Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@@H:10]([NH:15][CH3:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:18]1[CH:23]=[CH:22][N:21]=[C:20]2[N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=[CH:26][C:19]=12.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@@H:10]([N:15]([CH3:16])[C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=[CH:26][C:19]=23)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN[C@H]1CN(Cc2ccccc2)CC[C@H]1C
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ccnc21
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H]1CCN(Cc2ccccc2)C[C@@H]1N(C)c1ccnc2c1ccn2COCC[Si](C)(C)C
Temperature: 70 °C
Yield: 120.8 %

Procedure:
A degassed mixture of (3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine (0.210 g, 0.000962 mol), 4-chloro-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (0.29 g, 0.0010 mol), tris(dibenzylideneacetone)dipalladium(0) (0.088 g, 0.000096 mol), 0.049 M of tri-tert-butylphosphine in toluene (1.0 mL) and sodium tert-butoxide (0.139 g, 0.00144 mol) in toluene (3 mL, 0.03 mol) was heated to 70° C. for 5 h. After the reaction mixture was cooled to room temperature (rt), ethyl acetate and water were added. The resulting suspension was filtered. The aqueous phase was removed and the remaining organic phase was washed with sat. NaCl, dried, and concentrated under vacuum to give 540 mg orange oil. The crude product was chromatographed using 35% ethyl acetate/hex to give 280 mg orange oil (˜1:1 of two isomers). The mixture was chromatographed again with 35% ethyl acetate/hex several times to separate 44 mg of the higher Rf material.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[C:15]=1[C:23]#[N:24])(=[O:3])[CH3:2]>CCO.[Pd]>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[C:15]=1[C:23]#[N:24])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCCCCCCOc1cccc([N+](=O)[O-])c1C#N
Agent: [Pd]
Solvent: CCO
Product: CC(=O)OCCCCCCCCOc1cccc(N)c1C#N
Yield: 100 %

Procedure:
A solution of 8-(2-cyano-3-nitrophenoxy)octyl acetate (802 μmol, 268 mg) (Example 274c) in EtOH (15 mL) was hydrogenated in an H-cube apparatus using 10% Pd/C as catalyst. The solution was evaporated to give 8-(3-amino-2-cyanophenoxy)octyl acetate (244 mg, 244 mg). MS 305 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:13]2[CH:26]=[CH:25][C:16]([O:17][CH2:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[C:15]([CH3:27])[CH:14]=2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[CH3:28].C(N(CC)CC)C.C(Cl)Cl.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl.ClCCl>[CH3:21][C:20]([CH3:22])([CH3:23])[C:19](=[O:24])[CH2:18][O:17][C:16]1[CH:25]=[CH:26][C:13]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:40]([CH3:39])(=[O:42])=[O:41])=[C:3]([CH3:28])[CH:4]=2)([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:14][C:15]=1[CH3:27]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(CC)(c1ccc(N)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)(c1ccc(NS(C)(=O)=O)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To a 0° C. mixture of 1-{4-[1-(4-amino-3-methyl-phenyl)-1-ethyl-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one (763 mg, 2 mmol), triethylamine (0.42 mL, 3 mmol) and CH2Cl2 (7 mL) is added methanesulfonyl chloride (0.155 mL, 2 mmol). The reaction is warmed to RT and stirred for 3 h. The reaction is diluted with CH2Cl2 dichloromethane and washed with 0.2 N HCl. The organic phase is Na2SO4 dried, concentrated, and chromatogrpahed (0% to 25% EtOAc/Hex) to give the title compound (800 mg, 87%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[N+:15]([O-])([O-:17])=[O:16].[K+]>OS(O)(=O)=O>[N+:15]([C:7]1[CH:8]=[CH:9][C:4]2[N:3]=[C:2]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:1][C:5]=2[CH:6]=1)([O-:17])=[O:16]
Reactant: CCOC(=O)c1nc2ccccc2s1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1nc2ccc([N+](=O)[O-])cc2s1
Temperature: 0 °C

