Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8][CH:9]=1)([O-])=[O:2]>CCOC(C)=O.[Pd]>[OH:2][NH:1][C:4]1[N:5]=[CH:6][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:8][CH:9]=1
Reactant: CCOC(=O)Cc1cnc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cnc(NO)cn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of ethyl (5-nitropyrazin-2-yl)acetate (6.7 g, 31.7 mmol) and Pd/C (1 g, 10%) in 300 mL of EtOAc was stirred at room temperature under hydrogen baloon for 6 hours before filtration. The filtrate was concentrated to afford ethyl [5-(hydroxyamino)pyrazin-2-yl]acetate (incomplete reduction). 1H-NMR (400 MHz, CDCl3) δ ppm 8.35 (s, 1H), 8.05 (s, 1H), 4.17 (q, J=7.2 Hz, 2H), 3.75 (s, 2H), 1.24 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].[C:7]([N:15]=[C:16]=[S:17])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)(Cl)Cl>[C:7]([NH:15][C:16]([NH:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[S:17])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NCC(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C(NC(=S)NCC(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.3 %

Procedure:
Dissolve trifluoroethylamine (2.2 g, 22 mmol) in chloroform (20 mL) and add the solution to a mixture of benzoyl isothiocyanate (3.5 g, 22 mmol) in chloroform (20 mL) at room temperature. Stir the mixture in a sealed flask for 16 h at room temperature. Concentrate the mixture in vacuo to obtain the desired intermediate as a solid (5.5 g, 95%). MS (ES+) m/z: 263 (M+H)+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][C@@H:11]1[O:15][C:14](=[O:16])[N:13]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]3)=[C:19]([F:29])[CH:18]=2)[CH2:12]1)(=O)=O.C(OCC)(=O)C.O>CN(C=O)C.C1OCCOCCOCCOCCOCCOC1>[N:1]([CH2:10][C@@H:11]1[O:15][C:14](=[O:16])[N:13]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]3)=[C:19]([F:29])[CH:18]=2)[CH2:12]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cn(-c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)cn1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cn(-c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)cn1
Temperature: 90 °C
Yield: 71.7 %

Procedure:
Sodium azide (0.596 g, 9.08 mmol) and 18-crown-6 (0.025 g, 0.095 mmol) were added to a solution of (5R)-3-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]-2-oxo-1,3-oxazolidin-5-ylmethyl methanesulfonate (WO 01/81350) (3.161 g, 8.56 mmol) in DMF (8.5 ml). The reaction mixture was heated to 90° C. under an atmosphere of nitrogen for 19 h. It was poured into a mixture of ethyl acetate and water and was extracted three times with ethyl acetate. The combined organic layers were washed once with brine, dried over sodium sulfate, filtered and the solvent was removed under vacuum to give 1.94 g of product as a white solid.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8](=[NH:10])[N:7]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.N1(O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[F:40][C:41]1[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][C:42]=1[C:43](O)=[O:44].C(N(CC)CC)C>C1COCC1.CCOC(C)=O>[C:1]([C:5]1[O:9]/[C:8](=[N:10]\[C:43](=[O:44])[C:42]2[CH:46]=[C:47]([C:50]([F:51])([F:52])[F:53])[CH:48]=[CH:49][C:41]=2[F:40])/[N:7]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)c(=N)o1
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)o1
Temperature: 25 °C

Procedure:
A mixture of Example 32B (2 g, 8.92 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (1.37 g, 8.92 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (1.71 g, 8.92 mmol), 2-fluoro-5-(trifluoromethyl)benzoic acid (1.86 g, 8.92 mmol), and triethylamine (1.86 mL, 13.37 mmol) in 30 mL of THF was heated at 80° C. for 12 hr. The mixture was cooled to room temperature, diluted with EtOAc, washed with NaHCO3, dried over MgSO4 and concentrated. The residue was purified by flash chromatography on SiO2 (Hexanes: EtOAc, 0 to 50%) to give the title compound. MS (ESI) m/z 415 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([CH3:15])[CH:14]=2)[N:7]=[CH:6][C:5]1=[O:16].Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:29][O:28][C:24]1[CH:23]=[C:22]2[C:27]([C:18]([O:1][CH2:2][CH2:3][N:4]3[CH:9]=[C:8]([C:10]4[S:11][CH:12]=[C:13]([CH3:15])[CH:14]=4)[N:7]=[CH:6][C:5]3=[O:16])=[CH:19][CH:20]=[N:21]2)=[CH:26][CH:25]=1
Reactant: Cc1csc(-c2cn(CCO)c(=O)cn2)c1
Reactant: COc1ccc2c(Cl)ccnc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Solvent: Cc1ccccc1
Product: COc1ccc2c(OCCn3cc(-c4cc(C)cs4)ncc3=O)ccnc2c1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 52.9 %

