Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12](=[O:14])[CH3:13])=[C:10]([C:15]([F:18])([F:17])[F:16])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:19]Br>C(Cl)(Cl)Cl.CC(O)=O>[Br:19][CH2:13][C:12]([C:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][O:9][C:10]=1[C:15]([F:17])([F:18])[F:16])=[O:14]
Reactant: BrBr
Reactant: CC(=O)c1c(-c2ccccc2)noc1C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=C(CBr)c1c(-c2ccccc2)noc1C(F)(F)F
Temperature: 25 °C
Yield: 59.9 %

Procedure:
To a solution of 1-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-ethanone (2.88 g, 11 mmol) in chloroform (11 mL) and AcOH (0.6 mL) at 48° C. was added a solution of bromine (0.61 mL, 12 mmol) in chloroform (3.5 mL) over 5 min keeping the temperature below 50° C. After addition the reaction mixture was allowed to cool down to room temperature and poured into ice-water (200 mL). The layers were separated and the aqueous layer extracted with dichloromethane. The combined organic layers were then washed with water and brine, dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate: 100:0 to 4:1) afforded the title compound (2.2 g, 59%) which was obtained as a light yellow oil. MS: m/e=334.3/336.4 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[C:16]([F:25])[CH:15]=2)=[O:11])=[CH:6][CH:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[N:3]=1.[OH:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:25][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:13][NH:12][C:10](=[O:11])[CH:9]=[CH:8][C:7]1[C:2]([O:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[N:3][C:4]([C:26]([F:29])([F:28])[F:27])=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Cl)cc1F
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2Oc2cccnc2)cc1F
Reaction time: 8 h
Yield: 81.9 %

Procedure:
3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-N-(3-fluoro-4-methanesulfonylamino-benzyl)-acrylamide (48 mg, 0.11 mmol), 3-hydroxypyridine (97 mg) and potassium carbonate (421 mg) were added in 40 ml DMF. The reaction mixture was stirred overnight. The reaction mixture was extracted with ethyl acetate (30 ml×2) and water (30 ml). A combined organic layer was washed with H2O (30 ml×4) and brine (40 ml), dried with MgSO4, and then concentrated in vacuo. The residue was purified with column chromatography (hexane/ethylacetate=1/4) to yield the title compound (46 mg, 82%).
Reaction SMILES: Cl.[OH:2][C:3]1[C:4]([CH2:9][OH:10])=[N:5][CH:6]=[CH:7][CH:8]=1.[OH-].[K+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:13]([O:2][C:3]1[C:4]([CH2:9][OH:10])=[N:5][CH:6]=[CH:7][CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ncccc1O
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: OCc1ncccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 58 %

Procedure:
To a suspension of 3-hydroxy-2-hydroxymethylpyridine hydrochloride (7.0 g, 12.4 mmol) in ethanol (37.5 ml) was added a solution of KOH pellets (85% 1.6 g, 24.7 mmol) in ethanol (25 ml). The reaction was stirred for 5 minutes at ambient temperature and then benzyl bromide was added (2.11 g, 12.36 mmol). The reaction mixture was stirred at ambient temperature for 48 hours, filtered and evaporated. The residue was purified by chromatography (EtOAc, CH2Cl2) to give 3-benzyloxy-2-hydroxymethylpyridine as a colourless solid (1.55 g, 58%) [J. Med. Chem., 15, (1972) 615] m.p. 78.7°-79.2° C.
Reaction SMILES: Cl[C:2]1[C:7]([Br:8])=[CH:6][N:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([C:27]#[N:28])=[CH:19][CH:18]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[Br:8][C:7]1[C:2]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([C:27]#[N:28])=[CH:19][CH:18]=2)=[N:3][CH:4]=[N:5][CH:6]=1
Reactant: Clc1ncncc1Br
Reactant: CC1(C)OB(c2ccc(C#N)c3ccccc23)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#Cc1ccc(-c2ncncc2Br)c2ccccc12
Temperature: 80 °C
Yield: 69 %

