Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2](F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([S:27]([CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)(=[O:29])=[O:28])[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:36]([NH2:38])=[O:37])[CH:13]=[CH:14][CH:15]=1.[NH:39]1[CH:43]=[C:42]([C:44]([OH:46])=O)[N:41]=[CH:40]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH:39]1[CH:43]=[C:42]([C:44]([N:33]2[CH2:32][CH2:31][CH:30]([S:27]([C:24]3[CH:25]=[C:26]4[C:21](=[C:22]([CH3:2])[CH:23]=3)[N:20]=[CH:19][C:18]([C:36]([NH2:38])=[O:37])=[C:17]4[NH:16][C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH3:8])[CH:11]=3)(=[O:28])=[O:29])[CH2:35][CH2:34]2)=[O:46])[N:41]=[CH:40]1
Reactant: O=C(O)c1c[nH]cn1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3ccc(S(=O)(=O)C4CCNCC4)cc23)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)C4CCN(C(=O)c5c[nH]cn5)CC4)cc23)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.4 %

Procedure:
To a solution containing Intermediate 54 (0.041 g) in N,N-dimethylformamide (3 ml) were added imidazole-4-carboxylic acid (0.012 g, Aldrich), (1H-1,2,3-benzotriazol-1-yloxy)(tri-1-pyrrolidinyl)phosphonium hexafluorophosphate (PyBop) (0.053 g) and N,N-diisopropylethylamine (0.03 ml). The solution was stirred under nitrogen at room temperature for 18 h and was then concentrated in vacuo. The residual gum was purified using an aminopropyl SPE cartridge eluting with methanol followed by chromatography on silica gel (SPE cartridge), eluting with a gradient of 0% to 8% methanol in chloroform, to give the title compound as a yellow solid (0.031 g).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][CH2:9][C:10]2([C:25]([F:28])([F:27])[F:26])[C:15]3[CH:16]=[C:17](C(NC)=O)[CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[O:24])[O:11]2)=[O:7])=[CH:4][CH:3]=1.C1N=CN([C:36]([N:38]2[CH:42]=[N:41]C=C2)=[O:37])C=1.C([OH:45])C>NO.C(OCC)(=O)C>[F:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][CH2:9][C:10]2([C:25]([F:27])([F:28])[F:26])[C:15]3[CH:16]=[C:17]([C:42]4[NH:38][C:36](=[O:45])[O:37][N:41]=4)[CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[O:24])[O:11]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CNC(=O)c1ccc2c(c1)C(CNC(=O)c1ccc(F)cc1)(C(F)(F)F)OC(=O)N2
Reactant: CCO
Agent: NO
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(-c3noc(=O)[nH]3)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{[6-cyano-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methyl}-4-fluorobenzamide (50 mg, 0.127 mmol) synthesized in Example 159 in ethanol (0.5 mL), hydroxylamine (50% aqueous solution, 40 μL) was added, and the solution was stirred overnight at room temperature. The solution was diluted with ethyl acetate, which was washed sequentially with water and saturated brine and then dried over magnesium sulfate. The residue was dissolved in dioxane (1 mL), and under stirring the solution at room temperature, CDI (41 mg, 0.25 mmol) was added thereto. After the reaction solution was stirred at 90° C. for 3 hours, the temperature of the solution was brought to room temperature. Then, the solution was diluted with ethyl acetate, which was washed sequentially with water, 1 N hydrochloric acid and saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the residue was crystallized with ethanol and water, whereby the objective compound (18 mg, 31%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]([O:16]CC)=[O:15])=[CH:5]2.O.[OH-].[Li+]>C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]([OH:16])=[O:15])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(F)cnc2n(C)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1c(=O)c(C(=O)O)cc2cc(F)cnc21
Reaction time: 2 h