Procedure:
1-(2-hydroxyethyl)-5-(4-methylthiophen-2-yl)pyrazin-2(1H)-one (98.2 mg, 416 μmol), 4-chloro-7-methoxyquinoline (93.1 mg, 481 μmol), cesium carbonate (162 mg, 497 μmol), and palladium(II) acetate (23 mg, 102 μmol) were suspended in PhMe (2.8 mL) and racemic-2-(di-t-butylphosphino)-1,1′-binaphthyl (50 mg, 125 μmol) was added. The reaction was placed in a preheated oil bath (70° C.) and stirred under argon for 2.5 hours. The reaction was then cooled to room temperature and filtered through ˜0.5 inches of silica gel with 5:1 CH2Cl2/(2 N ammonia in MeOH). The filtrate was concentrated, and washed with Et2O and MeOH. The MeOH washings were combined with the solid, concentrated, and purified on HPLC (10%->95% MeCN/water with 0.1% TFA over 30 minutes) to afford the desired product (86.5 mg, 0.220 mmol, 53% yield). MS (ESI pos. ion) m/z (MH+): 394. Calc'd exact mass for C21H19N3O3S: 393. 1H NMR (400 MHz, CDCl3): 8.95 (d, J=7.0 Hz, 1H), 8.29 (s, 1H), 8.10 (d, J=9.0 Hz, 1H), 7.71 (d, J=3.0 Hz, 1H), 7.59 (s, 1H), 7.30 (dd, J=9 Hz, 3 Hz, 1H), 7.20 (s, 1H), 7.03 (d, J=7.0 Hz, 1H), 6.92 (s, 1H), 4.80 (t, J=5.0 Hz, 2H), 4.57 (t, J=5.0 Hz, 2H), 4.02 (s, H), 2.30 (s, 3H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:12]=[N:13][N:14]([C:17]2[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][N:18]=2)[C:15]=1[OH:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]O)=[CH:28][CH:27]=1>>[Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:12]=[N:13][N:14]([C:17]2[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][N:18]=2)[C:15]=1[O:16][CH2:32][C:29]1[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCc1cnn(-c2cc(C#N)ccn2)c1O
Reactant: OCc1ccc(F)cc1
Product: CC(C)(C)[Si](C)(C)OCCc1cnn(-c2cc(C#N)ccn2)c1OCc1ccc(F)cc1
Yield: 43 %

Procedure:
The title compound was prepared in 43% yield from 2-[4-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-hydroxypyrazol-1-yl]pyridine-4-carbonitrile and (4-fluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 0.00 (6H, s), 0.85 (9H, s), 2.50 (2H, t, J=6.4 Hz), 3.68 (2H, d, J=6.4 Hz), 5.12 (2H, s), 6.98-7.02 (2H, m), 7.30-7.34 (3H, m), 7.54 (1H, s), 7.98 (1H, s), 8.58 (1H, d, J=5.2 Hz). [M+H] Calc'd for C24H29FN4O2Si, 453; Found, 453.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.[NH2:12][OH:13].C(=O)([O-])[O-].[Na+].[Na+]>CO>[C:1]([N:4]1[CH2:9][CH2:8][C:7](=[N:12][OH:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)N1CCC(=NO)CC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 90.1 %