Procedure:
A mixture of 4-chloro-5-bromopyrimidine (193 mg, 1 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthonitrile (279 mg, 1 mmol) palladium tetrakis triphenylphoshine (0.023 g, 0.02 mmol) and aqueous sodium carbonate solution (2M, 1.5 mL, 3 mmol) in dioxane (3 mL) was heated to 80° C. for 12 hours. The reaction mixture cooled to room temperature, washed with water, extracted with ethyl acetate and purified by chromatography to yield 4-(5-bromopyrimidin-4-yl)-1-naphthonitrile (214 mg, 69%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[CH3:14][O:15][C:16](=[O:23])[C@@H:17]([CH2:19][CH:20]([CH3:22])[CH3:21])[NH2:18]>>[CH3:21][CH:20]([CH3:22])[CH2:19][C@@H:17]([NH:18][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=2)=[O:13])[C:16]([O:15][CH3:14])=[O:23]
Reactant: COC(=O)[C@H](N)CC(C)C
Reactant: Cc1ccc2[nH]c(C(=O)O)cc2c1
Product: COC(=O)[C@@H](CC(C)C)NC(=O)c1cc2cc(C)ccc2[nH]1
Yield: 50 %

Procedure:
Prepared in a similar manner to example 4 using 5-Methyl-1H-indole-2-carboxylic acid and D-leucine methyl ester. Yield: 50%. 1H NMR (500 MHz, CDCl3): 0.98 (d, 3H, J=6.3 Hz), 1.00 (d, 3H, J=6.1 Hz), 2.44 (s, 3H), 3.784 (s, 3H), 4.87 (m, 1H), 6.56 (d, 1H, J=8.39 Hz), 6.85 (dd, 1H, J=1.94 Hz, J=0.68 Hz), 7.12 (dd, 1H, J=8.46 Hz, J=1.55 Hz), 7.31 (d, 1H, J=8.45 Hz), 7.42 (s, 1H). MS (MH+, 303).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5]Br.[Mg].Cl[SiH:9]1[CH2:14][CH2:13][CH:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=3)[CH2:17][CH2:16]2)[CH2:11][CH2:10]1>C1COCC1>[F:30][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][C@H:18]2[CH2:17][CH2:16][C@H:15]([C@H:12]3[CH2:13][CH2:14][Si@H:9]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH2:10][CH2:11]3)[CH2:20][CH2:19]2)[CH:28]=[CH:27][C:26]=1[F:29]
Reactant: COCCCBr
Reactant: Fc1ccc(CC[C@H]2CC[C@H](C3CC[SiH](Cl)CC3)CC2)cc1F
Agent: [Mg]
Solvent: C1CCOC1
Product: COCCC[Si@H]1CC[C@H]([C@H]2CC[C@H](CCc3ccc(F)c(F)c3)CC2)CC1

Procedure:
3.1 g (20 mmol) of 3-methoxypropyl bromide was dripped into a mixture of 0.5 g (21 mmol) of magnesium and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 7.1 g (20 mmol) of 1-chloro-4-(trans-4-(2-(3,4-difluorophenyl) ethyl) cyclohexyl)-1-silacyclohexane. The silacyclohexane rings of the reacted mixture thus obtained were a mixture of trans isomers and cis isomers. After a conventional after treatment, they were separated by means of chromatography to obtain 6.5 g (yield 81%) of trans-4-(trans-4-(2-(3,4-difluorophenyl) ethyl) cyclohexyl)-1-(3-methoxypropyl)-1-silacyclohexane.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]([OH:24])=O.Cl.[C:26]1([C@:32]2([OH:53])[CH2:40][CH2:39][C:38]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:37]3[C@H:33]2[CH2:34][NH:35][CH2:36]3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>ClCCl>[C:26]1([C@:32]2([OH:53])[CH2:40][CH2:39][C:38]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C@@H:37]3[C@H:33]2[CH2:34][NH:35][CH:36]3[C:22](=[O:24])[CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH3:13])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccccc1CC(=O)O
Reactant: O[C@@]1(c2ccccc2)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1CC(=O)C1NC[C@@H]2[C@H]1C(c1ccccc1)(c1ccccc1)CC[C@@]2(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.4 %