Procedure:
To a stirred suspension of ethyl 6-fluoro-1-methyl-2-oxo-1,2-dihydro[1,8]-naphthyridine-3-carboxylate (0.46 g) in ethanol (15 ml) was added a solution of lithium hydroxide monohydrate (0.10 g) in water (5 ml) at ambient temperature. The mixture was stirred for 2 hours, evaporated under reduced pressure to a small volume, diluted with water then acidified with aqueous 2M hydrochloric acid. The solid formed was filtered from solution and sucked to dryness to give the required product as a colourless solid, 0.39 g. 1H NMR (CDCl3+d6-DMSO) δ: 14.4 (1H, s), 8.92 (1H, s), 8.72 (1H, d), 7.94 (1H, m), 3.98 (3H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2([CH3:15])[CH3:14].C([Sn](CCCC)(CCCC)[C:21]([O:23]CC)=[CH2:22])CCC.Cl>C(OCC)(=O)C.CCCCCC.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:21]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([CH3:13])([CH3:12])[CH2:6][C:5]2([CH3:15])[CH3:14])(=[O:23])[CH3:22]
Reactant: CC1(C)CC(C)(C)c2cc(Br)ccc2O1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(=O)c1ccc2c(c1)C(C)(C)CC(C)(C)O2
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
A solution of 6-bromo-2,2,4,4-tetramethyl chroman (see U.S. Pat. No. 6,252,090, 0.9 g, 3.34 mmol) in anhydrous tetrahydrofuran (50 mL) was sparged with argon for 5 min. and treated with dichlorobis(triphenylphosphine)palladium(II) (0.117 g, 0.167 mmol) followed by tributyl(1-ethoxyvinyl)tin (2.41 g, 6.7 mmol). The resulting reaction mixture was heated at 80° C. under argon for 18 h. The reaction mixture was then cooled to ambient temperature and treated with 10% aqueous hydrochloric acid (5 mL) and stirred for 30 min. The reaction mixture was then diluted with ethyl acetate and washed with water (×1) and brine (×1). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a residue that was subjected to flash column chromatography over silica gel (230-400 mesh) using 2-3%% ethyl acetate in hexane as the eluent to afford the title compound as a colorless oil (0.36 g, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH:13]3[O:18][CH2:17][CH2:16][N:15](CC4C=CC=CC=4)[CH2:14]3)[NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.Cl>[Pd].CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH:13]3[O:18][CH2:17][CH2:16][NH:15][CH2:14]3)[NH:11][CH:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(-c2c[nH]c(C3CN(Cc4ccccc4)CCO3)n2)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Clc1cccc(-c2c[nH]c(C3CNCCO3)n2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 116.7 %

Procedure:
Palladium on carbon (10 wt %, 208 mg, 0.195 mmol) was added to a solution of 2-[4-(3-chlorophenyl)-1H-imidazol-2-yl]-4-(phenylmethyl)morpholine (690 mg, 1.950 mmol) and hydrochloric acid (0.823 mL, 9.75 mmol) in CH3OH (50 mL) under nitrogen, and the reaction mixture was stirred under hydrogen at 25° C. for 1.5 hours. The mixture was filtered washing with CH3OH (150 mL), and concentrated to afford the crude HCl salt of title compound (600 mg) as a brown solid. LC-MS (ES) m/z=264 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:40])[C@@H:22]([C:29]3[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31]([Cl:39])[CH:30]=3)[CH2:23][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[N:16]2)[CH:9]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[CH2:14][N:15]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:40])[C@@H:22]([C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:31]([Cl:39])[CH:30]=2)[CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:16]1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cn2ccc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)c(Cl)c3)n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(Cc3cccc(N)c3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.7 %

Procedure:
(3-{3-[2-(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-ylmethyl}-phenyl)-carbamic acid tert-butyl ester (prepared in Example 57, 501 mg, 0.83 mmol) was dissolved in methylene chloride (5 mL) and trifluoroacetic acid (500 μL) was added. The reaction stirred at 25° C. for 3 h. The reaction was concentrated in vacuo to half the reaction volume, diluted with toluene and concentrated in vacuo to dryness. The reaction was dissolved in ethyl acetate (25 mL), washed with a saturated aqueous sodium bicarbonate solution (2×10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate and concentrated in vacuo to give the desired product, N-[1-(3-amino-benzyl)-1H-pyrazol-3-yl]-2-(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (348 mg, 83%) as an off white powder: ESI-LRMS m/e calcd for C25H29ClN4O3S [M+] 500.16, found 501.20 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.06-1.21 (m, 2H, CH2), 1.41-1.92 (m, 8H, 4×CH2), 2.14-2.32 (m, 1H, CH), 3.25 (s, 3H, SO2CH3), 3.53-3.68 (m, 1H, CH), 5.02 (s, 2H, NCH2), 6.45-6.55 (m, 1H, Ar), 6.56-0.665 (m, 2H, Ar), 6.68 (s, 1H, Ar), 7.00-7.14 (m, 1 H, Ar), 7.32 (s, 1H, Ar), 7.45 (d, Jo=7.8 Hz. 1H, Ar), 7.60 (s, 1H, Ar), 7.75-8.23 (m, 2H, Ar and NH).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:8]2[CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[ClH:19]>CO>[ClH:19].[NH:10]1[CH2:9][CH:8]([C:3]2[C:2]([Br:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC(c2ncccc2Br)C1
Agent: Cl
Solvent: CO
Product: Brc1cccnc1C1CNC1
Temperature: 25 °C
Reaction time: 92 h
Yield: 108.6 %