Procedure:
23.5 g (167 mmol) of 1-acetyl-4-piperidone (Aldrich Chemical Co., Milwaukee, Wis.) and 12.5 g (179 mol) of hydroxylamine hydrochloride were placed in a 250 mL flask with 200 mL of methanol. To the resulting mixture was added 19.0 g (180 mmol) of sodium carbonate, and the resulting mixture was allowed to stir at room temperature for 12-14 h. The reaction mixture was concentrated in vacuo to afford 23.5 g of 1-acetyl-4-hydroxyiminopiperidine as a white solid: 1H NMR (300 MHz, CDCl3) δ3.72 (dd, 2H, J=11.0, 6.0 Hz), 3.59 (ddd, 2H, J=13.8, 6.2, 6.2 Hz), 2.68 (ddd, 2H, J=10.6, 6.2, 6.2 Hz), 2.42 (ddd. 2H, J=12.2, 6.1, 6.1 Hz), 2.17 (d, 3H, J=3.9 Hz); 13C NMR (75 MHz, CDCl3) δ169.39, 169.29, 156.07, 155.78, 45.95, 44.31, 41.68, 39.65, 31.27, 30.46, 25.04, 24.42, 21.47, 21.44.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Br)=[O:8])=[CH:5][CH:4]=1.[C:12]([OH:16])([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl>[C:12]([O:16][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([CH2:2][Br:1])=[CH:4][CH:5]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(Br)c1ccc(CBr)cc1
Reactant: CC(C)(C)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 53.8 %

Procedure:
4-Bromomethylbenzoyl bromide (13.9 g, 50 mmol, 1.0 eq) was added to 50 mL of DCM, followed by t-butanol (9.6 mL, 100 mmol, 2.0 eq) and the mixture was slowly warmed to room temperature. After 20 hours, the reaction was concentrated under reduced pressure, dissolved into 350 mL EtOAc, washed with 400 mL sat. bicarbonate and 200 mL saturated aqueous NaCl. The organic was dried over MgSO4, filtered, and concentrated under reduced pressure to yield intermediate (19a) as a semisolid (7.3 g).
Reaction SMILES: [BH3-]C#N.[Na+].[Br:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][N:10]2[S:15]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[O:25][CH3:26])(=[O:17])=[O:16]>>[Br:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][N:10]2[S:15]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[O:25][CH3:26])(=[O:16])=[O:17]
Reactant: COc1ccc(C)cc1S(=O)(=O)n1ccc2c(Br)cccc21
Agent: [BH3-]C#N
Agent: [Na+]
Product: COc1ccc(C)cc1S(=O)(=O)N1CCc2c(Br)cccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80.8 %

Procedure:
NaBH3CN (480 mg, 7.63 mmol) was added portionwise, under N2, to ice cold TFA (15 mL). The mixture was stirred for 15 min. and 4-bromo-1-[(2-methoxy-5-methylphenyl)sulfonyl]-1H-indole (645 mg, 1.70 mmol; Intermediate 6) was added in portions. The mixture was allowed to attain rt. and stirred 1.5 h. Additional NaBH3CN (480 mg, 7.63 mmol) was added with continuous stirring 1 h. The reaction mixture was quenched with water (30 mL) and extracted twice with DCM. The DCM layers were combined and extracted with aq. Na2CO3 (˜pH 10). The organic layer was dried, filtered and concentrated to give the title compound (525 mg, 80%) as a yellow viscous oil. MS (ESI+) for C16H16BrNO3S m/z 382 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:8]O)=[N:4][CH:5]=[CH:6][CH:7]=1.ClC1C=C(OC)C=C(F)C=1C[N:14]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[S:17](=[O:25])(=[O:24])[N:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[C:28]([O:34][CH3:35])[CH:27]=2)[C:15]1=[O:36]>>[CH3:35][O:34][C:28]1[CH:27]=[C:26]([N:16]2[C:15](=[O:36])[N:14]([CH2:8][C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[S:17]2(=[O:24])=[O:25])[CH:31]=[CH:30][C:29]=1[O:32][CH3:33]
Reactant: OCc1ncccc1F
Reactant: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)c(OC)c3)S(=O)(=O)c3ccccc32)c(Cl)c1
Product: COc1ccc(N2C(=O)N(Cc3ncccc3F)c3ccccc3S2(=O)=O)cc1OC

