Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([O:32][N:33]1[C:39](=[O:40])[N:38]2[CH2:41][C@H:34]1[CH2:35][CH2:36][C@H:37]2[C:42]([OH:44])=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[NH:45]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[NH2:46].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:25]([O:32][N:33]1[C:39](=[O:40])[N:38]2[CH2:41][C@H:34]1[CH2:35][CH2:36][C@H:37]2[C:42]([NH:46][NH:45][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[O:44])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
HATU (8.3 g, 21.7 mmol) was added to a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (5.0 g, 18.1 mmol) and tert-butyl hydrazinecarboxylate (3.5 g, 27.2 mmol) in DCM (60 mL) at 0° C., followed by the addition of DIPEA (7.0 g, 54.3 mmol). The resulting mixture was stirred at 0° C. for 1 h. The reaction mixture was then diluted with DCM, washed with water (2×), and saturated sodium chloride, then dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (gradient elution 10:1 to 4:1 petroleum ether/EtOAc) to afford tert-butyl 2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbonyl)hydrazinecarboxylate (6 g, 85%). ESI-MS (EI+, m/z): 391 [M+H]+.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:13]=[C:12]([N:14]2[C:22]3[C:17](=[C:18]([N:23]4[CH:27]=[C:26]([C:28]5[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=5)[N:25]=[CH:24]4)[CH:19]=[CH:20][CH:21]=3)[C:16]([CH:34]([CH3:36])[CH3:35])=[N:15]2)[CH:11]=[CH:10][C:7]=1[C:8]#[N:9])([CH3:4])([CH3:3])[CH3:2].[OH-:37].[Na+].OO.O>CS(C)=O>[C:1]([NH:5][C:6]1[CH:13]=[C:12]([N:14]2[C:22]3[C:17](=[C:18]([N:23]4[CH:27]=[C:26]([C:28]5[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=5)[N:25]=[CH:24]4)[CH:19]=[CH:20][CH:21]=3)[C:16]([CH:34]([CH3:36])[CH3:35])=[N:15]2)[CH:11]=[CH:10][C:7]=1[C:8]([NH2:9])=[O:37])([CH3:4])([CH3:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(C)c1nn(-c2ccc(C#N)c(NC(C)(C)C)c2)c2cccc(-n3cnc(-c4cccnc4)c3)c12
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)c1nn(-c2ccc(C(N)=O)c(NC(C)(C)C)c2)c2cccc(-n3cnc(-c4cccnc4)c3)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
To a solution of compound (1b) in DMSO (4.41 mL) were added 4N aqueous sodium hydroxide solution (160 μL) and 30% aqueous hydrogen peroxide solution (60 μL), and the mixture was stirred at room temperature for 10 minutes. After completion of the reaction, water was poured into the reaction solution, and the precipitated solid was collected by filtration to obtain compound (1) (150 mg, yield 96%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12][OH:13])=[C:10]2[C:5]([NH:6][C:7]([CH3:16])([CH3:15])[C:8](=[O:14])[NH:9]2)=[CH:4][CH:3]=1.CI.[C:19](=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[Br:1][C:2]1[C:11]([CH2:12][OH:13])=[C:10]2[C:5]([NH:6][C:7]([CH3:16])([CH3:15])[C:8](=[O:14])[N:9]2[CH3:19])=[CH:4][CH:3]=1
Reactant: CC1(C)Nc2ccc(Br)c(CO)c2NC1=O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: O
Product: CN1C(=O)C(C)(C)Nc2ccc(Br)c(CO)c21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69 %

Procedure:
A mixture of 7-bromo-8-hydroxymethyl-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 1-(7), 62.7 mg, 0.220 mmol), methyl iodide (68.6 μL, 1.10 mmol), and cesium carbonate (180 mg, 0.552 mmol) was suspended in anhydrous N,N-dimethylformamide (1 mL) and stirred at room temperature for 2.5 hours. Ethyl acetate (10 mL) and water (10 mL) were added to the reaction mixture and partitioned. The organic layer was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (45.5 mg) as an orange amorphous product. (Yield 69%)
