Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][NH:14][C:15]2[C:16](=[O:32])[N:17]([C:28]([CH3:31])([CH3:30])[CH3:29])[S:18](=[O:27])(=[O:26])[C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=O)=O)=CC=1.[CH3:33][S:34]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[OH:44])(=[O:36])=[O:35].C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH3:33][S:34]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[O:44][CH2:12][CH2:13][NH:14][C:15]1[C:16](=[O:32])[N:17]([C:28]([CH3:31])([CH3:30])[CH3:29])[S:18](=[O:27])(=[O:26])[C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Oc1ccccc1O
Reactant: Cc1ccc(S(=O)(=O)OCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)N1C(=O)C(NCCOc2ccccc2OS(C)(=O)=O)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 60.7 %

Procedure:
2-[(2-tert-Butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]ethyl 4-methylbenzenesulfonate (150 mg, 0.313 mmol) was dissolved in dry MeCN (3 mL) under nitrogen atmosphere. 2-Hydroxyphenyl methanesulfonate (65 mg, 0.345 mmol) was added followed by potassium carbonate (217 mg, 1.567 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 15 mins. Potassium carbonate was filtered off and the reaction mixture was evaporated to dryness in a vacuum centrifuge. The crude product was purified by preparative HPLC affording the title compound (94 mg, 58.5%). 1H NMR (CDCl3, 500 MHz): δ 1.71 (s, 9H), 3.19 (s, 3H), 3.26 (q, 2H), 3.92 (t, 2H), 5.86 (t, 1H), 6.86 (d, 1H), 6.99 (t, 1H), 7.22 (t, 1H), 7.28 (d, 1H), 7.42-7.45 (m, 3H), 7.49-7.53 (m, 2H); 13C NMR (CDCl3, 125 MHz): δ 27.82, 38.53, 43.28, 61.78, 67.18, 108.11, 114.66, 122.30, 124.66, 125.15, 128.54, 129.08, 130.04, 131.69, 135.27, 138.61, 150.49, 159.51; Mass Spectrum: M+H+ 494.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1>>[Cl:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=1)[S:9]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)(=[O:11])=[O:10]
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Reactant: Clc1cccc(CBr)c1
Product: COc1ccc(CN(Cc2cccc(Cl)c2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from Methyl 4-(N-(4-methoxybenzyl)sulfamoyl)benzoate (Example 5-10b) and 1-(bromomethyl)-3-chlorobenzene. MS (M−H, 444.1); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.69 (s, 3H), 4.30 (m, 4H), 6.76-7.24 (m, 8H), 7.99 (m, 2H), 8.13 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:14]=[C:13]([CH:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH2:17][CH2:16]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:30])[CH:11]=2)[CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[F:30][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([CH2:4][C:3]([OH:31])=[O:2])[CH:14]=[C:13]2[CH:15]1[CH2:16][CH2:17][N:18]([S:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)(=[O:22])=[O:23])[CH2:19][CH2:20]1
Reactant: COC(=O)Cc1cc(C2CCN(S(=O)(=O)c3ccncc3)CC2)c2cc(F)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1cc(C2CCN(S(=O)(=O)c3ccncc3)CC2)c2cc(F)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 28 %