Procedure:
The title compound (152 mg, 0.34 mmol) was prepared from (IntA1) (167 mg, 0.50 mmol), and (3-fluoropyridin-2-yl)methanol (95 mg, 0.75 mmol) using the methods of (113).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.N(C(OCC)=O)=NC(OCC)=O.Cl.[Cl:44][C:45]1[CH:46]=[C:47]2[C:52](=[CH:53][CH:54]=1)[CH:51]=[C:50]([S:55]([N:58]1[CH2:63][CH:62]([CH2:64]O)[N:61]([N:66]([CH3:79])[CH:67]3[CH2:72][CH2:71][N:70]([C:73]4[CH:78]=[CH:77][N:76]=[CH:75][CH:74]=4)[CH2:69][CH2:68]3)[C:60](=[O:80])[CH2:59]1)(=[O:57])=[O:56])[CH:49]=[CH:48]2>C(Cl)Cl>[Cl:44][C:45]1[CH:46]=[C:47]2[C:52](=[CH:53][CH:54]=1)[CH:51]=[C:50]([S:55]([N:58]1[CH2:59][C:60](=[O:80])[N:61]([N:66]([CH3:79])[CH:67]3[CH2:72][CH2:71][N:70]([C:73]4[CH:74]=[CH:75][N:76]=[CH:77][CH:78]=4)[CH2:69][CH2:68]3)[CH:62]([CH2:64][N:24]3[C:20](=[O:30])[C:21]4[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:23]3=[O:25])[CH2:63]1)(=[O:57])=[O:56])[CH:49]=[CH:48]2
Reactant: CN(C1CCN(c2ccncc2)CC1)N1C(=O)CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1CO
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(C1CCN(c2ccncc2)CC1)N1C(=O)CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1CN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Yield: 89.4 %

Procedure:
A mixture of triphenylphosphine (0.49 g), phthalimide (0.29 g) and methylene chloride (15 ml) was combined with diethyl azodicarboxylate (0.29 ml) with stirring at 0° C., and stirred for 10 minutes. This solution was combined, at 0° C. with stirring, with a solution of 4-[(6-chloro-2-naphthyl)sulfonyl]-6-(hydoxymethyl)-1-[methyl[1-(4-pyridinyl)-4-piperidinyl]amino]-2-piperazinone hydrochloride (0.27 g) in methylene chloride (10 ml) and stirred at room temperature for 1 hour. The reaction mixture was washed with saturated aqueous sodium bicarbonate, dried, and concentrated under reduced pressure. The residue was purified by a column chromatography on a silica gel (dichloromethane: 10% aqueous ammonia-containing methanol=10:1) to obtain 2-[(4-[(6-chloro-2-naphthyl)sulfonyl]-1-[methyl[1-(4-pyridinyl)-4-piperidinyl]amino]-6-oxo-2-piperazinyl)methyl]-1H-isoindole-1,3(2H)-dione (0.28 g) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:9](C(OCC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.CS(C)=O.[Cl-].[Na+]>O>[Cl:1][C:2]1[C:3]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncc(Cl)cc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1ncc(Cl)cc1Cl
Temperature: 142.5 °C
Reaction time: 0.67 h
Yield: 92.2 %

