Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[I:34][C:35]1[CH:36]=[C:37]([CH2:41][OH:42])[CH:38]=[CH:39][CH:40]=1.[Cl:43][C:44]1[C:45]([OH:54])=[C:46]([C:51](=[O:53])[CH3:52])[CH:47]=[CH:48][C:49]=1O>ClCCl.O1CCCC1>[Cl:43][C:44]1[C:45]([OH:54])=[C:46]([C:51](=[O:53])[CH3:52])[CH:47]=[CH:48][C:49]=1[O:42][CH2:41][C:37]1[CH:38]=[CH:39][CH:40]=[C:35]([I:34])[CH:36]=1
Reactant: OCc1cccc(I)c1
Reactant: CC(=O)c1ccc(O)c(Cl)c1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1ccc(OCc2cccc(I)c2)c(Cl)c1O
Reaction time: 18 h
Yield: 64.5 %

Procedure:
Add triphenylphosphine (13.6 g, 51.7 mmol) and DIAD (10.5 g, 51.7 mmol) to a solution of (3-iodo-phenyl)-methanol (11.0 g, 47.0 mmol) and 1-(3-Chloro-2,4-dihydroxy-phenyl)-ethanone (8.77 g, 47.0 mmol) in dichloromethane:tetrahydrofuran (250 ml:250 ml) and stir. After 18 hours, concentrate the reaction, and load directly onto silica. Purify the residue by flash chromatography eluting with acetone:hexanes to yield the title product as a white solid (12.2 g, 64%): 1H NMR (DMSO-d6) δ 2.62 (s, 3H), 5.34 (s, 2H), 6.88 (d, 1H), 7.23 (t, 1H), 7.48 (d, 1H), 7.72 (d, 1H), 7.87 (s, 1H), 7.96 (d, 1H), 13.14 (s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[N:5]=[CH:6][O:7][CH:8]=1.[CH2:9]([O:11][C:12](=[O:32])[N:13]([C:21]1[CH:26]=[C:25](Br)[N:24]=[C:23]([NH2:28])[C:22]=1[N+:29]([O-:31])=[O:30])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:10]>[Cl-].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd+2]>[CH2:9]([O:11][C:12](=[O:32])[N:13]([C:21]1[CH:26]=[C:25]([C:6]2[O:7][CH:8]=[C:4]([CH2:3][O:2][CH3:1])[N:5]=2)[N:24]=[C:23]([NH2:28])[C:22]=1[N+:29]([O-:31])=[O:30])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:10]
Reactant: COCc1cocn1
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(Br)nc(N)c1[N+](=O)[O-]
Agent: [Pd+2]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)N(Cc1ccccc1)c1cc(-c2nc(COC)co2)nc(N)c1[N+](=O)[O-]

Procedure:
The title compound was prepared following the example in preparation 70, using 4-methoxymethyl-oxazole (114 mg), (2-amino-6-bromo-3-nitro-pyridin-4-yl)-benzyl-carbamic acid ethyl ester (200 mg) and palladium bis(triphenylphosphine)dichloride (71 mg), giving the product (160 mg) as a yellow gum.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:32])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH2:30][CH3:31])[N:9]=3)[CH2:2]1.[OH:33][C:34]([CH3:39])([CH3:38])[C:35](O)=[O:36].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:30]([C:22]1[N:21]([C:10]2[N:9]=[C:8]3[C:13]([N:14]=[C:6]([CH2:5][CH:3]4[CH2:2][N:1]([C:35](=[O:36])[C:34]([OH:33])([CH3:39])[CH3:38])[CH2:4]4)[N:7]3[CH3:32])=[C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[N:11]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=1)[CH3:31]
Reactant: CC(C)(O)C(=O)O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
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: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)C(C)(C)O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.5 %

