Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:12]([OH:14])=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.N1([C:27](=O)[C:26]2N(C)C=N[C:21]=2N(C)C1=O)C.C1(C)CCC(C(C)C)C(O)C1>O.C(O)C>[CH:26]([O:13][C:12](=[O:14])[C@H:3]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)[NH2:2])([CH3:27])[CH3:21]
Reactant: Cn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: CC1CCC(C(C)C)C(O)C1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)OC(=O)[C@@H](N)Cc1ccc(O)cc1

Procedure:
HCl (70 g) and tyrosine (7 g) were dissolved in water (1 L). Caffeine (50 g), ethanol (100 ml) and menthol (20 g) were added into the mixture and the mixture was stirred for a few minutes. The mixture was filled into either spray bottles or roll-on bottles.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([C:35]#[N:36])[CH2:10][C:11]([CH3:34])=[CH:12][CH2:13][C:14]1[C:15]([O:27]CC[Si](C)(C)C)=[C:16]2[C:20](=[C:21]([CH3:25])[C:22]=1[O:23][CH3:24])[CH2:19][O:18][C:17]2=[O:26])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([O:3][P:4]([CH:9]([C:35]#[N:36])[CH2:10][C:11]([CH3:34])=[CH:12][CH2:13][C:14]1[C:15]([OH:27])=[C:16]2[C:20](=[C:21]([CH3:25])[C:22]=1[O:23][CH3:24])[CH2:19][O:18][C:17]2=[O:26])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)C(C#N)CC(C)=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(C#N)CC(C)=CCc1c(O)c2c(c(C)c1OC)COC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
{1-Cyano-5-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-3-methyl-pent-3-enyl}-phosphonic acid diethyl ester (25 mg, 0.047 mmol) was dissolved in a solution of 10% TFA/CH2Cl2 (5 mL) and stirred at room temperature for 2 hours. The reaction mixture was dried under reduced pressure and the product was purified by RP-HPLC to provide 16 mg (80%) of the desired product as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.38 (t, 6H), 1.86 (s, 3H), 2.15 (s, 3H), 2.40-2.58 (m, 2H), 3.01-3.14 (m, 1H), 3.45 (d, J=7.2 Hz, 2H), 3.79 (s, 3H), 4.18-4.30 (m, 4H), 5.21 (s, 2H), 5.48 (t, J=7.2 Hz, 1H) ppm; 31P (121.4 MHz, CDCl3) δ 18.09 ppm; MS (m/z) 436 [M−H]−, 438 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[C:20]([C:22]3[CH:31]=[C:30]4[C:25]([CH2:26][CH2:27][NH:28][CH2:29]4)=[CH:24][CH:23]=3)[N:19]=[C:18]([NH2:32])[N:17]=2)[CH2:12][CH2:11]1.[CH:33]1([CH2:38][C:39](O)=[O:40])[CH2:37][CH2:36][CH2:35][CH2:34]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH:33]1([CH2:38][C:39]([N:28]2[CH2:27][CH2:26][C:25]3[C:30](=[CH:31][C:22]([C:20]4[CH:21]=[C:16]([N:13]5[CH2:12][CH2:11][N:10]([CH3:9])[CH2:15][CH2:14]5)[N:17]=[C:18]([NH2:32])[N:19]=4)=[CH:23][CH:24]=3)[CH2:29]2)=[O:40])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C(O)CC1CCCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)CC3CCCC3)CC4)nc(N)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (24 uL, 0.17 mmol) was added to a mixture of 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt (15 mg, 0.034 mmol), cyclopentaneacetic acid (5.2 uL, 0.041 mmol) (Aldrich, Cat. #125490), and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (17 mg, 0.038 mmol) (Chem-Impex, Cat. #00604) in N,N-dimethylformate (0.5 mL). The mixture was stirred at r.t. for 30 min., and then purified by RP-LCMS (pH=10) to afford the desired product. Analytic LCMS (M+H)+: m/z=435.2.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([F:25])([F:24])[F:23])=[CH:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=[O:14].[N+:28]([C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)([O-:30])=[O:29].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:28]([C:31]1[CH:36]=[CH:35][C:34]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:24])([F:23])[F:25])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:26])([F:27])[F:1])=[CH:33][CH:32]=1)([O-:30])=[O:29]
Reactant: O=C(O)/C=C/C=C(c1ccccc1C(F)(F)F)c1ccccc1C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(/C=C/C=C(c1ccccc1C(F)(F)F)c1ccccc1C(F)(F)F)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 97.3 %