Procedure:
6.75 g of diethyl (3,5-dichloro-2-pyridyl)malonate and 20 ml of dimethyl sulfoxide were mixed. To the mixture was added 1.57 g of sodium chloride and 0.79 g of water. The mixture was stirred for about 40 minutes at an inner temperature of 135 to 150° C. The mixture was allowed to cool to room temperature, then, water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated brine twice, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure, to obtain 4.76 g of ethyl (3,5-dichloro-2-pyridyl)acetate.
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]([CH3:20])[CH3:19])[C:13]=2[OH:21])=[CH:8][CH:7]=1.BrBr.C1(O)C=CC=CC=1>CO.C1(C)C=CC=CC=1.C1CCCCC1>[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[C:16]([S:1][C:2]#[N:3])[CH:15]=[C:14]([CH:18]([CH3:19])[CH3:20])[C:13]=2[OH:21])=[CH:10][CH:11]=1
Reactant: N#C[S-]
Reactant: CC(C)c1cccc(-c2ccc(F)cc2)c1O
Agent: BrBr
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: C1CCCCC1
Product: CC(C)c1cc(SC#N)cc(-c2ccc(F)cc2)c1O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A suspension of 70.9 g (838 mmol, 5.0 equivalents) of sodium thiocyanate in 200 ml of methanol was stirred at room temperature for 20 min. 40.0 9 (173.8 mmol, 1.0 equiv.) of 2-(p-fluorophenyl)-6-isopropylphenol were added and the mixture was stirred for 20 minutes. 14.32 ml (277.8 mmol, 1.6 equiv.) of bromine were dissolved in 50 ml of methanol (exothermic) and this solution was added dropwise at 15°-20° C. to the above reaction solution during the course of 20 minutes. The reaction mixture turned yellow and the phenol dissolved completely. The reaction mixture was stirred for 30 min. TLC (toluene/cyclohexane 1:1) showed complete conversion of the starting material (Rf =0.54). In addition to the title compound (Rf =0. 32), only a small amount of the corresponding para-bromo compound, which cochromatographed with the starting material (Rf =0. 54), was obtained as an impurity, but was able to be differentiated owing to different coloration. The reaction mixture was poured onto 400 g of ice/400 ml of 2N hydrochloric acid and extracted using 4×200 ml of toluene. The extracts were washed with aqueous sodium sulfite solution, filtered, washed with saturated sodium chloride solution, dried and concentrated in vacuo.
Reaction SMILES: C(S[C:4]1[S:5][C:6](=[CH:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=2[C:29]([F:32])([F:31])[F:30])[N:15]=[CH:14]3)[C:7](=[O:9])[N:8]=1)C.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][N:43](C2SC(=CC3C=C4C(=CC=3)N(CC3C=CC(C(O)(C)C)=CC=3C(F)(F)F)N=C4)C(=O)N=2)[CH2:42][CH:41]1[CH2:77][OH:78])=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][N:43]([C:4]2[S:5][C:6](=[CH:10][C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=3[C:29]([F:30])([F:32])[F:31])[N:15]=[CH:14]4)[C:7](=[O:9])[N:8]=2)[CH2:42][CH:41]1[CH2:77][OH:78])=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(C)(C)O)cc4C(F)(F)F)c3)S2)CC1CO
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(OC)cc3C(F)(F)F)c2)S1
Product: COc1ccc(Cn2ncc3cc(C=C4SC(N5CCN(C(=O)OC(C)(C)C)C(CO)C5)=NC4=O)ccc32)c(C(F)(F)F)c1

Procedure:
(2R) 2-Hydroxymethyl-4-{5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazine-1-carboxylic acid tert-butyl ester was prepared from 2-Ethylsulfanyl-5-[1-(4-methoxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one and (2R) 2-Hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[O:6]([CH2:13][C:14](Cl)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+]>O.CCOCC>[O:6]([CH2:13][C:14]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: NCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=C(O)CNC(=O)COc1ccccc1

Procedure:
Glycine (20 mmol) was reacted with distilled phenoxyacetyl chloride (22 mmol) in the presence of NaOH (40 mmol) in a mixture of water and ether as described in Example 5 Part A. The crude product was recrystallized from EtOAc (15 ml) to give title acid (2.38 gm, 57%).
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][O:12][CH3:13].[NH2:14][C:15]1[CH2:16][C:17]([C:33](OCC)=[O:34])=[CH:18][C:19]2[CH:25]=[CH:24][C:23]([C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[CH:22][C:20]=2[N:21]=1>C1(C)C=CC=CC=1.ClCCCl>[NH2:14][C:15]1[CH2:16][C:17]([C:33]([N:9]([CH2:10][CH2:11][O:12][CH3:13])[CH2:8][CH2:7][O:6][CH3:5])=[O:34])=[CH:18][C:19]2[CH:25]=[CH:24][C:23]([C:26]([F:32])([F:31])[C:27]([F:28])([F:29])[F:30])=[CH:22][C:20]=2[N:21]=1
Reactant: CCOC(=O)C1=Cc2ccc(C(F)(F)C(F)(F)F)cc2N=C(N)C1
Reactant: COCCNCCOC
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCCl
Product: COCCN(CCOC)C(=O)C1=Cc2ccc(C(F)(F)C(F)(F)F)cc2N=C(N)C1
Temperature: 75 °C

