Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)[CH:9]=1.C(Cl)(=O)C(C)(C)C.Br.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:37](=[O:41])[CH2:38][NH:39][CH3:40])[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]>ClCCl>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([C:37](=[O:41])[CH2:38][N:39]([CH3:40])[C:16](=[O:18])/[CH:15]=[CH:14]/[C:10]2[CH:9]=[N:8][CH:13]=[CH:12][CH:11]=2)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36]
Reactant: CNCC(=O)c1ccc(OC)c(OC)c1
Reactant: O=C(O)/C=C/c1cccnc1
Agent: Br
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)CN(C)C(=O)/C=C/c2cccnc2)cc1OC
Reaction time: 0.17 h
Yield: 56.1 %

Procedure:
Dichloromethane (50 ml) and triethylamine (2.69 ml, 19.30 mmol) were sequentially added to trans-3-(3-pyridyl)acrylic acid (1.44 g, 9.65 mmol) and stirred for 10 minutes. Then, pivaloyl chloride (1.18 ml, 9.65 mmol) was added and stirred for 13 minutes. 1-(3,4-Dimethoxyphenyl)-2-(methylamino)ethanone hydrobromide (2.79 g, 9.65 mmol) was dissolved in dichloromethane (4 ml) and triethylamine (1.34 ml, 9.65 mmol), added to the reaction mixture and stirred at room temperature for 30 minutes. After the reaction mixture was washed with water and aqueous saturated sodium bicarbonate solution, the organic phase was dried over magnesium sulfate and the solvent was distilled out under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol=10:1) to yield a crude product. The crude product was recrystallized to yield the titled compound (1.84 g, 5.41 mmol, 56%).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[CH2:20]([NH2:25])[CH2:21][CH2:22][CH2:23][CH3:24].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:25][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Reactant: CCCCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCNCc1ccc(Oc2ccc(C(N)=O)nc2)c(F)c1
Reaction time: 8 h

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.040 g, 0.154 mmol) amylamine (0.0139 g, 0.154 mmol) and 3 Å molecular sieves in a vial. Add methanol (1.5 mL), cap and stir overnight. Add NaBH4 (in excess over two portions) and stir until the gasses stop evolving. Load directly onto a 5 g SCX column. Wash with methanol (10 mL), then elute with 2.0 M NH3 in methanol. Purify by loading the product onto a 5 g loading cartridge and eluting through a 10 g ISCO® column with 50% ethyl acetate, 5% (2.0 M NH3 in methanol) and 45% hexanes to give the title compound (0.0387 g, 76.0%: TOF MS ES+ 332.2 (M+H)+, HRMS calcd for C18H23N3O2F 332.1774 (M+H)+, found 332.1765, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=6.9 min, 100% purity.
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[Br:1][C:2]1[C:7]([NH:8][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Nc1cc(Cl)cnc1Br
Reactant: COc1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNc2cc(Cl)cnc2Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
5.16 g (24.8 mmol) of 2-bromo-5-chloro-pyridin-3-ylamine, 7.09 g (52.1 mmol) of p-anisaldehyde and 13.1 g (62.0 mmol) of sodium triacetoxyborohydride were dissolved in 100 mL of DCM and stirred at r.t. overnight. The next day DCM was replaced with chloroform, 5 g excess of sodium triacetoxyborohydride and 3 g excess of p-anisaldehyde were added and the reaction was conducted at 65° C. for 3 h. The mixture was worked up with aqueous sodium bicarbonate and purified on silica followed by recrystallization from ethyl acetate/hexanes mixture to give 3.40 g (42%) of the product as a white solid. MS (M+H)/z=328.9
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:17])[NH:6][C:7]1[N:8]([CH3:16])[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH:20]([Si:23]([CH:56]([CH3:58])[CH3:57])([CH:53]([CH3:55])[CH3:54])[O:24][CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]2[N:36]3[CH:37]=[C:38]([O:41][C@H:42]4[C:51]5[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=5)[C@@H:45]([NH2:52])[CH2:44][CH2:43]4)[CH:39]=[CH:40][C:35]3=[N:34][N:33]=2)[CH2:28][CH2:27]1)([CH3:22])[CH3:21].CCN(C(C)C)C(C)C>O1CCOCC1.C(Cl)Cl>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:52][C@@H:45]2[C:46]3[C:51](=[CH:50][CH:49]=[CH:48][CH:47]=3)[C@H:42]([O:41][C:38]3[CH:39]=[CH:40][C:35]4[N:36]([C:32]([N:29]5[CH2:28][CH2:27][CH:26]([CH2:25][O:24][Si:23]([CH:20]([CH3:22])[CH3:21])([CH:56]([CH3:58])[CH3:57])[CH:53]([CH3:55])[CH3:54])[CH2:31][CH2:30]5)=[N:33][N:34]=4)[CH:37]=3)[CH2:43][CH2:44]2)=[O:17])[N:8]([CH3:16])[N:9]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)[Si](OCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(C)[Si](OCC1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](NC(=O)Nc5cc(C(C)(C)C)nn5C)c5ccccc54)cn23)CC1)(C(C)C)C(C)C
Yield: 58.8 %