Procedure:
0.28 g of carbonyldiimidazole is added to a solution of 0.28 g of (2-methoxyphenyl)acetic acid in 20 cm3 of dry dichloromethane. The mixture is stirred at room temperature for 1 hour and a suspension of 0.7 g of (3aS,4S,7aS)-4,7,7-triphenylperhydroisoindol-4-ol hydrochloride in 20 cm3 of dry dichloromethane and then 0.48 cm3 of triethylamine are subsequently added in succession. The reaction mixture is stirred at room temperature for 24 hours, diluted with 100 cm3 of dichloromethane, washed with 100 cm3 of water (twice) and then with 100 cm3 of an aqueous saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a Merck silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 16 cm) by eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (55/45 by volume) and collecting fractions of 20 cm3. Fractions 7 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 16 cm3 of acetonitrile. The crystals are filtered off and dried. 0.3 g of (3aS,4S,7aS)-4,7,7-triphenyl-2-(2-methoxyphenyl)acetylperhydroisoindol-4-ol is obtained in the form of white crystals which melt at 236° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16]([C:20]1[Se:24][C:23]([C:25]([NH2:27])=[O:26])=[C:22]([OH:28])[CH:21]=1)([CH3:19])([CH3:18])[CH3:17].[OH-].[Na+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[O:28][C:22]1[CH:21]=[C:20]([C:16]([CH3:19])([CH3:17])[CH3:18])[Se:24][C:23]=1[C:25]([NH2:27])=[O:26]
Reactant: CC(C)(C)c1cc(O)c(C(N)=O)[se]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3cc(C(C)(C)C)[se]c3C(N)=O)c2cc1OC

Procedure:
As shown in scheme R, 4-chloro-6,7-dimethoxyquinazoline is reacted with 5-tert-butyl-3-hydroxyselenophene-2-carboxamide in presence of NaOH and DMF to give 3-(6,7-dimethoxyquinazolin-4-yloxy)-5-tert-butylselenophene-2-carboxamide. The 5-tert-butyl-3-hydroxyselenophene-2-carboxamide is prepared in five steps from pinacolone and is described in examples.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[N:8][N:7]=[C:6]1SC.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[N:8][N:7]=[C:6]1[N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: CSc1nnc(C)c(=O)n1Cc1cc(F)ccc1Cl
Product: Cc1nnc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2cc(F)ccc2Cl)c1=O
Temperature: 130 °C
Reaction time: 0.08 h

Procedure:
The mixture of 4-(2-chloro-5-fluorobenzyl)-6-methyl-3-(methylthio)-1,2,4-triazin-5(4H)-one (30, 1.50 g, 5.0 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (1.500 g, 7.50 mmol) was ground for 5 min and then heated in a tube under nitrogen atmosphere at 130° C. for 14 h. The mixture was separated by silica gel column, and eluted with 10-50% ethyl acetate in petroleum ether to give (R)-tert-butyl 1-(4-(2-chloro-5-fluorobenzyl)-6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-ylpiperidin-3-ylcarbamate (31). MS: m/z, 396 (100%, M-56), 398 (35%), 452 (100%, M+1), 454 (35%), 474 (70%, M+23), 476 (25%).
Reaction SMILES: [NH2:1][C:2]1[N:6](C(NC)=O)[CH:5]=[N:4][C:3]=1[C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CO>CCN(CC)CC>[NH2:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CNC(=O)n1cnc(C(=O)NC(C)(C)C)c1N
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)NC(=O)c1nc[nH]c1N
Temperature: 80 °C
Yield: 119.1 %