Procedure:
In particular, commercially available ethyl benzothiazole-2-carboxylate 6 (24.1 mmol, 5.0 g) was suspended in 22 ml conc. H2SO4 at 0° C. At 10° C. KNO3 (26.4 mmol, 2.6 g) was added portionwise over 30 min to the stifling solution, not to exceed 15° C. Color of reaction changed from bright green/yellow to yellow over time. The reaction warmed from 25° C. to 40° C. for an additional 30 min. When the temperature of the reaction was decreased, the solution was poured over ice/water). The precipitate forming in solution was collected via glass frit vacuum filtration to yield a light yellow solid 7.
Reaction SMILES: C(OC([NH:11][C@H:12]1[C@@H:17]2[CH2:18][C@@H:14]([CH:15]=[CH:16]2)[C@H:13]1[C:19]([O:21][CH3:22])=[O:20])=O)C1C=CC=CC=1.[ClH:23].O1CCOCC1>C(OCC)(=O)C.[Pd].C(OCC)C>[ClH:23].[NH2:11][C@H:12]1[C@@H:17]2[CH2:18][C@@H:14]([CH2:15][CH2:16]2)[C@H:13]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)[C@H]1[C@@H](NC(=O)OCc2ccccc2)[C@H]2C=C[C@@H]1C2
Agent: [Pd]
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1[C@@H]2CC[C@@H](C2)[C@@H]1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Methyl (1S,2R,3S,4R)-3-{[(benzyloxy)carbonyl]amino}bicyclo[2.2.1]hept-5-ene-2-carboxylate (5.5 g, 18.27 mmol) was dissolved in ethyl acetate (75 mL). 5% Palladium on carbon (650 mg) was added. The flask was degassed and backfilled with hydrogen gas via balloon. The mixture was stirred at 25° C. for 16 h. The mixture was passed through a plug of Celite and the filtrate was concentrated in vacuo to afford a thick clear oil. The oil was dissolved in ethyl acetate (15 mL) and added dropwise, with vigorous stirring, to a mixture of a 4.0 M solution of hydrochloric acid in 1,4-dioxane (10 mL, 40 mmol) in diethyl ether (90 mL). The desired product began to precipitate as a white solid. The mixture was stirred for 20 min. The precipitate was collected by vacuum filtration, and was washed with additional diethyl ether (15 mL). The solid was further dried in vacuo for 1 h to afford the desired product, methyl (1R,2R,3S,4S)-3-aminobicyclo[2.2.1]heptane-2-carboxylate hydrochloride (2.61 g, 12.69 mmol, 69%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 1.34-1.43 (4H, m), 1.54 (1H, d, J=9.5 Hz), 1.68 (1H, d, J=11.4 Hz), 2.47-2.48 (2H, m), 3.03 (1H, dd, J1=11.0 Hz, J2=4.0 Hz), 3.49-3.53 (1H, m), 3.62 (3H, s), 8.07 (3H, bs). LC-MS (ESI) calcd for C9H15NO2 (free amine) 169.11, found 170.1 [M+H+] (100%), 339.2 [2M+H+] (50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[C:5]([CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:24])[CH2:10][CH2:9]1)=[O:6].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[NH:16][C:15]3=[O:24])[CH2:12][CH2:13]2)[CH:25]=[CH:26][CH:27]=1
Reactant: O=C(CN1CCC(N2Cc3ccccc3NC2=O)CC1)c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=C1Nc2ccccc2CN1C1CCN(CC(O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Yield: 57.7 %