Procedure:
A solution of (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (US 20040192653, 90 mg, 0.273 mmol), Intermediate 14e (150 mg, 0.273 mmol) and DIPEA (71 μL, 0.409 mmol) in dioxane (2 mL) was heated at 60° C. for 48 h. The reaction mixture was cooled and diluted with DCM (5 mL). The organic layer was washed with water (3×5 mL), passed through a phase separator and concentrated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to afford the title compound (117 mg, 59%). LCMS (Method 3): Rt: 5.12 min, m/z 729 [MH+].
Reaction SMILES: [C:1]([C:11]1[CH:31]=[CH:30][C:14]([CH2:15][NH:16][CH2:17][C:18]2[CH:29]=[CH:28][C:21]([O:22][CH2:23][C:24]([O:26]C)=[O:25])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:32]1([CH2:37][CH2:38][C:39](Cl)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:32]1([CH2:37][CH2:38][C:39]([N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:28][CH:29]=2)[CH2:15][C:14]2[CH:13]=[CH:12][C:11]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:31][CH:30]=2)=[O:40])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CCCCCCCCC#Cc1ccc(CNCc2ccc(OCC(=O)OC)cc2)cc1
Reactant: O=C(Cl)CCC1CCCC1
Product: CCCCCCCCC#Cc1ccc(CN(Cc2ccc(OCC(=O)O)cc2)C(=O)CCC2CCCC2)cc1

Procedure:
The title compound was prepared following the procedure G using methyl (4-{[(4-dec-1-ynylbenzyl)amino]methyl}phenoxy)acetate and 3-cyclopentylpropanoyl chloride (purification by flash chromatography on SiO2, c-Hex/EtOAc 9:1) as a colorless oil (77%). M+ (ESI): 546.1. HPLC, Rt: 6.4 min (purity: 100%). 1H NMR (CDCl3) δ: 7.40 (d, J=8.3 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.16-7.05 (m, 4H), 6.91 (d, J=8.7 Hz, 1H), 6.85 (d, J=8.3 Hz, 1H), 4.66 (s, 1H), 4.63 (s, 1H), 4.54 (s, 1H), 4.51 (s, 1H), 4.40 (s, 1H). 4.36 (s, 1H), 3.83 (s, 1.5H), 3.82 (s, 1.5H), 2.41 (m, 4H), 1.74-1.08 (m, 23H), 0.90 (t, J=6.4 Hz, 3H).
Reaction SMILES: Br[C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[OH:11].[N-:12]=[N+:13]=[N-:14].[Na+].CCOC(C)=O.O>CS(C)=O>[N:12]([CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@H:3]1[OH:11])=[N+:13]=[N-:14]
Reactant: O[C@@H]1c2ccccc2C[C@H]1Br
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NC1Cc2ccccc2[C@@H]1O
Temperature: 75 °C
Reaction time: 3 h

Procedure:
trans-2-Bromo-1-indanol (2 g, 9.39 mmol) and sodium azide (0.915 g, 14.08 mmol) were combined in DMSO (20 mL) and stirred at 75° C. for 3 hours. The mixture was worked up with EtOAc and H2O, and the combined organic layers were dried and concentrated to give the title compound.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:35])=[C:13]([C:30](OCC)=[O:31])[C:14](=[O:29])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][O:37][CH2:38][CH2:39][NH2:40]>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:35])=[C:13]([C:30]([NH:40][CH2:39][CH2:38][O:37][CH3:36])=[O:31])[C:14](=[O:29])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][CH:20]=2)=[N:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2ccc(S(C)(=O)=O)cc2)c1=O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2ccc(S(C)(=O)=O)cc2)c1=O

