Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.I[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14].[CH2:17]([O:22][CH3:23])[CH2:18][CH2:19][C:20]#[CH:21]>[Cu]I.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.C(N(CC)CC)C>[CH3:23][O:22][CH2:17][CH2:18][CH2:19][C:20]#[C:21][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([NH2:16])(=[O:15])=[O:14]
Reactant: C#CCCCOC
Reactant: NS(=O)(=O)c1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCCC#Cc1ccccc1S(N)(=O)=O
Reaction time: 22 h

Procedure:
135 ml of N,N-dimethylformamide and 22 ml of triethylamine are taken and 7.5 g of 2-iodobenzenesulfonamide, 2.6 g of pent-4-yn-1-yl-methyl ether as well as 0.067 g of copper(I) iodide and 0.144 g of bis(triphenylphosphine)palladium(II) dichloride are added. The reaction mixture is heated to 65° and stirred for 22 hours at that temperature under argon. After that time, the N,N-dimethylformamide is distilled off at 0.1 torr and 40°. The crude product is purified on 500 g of silica gel (Merck Si 60, 40-63 μm) with hexane/ethyl acetate=2/1 as eluant. The fractions containing the product are concentrated by evaporation at 15 torr and 40° to yield white crystalline 2-(5-methoxy-pent-1-yn-1-yl)-benzenesulfonamide, melting point: 59°-61°.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[C:17]1(=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18]1>C1COCC1>[OH:22][C:17]1([CH2:2][C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(=O)OC(C)(C)C
Reactant: O=C1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC1(O)CCCC1
Temperature: -60 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a solution of tert-butyl acetate (5.0 g, 42.8 mmol,) in THF (20 mL) was added lithium diisopropylamide (21.4 mL, 42.8 mmol) at −60° C. After stirred at −60° C. for 30 min, cyclopentanone (3.0 g, 35.7 mmol) was added at −60° C. The reaction was stirred 1 h; then it was quenched with aqueous ammonium chloride (5 mL) at −60° C. and the mixture was warmed to room temperature. The reaction was partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with petroleum ether/ethyl acetate (3:1) to give tert-butyl 2-(1-hydroxycyclopentyl)acetate (5.0 g, 70.1% yield) as a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][N:36]4C(OC(C)(C)C)=O)=[O:34])[CH2:29][CH2:28]3)[CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1)[CH3:17]>ClCCl>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C@H:16]([N:18]1[C:22]2[CH:23]=[C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:33]([C@H:35]4[CH2:39][CH2:38][CH2:37][NH:36]4)=[O:34])[CH2:31][CH2:32]3)[CH:25]=[CH:26][C:21]=2[N:20]=[CH:19]1)[CH3:17]
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(N3CCN(C(=O)[C@H]4CCCN4C(=O)OC(C)(C)C)CC3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(N3CCN(C(=O)[C@H]4CCCN4)CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added to a solution of (R)-t-butyl 2-(4-(1-((R)-1-(2,4-dichlorophenyl)ethyl)-1H-benzo[d]imidazol-6-yl)piperazine-1-carbonyl)pyrrolidine-1-carboxylate (0.036 g, 0.062 mmol) in dichloromethane (1 mL), and the reaction mixture was stirred at room temperature for 1 h. Excess solvent was removed in vacuo, and the residue was diluted with dichloromethane (10 mL). The organic layer was neutralized with saturated aqueous sodium bicarbonate, and the aqueous layer was further extracted with dichloromethane (2×15 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 15% methanol in dichloromethane) to give the desired compound (0.011 g, 0.024 mmol, 38%). The material was dissolved in acetonitrile and treated with 1 N aqueous hydrochloric acid solution (0.048 mL, 0.048 mmol). The solution was lyophilized to give the di-HCl salt as the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.02-9.92 (m, 1 H), 9.53 (s, 1 H), 8.49-8.42 (m, 1 H), 7.74 (d, J=2.0, 1 H), 7.69 (d, J=8.8 Hz, 1 H), 7.57 (d, J=8.8 Hz, 1 H), 7.51 (dd, J=1.6, 8.4 Hz, 1 H), 7.35 (d, J=9.2 Hz, 1 H), 6.98 (s, 1 H), 6.24 (q, J=6.8 Hz, 1 H), 4.65-4.62 (m, 1 H), 3.67-3.63 (m, 5 H), 3.22-3.16 (m, 4 H), 2.39-2.34 (m, 2 H), 1.97 (d, J=6.8 Hz, 3 H), 1.93-1.78 (m, 3H); MS: (ES) m/z calculated for C24H28Cl2N5O [M+H]+ 472.2, found 472.1.
Reaction SMILES: Cl.OC(COC1C=CC([Cl:26])=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.[OH:28][CH:29]([CH2:44][O:45][C:46]1[C:55]2C(=[CH:51][CH:52]=[CH:53][CH:54]=2)C=[CH:48][CH:47]=1)[CH2:30][NH:31][C:32]([CH3:43])([CH3:42])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1.Cl.OC(COC1C=CC(OC)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:26].[OH:28][CH:29]([CH2:44][O:45][C:46]1[CH:55]=[CH:54][C:53]([CH2:52][CH3:51])=[CH:48][CH:47]=1)[CH2:30][NH:31][C:32]([CH3:43])([CH3:42])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2cccc3ccccc23)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Agent: Cl
Product: CCc1ccc(OCC(O)CNC(C)(C)Cc2ccc(OC)cc2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 342 (M-15,.1), 237 (15), 236 (100), 163 (5), 121 (19), 114 (7).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]2[O:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=1.[NH:17]1[CH2:21][CH2:20][N:19]=[C:18]1S(O)(=O)=O>C(#N)C>[C:13]([C:11]1[C:5]2[O:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=[C:2]([NH:1][C:18]2[NH:19][CH2:20][CH2:21][N:17]=2)[CH:12]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc(N)cc2c1OCC2(C)C
Reactant: O=S(=O)(O)C1=NCCN1
Solvent: CC#N
Product: CC(C)(C)c1cc(NC2=NCCN2)cc2c1OCC2(C)C
Temperature: 25 °C
Yield: 32 %