Procedure:
To a mixture of 8-azetidin-3-ylmethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (60 mg, 0.14 mmol), 2-hydroxyisobutyric acid (17 mg, 0.17 mmol) and DIPEA (29 μL, 0.17 mmol) in DCM (1 mL) was added HATU (63 mg, 0.17 mmol). The resulting yellow mixture was stirred for 1.5 h at r.t. then the reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with DCM and MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-6%) affording 721 as a foam (41 mg, 56%). LCMS (method I): RT 3.00 min, [M+H]+ 519.2. 1H NMR (CDCl3, 400 MHz): δ 8.00-7.97 (1 H, m), 7.75-7.74 (1 H, m), 7.27-7.25 (2 H, m), 4.62 (1 H, s), 4.33 (5 H, s), 4.20 (1 H, s), 3.93 (1 H, s), 3.86 (4 H, t, J=4.72 Hz), 3.76 (3 H, s), 3.64 (1 H, s), 3.34 (3 H, q, J=7.44 Hz), 3.15-3.14 (2 H, m), 1.43-1.42 (9 H, m)
Reaction SMILES: BrC1C=CC=CC=1N[N:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12].[Br:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18].C(#N)CC#N.O.[NH2:29][NH2:30]>>[Br:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][N:9]=[C:10]1[C:11]([NH2:12])=[N:30][N:29]=[C:13]1[NH2:14]
Reactant: NN
Reactant: N#CC(C#N)=NNc1ccccc1Br
Reactant: Nc1ccccc1Br
Solvent: O
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1ccccc1Br
Temperature: 25 °C

Procedure:
4-[(2-bromophenyl)hydrazono]-4H-pyrazole-3,5-diamine was prepared using 125 mg (0.5 mmol) of 2-[(2-bromophenyl)hydrazono]malononitrile, which was derived from 2-bromoaniline (172 mg, 1.0 mmol) and malononitrile (1.5 mmol), and hydrazine hydrate. Very little solid had formed after heating the reaction at 75° C. for 1 hr, however, analysis of the reaction solution by TLC indicated that no starting material remained. The solution was allowed to cool to ambient temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and then precipitated by the addition of hexanes. The resulting solid was isolated by filtration and dried to yield 102 mg (73%) of the compound as an orange solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][C:9]([OH:11])=O)=[C:6]([CH3:12])[O:5][N:4]=1.[NH2:13][C@@H:14]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16]>>[CH2:34]([O:33][CH2:32][C@H:14]([NH:13][C:9](=[O:11])[CH2:8][C:7]1[C:3]([CH3:2])=[N:4][O:5][C:6]=1[CH3:12])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1noc(C)c1CC(=O)O
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: Cc1noc(C)c1CC(=O)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 72 %

Procedure:
Proceeding as in Example 1, but substituting 2-(3,5-dimethylisoxazol-4-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 150, (S)-3-(benzyloxy)-2-(2-(3,5-dimethylisoxazol-4-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (48 mg, 72%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.22 (br s, 1H), 8.52-8.50 (d, 1H), 7.63-7.60 (d, 2H), 7.33-7.27 (m, 5H), 7.23-7.19 (t, 2H), 7.03-6.98 (m, 4H), 4.73-4.68 (m, 1H), 4.53 (s, 2H), 3.70-3.63 (m, 1H), 3.31 (s, 2H), 2.28 (s, 3H), 2.11 (s, 3H). MS (EI) for C29H28FN3O5. found 518.0 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:10]2[C:14]([CH3:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[N:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].C1C(=O)N([Br:27])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([N:10]2[C:14]([CH2:15][Br:27])=[CH:13][C:12]([C:16]([F:18])([F:19])[F:17])=[N:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C(F)(F)F)nn1-c1ccc(F)c(C#N)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(-n2nc(C(F)(F)F)cc2CBr)ccc1F
Yield: 48.3 %