Procedure:
This compound was prepared from ethyl 7-benzyl-4-hydroxy-1-[4-(methylsulfonyl)benzyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine employing methods similar to those described in Example 2. The product was obtained as a white solid: 1H NMR (CDCl3) δ 10.22 (1H, br m), 8.61 (1H, s), 7.81 (2H, d, J=8 Hz), 7.29 (3H, m), 7.17 (2H, d, J=8 Hz), 7.06 (1H, s), 7.02 (2H, m), 5.41 (2H, br), 4.05 (2H, s), 3.67 (2H, m), 3.60 (2H, m), 3.40 (3H, s), 3.01 (3H, s); HRMS calcd for C27H27N3O6S+H+: 522.1699. Found: 522.1686.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C1CCN2C(=NCCC2)CC1>CN(C=O)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].C(OCC)(=O)C>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1

Procedure:
A solution of 2-chloro-5-nitropyridine (1.58 g, 10.0 mmol) in DMF (15 mL) was treated with 1-Boc-piperazine (1.96 g, 10.5 mmol) in the presence of DBU (3 mL) and Bu4NI (0.185 g, 0.5 mmol) at 80° C. for 18 h. The reaction mixture was diluted with ethyl acetate at 25° C. The organic phase was washed with H2O, saturated NaCl, dried over MgSO4 and then concentrated in vacuo to afford 4(5-nitropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester as a yellow solid which was used for next step reaction without further purification. MS (ES+) m/z 309.4 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:11]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:12]=3[S:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[O:9])=[CH:4][CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:49]([N:51]([CH2:56][CH3:57])[C:52](=[O:55])[CH:53]=[CH2:54])[CH3:50].C(#N)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[CH2:49]([N:51]([CH2:56][CH3:57])[C:52](=[O:55])/[CH:53]=[CH:54]/[C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[C:11]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:12]=3[S:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[O:9])=[CH:6][CH:7]=1)[CH3:50]
Reactant: O=C(c1ccc(Br)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Reactant: C=CC(=O)N(CC)CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN(CC)C(=O)/C=C/c1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Temperature: 85 °C
Yield: 55.1 %

Procedure:
To a screw cap seal tube is added 0.83 g (2.0 mmol) of the product from Example 2, 0.25 g (0.82 mmol) of tri-o-tolylphosphine, 0.30 g (2.3 mmol) of N,N-diethyl acrylamide, 0.045 g (0.21 mmol) of palladium acetate, 40 mL of acetonitrile and 4 mL of triethylamine. The solution was purged with nitrogen then capped and heated to 85° C. for 15 hours. At the end of this time, the solution was concentrated, then taken up in 100 mL of water:ethyl acetate (1:2). The organic layer was separated and the water layer extracted once with ethyl acetate. The ethyl acetate layers were combined, dried (MgSO4) and concentrated. The residue subjected to column chromatography on silica. Elution first with 60% ethyl acetate:hexane followed by ethyl acetate:hexane:isopropanol (60:35:5) yielded 0.52 g of product (55%) which was crystallized from chloroform:acetone:hexane mp 159°-163° C. (soft).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]2[CH2:24][CH2:25][O:26][CH3:27])=[CH:11][CH:10]=1)C1C=CC=CC=1>O1CCCC1.CO.[Pd]>[CH3:27][O:26][CH2:25][CH2:24][C:16]1[N:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[C:23]2[C:18]([CH:17]=1)=[CH:19][CH:20]=[CH:21][CH:22]=2
Reactant: COCCc1cc2ccccc2n1-c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COCCc1cc2ccccc2n1-c1ccc(O)cc1
Reaction time: 8 h

Procedure:
1-(4-Benzyloxyphenyl)-2-(2-methoxyethyl)-1H-indole (0.14 g, 0.39 mmol) was dissolved in tetrahydrofuran (2 mL) and methanol (1 mL). A catalytic amount of palladium on carbon (wet, 10% dry basis) was added, and the flask was purged with N2 and H2. The reaction was stirred under 1 atm of H2 overnight. The mixture was filtered through Celite, and the filtrate was concentrated to give the desired product. The reaction was assumed to be quantitative. LC-MS (C17H17NO2 calc'd 267) m/z 266 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[Br:10]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Br:8])[CH:7]=1)[CH2:9][Br:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)cc(Br)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: BrCc1cc(Br)cc(Br)c1
Reaction time: 8 h
Yield: 48.4 %