Procedure:
To a solution of tert-butyl 3-(3-bromopyridin-2-yl)azetidine-1-carboxylate (3) (266 g, 0.849 mol, 1 eq.) in methanol (6 L) was added concentrated HCl (350 mL, 4.2 mol, 4.95 eq.) and the resulting mixture was stirred at RT for 92 hrs. The mixture was concentrated and dried using a rotavapor to obtain 230 g of 2-(azetidin-3-yl)-3-bromopyridine hydrochloride (4).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C@@H:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:19]([O-])=[O:20].[Na+].O>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:19]=[O:20])[C:5]([NH:7][C@@H:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=N[O-]
Reactant: O=C(NCCCl)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: O=NN(CCCl)C(=O)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 98.3 %

Procedure:
A solution of 0.60 g of 1-(2-chloroethyl)-3-(β-D-glucopyranosyl)urea in 15 ml of 99% formic acid was admixed with 282 mg of sodium nitrite under ice-cooling and stirring. The mixture was stirred for 1 hour under ice-cooling to effect the nitrosation. The reaction mixture, after addition of 15 ml of cold water thereto, was ice-cooled for 30 minutes and then treated with 5 ml of Amberlite IR-120 (H+ form) for the removal of sodium cation. The reaction mixture so treated was concentrated to dryness below 30° C by distilling off the solvent under a reduced pressure. The residue was taken up into a small volume of n-propanol and the solution was admixed with a volume of petroleum ether to give precipitate. The precipitate which deposited was collected by filtration and then dried in a desiccator under vacuum, affording 0.65 g of the titled compound as an amorphous solid of pale yellow color. Yield 92%. mp. 85° C (decomposition). [α]D6 -14° (c 0.5, methanol).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.I[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: Ic1ccccn1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccccn2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 34, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 2-iodopyridine. The title compound was obtained in 88% yield as an orange oil. MS (m/e): 483.3 (MH+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1.BrC1C=CC(I)=C(S(C)(=O)=O)C=1.[Cl:30]C1C=C(B(O)O)C=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:30])[CH:9]=2)=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1-c1ccccc1
Reactant: OB(O)c1cccc(Cl)c1
Agent: CS(=O)(=O)c1cc(Br)ccc1I
Product: CS(=O)(=O)c1cc(Br)ccc1-c1cccc(Cl)c1

Procedure:
Following the general method as outlined in Intermediate 203, starting from 4-bromo-1-iodo-2-(methylsulfonyl)benzene (Intermediate 202) and 3-chlorophenylboronic acid, the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)=[O:4].BrBr.[NH2:12][C:13]1[N:17]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[N:14]=1>CC(C)=O>[Br-:1].[NH2:12][C:13]1[N:14]([CH2:2][C:3](=[O:4])[C:5]2[S:6][CH:7]=[CH:8][CH:9]=2)[C:15]2[CH:29]=[CH:28][CH:27]=[CH:26][C:16]=2[N+:17]=1[CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Nc1nc2ccccc2n1CCN1CCCCC1
Reactant: O=C(CBr)c1cccs1
Agent: BrBr
Solvent: CC(C)=O
Product: Nc1n(CC(=O)c2cccs2)c2ccccc2[n+]1CCN1CCCCC1
Product: [Br-]
Temperature: 25 °C

