). Reaction Mixture was warmed to 60° C. and stirred for 18 h. The reaction mixture was poured into H2O and extracted with EtOAc (2×). The combined organics were washed with brine and dried over Na2SO4. The title compound was carried on crude to the next step.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Br[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1)=[O:30]>C(O)(C)C>[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=3)=[O:30])[CH2:12][CH2:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=C(CN1CCN(C(c2ccccc2)c2ccccc2)CC1)c1ccc(O)cc1
Reaction time: 8 h
Yield: 84.6 %

Procedure:
2.52 g (10 mmol) of 1-diphenylmethylpiperazine and 1.11 g (11 mmol) of triethylamine were dissolved in 30 ml of isopropanol, followed by addition of a solution obtained by dissolving 2.15 g (10 mmol) of α-bromo-p-hydroxyacetophenone in 20 ml of isopropanol. The mixture was allowed to stand overnight at room temperature. Precipitated crystals were collected by filtration. The crystals were successively washed with isopropanol, water and isopropanol and then dried to give 3.27 g of crude crystals of 2-(4-diphenylmethylpiperazinyl)-1-(4-hydroxyphenyl)ethanone (yield: 84.6%).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CO>[N:27]1([CH2:2][C:3]2([OH:1])[CH2:4][CH2:5][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:7][CH2:8]2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Reactant: C1CNCCN1
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(CN4CCNCC4)CC3)c(F)c2)C(=O)O1
Yield: 80 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.37 mmol) with piperazine (2.06 mmol) in methanol (10 ml) at a temperature 25° C. for 14 hours and by purifying the compound by silica gel column chromatography in 80% yield.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([Br:10])[N:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=1[OH:15].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[Br:3][C:4]1[CH:9]=[C:8]([Br:10])[N:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)c1nc(Br)cc(Br)c1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc(Br)cc(Br)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
To a stirred mixture of sodium hydride (0.6 g) in DMF (50 mL) was slowly added 14 (7.1 g). After the addition was complete, the mixture was stirred at room temperature for 15 minutes, then benzyl chloride (3.05 g) was added all at once. The mixture was then heated at 90° C. for six hours, cooled, poured into water (500 mL) and extracted with ether (2×200 mL). The ether extracts were combined, washed with 2N NaOH (50 mL), dried (MgSO4) and the solvent was evaporated to give 15 as a light yellow solid (8.3 g). Recrystallization from a small volume of methanol gave an analytical sample, m.p. 75-76° C.