Procedure:
As in Example 115, (E)-5,5-bis[2-(trifluoromethyl) phenyl]-2,4-pentadienoic acid (1.135 g) and 4-nitrophenol (0.450 g) in dichloromethane (15 mL) was treated with 1,3-dicyclohexylcarbodiimide (0.607 g). The mixture was stirred at 0°-5° C. for 1 hour, then at room temperature for 30 minutes. The usual work up furnished 1.45 g of (E)-5,5-bis[2-(trifluoromethyl)phenyl]2,4-pentadienoic acid 4-nitrophenyl ester as an oil essentially homogeneous by tlc. This material was used without further purification in subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][C:12]1[N:16]=[CH:15][NH:14][N:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:14]2[CH:15]=[N:16][C:12]([CH3:11])=[N:13]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: Cc1nc[nH]n1
Reactant: O=Cc1cc(Cl)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ncn(-c2ccc(Cl)cc2C=O)n1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
In a 25 ml RBF, a mixture of 5-chloro-2-fluorobenzaldehyde (505 mg, 3.09 mmol), 3-methyl-1H-1,2,4-triazole (270 mg, 3.09 mmol), Cs2CO3 (1007 mg, 3.09 mmol) in DMSO (6179 μl) was heated at 45° C. for 4 hrs and stirred at rt overnight. The reaction mixture was diluted with EtOAc and washed with water. The combined organic phase was washed with brine, dried over MgSO4, filtered, concentrated and purified by flash chromatography to yield 74A as white solid product (140 mg, 20%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.95 (s, 1H), 9.02 (s, 1H), 7.96-7.88 (m, 2H), 7.80 (d, J=8.4 Hz, 1H), 2.37 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1N.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:22].[Na+]>O.C(O)(=O)C>[F:1][C:2]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[I:22])([F:12])[F:11]
Reactant: Nc1ccccc1SC(F)(F)F
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)Sc1ccccc1I
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
2-(trifluoromethylthio)benzenamine (1 g, 5.18 mmol) prepared in accordance with a method described in J. Fluorin. Chem. 1994, 69, 207 to 212, 5 ml of glacial acetic acid, and 3 ml of 50% sulfuric acid were added into a 50-ml eggplant flask equipped with a stirrer, and were dissolved. Then the mixture was cooled to 0° C. on an ice bath. To the mixture, 1 ml of an aqueous solution of sodium nitrite (0.43 g, 6.22 mmol) was added and the mixture was stirred for 1.5 hours. 1 ml of an aqueous solution of sodium iodide (0.95 g, 6.3 mmol) was added dropwise at 0° C. and the mixture was stirred for 30 minutes. After completion of the reaction, the reaction solution was gradually heated to room temperature and added to water, and the solution was extracted three times with ether. The obtained organic layer was washed three times with water, two times with a saturated sodium bisulfite aqueous solution, and three times with water, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (Hexane 100) to give target (trifluoromethyl)-(2-iodophenyl)sulfide (1.5 g, 95%) as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH:12]([OH:17])[C:13]([F:16])([F:15])[F:14]>>[F:14][C:13]([F:16])([F:15])[CH:12]([OH:17])[CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: OC(CBr)C(F)(F)F
Product: O=Cc1ccc(OCC(O)C(F)(F)F)cc1
Yield: 84 %

Procedure:
The title compound is prepared analogously to Example 12A from 4-hydroxybenzaldehyde and 3-bromo-1,1,1-trifluoropropan-2-ol.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.P(=O)(O)(O)O>[Pd].C(O)(C)C>[CH3:10][C:9]1[C:2]([OH:1])=[C:3]([CH3:4])[CH:6]=[CH:7][C:8]=1[OH:11]
Reactant: Cc1c(O)ccc(C=O)c1O
Agent: [Pd]
Agent: O=P(O)(O)O
Solvent: CC(C)O
Product: Cc1ccc(O)c(C)c1O
Yield: 72 %