Procedure:
3,5-Dibromotoluene (27.0 g; 108.0 mmol), N-bromosuccinimide (19.2 g; 108.0 mmol), and benzoyl peroxide (0.32 g) were added to benzene (200 ml), and the mixture was refluxed for 2.5 hours. The mixture was brought to room temperature, and the solvent was evaporated under reduced pressure. The residue was taken up in n-hexane (200 ml), and the mixture was left to stand overnight at room temperature. Crystals that precipitated were filtered off, and the filtrate was concentrated under reduced pressure, to thereby yield 17.2 g of the target compound (yield: 48.3%).
Reaction SMILES: OS(O)(=O)=O.[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N+:8]=1[O-:13].[N+:14]([O-])([OH:16])=[O:15].[OH-].[Na+]>CCOC(C)=O>[CH3:6][C:7]1[CH:12]=[C:11]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:9][N+:8]=1[O-:13]
Reactant: Cc1cccc[n+]1[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A 25 mL round bottom flask was charged with conc. H2SO4 (1 mL) and cooled to 0° C. 2-Methylpyridine 1-oxide (0.4 g, 0.003 mol, Aldrich) was added in one portion, followed by the addition of fuming HNO3 (1 mL, spectrochem, india) in a drop-wise fashion. The reaction was stirred at rt for 30 min and a further 12 h at 70° C. Reaction progress was monitored by TLC (50% EtOAc in petroleum ether). After completion of the reaction, EtOAc (10 mL) was added to the reaction mixture after cooling to 0° C. and the reaction was neutralized to pH-8-9 with 40% NaOH solution, and extracted with EtOAc (2×10 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.82 (d, J=5.4 Hz, 1H), 8.03 (d, J=1.8 Hz, 1H), 7.92 (dd, J=1.8, 5.1 Hz, 1H), 2.64 (s, 3H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([NH:20][NH2:21])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1.N1C=CC=CC=1.[C:28](Cl)(=[O:30])[CH3:29].Cl>C(OCC)(=O)C.O>[F:2][C:3]1[CH:4]=[C:5]([NH:20][NH:21][C:28](=[O:30])[CH3:29])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=1
Reactant: CC(=O)Cl
Reactant: NNc1ccc(Oc2cccc(C(F)(F)F)c2)c(F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)NNc1ccc(Oc2cccc(C(F)(F)F)c2)c(F)c1
Reaction time: 3 h

Procedure:
To [3-fluoro-4-[3-(trifluoromethyl)phenoxy]phenyl]hydrazine hydrochloride (0.35 g) prepared using the method described in Example 1, in ethyl acetate (5 mL), was added pyridine (0.24 mL) at −10° C. After dropwise addition of acetyl chloride (0.1 mL), the mixture was stirred for 3 h and then acidified with 6 M HCl. Water was added, and the product was extracted with ether. The organic layer was separated, dried, and concentrated. The residue was purified by column chromatography on silica (using dichloromethane, followed by 5:1 dichloromethane:ether as eluants) to give a solid (0.2 g).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH:8]=[CH:9][CH2:10][N:11]1[C:15](=[O:16])[N:14]([CH3:17])[C:13](=[O:18])[NH:12]1)=[O:4].[H][H]>C(COC)OC.[Pd]>[CH3:1][O:2][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15](=[O:16])[N:14]([CH3:17])[C:13](=[O:18])[NH:12]1)=[O:4]
Reactant: COC(=O)CCCC=CCn1[nH]c(=O)n(C)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: COCCOC
Product: COC(=O)CCCCCCn1[nH]c(=O)n(C)c1=O
Yield: 98.4 %

Procedure:
The 1-(6'-methoxycarbonyl-n-hex-2-enyl)-4-methyl-1,2,4-triazolidine-3,5-dione (12.4 g, 0.0486 mol) was dissolved in dimethoxyethane (200 ml) and 10% palladium on charcoal (3 g) was added and the resultant mixture was allowed to take up hydrogen (ca. 1100 mls). After the reaction was complete the resultant mixture was filtered through a kieselguhr bed and the filtrate evaporated in vacuo to afford 1-(6'-methoxycarbonyl-n-hexyl)-4-methyl-1,2,4-triazolidine-3,5-dione (12.3 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:15]1(=O)[CH2:18][CH2:17][CH2:16]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH:15]1([N:11]2[CH2:12][CH2:13][CH2:14][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)[CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCC1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCN(C2CCC2)CC1
Temperature: 22.5 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a stirred solution of [1,4]diazepane-1-carboxylic acid tert-butyl ester (5 g, 24.97 mmol) in DCE (70 ml) at 20 to 25° C. was added cyclobutanone (1.75 g, 24.97 mmol) followed by acetic acid (1.5 g, 24.97 mmol) dropwise. The resulting mixture was stirred at 20 to 25° C. for ca. 2 h. Sodium triacetoxyborohydride (7.94 g, 37.46 mmol) was added in 9 portions, keeping the temperature in the range of 20 to 25° C. The resulting suspension was stirred at 20 to 25° C. overnight. Saturated NaHCO3 (80 ml) was added in four portions and the biphasic mixture stirred at 20 to 25° C. for ca. ½ h. The organic layer was separated, washed with water (20 ml) and the aqueous phase back extracted at pH 9 with DCM (20 ml). The combined organic phases were dried (Na2SO4), filtered and concentrated in vacuo to provide the title compound as yellow oil (6.1 g, 96%).
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=4)=[CH:22][CH:21]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:37][CH3:38])C1C=CC=CC=1.C(N(CC)CC)C.[H][H]>CN(C)C=O.[OH-].[Pd+2].[OH-]>[C:33]([C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][C:13]3[C:12]4[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:37][CH3:38])[CH:11]=4)[N:16]=[CH:15][CH:14]=3)=[CH:21][CH:22]=2)=[CH:32][CH:31]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: [H][H]
Reactant: COc1cc2c(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)cc3)ccnc2cc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2c(Oc3ccc(Nc4ccc(C(C)(C)C)cc4)cc3)ccnc2cc1O
Yield: 62.4 %