Procedure:
To a 0.3 g (1.3 mmol) solution of 5-amino-7-tert-butyl-2,3-dihydro-3,3-dimethylbenzo[b]furan in 10 mL of acetonitrile at RT is added 0.2 g (1.3 mmol) of imidazoline-2-sulfonic acid, (Maryanoff et al., J. Org. Chem., 1986, 51, 1882). The reaction is then refluxed overnight. On cooling to RT, pure guanidine precipitates out of solution and is filtered from the solution to give 120 mg (32%) of product; mp 264° C. (decomp).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([C:12]3[C:13]([OH:18])=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:9]=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1.[N+:19]([O-])([OH:21])=[O:20].O>C(O)C>[N+:19]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([C:5]3[NH:1][N:2]=[N:3][N:4]=3)[CH:7]=2)[C:13]=1[OH:18])([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: Oc1ccccc1-c1cccc(-c2nnn[nH]2)c1
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cccc(-c2cccc(-c3nnn[nH]3)c2)c1O
Reaction time: 8 h
Yield: 26.7 %

Procedure:
3′-(1H-Tetrazol-5-yl)-biphenyl-2-ol 8d (3.5 g, 14.7 mmol) was dissolved in 145 mL of ethanol under argon atmosphere. Fuming nitric acid (0.565 mL, 13.2 mmol) was added dropwise at 35° C. After the reaction mixture was reacted at room temperature for 1 hour, 150 mL of water was added. After standing overnight, the mixture was filtered. The filter cake was washed with 100 mL of water and dissolved in 500 mL of ethyl acetate and 250 mL of water. The separated organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The mixture was purified by silica gel column chromatography to obtain the title compound 3-nitro-3′-(1H-tetrazol-5-yl)-biphenyl-2-ol 8e (1 g, yield 27.0%) as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[N:14]=[N:15][NH:16][N:17]=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(O[CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1)(C1C=CC(C)=CC=1)(=O)=O.OC1CCN(C(OC(C)(C)C)=O)CC1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[N:14]=[N:15][N:16]([CH:29]4[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]4)[N:17]=3)=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: c1ccc(-c2ncc(-c3nn[nH]n3)cn2)cc1
Agent: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(n2nnc(-c3cnc(-c4ccccc4)nc3)n2)CC1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
To a solution consisting of 2-phenyl-5-(2H-tetrazol-5-yl)pyrimidine (25 mg, 0.111 mmol) in DMF (2.0 mL) was added tert-butyl 4-(tosyloxy)piperidine-1-carboxylate (40 mg, 0.111 mmol), synthesized from tert-butyl 4-hydroxypiperidine-1-carboxylate (PCT International Application No. WO 2007/060026), and sodium carbonate (85 mg, 0.45 mmol). The suspension was vigorously stirred for 24 hours and an additional molar equivalent of tert-butyl 4-(tosyloxy)piperidine-1-carboxylate was added and the reaction was heated for another 24 hours at 70° C. After cooling to room temperature, the crude reaction mixture was diluted with ethyl acetate, washed sequentially with 1 M sodium carbonate, 5% citric acid, and brine. After solvent evaporation, the remaining crude solid was dissolved in a minimal amount of dichloromethane and purified by flash silica column chromatography. Elution through a 40-g Analogix® flash silica cartridge with 100% dichloromethane to 2% methanol in dichloromethane provided the title compound as an off-white solid. The solid was further purified by triturating with methanol to afford the title compound as a white solid (15 mg, 33% yield); Rf 0.37 with 95:2 v/v dichloromethane-methanol; melting point 178-180° C.; 1H-NMR (400 MHz; CDCl3) δ 9.47 (s, 2H), 8.52-8.49 (m, 2H), 7.52-7.50 (m, 3H), 4.96-4.95 (m, 2H), 4.23 (bs, 2H), 3.10-2.97 (m, 2H), 2.30-2.21 (m, 4H), 1.48 (s, 9H); MS (ESI+) m/z 408.2 (M+1).
Reaction SMILES: [SiH3]O.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:19]12([CH2:26][CH2:27][Si](C)(C)Cl)[CH2:25][CH:22]([CH:23]=[CH:24]1)[CH2:21][CH2:20]2>CO>[CH2:26]([C:19]12[CH2:25][CH:22]([CH2:23][CH2:24]1)[CH:21]=[CH:20]2)[CH3:27]
Reactant: C[Si](C)(Cl)CCC12C=CC(CC1)C2
Agent: CN(C)c1ccccn1
Agent: O[SiH3]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCC12C=CC(CC1)C2
Temperature: 75 °C
Reaction time: 3 h

