Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=O)=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][C:35]=2[NH:40][C:41]2[CH:46]=[CH:45][C:44]([I:47])=[CH:43][C:42]=2[F:48])=[O:33])[CH2:28][CH2:27]1.O>CS(C)=O>[F:48][C:42]1[CH:43]=[C:44]([I:47])[CH:45]=[CH:46][C:41]=1[NH:40][C:35]1[CH:36]=[N:37][CH:38]=[CH:39][C:34]=1[C:32]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:8](=[O:10])[CH2:7][C:4]2[CH:3]=[CH:2][C:1]([CH3:11])=[CH:6][CH:5]=2)[CH2:27][CH2:28]1)=[O:33]
Reactant: NC1CCN(C(=O)c2ccncc2Nc2ccc(I)cc2F)CC1
Reactant: Cc1ccc(CC(=O)O)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(CC(=O)NC2CCN(C(=O)c3ccncc3Nc3ccc(I)cc3F)CC2)cc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 109.2 %

Procedure:
A mixture of p-tolyl acetic acid (0.027 g, 0.180 mmol) and CDI (0.036 g, 0.222 mmol) in dry DMSO (2 mL) was heated to 50° C. for 2 h prior to addition of 4-[(4-aminopiperidin-1-yl)carbonyl]-N-(2-fluoro-4-iodophenyl)pyridin-3-amine hydrochloride (described above) (0.052 g, 0.109 mmol). The contents were then stirred at room temp. After 6 h, HPLC indicated near-complete reaction. The contents were poured into water (30 mL) and extracted with ethyl acetate (30 mL). The organics were washed with brine (2×30 mL), dried over sodium sulfate and concentrated to a yellow oil. The oil was further dried under high vacuum for 2 h at 40° C. to provide the desired product as a yellow semi-solid (0.068 g, 0.119 mmol, 66%). LC/MS [8.92 min; 573 (M+1)]
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:12])=[CH:9]/[CH2:10][OH:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:19]([C:22]1[CH:23]=[CH:24][C:25]([O:31][CH3:32])=[C:26](B(O)O)[CH:27]=1)([CH3:21])[CH3:20]>COCCOC.Cl>[CH:19]([C:22]1[CH:23]=[CH:24][C:25]([O:31][CH3:32])=[C:26]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([CH3:12])=[CH:9][CH2:10][OH:11])=[CH:4][CH:3]=2)[CH:27]=1)([CH3:21])[CH3:20]
Reactant: COc1ccc(C(C)C)cc1B(O)O
Reactant: C/C(=C\CO)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(C(C)C)cc1-c1ccc(C(C)=CCO)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Tetrakis(triphenylphoshine)palladium(0) (0.20 g, 0.18 mmol, 4 mol %) was added, under nitrogen, to a stirred solution of (E)-3-(4-bromophenyl)-but-2-en-1-ol (1.0 g, 4.40 mmol) {prepared as detailed in example 50b} in DME (55 ml), and the resulting orange coloured solution stirred at room temperature for 10 min. Aqueous 2M sodium carbonate (13.2 ml, 26.4 mmol) was then added, the mixture stirred for 10 min, then 5-isopropyl-2-methoxyphenylboronic acid (1.28 g, 6.60 mmol) was added, and the reaction mixture heated to 80° C. for 18 h, under reflux. The reaction mixture was diluted with 1N HCl (100 ml) and the products extracted into ethyl acetate (2×100 ml). The combined organic extracts were washed with brine, dried (MgSO4), and evaporated to give the crude product, which was purified by column chromatography on silica gel (1% methanol in dichloromethane eluent) to give the product, 3-(5′-isopropyl-2′-methoxy-biphenyl-4-yl)-but-2-en-1-ol as a colourless oil; 1.15 g (88%).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:20](I)[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:20]([N:10]1[C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=[C:9]1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:21]
Reactant: CCI
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)n1CC

Procedure:
The product is prepared according to the procedure described in example 67, using 600 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 1 and 0.23 ml of ethyl iodide in place of the methyl iodide, and replacing the potassium carbonate with cesium carbonate. After purification by silica column chromatography, eluent: 96/02/02 CH2Cl2/CH3CN/MeOH, 190 mg of ethyl [1-ethyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate are obtained in the form of a white solid the characteristics of which are the following:
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]3=[CH:11][C:10]=2[CH2:9]1)C1C=CC=CC=1>FC(F)(F)C(O)=O.[Pt]=O>[CH2:9]1[NH:8][CH2:17][CH2:16][C:15]2[N:14]=[C:13]3[CH2:18][CH2:19][CH2:20][CH2:21][C:12]3=[CH:11][C:10]1=2
Reactant: c1ccc(CN2CCc3nc4ccccc4cc3C2)cc1
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: c1c2c(nc3c1CNCC3)CCCC2
Reaction time: 24 h
Yield: 90.8 %