Procedure:
In this example, 1.50 g of 1-(3-chlorobenzoylmethyl)-4-[3,4-dihydro-2(1H)-quinazolinon-3-yl]-piperidine and 75 ml of methanol are mixed and stirred at room temperature. To the stirred mixture, 1.0 g of sodium borohydride is added over a period of 5 hours. Then, the mixture is stirred overnight at room temperature. The white crystals deposited are separated by filtration, successively washed with methanol and water and dried to obtain 1.21 g of a crude product. The crude product is recrystallized from a mixed solvent of chloroform and ethanol to obtain 0.87 g of the desired product.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O[N:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C:10]21[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19][CH2:18]2.C1COCC1.[OH-].[Na+]>C(OCC)C.O>[CH3:23][C:20]1([CH3:24])[O:19][CH2:18][C:10]2([CH2:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]2[NH2:8])[CH2:22][O:21]1
Reactant: CC1(C)OCC2(CO1)Cc1ccccc1C2=NO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)OCC2(CO1)Cc1ccccc1C2N
Temperature: 40 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
To a suspension of 384 mg of lithium aluminum hydride in 22 ml of diethyl ether were added 0.5 g of N-hydroxy-2,2-dimethylspiro[1,3-dioxane-5,2′-inden]-1′(3′H)-imine and 5 ml of THF under ice-cooling, followed by stirring at 40° C. for 8 hours. 0.55 ml of water, 0.55 ml of a 15% aqueous sodium hydroxide solution, and 1.65 ml of water were added thereto under ice-cooling. After filtration through Celite, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 146 mg of 2,2-dimethyl-1′,3′-dihydrospiro[1,3-dioxane-5,2′-inden]-1′-amine.
Reaction SMILES: [C:1](Cl)(=[O:10])[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:12][C@H:13]1[C@@H:17]2[O:18][C:19]([CH3:22])([CH3:21])[O:20][C@@H:16]2[C@@H:15]([OH:23])[CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCCC1.O>[OH:23][C@@H:15]1[C@H:16]2[O:20][C:19]([CH3:21])([CH3:22])[O:18][C@H:17]2[C@H:13]([NH:12][C:1](=[O:10])[O:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:14]1
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](O)C[C@H]2N
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](O)C[C@H]2NC(=O)OCc1ccccc1
Yield: 68 %

Procedure:
At about 0° C., benzyl carbonochloridate (18.4 g, 107.86 mmol, 1.05 equiv.) was added to the solution of (3aR,4S,6R,6aS)-6-amino-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (17.0 g, 98.15 mmol, 1.00 equiv.) and sodium carbonate (20.8 g, 196.24 mmol, 2.00 equiv) in tetrahydrofuran:water (5:1) (600 mL). Standard extractive workup with ethyl acetate (3×200 mL) gave the title product as a white solid (20.5 g; yield=68%). 1H NMR (300 MHz, CDCl3) δ: 7.30-7.39 (m, 5H), 5.20 (s, 2H), 4.60 (d, J=5.4 Hz, 1H), 4.50 (d, J=5.4 Hz, 1H), 4.27 (s, 1H), 4.19 (d, J=5.7 Hz 1H), 2.26 (m, 1H), 1.71 (d, J=14.4 Hz, 1H), 1.47 (s, 3H), 1.28 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[Na+].[Na+].O.Br[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.C1(C)C=CC=CC=1>[CH3:27][C:24]1[CH:25]=[CH:26][C:21]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:22][CH:23]=1
Reactant: Cc1ccc(Br)cc1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2cccc([N+](=O)[O-])c2)cc1
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
Under an inert atmosphere was added 3-nitrobenzene boronic acid (6.3 mmol) and sodium carbonate (11.6 mmol) to water (8 mL), toluene (8 mL) and ethanol (8 mL) and stirred for 5 minutes. p-Bromotoluene (5.8 mmol) and tetrakis(triphenylphosphine)palladium (0.3 mmol) added and heated to 70° C. for 7 hours. Concentrated under reduced pressure and extracted into chloroform (3×20 mL). The organics were then washed with 10% sodium bicarbonate (10 mL), water (10 mL) and brine (10 mL) before drying over sodium sulfate, filtering and evaporating to dryness. The residue was then purified by column chromatography and taken onto the next stage.
Reaction SMILES: Br.[Br:2][C:3]1[S:4][C:5]([Br:11])=[C:6]2[CH2:10][NH:9][CH2:8][C:7]=12.[C:12]1([C:18]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:19]2[CH:23]=[C:22]([CH2:24]Cl)[N:21]=[CH:20]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Br:2][C:3]1[S:4][C:5]([Br:11])=[C:6]2[CH2:10][N:9]([CH2:24][C:22]3[N:21]=[CH:20][N:19]([C:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:23]=3)[CH2:8][C:7]=12
Reactant: Brc1sc(Br)c2c1CNC2
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Brc1sc(Br)c2c1CN(Cc1cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn1)C2
Reaction time: 2 h
Yield: 32.2 %