Procedure:
Trimethylaluminum (0.34 mL of a 2.0 M solution in toluene) was added to bis(2-methoxyethyl)amine (92 mg, 0.69 mmol) in DCE (3 mL). After 10 minutes solid (1E,4E)-ethyl 2-amino-8-(perfluoroethyl)-3H-benzo[b]azepine-4-carboxylate (80 mg, 0.23 mmol) was added and the vessel was sealed and heated to 75° C. for 16-20 hours. Upon cooling the reaction was quenched with saturated Rochelle's salt (2 mL) and after 20 minutes the mixture was partitioned between CH2Cl2 (50 mL) and brine (50 mL). The phases were separated and the aqueous was extracted with CH2Cl2 (2×20 mL). The combined organics were dried and concentrated. The crude material was purified via preparative TLC (2, 0.5 mm plates, eluting with 5-10% MeOH/CH2Cl2 with 4-6 drops of NH4OH). 1H NMR (CDCl3) δ 2.81 (s, 2H), 3.36 (s, 6H), 3.55-3.74 (m, 8H), 6.98 (s, 1H), 7.20 (d, 1H), 7.40 (d, 1H), 7.39 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].ClCCl.Cl[S:8]([C:11]1[CH:26]=[CH:25][C:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9]>O1CCCC1>[CH3:1][N:2]([CH3:3])[S:8]([C:11]1[CH:12]=[CH:13][C:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[CH:25][CH:26]=1)(=[O:9])=[O:10]
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(Cc2ccc(S(=O)(=O)Cl)cc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution of dimethylamine in tetrahydrofuran (2M, excess) was added 4-(4-chlorosulfonylbenzyl)-nitrobenzene dichloromethane hemisolvate (354 mg, 1 mmol) dissolved in tetrahydrofuran (5 mL). The mixture was stirred for 1 hour and extracted with a solution of diethyl ether and dilute potassium carbonate. The organic layer was separated and solvents evaporated. The residue was recrystallized from acetone/hexanes to give 4-(4-dimethylaminosulfonylbenzyl)-nitrobenzene (311 mg, 98%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][NH2:13])=[N:4][N:3]=1.[CH3:14][C:15]1[O:19][N:18]=[C:17]([C:20](O)=O)[CH:16]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:20]([C:17]3[CH:16]=[C:15]([CH3:14])[O:19][N:18]=3)[N:4]2[N:3]=1
Reactant: NNc1nnc(Cl)c2ccccc12
Reactant: Cc1cc(C(=O)O)no1
Product: Cc1cc(-c2nnc3c4ccccc4c(Cl)nn23)no1

Procedure:
Intermediate 14b was prepared in two steps from intermediate 11 in an analogous fashion to the preparation of intermediate 14a (see Example 1). Commercially available 5-methylisoxazole-3-carboxylic acid (12c) was used in the first step.
Reaction SMILES: CO[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[CH:5][CH:4]=1.Cl[C:15]1C2C(=CC=CC=2)C(O)=CC=1.CC1C=CC2C(=CC=CC=2)C=1O>>[CH3:15][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:13])=[CH:5][CH:4]=1
Reactant: Oc1ccc(Cl)c2ccccc12
Reactant: COc1ccc(O)c2ccccc12
Agent: Cc1ccc2ccccc2c1O
Product: Cc1ccc(O)c2ccccc12

Procedure:
4-methoxy-1-naphthol; 4-chloro-1-naphthol; and 2-methyl-1-naphthol. For additional compounds see U.S. Pat. No. 5,262,295 at column 6, lines 17-20, incorporated herein by reference.