Procedure:
Silanol fluid, Rhone Poulenc 48V3500, (0.092 eq OH) was stirred under nitrogen and warmed to 70° C. with triethylamine-dimethylaminopyridine (1.05 eq, 1% DMAP by weight). The product of example 2 (0.0956 eq, 20.5 g) was added. The reaction mixture was stirred at 75° C. for three hours then methanol (50 g) was added slowly. After one hour, volatiles were removed by concentration on a rotary evaporator, the reaction mixture was diluted with hexane and filtered through diatomaceous earth. Removal of solvent on a rotary evaporator at 75° C. (0.1 mm Hg) gave the product: Viscosity 4680 cps, GPC MWwt 30787, MWnumber 23943.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH3:16].[Br:17][C:18]1[N:19]=[C:20]([C:24](O)=[O:25])[NH:21][C:22]=1[Br:23].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C>[Br:17][C:18]1[N:19]=[C:20]([C:24]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH3:16])=[O:25])[NH:21][C:22]=1[Br:23]
Reactant: O=C(O)c1nc(Br)c(Br)[nH]1
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Br)c(Br)[nH]1
Yield: 72 %

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-methoxypiperidine-1-carboxylate obtained by the method described in Example (1e) (300 mg, 1.30 mmol), 4,5-dibromoimidazole-2-carboxylic acid obtained in Example (2a) (300 mg, 1.11 mmol), WSC hydrochloride (460 mg, 2.40 mmol) and DMAP (50 mg, 0.41 mmol), to obtain 384 mg of the title compound as a white solid (72%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19](C)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>C1(C)C=CC=CC=1>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[N:7]=[C:6]([Cl:8])[CH:5]=[CH:4][N:3]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Clc1ccnc(Cl)n1
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2nccc(Cl)n2)CC1
Temperature: 25 °C
Yield: 56.9 %

Procedure:
To a suspension of 2,4-dichloropyrimidine (1.00 g, 6.71 mmol) in 13.4 mL of toluene was added 4-methyl-piperazine-1-carboxylic acid tert-butyl ester (1.34 g, 6.71 mmol). The reaction was heated to reflux overnight, then cooled to room temperature and concentrated in vacuo. The residue was taken up in 20 mL of water and extracted with ethyl acetate (2×40 mL). The combined organic layers were washed with brine (25 mL), then dried over sodium sulfate, filtered, and concentrated in vacuo to an off-white solid. Flash column chromatography (silica gel, gradient elution from 5% ethyl acetate-hexanes to 20% ethyl acetate-hexanes) yielded 1.14 g of the title compound (I-2a).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[F:9][C:10]([F:23])([F:22])[C:11]1[CH:12]=[C:13]([C:17](=O)[C:18](=O)[CH3:19])[CH:14]=[CH:15][CH:16]=1.Cl>O>[CH3:19][C:18]1[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:9])([F:22])[F:23])[CH:12]=2)=[N:8][C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:7]=1
Reactant: Nc1ccccc1N
Reactant: CC(=O)C(=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: O
Product: Cc1nc2ccccc2nc1-c1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 54 %