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([O:6][N:7]=[C:8]([C:12]1[C:13](=[O:27])[CH2:14][CH2:15][CH:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:17]=1[OH:18])[CH2:9][CH2:10][CH3:11])[CH:4]=[CH2:5]>CC(C)=O>[CH2:3]([O:6][N:7]=[C:8]([C:12]1[C:13](=[O:27])[CH2:14][CH2:15][CH:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:17]=1[O:18][C:8](=[O:1])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:9][CH2:10][CH3:11])[CH:4]=[CH2:5]
Reactant: C=CCON=C(CCC)C1=C(O)C(c2ccc(OC)cc2)CCC1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C=CCON=C(CCC)C1=C(OC(=O)c2ccccc2)C(c2ccc(OC)cc2)CCC1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Aqueous 1% sodium hydroxide (14 ml) was added to a stirred solution of 2-[1-(allyloxyimino)-n-butyl]-3-hydroxy-4-(4-methoxyphenyl)-cyclohex-2-en-1-one (1.2 g) in acetone (150 ml). The mixture was stirred at ambient temperature for 5 minutes and then benzoyl choloride (0.5 g) was added dropwise. After 30 minutes, the mixture was evaporated in vacuo and the residue purified on a silica gel column using 10% v/v diethyl ether- methylene chloride as eluant to give the title compound (1 g) as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]2[C:5]([CH2:6][C:7]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[NH:9][C:8]=32)=[CH:4][CH:3]=1.[OH-].[Na+].I[CH3:21]>C1C=CC=CC=1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:1][C:2]1[CH:17]=[C:16]2[C:5]([CH2:6][C:7]3[C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]([CH3:21])[C:8]=32)=[CH:4][CH:3]=1
Reactant: CI
Reactant: Fc1ccc2c(c1)-c1[nH]c3ccccc3c1C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: Cn1c2c(c3ccccc31)Cc1ccc(F)cc1-2
Temperature: 40 °C
Reaction time: 19 h
Yield: 71 %

Procedure:
To a solution of 37b (1.38 g, 6.17 mmol) in benzene (12 mL) was added aqueous sodium hydroxide (33% by mass, 3.2 mL), tetrabutylammonium iodide (122.5 mg, 0.33 mmol), and iodomethane (3.04 mL, 48.78 mmol). The reaction mixture was stirred vigorously at 40° C. for 19 hours and then cooled to room temperature. The mixture was diluted with benzene (20 mL) and H2O (20 mL), and the aqueous layer was extracted 2×15 mL ethyl acetate. Organic layers were combined, washed 1×25 mL H2O, dried over anhydrous magnesium sulfate and concentrated to yield an orange/brown solid. Crude product was purified by flash column chromatography (10:1 to 4:1 hexanes-ethyl acetate) to give a 38b as a white solid in 71% yield (976 mg, 4.37 mmol). 1H NMR (600 MHz, CDCl3): δ 7.64 (d, 1H, J=7.8 Hz), 7.39-7.41 (dd, 1H, J=7.8, 4.8 Hz), 7.49 (d, 1H, J=8.4 Hz), 7.25-7.30 (m, 2H), 7.20-7.23 (t, 1H, J=7.8 Hz), 6.90-6.94 (m, 1H), 3.88 (s, 3H), 3.55 (s, 2H). 13C NMR (150 MHz, CDCl3): δ 162.1 (d, J=240 Hz), 143.5 (d, J=3 Hz), 143.1 (d, J=2.6 Hz), 141.8, 136.7 (d, J=9.5 Hz), 125.9 (d, J=9.2 Hz), 123.8, 122.1, 121.6, 119.6, 119.1, 110.6 (d, J=22.5 Hz), 109.7, 104.9 (d, J=24.6 Hz), 30.7 (d, J=1.7 Hz), 29.3.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[C:6]([N+:10]([O-])=O)[C:5]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][C:17]([O:25][CH3:26])=[C:18]([O:23][CH3:24])[CH:19]=4)[C:14]=3[CH:27]=O)=[CH:4][C:3]=2[O:2]1>C(O)(=O)C.[Zn]>[CH3:24][O:23][C:18]1[C:17]([O:25][CH3:26])=[CH:16][C:15]2[C:14]3[CH:27]=[N:10][C:6]4[CH:7]=[C:8]5[O:9][CH2:1][O:2][C:3]5=[CH:4][C:5]=4[C:13]=3[CH:22]=[CH:21][C:20]=2[CH:19]=1
Reactant: COc1cc2ccc(-c3cc4c(cc3[N+](=O)[O-])OCO4)c(C=O)c2cc1OC