Procedure:
A solution of 2,4-dihydroxy-3-methylbenzaldehyde (30.0 g, 197 mmol) with isopropanol (3 L) was ice-cooled in a 5 L 3-neck flask fitted with a magnetic stirrer. Phosphoric acid (4 mL) and 10% palladium on carbon were added and the solution was sparged with nitrogen, then hydrogen. When uptake was judged to be complete (c. 1.5 hour) the solution was again sparged with nitrogen and then filtered through Celite®. The solvent was stripped off, the residue taken up in ethyl acetate, and the resulting solution washed with water (4×100 mL). The water washes were back-extracted with ethyl acetate and the combined organic layers dried over sodium sulfate and stripped down. Sublimation (95°, 0.05 torr) afforded a colorless solid (19.6 g, 72%). M.p. 107°-8° C. (Lit. 108°-109° C. [W. Baker et al., J. Chem. Soc., 2834-5 (1949).]). NMR (DMSO-d6): δ1.969 (s, 3H), 2.037 (s, 3H), 6.220 (d, J=8.1 hz, 1H), 6.637 (d, J=8.1 hz, 1H), 7.929 (s, 1H), and 8.785 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:21]([NH:23][C:24]3[N:28]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)[N:27]=[C:26]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH:25]=3)=[O:22])=[CH:12][CH:11]=2)[CH:6]=1.CCN(C(C)C)C(C)C.[CH3:49][O:50][CH2:51][C:52](Cl)=[O:53]>C(Cl)Cl>[C:36]([C:26]1[CH:25]=[C:24]([NH:23][C:21](=[O:22])[NH:20][C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([O:9][CH2:8][CH2:7][N:5]3[CH:6]=[C:2]([NH:1][C:52](=[O:53])[CH2:51][O:50][CH3:49])[N:3]=[CH:4]3)=[CH:11][CH:12]=2)[N:28]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)[N:27]=1)([CH3:39])([CH3:38])[CH3:37]
Reactant: COCC(=O)Cl
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCn3cnc(N)c3)c3ccccc23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC(=O)Nc1cn(CCOc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)c3ccccc23)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.1 %

Procedure:
To a suspension of 1-(4-(2-(4-amino-1H-imidazol-1-yl)ethoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate I) (50 mg, 0.095 mmol) in DCM (2.0 mL) was added DIPEA (33 μl, 0.191 mmol) and 2-methoxyacetyl chloride (10 μl, 0.105 mmol). The mixture was stirred at RT overnight and then partitioned between saturated aq NaHCO3 solution (5.0 mL) and DCM (2.0 mL). The layers were separated through a phase separator cartridge and the organics were collected and evaporated under reduced pressure. The resulting residue was subjected to SCX capture and release and column chromatography (12 g), eluting with 0 to 10% MeOH in EtOAc. Trituration with EtOAc (5.0 mL) gave N-(1-(2-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)ethyl)-1H-imidazol-4-yl)-2-methoxyacetamide (Example 24) as a white solid (8 mg, 14%): m/z 596 (M+H)+ (ES+). 1H NMR (400 MHz, DMSO-d6) δ: 1.26 (9 H, s), 2.38 (3 H, s), 3.29 (3 H, s), 3.93 (2 H, s), 4.37 (2 H, t), 4.47 (2 H, t), 6.34 (1 H, s), 6.93 (1 H, d), 7.34 (2 H, m), 7.41-7.45 (3 H, m), 7.48-7.62 (4 H, m), 7.88 (1 H, d), 8.13-8.15 (1 H, dd), 8.54 (1 H, s), 8.75 (1 H, s), 9.84 (1 H, s).
Reaction SMILES: [C:1]([N:8]1[C@H:12]([CH3:13])[C@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:10][C:9]1=[O:20])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:31](Br)[CH:32]=[CH2:33]>C1COCC1>[CH2:33]([C@H:2]([CH2:3][CH2:4][CH2:5][CH3:6])[C:1]([N:8]1[C@H:12]([CH3:13])[C@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:10][C:9]1=[O:20])=[O:7])[CH:32]=[CH2:31]
Reactant: CCCCCC(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Reactant: C=CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@H](CCCC)C(=O)N1C(=O)O[C@@H](c2ccccc2)[C@H]1C
Reaction time: 0.17 h
Yield: 57.5 %