Procedure:
To a solution of 1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-methyl pyrazole(4.0 g, 14.87 mmol) in carbon tetrachloride(50 mL) was added NBS(2.65 g, 14.87 mmol) and benzoyl peroxide(0.36 g, 1.48 mmol). The reaction mixture was brought to reflux overnight. Solvent was removed on rotary evaporator under reduced pressure. Residue was partitioned between ethyl acetate(80 mL) and sodium bicarbonate(sat. 80 mL). Organic phase was separated and washed with water(60 mL); dried over sodium sulfate; filtered, concentrated and subjected to silica-gel flash chromatography (ethyl acetate : hexane, 1:10) to afford 1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-bromomethyl pyrazole(2.5 g). CI mass spectrum m/z (rel. intensity) 348 (M+H, 100).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1Br)[CH3:2].[Li]CCCC.[B:17](OC)([O:20]C)[O:18]C.Cl>C1COCC1>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[B:17]([OH:20])[OH:18])[CH3:2]
Reactant: COB(OC)OC
Reactant: CCc1cccc(CC)c1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cccc(CC)c1B(O)O
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
2,6-Diethyl bromobenzene (38.2 g, 180.2 mmol) is added dropwise through an additional funnel over a 1 hour period to a solution of n-BuLi (2.0 M in cyclohexane, 99.1 mL, 198.2 mmol) in THF (380 mL) at −75° C. After addition, the reaction mixture is stirred at −75° C. for 30 min; trimethyl borate (28.1 g, 270.3 mmol) is added slowly over a 40 minute period. The reaction mixture is warmed to room temperature overnight. 2N HCl (250 mL) is added slowly and the resulting mixture is stirred for 1 hour. The organic layer is separated and the aqueous layer is extracted with ether (2×200 mL). The combined organic layers are dried over anhydrous Na2SO4 and the solvents are removed in vacuo. Hexane (400 mL) is added to the residue and a white precipitate is formed. Filtration and drying in vacuo give 2,6-diethylphenyl boronic acid as a white solid. 1H NMR: (CDCl3) 7.22 (t, 1H), 7.04 (s, 2H), 4.65 (s, 2H), 2.64 (q, 4H), 1.22 (t, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[O:13][CH2:14][C:15](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:27][N:28]=[C:29]([C:31]1[CH:47]=[CH:46][C:34]([C:35]([O:37][CH2:38][CH2:39][CH2:40][CH:41]2[O:45][CH2:44][CH2:43][O:42]2)=[O:36])=[CH:33][CH:32]=1)[NH2:30]>C(#N)C.N1C=CC=CC=1.[Cl-].[Na+].O>[C:1]([O:5][C:6]([NH:8][CH:9]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[O:13][CH2:14][C:15]1[O:27][N:28]=[C:29]([C:31]2[CH:32]=[CH:33][C:34]([C:35]([O:37][CH2:38][CH2:39][CH2:40][CH:41]3[O:42][CH2:43][CH2:44][O:45]3)=[O:36])=[CH:46][CH:47]=2)[N:30]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC(=NO)c1ccc(C(=O)OCCCC2OCCO2)cc1
Reactant: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCC(=O)O)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC(c1ccccc1)c1cccc(OCc2nc(-c3ccc(C(=O)OCCCC4OCCO4)cc3)no2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-(3-(((tert-butoxycarbonyl)amino)(phenyl)methyl)phenoxy)-acetic acid (0.087 g. 0.34 mmol) and 3-(1,3-dioxolan-2-yl)propyl 4-(N′-hydroxy-carbamimidoyl)benzoate (0.10 g, 0.28 mmol) in acetonitrile (1 mL), was added 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (0.087 g, 0.42 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was diluted with pyridine and heated at 150° C. for 30 minutes in a microwave. The reaction was diluted with saturated brine and extracted with ethyl acetate (×3). The combined organic fractions were dried with magnesium sulfate, and the solvent evaporated at reduced pressure. The material was used directly in the next step without further purification (0.142 g, 87%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:7]([NH:9][NH2:10])=[O:8])([O-:3])=[O:2].[CH2:18](OC(OCC)(OCC)C)[CH3:19]>>[CH3:18][C:19]1[O:8][C:7]([C:6]2[CH:11]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[N:9][N:10]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: NNC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Product: Cc1nnc(-c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)o1
Reaction time: 12 h
Yield: 82.4 %