Procedure:
A mixture of 1,2-phenylenediamine (1.00 g, 9.25 mmol) and 1-[3-(trifluoromethyl)phenyl]propane-1,2-dione (2.00 g, 9.25 mmol) in water (80 mL) was heated at 60° C. overnight, then for 5 h with vigorous stirring. The reaction mixture was allowed to cool to r.t. then acidified with 2N HCl (ca 20 mL) and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was triturated with heptane to give the title compound (1.44 g, 54%) as a cream-coloured solid. δH (CDCl3) 8.05-8.16 (m, 2H), 7.96 (s, 1H), 7.85-7.90 (m, 1H), 7.72-7.82 (m, 3H), 7.64-7.71 (m, 1H), 2.79 (s, 3H). LCMS (ES+) 289.3 (M+H)+, RT 4.21 minutes (Method 3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[F:12].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH2:27]([C@@H:34]1[CH2:38][O:37][C:36](=[O:39])[NH:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[Li]CCCC>C1COCC1>[CH2:27]([C@@H:34]1[CH2:38][O:37][C:36](=[O:39])[N:35]1[C:9](=[O:11])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:12])[CH:4]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O)Cc1ccc(Cl)c(F)c1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(Cl)c(F)c1)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
2-(4-Chloro-3-fluorophenyl)acetic acid (1.00 g, 5.30 mmol) was dissolved in THF (14 mL) at 0° C. and treated with triethylamine (0.81 mL, 5.8 mmol). Pivaloyl chloride (0.69 mL, 5.6 mmol) was then added to the solution, and the mixture was allowed to stir for one hour at 0° C. In a separate flask, (R)-4-benzyloxazolidin-2-one (0.987 g, 5.57 mmol) was dissolved in THF (14 mL) at −78° C. and treated with n-BuLi (2.54 mL, 5.83 mmol). The above anion solution was stirred for 20 minutes and then cannulated into the anhydride at −78° C. The reaction was then allowed to stir for one hour at −78° C., and then warmed to 0° C. for two hours. The mixture was quenched with the addition of saturated NH4Cl solution (20 mL) and concentrated in vacuo. The resulting residue was then partitioned between ethyl acetate and water. The aqueous layer was extracted once with ethyl acetate, and the organic fractions were combined, washed with brine, separated, dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by column chromatography (3:1 hexanes:ethyl acetate) to give (R)-4-benzyl-3-(2-(4-chloro-3-fluorophenyl)acetyl)oxazolidin-2-one (0.95 g, 51%) as an oil, which solidified upon standing.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]1[C:21](O)=[O:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH:8]1[C:9]2[C:4](=[CH:3][C:2]([NH:1][C:21]([CH:13]3[CH2:14][C:15]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[NH:12]3)=[O:22])=[CH:11][CH:10]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1ccc2cnccc2c1
Reactant: O=C(O)C1Cc2ccccc2N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc2cnccc2c1)C1Cc2ccccc2N1
Temperature: 40 °C
Reaction time: 8 h
Yield: 6.1 %

Procedure:
To a solution of 6-aminoisoquinoline (25 mg, 0.17 mmol) in DMF (1.0 mL) was added indoline-2-carboxylic acid (30 mg, 0.17 mmol), HATU (70 mg, 0.19 mmol), diisopropylethylamine (35 μL, 0.19 mmol) and stirred overnight at 40° C. The reaction mixture was concentrated and purified by prep-HPLC to afford the titled compound (3.0 mg): 1H NMR (400 MHz, METHANOL-d4) δ ppm 3.18 (dd, J=16.11, 8.30 Hz, 1H) 3.56 (dd, J=16.20,10.54 Hz, 1H) 4.52 (dd, J=10.54, 8.40 Hz, 1H) 6.70-6.81 (m, 2H) 6.99-7.10 (m, 3H) 7.73 (d, J=6.05 Hz, 1H) 7.81 (dd, J=8.88, 2.05 Hz, 1H) 8.05 (d, J=8.98 Hz, 1H) 8.35 (d, J=5.86 Hz, 1H) 8.40 (d, J=1.95 Hz, 1H) 9.11 (s, 1H); LCMS: 290 (M+H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH3:10])=[CH:5][C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:17][N:18]([CH3:21])[C:19]#[N:20].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>C1C(O)=CC=CC=1C.CO>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[CH3:17][N:18]([CH3:21])[C:19]([NH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH3:10])=[CH:5][C:4]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[NH:20].[CH3:17][N:18]([CH3:21])[C:19]([NH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH3:10])=[CH:5][C:4]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[NH:20]
Reactant: CSc1ccc(N)c(-c2ccccc2)c1
Reactant: CN(C)C#N
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: Cc1cccc(O)c1
Solvent: CO
Product: CSc1ccc(NC(=N)N(C)C)c(-c2ccccc2)c1