Procedure:
To a solution of the compound of step G (1) (208 mg, 756 μmol) in THF (1.5 mL) at −78° C. was added 1 M NaHMDS (832 μL, 832 μmol) dropwise. After 10 minutes, allyl bromide (196 μL, 2.27 mmol) was added in one shot. The reaction was continued at −78° C. until TLC showed complete reaction (˜6 hours). The reaction was quenched with saturated ammonium chloride solution and allowed to come to room temperature. The mixture extracted 3 times with ethyl acetate. The combined organic layers were dried with MgSO4, filtered, and concentrated in vacuo. Silica gel chromatography (0% to 10% EtOAc/Hexane gradient) afforded pure product (137 mg, 58%). 1H NMR (500 MHz, CDCl3) δ ppm 0.93-0.81 (m, 6H) 1.35-1.21 (m, 4H) 1.53-1.44 (m, 1H) 1.75-1.66 (m, 1H) 2.34-2.22 (m, 1H) 2.47-2.36 (m, 1H) 3.98-3.86 (m, 1H) 4.82-4.74 (m, 1H) 5.08-4.94 (m, 2H) 5.63 (d, J=7.32 Hz, 1H) 5.87-5.75 (m, 1H) 7.46-7.24 (m, 5H). HPLC retention time: 1.92 min (method A). MS (ESI) (M+H)+ 316.
Reaction SMILES: I[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:7]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=1)=[O:4].[C:35]([O:38][C@@H:39]1[C@@H:45]([O:46][C:47](=[O:49])[CH3:48])[C@H:44]([O:50][C:51](=[O:53])[CH3:52])[C@@H:43]([CH2:54][O:55][C:56](=[O:58])[CH3:57])[O:42][C@H:40]1[OH:41])(=[O:37])[CH3:36].[H-].[Na+].O>C(Cl)Cl>[C:35]([O:38][C@@H:39]1[C@@H:45]([O:46][C:47](=[O:49])[CH3:48])[C@H:44]([O:50][C:51](=[O:53])[CH3:52])[C@@H:43]([CH2:54][O:55][C:56](=[O:58])[CH3:57])[O:42][C@H:40]1[O:41][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:7]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=1)=[O:4])(=[O:37])[CH3:36]
Reactant: O=C(CI)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: CC(=O)OC[C@H]1O[C@@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](OCC(=O)c2cc(OCc3ccccc3)c(OCc3ccccc3)c(OCc3ccccc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Iodo-3′,4′,5′-tribenzyloxyacetophenone (20) (5.64 g, 10 mmol) and β-D-glucose-2,3,4,6-tetraacetate (8) (4.18 g, 12 mmol) was dissolved in dry DCM (50 mL) and sodium hydride (0.48 g, 20 mmol) (0.8 g 60% NaH suspension in oil)) was added in small portions. The reaction mixture was allowed to be stirred at room temperature overnight. Excess of sodium hydride was decomposed by addition of suitable amount water. Dichloromethane was removed under vacuum in order to simplify the work up. Water (100 mL) was added and the water phase extracted with diethyl ether (4×75 mL). The organic layers were combined and washed with water (2×50 mL), dried (MgSO4) and evaporated to give a dark viscous oil. The product was isolated by dry flash chromatography (PE/EtOAc 6:4). Recrystallisation from a mixture of methylcyclohexane and ethyl acetate afforded the desired compound as white crystals, m.p. 156-158° C. Yield 5.1 g (65%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:17])=[N:4][C:5]([Cl:16])=[CH:6][C:7]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[CH3:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([CH:25]=O)[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:17][C:3]1[C:2]([NH:1][CH2:18][C@H:19]2[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]2)=[C:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH:6]=[C:5]([Cl:16])[N:4]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)nc(Cl)c1N
Reactant: C[C@H]1CC[C@H](C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cc(Cl)nc(Cl)c1NC[C@H]1CC[C@H](C)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl (3-amino-2,6-dichloropyridin-4-yl)carbamate (353 g, 1.27 mol) and trans-4-methylcyclohexanecarbaldehyde (160 g, 1.27 mol) in DCM (8.0 L) and acetic acid (2 ml) was added sodium triacetoxyborohydride (807.7 g, 3.81 mol) at 0° C. The mixture was stirred for 15 min, and then warmed to room temperature. The mixture was stirred for 15 h at room temperature and then quenched with water (10 L). The mixture was filtered, the filtrate was separated, and the organic layer was concentrated under reduced pressure to give crude product. The crude product was purified over a silica gel column, eluting with EtOAc: petroleum ether (0-1:10), to give tert-butyl (2,6-dichloro-3-(((trans-4-methylcyclohexyl)methyl)amino)pyridin-4-yl)carbamate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Product: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccccc1