Procedure:
To a stirred solution of {6-fluoro-4-[1-(pyridine-4-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid methyl ester (which may be prepared as described above; 44.5 mg, 0.1 mmol) in THF (4 mL) was added a solution of lithium hydroxide monohydrate (20 mg, 0.48 mmol) in water (1 mL) and the reaction mixture was stirred for 24 hours at room temperature. The reaction mixture was concentrated under reduced pressure and washed with diethyl ether (3×5 mL). The washings were discarded. Water (5 mL) was added to the residue, and the mixture acidified (pH ˜2-3) with an aqueous solution of hydrochloric acid (2 N) and extracted with ethyl acetate (3×5 mL). The combined organic extracts were dried over Na2SO4 and evaporated under reduced pressure to give {6-fluoro-4-[1-(pyridine-4-sulfonyl)-piperidin-4-yl]-naphthalen-2-yl}-acetic acid (12 mg) as a yellow solid. LCMS analysis indicated that the purity of this material was 42%. MS cald. for C22H22FN2O4S [(M+H)+]: 429, obsd. 429.2.
Reaction SMILES: [F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:7][C:6]=1B1OC(C)(C)C(C)(C)O1.Br[C:32]1[C:33]2[CH:42]=[CH:41][O:40][C:34]=2[C:35](=[O:39])[N:36]([CH3:38])[CH:37]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[O:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][S:12]([CH2:15][CH3:16])(=[O:13])=[O:14])=[CH:7][C:6]=1[C:32]1[C:33]2[CH:42]=[CH:41][O:40][C:34]=2[C:35](=[O:39])[N:36]([CH3:38])[CH:37]=1
Reactant: CCS(=O)(=O)Nc1cnc(Oc2ccc(F)cc2F)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cn1cc(Br)c2ccoc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)Nc1cnc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3occc23)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 32.8 %

Procedure:
A mixture of N-[6-(2,4-difluorophenoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]ethanesulfonamide (145 mg, 0.38 mmol), 4-bromo-6-methyl-6H,7H-furo[2,3-c]pyridin-7-one (75 mg, 0.33 mmol), K3PO4 (175 mg, 0.83 mmol), Pd(dppf)Cl2 (24 mg, 10%) in dioxane/H2O (2.2 mL/200 uL) was bubbled with nitrogen for 5 min. The sealed vial was stirred at 70° C. for 4 h. After the reaction mixture was filtered through a short plug of celite, the plug was washed with EtOAc (15 mL). The filtrate was washed with water and brine, the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford a tan residue. The resulting residue was purified by prep-HPLC to afford the title compound (50 mg, 33%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18-1.28 (m, 3H) 3.10-3.21 (m, 2H) 3.59-3.65 (m, 3H) 6.85-6.95 (m, 1H) 7.07-7.19 (m, 1H) 7.35-7.51 (m, 2H) 7.73-7.79 (m, 1H) 7.80-7.85 (m, 1H) 7.90-7.97 (m, 1H) 8.14-8.20 (m, 1H) 9.78-10.09 (m, 1H). LCMS (M+H)+=461.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15](=[O:27])[C:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:18])[CH3:17])[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH2:33][C@H:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@:31]2([CH2:44][CH2:43][CH2:42][NH:41][CH2:40]2)[C:30]1=[O:45].CN1C[C@@H](C2C=CC=CC=2)[C@@]2(CCCNC2)C1=O.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[CH2:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15](=[O:27])[C:16]([NH:19][C:20](=[O:21])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])([CH3:18])[CH3:17])[C:11]([N:41]1[CH2:42][CH2:43][CH2:44][C:31]2([C:30](=[O:45])[N:29]([CH3:28])[CH2:33][CH:32]2[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:40]1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)O
Reactant: CN1C[C@H](c2ccccc2)[C@]2(CCCNC2)C1=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN1C[C@@H](c2ccccc2)[C@@]2(CCCNC2)C1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture comprising (R)-3-(benzyloxy)-2-(2-(tert-butoxycarbonylamino)-2-methyl propanamido)propanoic acid (Intermediate 3A) (800 mg, 2.103 mmol) and a racemic mixture of (4R,5S)-2-Methyl-4-phenyl-2,7-diazaspiro[4.5]decan-1-one and (4S,5R)-2-Methyl-4-phenyl-2,7-diazaspiro[4.5]decan-1-one (Intermediate 1A) (514 mg, 2.103 mmol) in DMF (10 ml) was treated with DIPEA (1.102 ml, 6.31 mmol) and ®T3P (amide coupling agent 50% in DMF, 2.455 ml, 4.21 mmol) and stirred at RT for 1 hour. The resulting mixture was concentrated in vacuo and the residue was suspended in water (50 ml) and extracted with EtOAc (2×100 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification by chromatography on silica eluting with 0-100% EtOAc in iso-hexane afforded the title compound as a white foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][NH:13]C(=O)C(C)(C)C)=[CH:6][CH:5]=1.Cl>CCO>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(OCCNC(=O)C(C)(C)C)cc1
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccc(OCCN)cc1
Temperature: 25 °C
Yield: 108.7 %