Procedure:
5-Amino-N4-(1,1-dimethylethyl)-N1-methyl-1H-imidazole-1,4-dicarboxamide 6 (10.4 g, 0.041 mol, 93% pure), MeOH (100 mL) and Et3N (5 mL) were placed into a 250 mL, three-necked flask equipped with a nitrogen inlet, a gas outlet tube, reflux condenser, thermometer, magnetic stirrer bar, and maintained under a positive pressure of nitrogen. The mixture was heated at 80° C. (oil bath) for 3 hour with vigorous stirring (when HPLC analysis indicated that no more starting material was present), gradually cooled to room temperature, and concentrated under reduced pressure. The gummy residue was treated with a solution of t-BuOMe (10 mL), n-heptane (100 mL) and acetone (2 mL), and stirred at room temperature for 1 hour. The resulting precipitate was collected by vacuum filtration and dried (20 mm Hg, 20° C., 18 hours) to yield 8.9 g (theoretical yield is 7.37 g) of 5-amino-N-(1,1-dimethyl-ethyl)-1H-imidazole-4-carboxamide 17 as a tan solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.I[C:26]1[CH:39]=[N:38][C:29]2[NH:30][C:31]3[CH:36]=[N:35][C:34]([Br:37])=[CH:33][C:32]=3[C:28]=2[CH:27]=1>[F-].[K+].C(#N)C.C(OCC)(=O)C>[Br:37][C:34]1[N:35]=[CH:36][C:31]2[NH:30][C:29]3[N:38]=[CH:39][C:26]([C:12]4[CH:11]=[CH:10][C:9]([CH2:8][N:5]5[CH2:4][CH2:3][C:2]([CH3:1])([CH3:24])[CH2:7][CH2:6]5)=[CH:14][CH:13]=4)=[CH:27][C:28]=3[C:32]=2[CH:33]=1
Reactant: CC1(C)CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Brc1cc2c(cn1)[nH]c1ncc(I)cc12
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1(C)CCN(Cc2ccc(-c3cnc4[nH]c5cnc(Br)cc5c4c3)cc2)CC1
Temperature: 80 °C
Yield: 32.5 %