Procedure:
1.5 g (4.1 mmol) of 1,3-dibromo-5,6-dihydro-4H-thieno[3,4-c]pyrrole hydrobromide, 2.12 g (5.9 mmol) of 1-triphenylmethyl-4-chloromethylimidazole, 30 ml of dimethylformamide and 1.54 ml (9 mmol) of N,N-diisopropylethylamine are introduced into a 50 ml round-bottomed flask. The reaction mixture is subjected to ultrasound for 2 hours and is then poured onto ice. The precipitate obtained is filtered, washed with water, taken up in 50 ml of ethyl acetate, dried over sodium sulphate, filtered and evaporated to dryness. The residue is purified by chromatography on silica gel using the 1/1 ethyl acetate/hexane eluent mixture. 0.8 g of a white solid is obtained. Yield 32%.
Reaction SMILES: [SH:1][CH:2]1[CH2:19][CH2:18][C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][C:13]3[CH:17]=[CH:16][O:15][CH:14]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.Cl.Cl[CH2:22][C@@H:23]([C:25]([OH:27])=[O:26])[NH2:24]>>[NH2:24][CH:23]([C:25]([OH:27])=[O:26])[CH2:22][S:1][CH:2]1[CH2:3][CH2:4][C:5]2([CH2:6][CH2:7][CH:8]([CH2:11][CH2:12][C:13]3[CH:17]=[CH:16][O:15][CH:14]=3)[CH2:9][CH2:10]2)[CH2:18][CH2:19]1
Reactant: N[C@@H](CCl)C(=O)O
Reactant: SC1CCC2(CC1)CCC(CCc1ccoc1)CC2
Agent: Cl
Product: NC(CSC1CCC2(CCC(CCc3ccoc3)CC2)CC1)C(=O)O

Procedure:
Using the experimental conditions described in Ex. 24 and 9-mercapto-3-(2-(3-furyl)ethyl)-spiro[5.5]undecane and 3-chloroalanine hydrochloride as starting materials, the title compound (I-aa) was obtained as an amorphous solid. TLC: Rf=0.28 (SiO2 plates, n-butanol/acetic acid/water 40/10/50). 1H-NMR (300 MHz, CDCl3, ppm from TMS): 7.37 (1H, m), 7.24 (1H, m), 6.26 (1H, m), 4.4-4.2 (3H, m), 3.48 (1H, m), 2.70 (1H, m), 2.45 (2H, t), 2.42 (2H, t), 1.90-0.85 (19H, m).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[C:8]([CH3:13])=[N:7]2.Cl.[CH3:16][C:17]1([NH2:20])[CH2:19][CH2:18]1.CCN(C(C)C)C(C)C>CS(C)=O>[Br:1][C:2]1[C:3]([F:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:20][C:17]1([CH3:16])[CH2:19][CH2:18]1)[C:8]([CH3:13])=[N:7]2
Reactant: CC1(N)CC1
Reactant: Cc1nc2ccc(F)c(Br)c2[nH]c1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1nc2ccc(F)c(Br)c2nc1NC1(C)CC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 77.9 %