Procedure:
To a solution of 4-[2-(2,2-dimethyl-propionylamino)-ethoxy]-benzoic acid methyl ester (350 mg) in EtOH (6 mL) at 0° C. was added concentrated HCl (3 mL). The solution was warmed to room temperature and was concentrated in vacuo to provide the hydrochloride salt of 4-(2-amino-ethoxy)-benzoic acid methyl ester (266 mg) as a white solid which was used in the next step without further purification.
Reaction SMILES: [F:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[N:10])[CH2:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH2:10])[CH2:4][CH2:3]1
Reactant: N#CCN1CCC(F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCN1CCC(F)CC1
Temperature: 50 °C
Yield: 71.6 %

Procedure:
A mixture of (4-fluoro-piperidin-1-yl)-acetonitrile (0.480 mg, 3.2 mmol) in THF 92 mL0 was added to LAH (148 mg, 1.2 eq.) in THF (15 mL). The mixture was heated at 50° C. for 18 hours. The cooled reaction was quenched with NaOH solution until white solid precipitated out. The solid was filtered off and the filtrate was concentrated to give 335 mg (71%) of 2-(4-fluoro-piperidin-1-yl)-ethylamine.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][Br:10])=[CH:5][CH:4]=1.[CH2:11]([O:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17])[CH3:12]>C1(C)C=CC=CC=1>[Br:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][P:14]([O:15][CH2:16][CH3:17])([O:13][CH2:11][CH3:12])=[O:18])=[CH:4][CH:5]=1
Reactant: CCOP(OCC)OCC
Reactant: BrCc1ccc(CBr)cc1
Solvent: Cc1ccccc1
Product: CCOP(=O)(Cc1ccc(CBr)cc1)OCC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
α,α'-Dibromo-p-xylene (22.9 gm) was combined with toluene (70 mL) and heated to reflux. Once the dibromide had completely dissolved, triethylphosphite (5.9 mL) was added all at once and heating continued for 6 hours. The reaction mixture was allowed to cool to room temperature and the excess solid dibromide was removed by suction filtration and washed with a small amount of methylene chloride. The organic solutions were combined and concentrated, on a rotatory evaporator, to a white solid. The solid was taken up in methylene chloride (50 mL) and chromatographed on silica (350 gm). The column was eluted with methylene chloride and fractions of about 25 mL were collected The first peak eluted in fractions 14-24 (excess dibromide), then the solvent was changed to 5% ethanol/methylene chloride. The second major peak, fractions 37-53, was the desired product obtained as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:21][CH:20]=[CH:19][N:5]2[C:6](=[O:18])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=O)[CH:23]=1.[O-]CC.[Na+]>C(O)C>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](/[CH:28]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:21][CH:20]=[CH:19][N:5]3[C:6](=[O:18])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:10][CH:9]=2)[CH:23]=1
Reactant: O=Cc1cccnc1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=c1c(-c2ccc(C(F)(F)F)cc2)c(/C=C/c2cccnc2)nc2sccn12
Yield: 51.9 %

Procedure:
The title compound was synthesized by condensation of Intermediate 5 (400 mg, 1.289 mmol) with pyridine-3-carbaldehyde (200 mg, 1.867 mmol) in presence of sodium ethoxide (175 mg, 2.578 mmol) in ethanol (20 ml) according to the procedure described in Example 24 to give 267 mg of the desired product as a pale yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 6.91 (d, J=15.6 Hz, 1H), 7.31-7.38 (m, 1H), 7.55-7.61 (m, 3H), 7.80-7.88 (m, 4H), 8.00-8.06 (m, 1H), 8.41-8.49 (m, 1H), 8.65-8.72 (m, 1H); ESI-MS (m/z) 400.25 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:17]1[CH:18]=[CH:19][C:20]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:21]([CH:31]=1)[C:22]([NH:24][C:25]1[CH:30]=[CH:29][N:28]=[N:27][CH:26]=1)=[O:23]>COCCOC.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>[C:34]1([CH2:33][O:32][C:20]2[CH:19]=[CH:18][C:17]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[CH:31][C:21]=2[C:22]([NH:24][C:25]2[CH:30]=[CH:29][N:28]=[N:27][CH:26]=2)=[O:23])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C(Nc1ccnnc1)c1cc(Br)ccc1OCc1ccccc1
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: COCCOC
Product: O=C(Nc1ccnnc1)c1cc(-c2ccncc2)ccc1OCc1ccccc1
Temperature: 140 °C