Procedure:
A mixture of 3-nitro-5-(trifluoromethyl)benzohydrazide (20 g, 80 mmol) in 1,1,1-triethoxyethane (156 g, 963 mmol) was heated to reflux and stirred for 12 h. Then the solvent was concentrated to yield a black solid of 2-methyl-5-(3-nitro-5-(trifluoromethyl)phenyl)-1,3,4-oxadiazole (20 g, 65.9 mmol, 82% yield): 1H NMR (400 MHz, CD3OD) δ 9.04 (s, 1H), 8.71 (s, 1H), 8.66 (s, 1H), 2.67 (s, 1H); ES-LCMS m/z 274 (M+H).
Reaction SMILES: [OH:1][CH:2]([C:29]([NH:31][O:32][CH3:33])=[O:30])[CH:3]([NH:11][C:12](=[O:28])[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[N:19]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][CH:24]=[CH:25]2)=[N:20]1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CS(C)=O.IC1C=CC=CC=1C(O)=O.C([O-])(O)=O.[Na+]>ClCCl.O>[N:20]1[N:19]([C:14]2[N:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]([NH:11][CH:3]([C:2](=[O:1])[C:29]([NH:31][O:32][CH3:33])=[O:30])[CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:28])[CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[CH:25]2
Reactant: CONC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2ccccc2n1
Agent: O=C(O)c1ccccc1I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: CONC(=O)C(=O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc2ccccc2n1
Reaction time: 3 h
Yield: 92.6 %

Procedure:
To a solution of N-[3-hydroxy-4-(methoxyamino)-4-oxo-1-phenylbutan-2-yl]-2-(2H-indazol-2-yl)nicotinamide (1050 mg; 2.357 mmol) in DMSO (30 ml) 2-iodobenzoic acid (470 mg, 0.755 mmol) was added. After stirring for 4 hours at 30° C. additional 2-iodobenzoic acid (470 mg, 0.755 mmol) was added and stirring was continued for 3 hour at 30° C. and then overnight at room temperature. After cooling the reaction mixture to 15° C. a saturated aqueous solution of NaHCO3 (40 ml), water (40 ml) and dichloromethane (80 ml) were added. The organic layer was collected and the aqueous layer re-extracted twice with dichlormethane (CH2Cl2). The combined organic layers were then dried over MgSO4, filtered and concentrated to give 968 mg of a yellow-brown solid. Purification by chromatography over silica gel (eluent: CH2Cl2+0 to 10% (v/v) methanol) gave 800 mg of a raw product which was recrystallized from isopropanole yielding 456 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:5]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:4]=[N:3]1.Cl.Cl[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([O:13][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)=[CH:11][CH:12]=2)=[C:5]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:4]=[N:3]1
Reactant: Cn1nnc(-c2ccncc2)c1-c1ccc(O)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccncc2)c1-c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 65 °C
Reaction time: 20 h

Procedure:
A mixture of 4-(3-methyl-5-(pyridin-4-yl)-3H-1,2,3-triazol-4-yl)phenol (88 mg, 0.35 mmol), 2-(chloromethyl)quinoline hydrochloride (82 mg, 0.38 mmol), and cesium carbonate (455 mg, 1.4 mmol) in dimethylformamide was stirred at 65° C. for 20 h, filtered, and concentrated. The residue was chromatographed on silica eluting with a gradient of 50% to 100% ethyl acetate in hexanes giving a light yellow solid (100 mg, 73%). 1H NMR (CDCl3, 400 mHz) δ 8.48 (d, 2H, J=6.2 Hz), 8.24 (d, 1H, J=8.3 Hz), 8.09 (d, 1H, J=8.3 Hz), 7.85 (d, 1H, J=7.9 Hz), 7.76 (ddd, 1H, J=8.5, 7, 1 Hz), 7.70 (d, 1H, J=8.7 Hz), 7.57 (m, 1H), 7.54 (m, 2H), 7.24 (m, 2H), 7.20 (m, 2H). 5.46 (s, 2H), 3.90 (s, 3H). MS (AP+) m/e 394 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH:4](C1C=CC=CC=1O[Si](C(C)(C)C)(C)C)[NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[H-].[Na+].I[CH3:38]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:34])[CH2:4][N:5]([S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:38]
Reactant: CI
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)c2ccccc2O[Si](C)(C)C(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7.06 g (0.014 mmol) of [(tert-butyl-dimethylsilanyloxy)-phenyl]-(4-but-2-ynyloxy-benzenesulfonylamino)-acetic acid methyl ester dissolved in 50 mL of DMF was added 0.618 g (0.015 mmol) of a 60% oil dispersion of sodium hydride. The reaction was stirred for 30 min at room temperature and then 2.62 mL of iodomethane was added. After 5 h the reaction was diluted with water and extracted with ether. The combined organics were washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:3) to provide [4-tert-butyl-dimethyl-silanyloxy)-phenyl]-[(4-but-2-ynyloxy-benzenesulfonyl)-methyl-amino]-acetic acid methyl ester as a white waxy solid. Electrospray Mass Spec 518.4 (M+H)+
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][C:4]#[C:5][CH2:6][CH2:7][CH2:8][NH2:9].CO[C:13]1[C:17](OC)=[N:16][S:15](=[O:21])(=[O:20])[N:14]=1.[CH3:22][NH2:23]>>[CH3:22][NH:23][C:13]1[C:17]([NH:9][CH2:8][CH2:7][CH2:6][C:5]#[C:4][CH2:3][N:2]([CH3:10])[CH3:1])=[N:16][S:15](=[O:21])(=[O:20])[N:14]=1
Reactant: CN(C)CC#CCCCN
Reactant: COC1=NS(=O)(=O)N=C1OC
Reactant: CN
Product: CNC1=NS(=O)(=O)N=C1NCCCC#CCN(C)C