Procedure:
To a 15-mL glass reaction vial was added 5-bromo-3-chloro-6-fluoro-2-methylquinoxaline (600) (2.02 g, 7.33 mmol), 1-methylcyclopropanamine hydrochloride (ChemBridge, San Diego, Calif.) (1.420 g, 13.20 mmol) and DIEA (5.10 mL, 29.3 mmol) in DMSO (6 mL). The reaction mixture was stirred at 100° C. for 5 h. The reaction mixture was cooled to RT and poured over ice water. The precipitated orange solid was filtered, washed with water (2×5 mL), ether (2×5 mL). The orange solid was dried overnight to afford 1.77 g of 8-bromo-7-fluoro-3-methyl-N-(1-methylcyclopropyl)quinoxalin-2-amine (610a). The filtrate was extracted with EtOAc (2×10 mL). The organic extracts were washed with water and dried over Na2SO4, and concentrated in vacuo to give the crude material as an orange solid. The crude material was absorbed onto a plug of silica gel and purified by chromatography (with a gradient of 0-20% EtOAc in hexanes) to provide 8-bromo-7-fluoro-3-methyl-N-(1-methylcyclopropyl)quinoxalin-2-amine (610a) (474 mg) as an orange solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.74 (1H, dd, J=9.1, 5.8 Hz), 7.17 (1H, t, J=8.7 Hz), 5.29 (1H, br. s.), 2.49 (3H, s), 1.61 (3H, s), 0.86 (3H, d, J=4.7 Hz). 19F NMR (376 MHz, CDCl3) δ ppm −103.55 (1F, s). m/z (ESI, +ve ion) 310.0/312.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([C:13]([CH3:36])([CH3:35])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([NH:31][CH2:32][CH2:33][OH:34])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.ClCCl.C(N(CC)CC)C.[S:49](Cl)(Cl)=[O:50]>O>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([C:13]([CH3:35])([CH3:36])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:31]3[CH2:32][CH2:33][O:34][S:49]3=[O:50])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(NCCO)cc1-c1ccccc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(N2CCOS2=O)cc1-c1ccccc1Cl
Yield: 77.9 %

Procedure:
To a solution of 0.20 g (0.36 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-hydroxy-ethylamino)-pyridin-3-yl]-N-methyl-isobutyramide in a 5 ml dichloromethane were added consecutively 0.11 g (1.1 mmol) triethylamine and 0.05 g (0.4 mmol) thionyl chloride at room temperature. After 1 h the reaction mixture was diluted with water and extracted with three portions of dichloromethane. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 0.17 g (77%) of the title compound as a white solid.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][C:11]2([C:24]#[N:25])[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:7]([C:26]([O:28]CC)=[O:27])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].NC(N)=[O:33].OO>CO.[OH-].[Na+]>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][C:11]([CH2:10][C:8]2[C:7]([C:26]([OH:28])=[O:27])=[N:6][N:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH:9]=2)([C:24](=[O:33])[NH2:25])[CH2:12][CH2:13]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)c1nn(C(C)(C)C)cc1CC1(C#N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: NC(N)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Cc2cn(C(C)(C)C)nc2C(=O)O)(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.9 %

Procedure:
To a 0° C. solution of tert-butyl 4-((1-tert-butyl-3-(ethoxycarbonyl)-1H-pyrazol-4-yl)methyl)-4-cyanopiperidine-1-carboxylate (455 mg, 1.09 mmol) in methanol (11 mL) was added a solution of urea-hydrogen peroxide (1.05 g, 10.9 mmol) in 1 M aqueous sodium hydroxide (10.9 mL), dropwise. After stirring for 18 hours at room temperature, volatiles were removed under reduced pressure and the resultant slurry was taken up in water (50 mL), acidified with 2 N aqueous hydrochloric acid and extracted with ethyl acetate (2×50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to yield 4-((1-(tert-butoxycarbonyl)-4-carbamoylpiperidin-4-yl)methyl)-1-tert-butyl-1H-pyrazole-3-carboxylic acid (418 mg) as a colorless solid. −APCI (M−H) 407.3; 1H NMR (400 MHz, DMSO-d6, δ): 12.33 (br. s., 1H), 7.47 (s, 1H), 7.11 (br. s., 1H), 6.99 (s, 1H), 3.59 (d, J=13.3 Hz, 2H), 2.89 (s, 2H), 2.77 (m, 2H), 1.84 (m, 2H), 1.44 (s, 9H), 1.31 (s, 9H), 1.16 (m, 2H).
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)C.[Cl:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH2:31])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1>CCO>[Cl:17][C:18]1[CH:33]=[CH:32][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][NH:31][C:4]3[C:5](=[O:16])[C:6](=[O:15])[C:7]=3[NH:8][C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)=[CH:25][CH:24]=2)=[CH:20][CH:19]=1
Reactant: NCCc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CCOc1c(Nc2cccnc2)c(=O)c1=O
Solvent: CCO
Product: O=c1c(NCCc2ccc(Oc3ccc(Cl)cc3)cc2)c(Nc2cccnc2)c1=O
Temperature: 150 °C