Procedure:
[4-(7-Benzyloxy-6-methoxy-4-quinolyloxy)phenyl](4-tert-butylphenyl)amine (starting compound 2) (400 mg) was dissolved in N,N-dimethylformamide (10 ml) to prepare a solution. Triethylamine (2 ml) and 20% palladium hydroxide (0.58 g) were then added to the solution, and the mixture was stirred in a hydrogen atmosphere at room temperature overnight. The insolubles were removed by filtration, and the solvent was then removed by evaporation under the reduced pressure. Water and ethyl acetate were added to the crude, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and was dried over sodium sulfate. The solvent was removed by evaporation under the reduced pressure, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (205 mg, yield 62%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4S[CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]4)[C:20]4[C:15](=[N:16][CH:17]=[CH:18][N:19]=4)[CH:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=O.[S:49]([O-:53])([O-])(=[O:51])=S.[Na+].[Na+]>C(Cl)Cl>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[S:49](=[O:53])(=[O:51])[CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:26]4)[C:20]4[C:15](=[N:16][CH:17]=[CH:18][N:19]=4)[CH:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCSC(CNc2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1
Reactant: O=S([O-])([O-])=S
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCS(=O)(=O)C(CNc2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 2-((7-(4-morpholinophenyl)pyrido[4,3-b]pyrazin-5-ylamino)methyl)thiomorpholine-4-carboxylate (178 mg, 0.34 mmol) in CH2Cl2 (5 mL) was added 3-chloroperoxybenzoic acid (70%, 251 mg, 1.02 mmol) at 0° C. The resulting mixture was stirred at room temperature for 3 hours, and subsequently, a saturated aqueous sodium thiosulfate solution was added and the mixture was stirred for another 30 minutes. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined EtOAc layers were washed twice with an aqueous Na2CO3 solution. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to afford title compound 52 mg. MS (m/z): 555 (M+H)+
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:22]=[CH:21][C:6](/[CH:7]=[C:8]2/[C:9](=[O:20])[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:11]=[C:12]/2[CH3:13])=[CH:5][CH:4]=1.[S:24]([O:29]C)([O:27][CH3:28])(=[O:26])=[O:25]>CC(C)=O>[CH3:28][O:27][S:24]([O-:29])(=[O:26])=[O:25].[CH3:23][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6](/[CH:7]=[C:8]2\[C:12]([CH3:13])=[N:11][N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N+:15]=3[CH3:28])[C:9]\2=[O:20])=[CH:21][CH:22]=1
Reactant: COS(=O)(=O)OC
Reactant: CC1=NN(c2ccccn2)C(=O)/C1=C/c1ccc(N(C)C)cc1
Solvent: CC(C)=O
Product: CC1=NN(c2cccc[n+]2C)C(=O)/C1=C/c1ccc(N(C)C)cc1
Product: COS(=O)(=O)[O-]

Procedure:
In 40 ml of acetone, 0.4 g (1.3 mmol) of (4E)-4-[4-(dimethylamino)benzylidene]-5-methyl-2-(2-pyridinyl)-2,4-dihydro-3H-pyrazol-3-one and 1.66 g (13.06 mmol) of dimethyl sulfate are stirred under reflux for one hour. The precipitated product is filtered off with suction, washed with acetone and dried under reduced pressure.