Procedure:
In a manner similar to Example 1, reaction of 6-dimethylaminohex-4-ynylamine and 3,4-dimethoxy-1,2,5-thiadiazole-1,1-dioxide followed by treatment with methylamine gives the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.C[O:16][C:17](=[O:29])[CH2:18][CH:19]1[C:23]2[CH:24]=[CH:25][C:26]([OH:28])=[CH:27][C:22]=2[O:21][CH2:20]1>>[CH:10]1([S:9][C:4]2[C:3]([CH2:2][O:28][C:26]3[CH:25]=[CH:24][C:23]4[CH:19]([CH2:18][C:17]([OH:29])=[O:16])[CH2:20][O:21][C:22]=4[CH:27]=3)=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccnc1SC1CCCC1
Reactant: COC(=O)CC1COc2cc(O)ccc21
Product: O=C(O)CC1COc2cc(OCc3cccnc3SC3CCCC3)ccc21
Yield: 70.5 %

Procedure:
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (0.21 g, 0.92 mmol) obtained in Step C of Preparation Example 8 and (6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (0.19 g, 0.92 mmol) obtained in Preparation Example 52 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.25 g, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.IC.[C:14](=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:14][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[CH3:11]
Reactant: O=C([O-])O
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(Br)cc1C
Temperature: 80 °C
Yield: 103.3 %

Procedure:
A mechanically stirred mixture of 4-bromo-2-methyl-benzoic acid (100 g, 465 mmol), iodomethane (95 g, 670 mmol) and sodium bicarbonate (112 g, 1340 mmol) in DMF (325 mL) was heated at 80° C. overnight. The reaction mixture was cooled to room temperature and partitioned between water (1500 mL) and 4:1 hexanes:ethyl acetate (1500 mL). The organic layer was washed with water and dried (Na2SO4). The solvent was removed under vacuum to give 110 g of 4-bromo-2-methyl-benzoic acid methyl ester as an oil, in 100% yield; 1H NMR (DMSO-d6) δ 2.51 (s, 3H), 3.84 (s, 3H), 7.40-7.78 (m, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1([C:21]([NH2:23])=[O:22])[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N+:18]([O-:20])=[O:19])[CH:15]=2)[CH2:10]1.CO[C:26](OC)(OC)[CH2:27][CH2:28][CH3:29]>C1(C)C=CC=CC=1>[N+:18]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH2:10][C:9]1([C:21](=[O:22])[NH:23][C:26]([CH2:27][CH2:28][CH3:29])=[N:8]1)[CH2:17]2)([O-:20])=[O:19]
Reactant: NC(=O)C1(N)Cc2ccc([N+](=O)[O-])cc2C1
Reactant: CCCC(OC)(OC)OC
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCC1=NC2(Cc3ccc([N+](=O)[O-])cc3C2)C(=O)N1