Procedure:
The title compound was prepared from ethyl 5-bromo-1H-indole-2-Carboxylate and benzyl bromide in substantially the same manner, as described in step 1 of Example 1. The product was obtained as a light yellow solid. Mass spectrum (ESI, [M+H]+) m/z 358. 1H NMR (300 MHz, DMSO-d6) δ 7.94 (s, 1H), 7.55 (d, 1H, J=9.01 Hz), 7.42 (d, 1H, J=8.85 Hz), 7.34 (s, 1H), 7.30–7.21 (m, 3H), 6.99 (d, 2H, J=7.94 Hz), 5.85 (s, 2H), 4.28 (q, 2H), and 1.28 ppm (t, 3H).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([CH2:30][O:31][NH2:32])=[CH:28][CH:27]=1.CC([O-])=O.[Na+]>CCO>[Br:25][C:26]1[CH:34]=[CH:33][C:29]([CH2:30][O:31][N:32]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=2[NH:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])=[CH:28][CH:27]=1
Reactant: NOCc1ccc(Br)cc1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(Nc1ccc(Cl)cc1C(=NOCc1ccc(Br)cc1)c1ccccc1)C(F)(F)F
Yield: 37.6 %

Procedure:
A solution of N-(2-benzoyl-4-chlorophenyl)trifluoromethanesulfonamide 25 (370 mg, 1.02 mmol), O-(4-bromobenzyl)hydroxylamine hydrochloride (270 mg, 1.13 mmol) and anhydrous NaOAc (90 mg, 1.10 mmol) in EtOH (20 mL) was stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum and the residue filtered through a pad of silica (eluting with CH2Cl2/PE, 3:2). Purification by radial thin layer chromatography (eluting with CH2Cl2/PE, 1:9) afforded N-{2-[(4-bromobenzyloxyimino)phenylmethyl]-4-chlorophenyl}trifluoromethanesulfonamide 64 (210 mg, 38%), as a yellow solid. M.p. 55-56° C. 1H n.m.r. (200 MHz, CDCl3) δ 11.32, br s, 1H; 7.66, d, J=9.0 Hz, 1H; 7.55-7.48, m, 5H; 7.33-7.20, m, 5H; 6.88, d, J=2.4 Hz, 1H; 5.11, s, 2H.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:5]1.[Cl:17][C:18]1[CH:23]=[C:22](F)[CH:21]=[CH:20][N:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([NH:1][CH2:2][CH2:3][N:4]2[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:5]2)[CH:21]=[CH:20][N:19]=1
Reactant: Fc1ccnc(Cl)c1
Reactant: NCCn1nc(-c2ccccc2)ccc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1ccc(-c2ccccc2)nn1CCNc1ccnc(Cl)c1
Temperature: 75 °C
Reaction time: 72 h