Procedure:
Pyridine 4-boronic acid (35.2 mg, 0.29 mmol), 1M Na2CO3 (0.52 ml, 0.52 mmol) and tetrakis(triphenylphosphine)palladium(0) (18 mg, 6 mol %) were added to a solution of 5-bromo-2-[(phenylmethyl)oxy]-N-4-pyridazinylbenzamide (may be prepared as described in Example 6; 100 mg, 0.26 mmol) in 1,2-dimethoxyethane (3 ml). The solution was heated at 140° C. in microwave for 25 minutes. The solvent was removed in vacuo and the residue purified by MDAP to yield the title compound as an off white solid. 22 mg.
Reaction SMILES: I.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8](=[NH:11])SC.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2([CH2:27][NH2:28])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C(O)CCC>O.C(OCC)(=O)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2([CH2:27][NH:28][C:8]([NH:7][N:6]=[CH:5][C:4]3[C:12]([Cl:16])=[CH:13][CH:14]=[CH:15][C:3]=3[Cl:2])=[NH:11])[CH2:25][CH2:26]2)=[CH:22][CH:23]=1
Reactant: CSC(=N)NN=Cc1c(Cl)cccc1Cl
Reactant: NCC1(c2ccc(Cl)cc2)CC1
Agent: I
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: O
Product: N=C(NCC1(c2ccc(Cl)cc2)CC1)NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 7.80 g. of methyl 3-(2,6-dichlorobenzylidene)thiocarbazimidate hydroiodide and 4.37 g. of 1-(p-chlorophenyl)cyclopropanemethylamine in 100 ml. of n-butanol and 25 ml. of water is heated at reflux for 24 hours. The solution is cooled, diluted with water to a final volume of 2 liters and allowed to stand. Filtration gives a tan solid which is dissolved in ethyl acetate and purified by silica gel column chromatography. Crystallization of the product from diethyl ether gives the desired final product as colorless crystals, m.p. 126°-128° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][CH2:11][CH2:12][C:13]1([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)(=O)=O>CN(C)C=O.C(OCC)C>[N:1]([CH2:10][CH2:11][CH2:12][C:13]1([O:19][Si:20]([C:23]([CH3:24])([CH3:26])[CH3:25])([CH3:21])[CH3:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)OC1(CCCOS(C)(=O)=O)CCCCC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OC1(CCCN=[N+]=[N-])CCCCC1
Reaction time: 60 h
Yield: 95.2 %

Procedure:
Sodium azide (1.78 g, 27.4 mmol) was added to a solution of 3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propyl methanesulfonate (prepared as described in Part D, 24.9 mmol) in dimethylformamide (100 mL). The reaction mixture was stirred for 2.5 d and additional sodium azide (160 mg) was added. The mixture was stirred an additional 1d, then was diluted with diethyl ether (250 mL) and washed with water (3×75 mL). The combined aqueous layers were back-extracted with diethyl ether (50 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated to afford {[1-(3-azidopropyl)cyclohexyl]oxy}(tert-butyl)dimethylsilane (7.05 g, 95% over two steps) as a pale yellow oil. A mixture of the {[1-(3-azidopropyl)cyclohexyl]oxy}(tert-butyl)dimethylsilane (7.05 g, 23.7 mmol) and 5% palladium on carbon (0.71 g) in ethanol (100 mL) was hydrogenated at 30 psi (2.1×105 Pa) for 4 h on a Parr apparatus. The reaction mixture was filtered through CELITE filter agent, which was rinsed afterwards with dichloromethane, and the filtrate was concentrated to give 3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propan-1-amine as a pale yellow oil (6.57 g, 102%) that contained a trace amount of solvent.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[C:18](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:17]=2)=[N:13][C:12]=1[CH3:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([C:16]2[CH:21]=[N:20][CH:19]=[C:18]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:17]=2)=[N:13][C:12]=1[CH3:30])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(-c2cncc(/C=C/c3ccccc3)n2)sc1C(=O)NCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cncc(CCc3ccccc3)n2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.3 %