Procedure:
A solution of (±)-2-amino-5-nitroindane-2-carboxamide, trifluoroacetate salt (described in Intermediate 3, 25.0 mg, 0.075 mmol) and 1,1,1-trimethoxybutane (0.060 mL, 0.373 mmol) in toluene (5 mL) was heated at reflux for 16 h. The reaction mixture was concentrated under reduced pressure to give the title compound. MS: m/z=274 (M+1).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[CH2:7]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:24]2[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[O:29])=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CS(O)(=O)=[O:35].C(=O)(O)[O-].[Na+]>O>[CH2:7]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([NH2:30])=[O:29])=[CH:31][CH:32]=2)=[O:35])=[CH:19][CH:18]=1)[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NC(=O)c1ccc(Sc2ccc(CNCCc3ccccc3)cc2)cc1
Reactant: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: NC(=O)c1ccc(S(=O)c2ccc(CNCCc3ccccc3)cc2)cc1
Temperature: 25 °C
Yield: 34.3 %

Procedure:
Sodium periodate (43 mg) was added to a solution of 4-[4-(phenethylamino-methyl)-phenylsulfanyl]-benzamide (73 mg, 0.2 mmol), water (10 mL), and methane sulfonic acid (39 mg, 0.4 mmol) while stirring at room temperature. After 1 and 2 hours, and an additional equivalent of sodium periodate (43 mg) and continue to stir at room temperature. Pour the reaction into saturated aqueous sodium bicarbonate solution then extract with ethyl acetate (3×50 mL). The combined ethyl acetate extracts were dried over sodium chloride/magnesium sulfate, filtered, and concentrated on a rotary evaporator to yield the crude product (60 mg). The crude product was purified by flash column chromatography on silica gel eluting with 10% aqueous ammonium hydroxide in ethanol and chloroform to yield 4-[4-(Phenethylamino-methyl)-benzenesulfinyl]-benzamide (26 mg): 1H NMR (DMSO-D6, 300.00 MHz): 8.98 (d, 1H, J=1.3 Hz), 8.46 (dd, 1H, J=7.9, 2.2 Hz), 8.23 (s, 1H), 8.09 (d, 1H, J=8.3 Hz), 7.75-7.66 (m, 4H), 7.49 (d, 2H, J=8.3 Hz), 7.30-7.15 (m, 5H), 3.76 (s, 2H), 2.75-2.70 (m, 4H); m/z=380.04 (M+1); HPLC=100%@5.67 minutes (5/95 to 95/5 ACN/(0.1% TFA in water) over 10 minutes, Zorbax SB-Phenyl 4.6 mm×15 cm×5 micron, λ=254 nM.
Reaction SMILES: [N+](C1C=CC(O[C:9]([NH:11][C@H:12]([C@@H:20]([O:43][Si](C)(C)C)[CH2:21][C@@H:22]([NH:30][C:31]([O:33]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])=CC=1)([O-])=O.[NH2:50][CH2:51][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1>CN(C=O)C>[N:54]1[CH:55]=[CH:56][CH:57]=[C:52]([CH2:51][NH:50][C:9]([NH:11][C@H:12]([C@@H:20]([OH:43])[CH2:21][C@@H:22]([NH:30][C:31]([NH:50][CH2:51][C:52]2[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=2)=[O:33])[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:10])[CH:53]=1
Reactant: NCc1cccnc1
Reactant: C[Si](C)(C)O[C@@H](C[C@H](Cc1ccccc1)NC(=O)Oc1ccc([N+](=O)[O-])cc1)[C@H](Cc1ccccc1)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Product: O=C(NCc1cccnc1)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)NCc1cccnc1
Reaction time: 18 h

Procedure:
To a solution of 87 mg of the resultant compound from Example 218 in 1 ml of DMF was added 0.028 ml of 3-aminomethylpyridine. After 18 hours, the solvent was removed in vacuo and the residue was dissolved in 1 ml of methanol and 0.05 ml of chlorotrimethylsilane was added. After 0.5 hour, the solvent was removed in vacuo, neutralized with sodium bicarbonate solution and extraction with ethyl acetate (2×25 ml). The organic solution was dried and concentrated. Purification by silica gel column chromotography provided 35 mg of desired product. 1H NMR (CD3OD): δ 1.60 (t, 2H), 2.60-2.80 (m, 4H), 3.70 (m, 1H), 4.00 (m, 1H), 4.10 (m, 1H), 4.25-4.35 (m, 4H), 7.10-7.25 (m, 10H), 7.35 (m, 2H), 7.60 (m, 2H), 8.40 (m, 4H). Mass spectrum: (M+H)+ =553.