Procedure:
An ethereal solution of 2-bromoacetylthiophene (obtained by brominating 2-acetylthiophene (1.9 g, 15 mmol) with 0.8 ml (15 mmol) of bromine in 10 ml of dioxane and 15 ml of ether) is added to a hot solution of 2-amino-1-(2-piperidinoethyl)benzimidazole (2.44 g; 10 mmol) in 100 ml of acetone. Stir and maintain at room temperature. The next day, the title compound precipitate is collected by means of filtration and washed with acetone and with ether.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:21][C@H:20]2[C:22](O)=[O:23])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:52][CH2:53][C:54]1[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=1>ClCCl.CN(C=O)C>[C:2]1([O:1][C:8]2[CH:9]=[C:10]([CH2:11][NH:12][C:13]3[CH:18]=[CH:17][C:16]([C@@H:19]4[CH2:21][C@H:20]4[C:22]([NH:52][CH2:53][C:54]4[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=4)=[O:23])=[CH:15][CH:14]=3)[CH:25]=[CH:26][CH:27]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1
Reactant: NCc1ccncc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCc1ccncc1)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1
Reaction time: 0.25 h
Yield: 77 %

Procedure:
To a mixture of racemic-(trans)-2-{4-[(3-phenoxybenzyl)amino]phenyl}cyclopropanecarboxylic acid (I-2a) (0.10 g, 0.231 mmol) in dichloromethane (2 mL) and DMF (3 mL) was added HATU (0.27 g, 0.71 mmol). The mixture was stirred for 15 min followed by addition of 4-(aminomethyl)pyridine (0.10 g, 0.94 mmol). The solution stirred for 6 h after which the dichloromethane was removed via rotavap. Sat. NaHCO3 and ethyl acetate were added and the organic layer separated and washed with H2O, dried over MgSO4, filtered and concentrated. The resulting oil was triterated with Et2O and formed a cream ppt which was filtered and dried under high vacuum to give the title compound as a cream powder (0.08 g, 40%). 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J=5.4 Hz, 2H), 7.34-7.28 (m, 3H), 7.26 (d, J=5.5 Hz, 2H), 7.11-7.07 (m, 2H), 7.01-6.99 (m, 3H), 6.92-6.90 (m, 3H), 6.55 (d, J=8.4 Hz, 2H), 6.01-5.98 (m, 1H), 4.50-4.47 (m, 2H), 4.29 (s, 2H), 4.03 (s, 1H), 2.48-2.43 (m, 1H), 1.58-1.51 (m, 1H), 1.24-1.19 (m, 2H). ES-MS m/z 450 (MH+).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[Cl:15][CH:16]([Cl:20])[C:17](Cl)=[O:18]>>[NH:7]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:17](=[O:18])[CH:16]([Cl:20])[Cl:15])=[CH:10][CH:9]=1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: Nc1ccc(Nc2ccccc2)cc1
Product: O=C(Nc1ccc(Nc2ccccc2)cc1)C(Cl)Cl

Procedure:
This compound is prepared from 4-aminodiphenylamine (36.8 g) in the same manner as Compound 1, except that dichloroacetyl chloride (29.8 g) is used in place of trichloroacetyl chloride. The product is recrystallized from benzene. The m.p. and chemical analysis are reported in Table I.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[C:20]([Cl:25])[N:19]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:22]2[CH:21]=[C:20]([Cl:25])[N:19]=[C:18]([Cl:17])[N:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Cl)nc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
To a solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.0 g, 20.0 mmol, 1.3 equiv) in dry DMF (100 mL) under Ar was added sodium hydride (1.01 g, 23.1 mmol, 1.5 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt. After 2 h, 2,4,6-trichloro-pyrimidine (2.82 g, 15.4 mmol, 1.0 equiv; commercially available) was added and the mixture stirred at rt for 48 h. The solvent was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (100 mL) with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate to provide 3.1 g (57%) of the title compound. 1H NMR (400 MHz, DMSO): δ 1.24-1.33 (m, 2H), 1.40 (s, 9H), 1.78-1.85 (m, 2H), 2.86-2.96 (m, 2H), 3.49-3.97 (m, 3H), 6.47 (s, 1H). MS (ISP): 347.3 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([C@H:22]2[CH2:27][CH2:26][C@H:25]([CH3:28])[CH2:24][CH2:23]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19]C#N)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].SC[C@@H]([C@@H](CS)O)O.[CH2:37]([N:39]([CH2:43][CH3:44])[CH2:40][CH2:41]S)[CH3:38]>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]([C@H:22]2[CH2:23][CH2:24][C@H:25]([CH3:28])[CH2:26][CH2:27]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19][CH2:38][CH2:37][N:39]([CH2:43][CH3:44])[CH2:40][CH3:41])=[CH:17][N:18]=2)=[O:12])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CCN(CC)CCS
Reactant: CC(=O)N1CCC(N(C(=O)Nc2ncc(SC#N)s2)[C@H]2CC[C@H](C)CC2)CC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: CCN(CC)CCSc1cnc(NC(=O)N(C2CCN(C(C)=O)CC2)[C@H]2CC[C@H](C)CC2)s1