Procedure:
A degassed mixture of 4,4-dimethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]piperidine (836 mg, 2.5 mmol), 3-iodo-6-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (500 mg, 1.3 mmol), 1,1′-[bis(diphenylphosphino)ferrocene] dichloropalladium(II) (109 mg, 0.13 mmol) in 1N aqueous potassium fluoride solution (25 mL) and acetonitrile (25 mL) was heated at 80° C. for 18 h. The cooled reaction mixture was diluted with ethyl acetate (100 mL) then washed with water (75 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 120 g column, ISCO, 0-15% methanol in DCM) to afford the title compound as an off-white solid (190 mg, 33%). 1H NMR (CDCl3 plus CD3OD, 300 MHz): 8.85 (d, J=2.2 Hz, 1H), 8.76 (d, J=2.2 Hz, 1H), 8.70 (d, J=0.9 Hz, 1H), 8.32 (d, J=0.9 Hz, 1H), 7.73 (d, J=8.0 Hz, 2H), 7.54 (d, J=8.0 Hz, 2H), 3.82 (s, 2H), 2.77-2.63 (m, 4H), 1.52 (t, J=5.6 Hz, 4H), 1.00 (s, 6H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=1)[C@H:3]([OH:19])[CH2:4][NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH3:17])[CH:14]=2)[N:9]([CH3:18])[CH2:8][CH2:7]1.[C:29](N1C=CN=C1)(=[O:31])[CH3:30]>ClCCl>[F:27][C:25]1[CH:26]=[C:21]([CH:22]=[C:23]([F:28])[CH:24]=1)[CH2:20][C@H:2]([NH:1][C:29](=[O:31])[CH3:30])[C@H:3]([OH:19])[CH2:4][NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH3:17])[CH:14]=2)[N:9]([CH3:18])[CH2:8][CH2:7]1
Reactant: CCc1ccc2c(c1)C(NC[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1)CCN2C
Reactant: CC(=O)n1ccnc1
Solvent: ClCCl
Product: CCc1ccc2c(c1)C(NC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(C)=O)CCN2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a solution of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(6-ethyl-1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino]butan-2-ol (0.218 g) in dichloromethane (15 mL) was added 1-acetylimidazole (0.062 g). The mixture was stirred overnight at room temperature. The mixture was partitioned between dichloromethane and brine, and the organic was extracted three times, dried with sodium sulfate, filtered, and concentrated. A silica gel column was run for purification using 3% MeOH in dichloromethane with 0.5% NH4OH as the solvent solution. HPLC still showed small amounts of starting material present, so the mixture was washed one time with 1N HCl, dried with magnesium sulfate, filtered, and concentrated. 0.115 g of the title product were recovered. (48% yield). MS (ESI+) for C24H31F2N3O2 m/z 432.18 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)OCC(C)C.[NH3:25].O.O>C1COCC1>[C:14]([CH:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]1)(=[O:16])[NH2:25]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: N
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(C(N)=O)C1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
A 1-L 3-necked round-bottomed flask was charged with a solution of 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (10 g, 42.79 mmol, 1.00 equiv, 98%), TEA (5.2 g, 50.46 mmol, 1.18 equiv, 98%) in THF (100 mL). To this mixture was added isobutyl carbonochloridate (6.8 g, 49.00 mmol, 1.15 equiv, 98%) drop wise at 10° C. The resulting solution was stirred for 15 minutes at 10° C. in a water/ice bath. Then, to the mixture was added NH3.H2O (25%, 60 mL) and allowed to stir for 10 minutes at 10° C. Then, it was treated with water (40 mL) to afford off-white solids after filtration. The solid was dried in an oven under reduced pressure affording tert-butyl 3-carbamoylpiperidine-1-carboxylate as white solid (7 g, 72%).
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].[C:28]([O:32][C:33]([NH:35][C@:36]([CH:71]1[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]1)([C:38]([N:40]1[CH2:70][CH2:69][CH2:68][C@H:41]1[C:42]([NH:44][CH2:45][C:46]1[CH:51]=[C:50]([Cl:52])[CH:49]=[CH:48][C:47]=1[CH2:53][CH:54]([NH:59]C1C=CC(OC)=CC=1)[C:55]([F:58])([F:57])[F:56])=[O:43])=[O:39])N)=[O:34])([CH3:31])([CH3:30])[CH3:29]>O.CC#N>[NH2:59][CH:54]([C:55]([F:58])([F:57])[F:56])[CH2:53][C:47]1[CH:48]=[CH:49][C:50]([Cl:52])=[CH:51][C:46]=1[CH2:45][NH:44][C:42](=[O:43])[C@@H:41]1[CH2:68][CH2:69][CH2:70][N:40]1[C:38](=[O:39])[C@H:36]([NH:35][C:33]([O:32][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:34])[CH:71]1[CH2:72][CH2:73][CH2:74][CH2:75][CH2:76]1
Reactant: COc1ccc(NC(Cc2ccc(Cl)cc2CNC(=O)[C@@H]2CCCN2C(=O)[C@](N)(NC(=O)OC(C)(C)C)C2CCCCC2)C(F)(F)F)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CC(N)C(F)(F)F)C1CCCCC1
Temperature: 25 °C
Yield: 41.6 %

Procedure:
A solution of CAN (1.259 g, 2.30 mmol) in water (12 mL) was added to a stirred solution of 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylglycyl}-N-(5-chloro-2-{3,3,3-trifluoro-2-[(4-methoxyphenyl)amino]propyl}benzyl)-L-prolinamide (0.798 g, 1.15 mmol) in CH3CN (20 mL) at 0° C. and the resulting solution was warmed to ambient temperature. The solution was partitioned between EtOAc and 10% aqueous NH4OH and the resulting two phase suspension was filtered and the organic layer was washed with 10% sodium sulfite and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash column chromatography on silica (eluting with 1-10% of 10% ammonium hydroxide in methanol/chloroform gradient) to give N-[2-(2-amino-3,3,3-trifluoropropyl)-5-chlorobenzyl]-1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl}-L-prolinamide (0.282 g) as a foam; MS m/z=589.6.
Reaction SMILES: Cl[CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>O1CCCC1>[O:20]1[CH2:21][CH2:22][N:17]([CH:2]2[C:14]3[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=3[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]2=3)[CH2:18][CH2:19]1
Reactant: C1COCCN1
Reactant: O=c1[nH]c2c([nH]c1=O)C(Cl)c1ccccc1-2
Solvent: C1CCOC1
Product: O=c1[nH]c2c([nH]c1=O)C(N1CCOCC1)c1ccccc1-2
Reaction time: 20 h
Yield: 42.3 %