Procedure:
3-Ethoxy-4-(pyridine-3-ylamino)-3-cyclobutene-1,2-dione (70 mg, 0.32 mmol) prepared according to example 1A and 2-[4-(4-chlorophenoxy)-phenyl]-ethylamine (105 mg, 0.45 mmol) in EtOH (1.5 mL) were stirred and heated to 150° C. in a sealed vessel in a microwave synthesizer for 1 min. After cooling to r.t. the precipitate was filtered off, washed with EtOH (3×3 mL) and dried in vacuo.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:6][N:7]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:10]([C:18](N2CCOCC2)=[O:19])[N:9]=[N:8]1.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1.C1(C)C=CC=CC=1>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[CH2:6][N:7]1[C:11]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:10]([CH:18]=[O:19])[N:9]=[N:8]1
Reactant: O=C(c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1N1CCOCC1)N1CCOCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=Cc1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1N1CCOCC1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Dissolve [1-(3,5-bis-trifluoromethyl-benzyl)-5-morpholin-4-yl-1H-[1,2,3]triazol-4-yl]-morpholin-4-yl-methanone in THF. Cool to −78° C., slowly add 28.3 ml (4 eq) of 1M diisobutyl aluminum hydride in toluene, and stir 2.5 hours. Move to 0° C. ice bath and allow reaction to slowly warm while stirring overnight. Slowly quench by adding ˜5 ml 1N HCl while still at 0° C. then warming to RT. Pour into 50 ml 1N NaOH. Extract with EtOAc, then wash organic layer with 1N HCl. Concentrate organic layer to give the desired aldehyde, which can be used without further purification. MS (IS) 409.2 (M+1). Rf=0.61 (1:1 Hexanes:EtOAc)
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][C:8]1[O:9][CH:10]=[C:11]([CH3:13])[N:12]=1.C(N(CC)CC)C>CCOCC>[CH3:13][C:11]1[N:12]=[C:8]([NH:7][C:2](=[O:3])[O:4][CH2:5][CH3:6])[O:9][CH:10]=1
Reactant: Cc1coc(N)n1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)Nc1nc(C)co1
Reaction time: 2 h

Procedure:
Ethyl chloroformate (1.05 ml, 0.011 mol) was added dropwise to a stirred solution of 2-amino-4-methyloxazole (1.0 g, 0.010 mol) and triethylamine (1.5 ml, 0.011 mol) in dry ether (50 ml) at 5°-10° C. The mixture was stirred for 2 hours at 0°-5° C. then the white solid was filtered off and washed well with water to remove triethylamine hydrochloride. Residue (0.5 g) was recrystallised from chloroform-petroleum spirit, m.p. 126° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([NH2:7])=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][N:3]=1.[CH3:14][O:15][CH2:16][C:17](Cl)=[O:18]>N1C=CC=CC=1>[CH3:14][O:15][CH2:16][C:17]([NH:7][C:6]1[C:2]([CH3:1])=[N:3][NH:4][C:5]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:18]
Reactant: Cc1n[nH]c(-c2ccccc2)c1N
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Product: COCC(=O)Nc1c(C)n[nH]c1-c1ccccc1
Reaction time: 2 h

Procedure:
To a RT solution of 416 mg of 3-methyl-5-phenyl-1H-pyrazol-4-ylamine in 4.6 mL pyridine was added 242 μL of methoxyacetyl chloride. After 2 h at RT, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in chloroform and washed with 0.5 N hydrochloric acid and saturated aqueous sodium carbonate and brine. The organic portion was dried with sodium sulfate and concentrated under reduced pressure. The residue contained the title compound as a tan, amorphous solid and was used without further purification.