Procedure:
Prepared as described in general procedures (H) and (I) using 1-(1-acetyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 2-diethylamino-ethanethiol
Reaction SMILES: [C:1]([O:4]C(C)(C)C)(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24]([CH2:30][C:31]1[C:36](=[O:37])[CH2:35][CH2:34][CH2:33][C:32]=1OS(C(F)(F)F)(=O)=O)=[CH:25]2.FC(F)(F)C(O)=O>C1COCC1.C(Cl)Cl>[Br:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24]([CH2:30][C:31]1[C:36](=[O:37])[CH2:35][CH2:34][CH2:33][C:32]=1[CH2:2][C:1]([OH:4])=[O:3])=[CH:25]2
Reactant: O=C1CCCC(OS(=O)(=O)C(F)(F)F)=C1Cc1ccc2c(Br)cccc2c1
Reactant: CC(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1=C(Cc2ccc3c(Br)cccc3c2)C(=O)CCC1
Reaction time: 1 h

Procedure:
In to a cold (-78° C.) solution of tert-butyl acetate (2.7 mL, 19.96 mmol) in THF (35 mL) was added lithium bis(trimethylsilyl)amide solution (1 .0M, 21.62 mL, 21.62 mmol). After stirring for 2 hours a solution of trifluoromethanesulfonic acid 2-(5-bromo-naphthalen-2-ylmethyl)-3-oxo-cyclohex-1-enyl ester (7.7 g, 16.63 mmol) in THF (15 mL) was added dropwise. The mixture was stirred for 1 hour, quenched with aqueous NH4Cl, poured in to H2O and extracted with EtOAc, The organic extracts were dried over MgSO4. Evaporation gave a yellow oil residue which was taken up in methylene chloride (100 mL) and treated with trifluoroacetic acid (10 mL). The mixture was stirred for 5 hours and then the volatiles were removed in vacuo. The residue was purified by flash chromatography on acidic silica gel (eluting solvent hexane/EtOAc 1/1) to give a yellow solid (4.1 g, 66% yield, m.p 56°-58 ° C.).
Reaction SMILES: ClC(OCC(C)C)=O.C(N(CC)CC)C.[CH3:16][C:17]1([CH3:45])[CH2:43][C:21]2[C:22]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:42])[C:39]([OH:41])=O)[CH:34]=[CH:35][CH:36]=3)=[C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[S:24][C:20]=2[C:19](=[O:44])[CH2:18]1.[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49][NH2:50]>C(Cl)Cl>[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49][NH:50][C:39](=[O:41])[C:38]([NH:37][C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([C:22]2[C:21]3[CH2:43][C:17]([CH3:16])([CH3:45])[CH2:18][C:19](=[O:44])[C:20]=3[S:24][C:23]=2[N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[CH:32]=1)=[O:42]
Reactant: CC1(C)CC(=O)c2sc(N3CCOCC3)c(-c3cccc(NC(=O)C(=O)O)c3)c2C1
Reactant: CN(C)CCN
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCNC(=O)C(=O)Nc1cccc(-c2c(N3CCOCC3)sc3c2CC(C)(C)CC3=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.7 %

Procedure:
Isobutyl chloroformate (30 μL, 0.23 mmol) and triethylamine (30 μL, 0.23 mmol) were added to a solution of Example 292 (50 mg, 0.12 mmol) in DCM (5.0 mL) and the reaction mixture was stirred at room temperature for 1 h. N,N-Dimethylethylenediamine (60 μL, 0.58 mmol) was then added and the reaction mixture was stirred at room temperature for 72 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC (pH 5.8) to give the title compound (4 mg, 6%) as a yellow solid. δH (CDCl3) 9.12 (1H, s), 8.41 (1H, br s), 7.55-7.46 (2H, m), 7.29 (1H, t, J 7.9 Hz), 7.05-7.00 (1H, m), 3.61-3.49 (6H, m), 2.90-2.77 (6H, m), 2.49 (6H, s), 2.33 (2H, s), 2.29 (2H, s), 0.90 (6H, s). LCMS (ES+) 499.3 (M+H)+.