Procedure:
9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H,4H)-dione (0.50 g, 2.13 mmol) was suspended in 5 ml of dry tetrahydrofuran, while cooling in an ice bath. Morpholine(0.37 ml, 4.27 mmol) dissolved in 2 ml of dry tetrahydrofuran was added over 2 min. After 1 hour the ice bath was removed and stirring was continued for 20 hours at room temperature. The precipitate was filtered off and washed with tetrahydrofuran, 10% acetic acid, water and dried to give 0.365 g of the crude product. Recrystallization from ethanol afforded 0.257 g (42%) of the title compound. M.p. 265°-267° C. 1H-NMR (DMSO-d6, δ): 2.47 (m, 2H), 2.61 (m, 2H), 3.56 (m, 4H), 4.54 (s, 1H), 7.13 (t, 1H), 7.3 (t, 1H), 7.47 (d, 1H), 7.53 (d, 1H), 11.8 (s, 1H), 12.25 (s, 1H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[CH:4]=1.[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2=[O:24]>C1COCC1>[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[C:17]2([OH:24])[C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([O:11][CH3:12])[CH:4]=1
Reactant: COc1cc(Br)cc(OC)c1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C2(O)C(=O)Nc3ccc(Cl)cc32)c1
Yield: 60.6 %

Procedure:
This compound is prepared according to the procedure described in step A of Preparation 1.6, starting with 1.2 g of magnesium, 9.5 g of 1-bromo-3,5-dimethoxybenzene, 50 ml of THF and a solution of 3 g of 5-chloro-1H-indole-2,3-dione in 50 ml of THF. 3.2 g of the expected product are obtained after crystallization from iso ether; m.p.=191° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].C[Al](C)C.C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>>[CH2:25]([N:22]1[CH2:23][CH2:24][C:19]([C:16]2[CH:17]=[CH:18][C:13]([C:12]([N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[O:11])=[CH:14][CH:15]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=2)[CH2:20][CH2:21]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)c1ccc(C2(c3cccc(OC)c3)CCN(Cc3ccccc3)CC2)cc1
Reactant: CCNCC
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Product: CCN(CC)C(=O)c1ccc(C2(c3cccc(OC)c3)CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a solution of diethyl amine (1.88 mL, 18.2 mmol) in CH2ClCH2Cl (7 mL) at room temperature was added a trimethylaluminum (9.1 mL, 18.2 mmol, 2M in hexanes) dropwise. The reaction mixture was stirred at room temperature for 1 hour. A solution of of 4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoic acid methyl ester (1.51 g, 3.64 mmol) in (CH2)2Cl2 (6 mL) was added and the reaction mixture was heated to reflux for 14 hours. The solution was then cooled 0° C. and sat. aqueous NaHCO3 (15 mL) was added dropwise. The mixture was filtered through celite. The celite cake was washed with CH2Cl2 (40 mL). The organic layer was separated and the aqueous layer was washed with CH2Cl2 (3×30 mL). The combined organic layers were dried (MgSO4) and concentrated. The crude residue was purified by flash chromatography with EtOAc to afford 1.4 g (84% yield) of 4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-N,N-diethyl-benzamide. 1HNMR (400 MHz, CDCl3) δ 7.28-7.16 (comp, 10H), 6.84-6.80 (comp, 2H), 6.68 (dd, 1H), 3.74 (s, 3H), 3.52-3.48 (comp, 2H), 3.39 (s, 2H), 3.24-3.21 (comp, 2H), 2.47-2.42 (comp, 8H), 1.22-1.20 (comp, 3H), 1.19-1.16 (comp, 3H); MS (M+1) 457.2.