Procedure:
A suspension of 2-(2-aminoethyl)-6-phenylpyridazin-3(2H)-one (425 mg, 1.97 mmol), 2-chloro-4-fluoropyridine (312 mg, 2.37 mmol), and K2CO3 (546 mg, 3.95 mmol) in DMF (5 mL) was stirred under nitrogen at 75° C. for 3 days. The reaction mixture was partitioned between CH2Cl2 (40 mL) and 5% NaHCO3 (20 mL), and the aqueous was extracted with 9:1 CHCl3/iPrOH (3×25 mL). The combined organics was dried over MgSO4 and concentrated to a solid from toluene. The solid was triturated with toluene (2×5 mL) and diethyl ether (10 mL) to give a white solid. MS (ESI pos. ion) m/z (MH+): 327. Calc'd exact mass for C17H15ClN4O: 326. 1H NMR (400 MHz, Chloroform-d) δ ppm 3.61-3.68 (m, 2 H) 4.52-4.59 (m, 2 H) 5.35 (br. s., 1 H) 6.37 (dd, J=5.77, 2.26 Hz, 1 H) 6.45 (d, J=2.01 Hz, 1 H) 7.05 (d, J=9.54 Hz, 1 H) 7.44-7.52 (m, 3 H) 7.66-7.78 (m, 3 H) 7.91 (d, J=6.02 Hz, 1 H).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH2:26][CH2:27][S:28][CH3:29])(=[O:5])[CH2:2][CH2:3][CH3:4].[OH2:30].Cl[O-].[Na+]>C(Cl)Cl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH2:26][CH2:27][S:28]([CH3:29])=[O:30])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1c(C)cccc1Cl
Reactant: O
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(OCCS(C)=O)cccc2c1Nc1c(C)cccc1Cl
Reaction time: 3 h
Yield: 27 %

Procedure:
3-butyryl-4-(2-methyl,6-chlorophenylamino)-8-(2-methylthioethoxy) quinoline (0.35 g, 0.82 mmol) was dissolved in methylene chloride (4 ml). Water (2 ml) and sodium hypochlorite (5% in water) (1.7 ml) were added and the mixture was stirred for 3 h. The organic layer was dried over sodium sulfate and evaporated. The residue crystallized from ethyl acetate and 0.10 g (27%) of the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[CH:7][C:6]=2[CH:12]=1.[Cu][C:14]#[N:15].CN1CCCC1=O.C(N)CN>O>[OH:11][CH2:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][C:2]([C:14]#[N:15])=[CH:12][C:6]=2[CH:7]=1
Reactant: OCc1cc2cc(Br)ccc2o1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: NCCN
Solvent: O
Product: N#Cc1ccc2oc(CO)cc2c1
Temperature: 200 °C
Reaction time: 3.5 h
Yield: 73.9 %

Procedure:
A solution of 5-bromo-2-benzofuranylmethanol (1.19 g, 5.24 mmol), copper (I) cyanide (0.470 g, 5.25 mmol) and N-methylpyrrolidinone (15 ml) was left under stirring at 200° C. for 3.5 h, then was poured onto a solution of ethylenediamine (6 g) in water (80 ml) and extracted with ethyl acetate (3×75 ml). The organic phase was dried and the solvents were evaporated off under reduced pressure. The resulting crude was purified by chromatography through a silica gel column, eluting with n-hexane:ethyl acetate mixtures of increasing polarity, thereby obtaining 0.671 g of title product as a yellow solid with melting point 113-114° C. (74% yield).
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([C:8]([OH:10])=[O:9])[CH2:4][N:5]([CH3:7])[CH3:6].[CH3:11]O>>[ClH:1].[CH3:11][O:9][C:8](=[O:10])[CH:3]([CH2:4][N:5]([CH3:7])[CH3:6])[NH2:2]
Reactant: CO
Reactant: CN(C)CC(N)C(=O)O
Agent: Cl
Product: COC(=O)C(N)CN(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanol (150 mL) was saturated with anhydrous hydrogen chloride gas. To this was added 4-aza-DL-leucine (4.86 g)(commercially available) and the reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo to yield the title compound (quantitative yield).