Procedure:
To a solution of 4-methyl-2-[6-((E)-styryl)-pyrazin-2-yl]-thiazole-5-carboxylic acid benzylamide (32 mg, 0.08 mmol, 1.0 equiv.) in ethyl acetate was added Pd/C (15 mg, 10%). The flask was first purged with nitrogen, then with hydrogen. The reaction mixture was stirred at ambient temperature for 18 hr and monitored by LCMS. Upon completion, the reaction mixture was diluted with ethyl acetate, filtered through Celite and concentrated in vacuo. The crude product was purified by column chromatography [SiO2, methanol/dichloromethane, 0:100 to 5:95, v/v] and recrystallization (methanol) to afford 4-methyl-2-(6-phenethyl-pyrazin-2-yl)-thiazole-5-carboxylic acid benzylamide (18 mg, 56%). 1H NMR (400 MHz, CD2Cl2) δ 9.15 (s, 1H), 8.36 (s, 1H), 7.14-7.37 (m, 10H), 6.21 (bs, 1H), 4.60 (d, J=8.0 Hz, 2H), 3.09-3.16 (m, 4H), 2.73 (s, 3H); HRMS (M+H)+=415.16.
Reaction SMILES: C1(C(O[C:10]2[CH:19]=[CH:18][C:13]3[N:14]=[C:15]([NH2:17])[S:16][C:12]=3[CH:11]=2)C)C=CC=CC=1.NC1SC2C=C(O)C=CC=2N=1.BrC(C1C=CC=CC=1)C>>[S:16]1[C:12]2[CH:11]=[CH:10][CH:19]=[CH:18][C:13]=2[N:14]=[C:15]1[NH2:17]
Reactant: CC(Oc1ccc2nc(N)sc2c1)c1ccccc1
Agent: CC(Br)c1ccccc1
Agent: Nc1nc2ccc(O)cc2s1
Product: Nc1nc2ccccc2s1

Procedure:
6-(1-Phenylethoxy)-1,3-benzothiazol-2-amine can be prepared as in Example 8 but from 0.5 g of 2-amino-1,3-benzothiazol-6-ol and 0.555 g of (1-bromoethyl)benzene. After purification of the residue by silica-column flash chromatography [eluent: dichloromethane/methanol (95/5 by volume)], we obtain 0.308 g of 641-phenylethoxy)-1,3-benzothiazol-2-amine in the form of a thick brown oil, which has the following characteristics:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2[C:14](=[O:32])[O:15][C:16]3[CH:21]=[C:20]([CH:22]([CH:24]([CH3:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:23])[CH:19]=[C:18]([OH:31])[C:17]=3[C:10]=2[CH2:9]1)C1C=CC=CC=1>[Pd].C1(C)C(C)=CC=CC=1>[OH:31][C:18]1[C:17]2[C:10]3[CH:9]=[N:8][CH:13]=[CH:12][C:11]=3[C:14](=[O:32])[O:15][C:16]=2[CH:21]=[C:20]([CH:22]([CH:24]([CH3:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:23])[CH:19]=1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c3c(c(=O)oc2c1)CCN(Cc1ccccc1)C3
Agent: [Pd]
Solvent: Cc1ccccc1C
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)oc(=O)c1ccncc12