Agent: [Zn]
Solvent: CC(=O)O
Product: COc1cc2ccc3c4cc5c(cc4ncc3c2cc1OC)OCO5
Yield: 80 %

Procedure:
A mixture of 2-(3,4-methylenedioxy-6-nitrophenyl)-6,7-dimethoxy-1-naphthaldehyde (46 mg, 0.12 mmol) in acetic acid (3 mL) and zinc dust (100 mg, 1.5 mmol) was heated to reflux for 3 hours. Acetic acid was evaporated in vacuo and the residue extacted with chloroform. The chloroform solution was filtered through a celite bed. The filtrate was washed successively with saturated sodium bicarbonate solution and brine and evaporated to dryness. The residue obtained was chromatographed on 75 g silica using a 1:1 mixture of hexanes:ethyl acetate as eluent to give the title compound (32 mg, 80%); mp 171-171° C. IR (KBr) 1610, 1461, 1277; 1H NMR (CDCl3), δ4.06 (3H, s), 4.15 (3H, s), 6.15 (2H, s) 7.27 (11, s). 7.54 (1H, s), 7.85(11H, s), 7.94 (1H, d, J=8.7), 8.09(1H, s), 8.15 (1H, d, J=8.7), 9.88 (1H, s); 13C NMR (CDCl3) δ56.4, 56.6, 99.7, 102.3, 102.4, 107.7, 108.5, 118.5, 21.0, 121.2, 125.6, 127.7, 130.8, 131.2, 142.8, 145.9, 148.8, 149.7, 150.1; HRMS calcd for C20H15NO4+H; 334,.1079.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH3:2].[NH:21]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C@@H:22]([C:31](O)=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>C(Cl)Cl>[C:37]([O:36][C:34](=[O:35])[NH:21][CH:22]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=1)[C:31]([N:9]1[CH2:8][CH2:7][N:6]([CH:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH2:4][N:3]([CH2:1][CH3:2])[CH2:19][CH3:20])[CH2:11][CH2:10]1)=[O:32])([CH3:40])([CH3:38])[CH3:39]
Reactant: CCN(CC)CC(c1ccccc1F)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: CCN(CC)CC(c1ccccc1F)N1CCN(C(=O)C(Cc2ccc(Cl)cc2)NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
To Diethyl-[2-(2-fluoro-phenyl)-2-piperazin-1-yl-ethyl]-amine (513) (0.206 g, 0.738 mmol) was added Boc-4-chloro-D-Phe (0.221 g, 0.738 mmol), 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.141 g, 0.738 mmol), 1-Hydroxybenzotriazole hydrate (0.099 g, 0.738 mmol), DCM (5.0 mL) and 4-methylmorpholine (0.243 mL, 2.215 mmol). The reaction was allowed to stir at room temperature for 4 h. The reaction mixture was concentrated to dryness. The resulting residue was taken up in EtOAc (30 mL) and washed with sat. NaHCO3 and brine. The crude material was purified by chromatography (silica gel 60 mesh, eluting with 5% MeOH/5% TEA in EtOAc) yielding 0.41 g (99%) pure product.
Reaction SMILES: [C:1](=[O:14])([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)[O:2][CH2:3][CH3:4].C(OC(=O)C)(=O)C.[N+:22]([O-])([OH:24])=[O:23]>>[C:1](=[O:14])([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([N+:22]([O-:24])=[O:23])[CH:7]=1)[O:2][CH2:3][CH3:4]
Reactant: CCOC(=O)Oc1ccc(OC)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)Oc1ccc(OC)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
Ethyl 4-methoxyphenyl carbonate (0.700 g, 3.57 mmol) was dissolved in acetic anhydride (2 mL, 21.20 mmol), and the solution was cooled to 0° C. with an ice-water bath. 65% nitric acid (0.4 mL, 5.78 mmol) was added drop-wise at the same temperature. When the addition was completed, the cold bath was removed and the resulting mixture was allowed to warm to RT and stirred for 2 hours. The reaction mixture was poured into ice-water, and the resulting precipitate was collected by filtration affording ethyl 4-methoxy-3-nitrophenyl carbonate (0.720 g, 2.99 mmol, 88% yield, MS/ESI+ 242.2 [MH]+).