Procedure:
Reaction of 2-amino-5-methylthiobiphenyl hydrochloride (1.6 g) with N,N-dimethylcyanamide (0.83 g) in m-cresol (1 ml) at 80° C. for 6 hours yielded a colourless solid which was dissolved in methanol (50 ml) and treated with a solution of fumaric acid (0.61 g) in methanol (50 ml) to give N,N-dimethyl-N'-(5-methylthio-2-biphenylyl)guanidine hemifumarate as a colourless solid (m.p. 207° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:16])[CH:14]=[O:15])[CH:7]=[CH:6]2.[N+]1([O-:23])C=CC=CC=1.C(O)(=O)C.C(OO)(=O)C>C(OCC)(=O)C>[CH3:16][C@H:13]([C:14]([OH:23])=[O:15])[C:8]1[CH:7]=[CH:6][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:10]=2[CH:9]=1
Reactant: COc1ccc2cc([C@H](C)C=O)ccc2c1
Reactant: [O-][n+]1ccccc1
Agent: CC(=O)OO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Yield: 80.3 %

Procedure:
To a stirred solution of 2.00 g (9.3 mmol) of (S)-2-(6-methoxy-2-naphthyl)propionaldehyde in ethyl acetate (10 mL) cooled in a wet-ice bath (ca. 2° C.) was added concurrently 0.89 g (9.3 mmol) of pyridine N-oxide and 0.56 g (9.3 mmol) of acetic acid. To this solution was then added slowly dropwise 5.8 mL (14.0 mmol) of a 20.4 weight percent solution of peracetic acid in ethyl acetate, at a rate slow enough such that the reaction temperature did not exceed 10° C. (ca. 15 minutes). After the initial exotherm, the temperature returned to 2° C., and the reaction was maintained at this temperature for an additional 4 hours. The reaction solution was transferred into a separatory funnel, was diluted with ethyl acetate (15 mL), and was washed with a 0.1N aqueous solution of sodium thiosulfate (Na2S2 O3, 25 mL). The ethyl acetate layer was further washed with water (10 mL), and the combined water washes were back-extracted with ethyl acetate (10 mL). The combined ethyl acetate layers were extracted with two portions of a 5% aqueous solution of potassium hydroxide (KOH, 65 mL then 25 mL). The combined KOH solutions of potassium naproxenate were acidified to pH=1 with a 5% aqueous solution of hydrochloric acid, precipitating the naproxen acid. The mixture was cooled in a wet-ice bath, and then was vacuum filtered through a #1 Whatman filter. The filter cake was washed with cold water (20 mL) and the white solid thus obtained was dried in a vacuum oven 18 hours at 55° C. (25 mm Hg), giving 1.72 g (80.0%) of naproxen.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1>>[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)=[CH:23][CH:22]=1
Reactant: Cc1ccc(S)cc1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Product: Cc1ccc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-methyl-thiophenol.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]([OH:15])=O)[CH2:8][CH2:7]1.[CH2:16]([C@H:23]1[CH2:27][NH:26][C@H:25]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)=[CH:33][CH:32]=2)=[O:29])[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([C@H:23]1[CH2:27][N:26]([C:13](=[O:15])[CH2:12][N:9]2[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][O:3][CH3:2])[CH2:11][CH2:10]2)[C@H:25]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)=[CH:33][CH:32]=2)=[O:29])[CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: COCCN1CCN(CC(=O)O)CC1
Agent: Cl
Product: COCCN1CCN(CC(=O)N2C[C@H](Cc3ccccc3)C[C@H]2C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)CC1
Yield: 26.3 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(2-methoxyethyl)piperazin-1-yl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 100, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(4-(2-methoxyethyl)piperazin-1-yl)acetyl)pyrrolidine-2-carboxamide (10.6 mg, 26.3%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.96 (s, 1H), 7.61 (d, 1H), 7.54 (d, 1H), 7.28 (m, 2H), 7.22-7.13 (m, 5H), 6.99-6.92 (m, 4H), 4.45 (m, 1H), 3.73 (m, 1H), 3.39 (m, 2H), 3.23 (t, 1H), 3.20 (s, 2H), 3.13 (s, 2H), 3.07 (m, 1H), 2.63 (m, 2H), 2.48 (m, 8H), 2.43 (t, 2H), 2.09 (t, 1H), 1.91 (m, 2H). MS (EI) for C33H39FN4O4. found 575.7 (MH+).