Procedure:
A mixture of 3.42 g. of 2-benzyl-10-hydroxy-8-(3-methyl-2-octyl)-5-oxo-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine, 1.0 g. of 10% palladium on carbon, and 120 ml. of xylene was stirred and refluxed for 23 hours. The mixture was filtered to remove the catalyst and the filtrate was evaporated to dryness in vacuo. The residue was recrystallized from acetonitrile to yield the pure product; m.p. 122°-123°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH3:13])[CH:3]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl-].CC1C=C(C)C=C(C)C=1[N+]1C=CN(C2C(C)=CC(C)=CC=2C)C=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:9][O:8][C:6]1[N:5]=[C:4]([NH:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH3:13])[CH:3]=[C:2]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:7]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1nc(Cl)cc(NN=C(C)c2ccc(N(C)C)cc2)n1
Agent: [Pd]
Agent: Cc1cc(C)c(-n2cc[n+](-c3c(C)cc(C)cc3C)c2)c(C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1nc(NN=C(C)c2ccc(N(C)C)cc2)cc(-c2ccccc2)n1

Procedure:
The title compound was prepared from (4-{1-[(6-chloro-2-methoxy-pyrimidin-4-yl)hydrazono]-ethyl}-phenyl)-dimethylamine (100 mg, 0.31 mmol), phenyl boronic acid (190 mg, 1.6 mmol), 1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride (15 mg, 0.04 mmol), tris(dibenzylideneacetone)dipalladium (20 mg, 0.02 mmol) and cesium carbonate (611 mg, 1.9 mmol) in 1,4-dioxane (3 mL) by a procedure similar to Example 9, Step 3 yielding 61 mg (54%) of a yellow solid. HPLC Purity: 92%.
Reaction SMILES: ClC1C=C2C(CC(=O)N2)=CC=1.ClC1C=C(C=CC=1[F:21])C=O.[Cl:22][C:23]1[CH:31]=[C:30]2[C:26](/[C:27](=[CH:33]/[C:34]3[CH:39]=[CH:38][C:37](F)=[C:36]([Cl:41])[CH:35]=3)/[C:28](=[O:32])[NH:29]2)=[CH:25][CH:24]=1>C(O)(C)C>[Cl:22][C:23]1[CH:31]=[C:30]2[C:26](/[C:27](=[CH:33]/[C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([Cl:41])[C:35]=3[F:21])/[C:28](=[O:32])[NH:29]2)=[CH:25][CH:24]=1
Reactant: O=Cc1ccc(F)c(Cl)c1
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccc(F)c(Cl)c1
Agent: O=C1Cc2ccc(Cl)cc2N1
Solvent: CC(C)O
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in example 1, 6-chlorooxindole (5.20 g, 31.2 mmol) (Crescent) and 3-chloro-4-fluoro-benzaldehyde (5.0 g, 31.2 mmol) (Aldrich) in isopropanol to give a mixture of E/Z-6-chloro-3-(3-chloro-4-fluoro-benzylidene)-1,3-dihydro-indol-2-one as a bright yellow solid (Yield 8.89 g, 92.5%) and used for the next step without further purification.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1.O[N:15]=[C:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.N>>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]2[N:23]=[C:11]([C:9]3[CH:8]=[CH:7][C:5]4[NH:6][C:2](=[S:1])[NH:3][C:4]=4[CH:10]=3)[O:13][N:15]=2)[CH:18]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1ccc2nc(S)[nH]c2c1
Agent: N
Product: S=c1[nH]c2ccc(-c3nc(-c4cccnc4)no3)cc2[nH]1

Procedure:
The title compound was prepared according to Method C using 2-mercapto-5-benzimidazolecarboxylic acid (Princeton) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, CD3OD) δ 7.38 (d, J=8.5 Hz, 1H), 7.65 (ddd, J=8.0, 4.9, 0.7 Hz, 1H), 7.86 (d, J=1.0 Hz, 1H), 8.00 (dd, J=8.1, 1.7 Hz, 1H), 8.45 (dt, J=8.0, 1.9 Hz, 1H), 8.81 (dd, J=4.9, 1.5 Hz, 1H), 9.26 (dd, J=2.2, 0.9 Hz, 1H) ppm; MS (DCI/NH3) m/z 296 (M+H)+.