Reaction SMILES: C([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2Br)[CH2:8][CH:7]([CH2:22][O:23]C(=O)C)[CH:6]1[O:27]C(=O)C)(=O)C.O.[NH2:32]N>C(O)C>[Cl:19][C:17]1[C:16]([Cl:20])=[CH:15][C:14]2[N:10]([CH:9]3[CH:5]([OH:4])[CH:6]([OH:27])[CH:7]([CH2:22][OH:23])[CH2:8]3)[C:11]([NH2:32])=[N:12][C:13]=2[CH:18]=1
Reactant: CC(=O)OCC1CC(n2c(Br)nc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Reactant: NN
Solvent: O
Solvent: CCO
Product: Nc1nc2cc(Cl)c(Cl)cc2n1C1CC(CO)C(O)C1O
Reaction time: 0.5 h
Yield: 20.3 %

Procedure:
(±)(1R*, 2S*, 3S*, 5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (750 mg, 1.44 mmol) was dissolved in ethanol (10 mL). Hydrazine hydrate (55%, 0.41 mL, 7.2 mmol) was added and the solution was refluxed for 2 hours. Volatiles were evaporated and the residual white solid was resolidified from ethanol-water and stirred with Raney nickel (preequilibrated under hydrogen) in methoxyethanol (20 mL) for 30 minutes. Catalyst was filtered off and the filtrate made slightly basic with aqueous sodium hydroxide to complete removal of the acetate groups. The solution was neutralized, and volatiles evaporated. The residual solid was recrystallized from ethanol-water to give title compound as pale pink solid (97 mg, 20%), m.p. 283°-284° C. dec.; 1H-NMR(DMSO-d6)δ: 7.61 and 7.30 (both s, 2, aromatic CH), 6.65 (br s, 2, NH2), 5.07 (t, J=4.3 Hz, 1, OH), 4.80 (d, J=7.0 Hz, 1, OH), 4.66 (d, J=3.7 Hz, 1, OH), 4.65-4.50 (m, 1, NCH), 4.45-4.30 (m, 1, OCH), 3.90-4.80 (m, 1, OCH), 3.70-3.40 (two m, 2, OCH2), 2.20-1.80 (m, 3, CH2 and CH of cyclopentane); mass spectrum (CI): 332 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[NH:5][C:6]([CH2:9][CH3:10])=[CH:7][CH:8]=1)#[N:2].P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:4]1[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[C:6]([CH2:9][CH3:10])[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1ccc(C#N)c(=O)[nH]1
Product: CCc1ccc(C#N)c(Cl)n1
Yield: 49 %

Procedure:
A mixture of 3-cyano-6-ethyl-2(1H)-pyridone (36.2 g, 0.24 mol) and phosphorus oxychloride (250 ml) was heated under reflux for 2 hours. The reaction solution was concentrated under a reduced pressure, and the resulting residue was mixed with toluene and concentrated under a reduced pressure. The thus obtained residue was diluted with chloroform and washed with 1 N sodium hydroxide aqueous solution. The aqueous layer was extracted with chloroform, and the chloroform layers were combined and dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration, the filtrate was concentrated under a reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 2-chloro-3-cyano-6-ethylpyridine (19.6 g, 49%) as an oily material.
Reaction SMILES: [N+:1]([C:4]1[CH:50]=[CH:49][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:33]3[CH:38]=[CH:37][C:36]([O:39][C:40]4[CH:45]=[CH:44][C:43]([N+:46]([O-])=O)=[CH:42][CH:41]=4)=[CH:35][CH:34]=3)([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[CH3:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O>[Pd].C1COCC1>[NH2:30][C:27]1[CH:26]=[CH:25][C:24]([O:23][C:20]2[CH:19]=[CH:18][C:17]([C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][C:7]4[CH:49]=[CH:50][C:4]([NH2:1])=[CH:5][CH:6]=4)=[CH:10][CH:11]=3)([C:33]3[CH:34]=[CH:35][C:36]([O:39][C:40]4[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][CH:41]=4)=[CH:37][CH:38]=3)[CH3:16])=[CH:22][CH:21]=2)=[CH:29][CH:28]=1
Reactant: CC(c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1)(c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(c1ccc(Oc2ccc(N)cc2)cc1)(c1ccc(Oc2ccc(N)cc2)cc1)c1ccc(Oc2ccc(N)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.8 %

Procedure:
1,1,1-Tris[4-(4-nitrophenoxy)phenyl]ethane (Example 1; 3; 5.0 g, 7.5 mmol), THF (50 mL) and 5% palladium on activated carbon (0.50 g) were added to a hydrogenation bottle. The bottle was secured on a Parr hydrogenation apparatus, flushed three times with hydrogen, and then pressurized to 55 psi. After the mixture had been agitated at room temperature for 24 hours under the hydrogen pressure of 55 psi, it was filtered through Celite. The filter cake was washed with THF, and then the filtrate was evaporated to dryness on a rotary evaporator to afford a 4.25 g (98%) of yellow crystal, which was used without further purification, m.p. 220-221° C. MS (m/e): 579 (M+). Anal. Calcd. for C38H33N3O3: C, 78.73%; H, 5.74%; N, 7.25%. Found: C, 78.17%; H, 5.78%; N, 7.04%. FT-IR (KBr, cm−1): 3441, 3361 (NH2), 3035, 2970, 1617, 1581, 1497, 1384, 1232, 1173, 1117, 1010, 871, 842. 1H-NMR (DMSO-d6, δ in ppm): 2.02 (s, 3H, CH3), 4.99 (s, 6H, NH2), 6.53-6.58 (d, 6H, Ar—H), 6.68-6.74 (m, 12H, Ar—H), 6.88-6.93 (d, 6H, Ar—H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][NH:12][CH2:13]2.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CC(N(C)C)=O>[C:31]([N:12]1[CH2:11][CH2:10][C:9]2[C:14](=[CH:15][C:16]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])=[CH:17][C:8]=2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:13]1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)C(=O)Nc1cc2c(c(-c3ccccc3Cl)c1)CCNC2
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC(C)C(=O)Nc1cc2c(c(-c3ccccc3Cl)c1)CCN(C(=O)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 27 %

Procedure:
N-[5-(2-Chloro-phenyl)-1,2,3,4-tetrahydro-isoquinolin-7-yl]2-methylpropanamide (39 mgs, 0.12 mmoles) was dissolved in dimethylacetamide (1 ml) followed by the addition of triethylamine (20 ul, 0.144 mmoles) and finally benzoyl chloride (16.7 ul, 0.144 mmoles). The reaction was stirred at room temperature for 1.5 hours and purified by C18 reverse phase automated HPLC (14 mgs, 27% yield, 100% pure, CO-AAWO0025).
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[C:11]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=2[F:27])=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][N:14]=[CH:13]2)=[O:9])=C.Cl>CO>[OH:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[C:11]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=2[F:27])=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][N:14]=[CH:13]2)=[O:9]
Reactant: C=COCCONC(=O)c1ccc2[nH]ncc2c1Nc1ccc(Br)cc1F
Agent: Cl
Solvent: CO
Product: O=C(NOCCO)c1ccc2[nH]ncc2c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-bromo-2-fluorophenylamino)-1H-indazole-5-carboxylic acid (2-vinyloxy-ethoxy)-amide (96 mg, 0.22 mmol) in methanol (5 mL) was added hydrochloric acid (1 mL, 1N, 1 mmol). The reaction was stirred at room temperature for 30 minutes before being concentrated in vacuo. The resultant residue was dissolved in methanol (2 mL) and a few drops of water added causing the product to precipitate. The product was collected by filtration and dried in vacuo to yield the title compound as an off white solid (50 mg, 55%). LCMS (Method A): RT=7.99 min, [M+H]+=409/411. 1H NMR (DMSO-d6, 400 MHz) 13.20 (1H, s), 11.61 (1H, s), 9.95 (1H, s), 7.58 (1H, dd, J=10.48, 2.24 Hz), 7.47 (1H, d, J=8.77 Hz), 7.29 (1H, ddd, J=8.60, 2.21, 1.05 Hz), 7.23 (1H, s), 7.08 (1H, t, J=8.81 Hz), 7.01 (1H, d, J=8.81 Hz), 4.68 (1H, s), 3.86 (2H, t, J=4.95 Hz), 3.56 (3H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH:18]([CH3:22])[C:19](=[O:21])[CH3:20]>O.CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH:18]([CH3:22])[C:19](=[O:21])[CH3:20]
Reactant: Oc1ccccc1Br
Reactant: CC(=O)C(C)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)C(C)Oc1ccccc1Br
Temperature: 80 °C
Yield: 89 %

Procedure:
60 g (347 mmol) of 2-bromophenol, 57.43 g (416 mmol) of potassium carbonate, 57 g (347 mmol) of potassium iodide, 600 ml of N,N-dimethylformamide and 4.34 g (416 mmol) of 3-chloro-2-butanone are introduced into a 1 liter three-necked flask equipped with a reflux condenser. The mixture is heated at 80° C. for 16 hours. 1500 ml of water are added and extraction is then carried out with ethyl acetate (3×400 ml). The organic phases are combined, washed with a molar sodium hydroxide solution (2×500 ml), dried over magnesium sulphate and concentrated. The residue is purified by chromatography on a silica column (elution solvent cyclohexane:ethyl acetate 9:1). 75.07 g (Yield: 89%) of 3-(2-bromophenoxy)-2-butanone (yellow oil) are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:15]2[CH:11]([N:12]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:13][CH:14]2[C:16]([OH:18])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:31])=[N-].N(N(C)C(N)=O)=O.[OH-].[K+]>CCOC(C)=O.CCOCC>[CH3:31][O:17][C:16]([CH:14]1[CH2:13][N:12]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:15]12)=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCC2C1C(C(=O)O)CN2C(=O)OCc1ccccc1
Reactant: C=[N+]=[N-]
Agent: CN(N=O)C(N)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)C2CCN(C(=O)OC(C)(C)C)C12

Procedure:
To a solution of crude 72 (0.47 g) in EtOAc (10 mL) and Et2O (10 mL) was added an ethereal solution of diazomethane that was prepared by treatment of N-nitroso-N-methyl urea (0.5 g) in Et2O (10 mL) with 1M KOH (10 mL). After consumption of starting material (monitored by TLC), the reaction mixture was diluted with HOAc. The solution was extracted with EtOAc, washed with saturated NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated to give a dark oil that was purified by HPLC (2″ Dynamax® SiO2, 10% EtOAc/hexane to 100% EtOAc over 30 min) to give 76 (0.19 g) as a yellow-colored oil. 1H NMR (CDCl3, 300 MHz): δ7.40-7.29 (m, 5H), 5.23-5.09 (m, 2H), 4.56-4.52 (m, 2H), 4.11-4.04 (m, 1H), 3.69 (s, 3H), 3.45-3.42 (m, 1H), 3.22-3.12 (m, 1H), 2.27-2.10 (m, 1H), 1.96 (m, 1H), 1.47 (s, 9H) ppm. Mass spectrum, m/z [405.2] (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:12]([C:14]1[CH:15]=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:18][CH:19]=1)=[O:13])[CH:6]=[CH:5]2.[Cl:27][S:28](O)(=[O:30])=[O:29]>CC#N>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:12]([C:14]1[CH:15]=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:18][CH:19]=1)=[O:13])[CH:6]=[C:5]2[S:28]([Cl:27])(=[O:30])=[O:29]
Reactant: O=C(Nn1ccc2cc(F)ccc21)c1cnc(-c2cccc(F)c2)nc1
Reactant: O=S(=O)(O)Cl
Solvent: CC#N
Product: O=C(Nn1cc(S(=O)(=O)Cl)c2cc(F)ccc21)c1cnc(-c2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
A solution of 2-(3-fluorophenyl)pyrimidine-5-carboxylic acid-(5-fluoroindol-1-yl)amide (0.35 g,) in dry CH3CN (20 mL) is treated with chlorosulfonic acid (0.5 mL) and stirred at rt for 24 h. The reaction mixture is poured onto ice/water (150 mL) and extracted with EtOAc. The organic layer is washed with water, brine and dried (MgSO4), filtered and concentrated in vacuo to afford 5-fluoro-1-{[2-(3-fluorophenyl)pyrimidine-5-carbonyl]amino}-1H-indole-3-sulfonyl chloride (0.43 g, 95%). MS: 449 (M+H).
Reaction SMILES: [C:1]([CH:3]1[CH2:5][CH2:4]1)#[CH:2].[N+:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])([O-])=[O:7].C1N2CCN(CC2)C1>C(O)C>[CH:3]1([C:1]2[O:7][N:6]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=2)[CH2:5][CH2:4]1
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: C#CC1CC1
Agent: C1CN2CCN1CC2
Solvent: CCO
Product: CCOC(=O)c1cc(C2CC2)on1
Yield: 92.2 %

Procedure:
A solution of ethynylcyclopropane (0.40 mL; 4.58 mmol), ethyl 2-nitroacetate (1.30 mL; 11.46 mmol), and 1,4-diazobicyclo[2.2.2]octane (DABCO, 0.053 g; 0.458 mmol) in ethanol (3 mL) was irradiated in a microwave oven at 150° C. for 20 min and was then evaporated. The residue was dissolved in ethyl acetate and the solution was washed with water. The organic layer was evaporated and the residue was purified by flash chromatography on silica gel (eluent: 20 to 100% of dichloromethane in heptane) to afford 0.765 g (92%) of ethyl 5-cyclopropylisoxazole-3-carboxylate as a yellow oil.