Procedure:
Platinum oxide (850 mg) was added to a solution of 2-benzyl-1,2,3,4-tetrahydrobenzo[b][1,6]-naphthyridine (8.5 g, 31 mmol) in trifluoroacetic acid (155 ml), and catalytic reduction was carried out at 50° C. for 24 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was made basic with 6N sodium hydroxide and extracted with toluene. The extract solution was dried over anhydrous sodium sulfate, and the organic solvent was removed by concentration under reduced pressure and the residue was recrystallized from isopropyl ether to obtain the desired compound (5.3 g, 90%) as white crystals.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:20]4[CH:21]=[CH:22][C:23]5[N:24](S(C6C=CC=CC=6)(=O)=O)[C:25]6[C:30]([C:31]=5[CH:32]=4)=[CH:29][C:28]([N:33]4[C:45]5[CH:44]=[CH:43][C:42]([C:46]7[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=7)=[CH:41][C:40]=5[C:39]5[C:34]4=[CH:35][CH:36]=[CH:37][CH:38]=5)=[CH:27][CH:26]=6)[C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl>CS(C)=O.O>[C:46]1([C:42]2[CH:43]=[CH:44][C:45]3[N:33]([C:28]4[CH:27]=[CH:26][C:25]5[NH:24][C:23]6[C:31]([C:30]=5[CH:29]=4)=[CH:32][C:20]([N:11]4[C:10]5[CH:9]=[CH:8][C:7]([C:1]7[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=7)=[CH:19][C:18]=5[C:17]5[C:12]4=[CH:13][CH:14]=[CH:15][CH:16]=5)=[CH:21][CH:22]=6)[C:34]4[C:39]([C:40]=3[CH:41]=2)=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: O=S(=O)(c1ccccc1)n1c2ccc(-n3c4ccccc4c4cc(-c5ccccc5)ccc43)cc2c2cc(-n3c4ccccc4c4cc(-c5ccccc5)ccc43)ccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(-c2ccc3c(c2)c2ccccc2n3-c2ccc3[nH]c4ccc(-n5c6ccccc6c6cc(-c7ccccc7)ccc65)cc4c3c2)cc1
Temperature: 25 °C

Procedure:
97 g (123 mmol) of 3,3″-bis(phenyl)-9′-[(phenyl)sulfonyl]-9,3′:6′,9″-ter-9H-carbazole and 48 g (856 mmol) of potassium hydroxide in 65 ml of dimethyl sulfoxide and 21 ml of water are heated under reflux for 1 h. The mixture is subsequently cooled to room temperature and neutralised using 1 M HCl solution. The mixture is then extracted with dichloromethane. The solvent is evaporated in vacuo, and the residue is purified by chromatography (heptane/ethyl acetate 10:1). Yield: 64.8 g (100 mmol), 80%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[C:12]1([CH2:18][C:19](Cl)=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>O1CCOCC1>[CH2:18]([C:19]1[O:11][C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[N:1]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc2oc(Cc3ccccc3)nc2c1
Temperature: 210 °C
Yield: 33.3 %

Procedure:
To 2-amino-4-nitrophenol (300 mg, 1.95 mmol) in dioxane (2.5 mL) was added 2-phenylacetyl chloride (290 μL, 2.15 mmol) at room temperature. The reaction vessel was heated in the microwave at 210° C. for 15 min. After cooling, the mixture was slowly poured into 1M aqueous sodium hydroxide (50 mL), and the resulting precipitate filtered and washed with water. The resulting solid was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 1:7 v/v to ethyl acetate/hexanes 1:5 v/v) to afford 165 mg (33%) of the title compound (LCMS RT=6.47 min, MH+ 255.2)
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH:34](=[C:41]1/[CH2:42][N:43]([C:48]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:44][CH2:45][CH:46]/1O)/[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[C:67]([OH:70])(=[S:69])[CH3:68]>O1CCCC1.C1(C)C=CC=CC=1>[C:67]([S:69][CH:46]1[CH2:45][CH2:44][N:43]([C:48]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)([C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=2)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:42]/[C:41]/1=[CH:34]\[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:70])[CH3:68]
Reactant: CC(O)=S
Reactant: OC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)SC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of triphenylphosphine (6.39 g) in tetrahydrofuran (100 ml) was added a solution of diisopropyl azodicarboxylate in toluene (13.11 ml) under ice-cooling, and the resulting mixture was stirred at the same temperature for 1 hour. Subsequently, to the reaction mixture was added dropwise a solution of (E)-3-benzylidene-1-(triphenylmethyl)piperidin-4-ol (5.26 g) and thioacetic acid (1.74 ml) in tetrahydrofuran (50 ml) at the same temperature, and the resulting mixture was furthermore stirred at room temperature for 2.5 hours. The reaction mixture was evaporated in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (2:23) as the eluent to afford (E)-4-(acetylsulfanyl)-3-benzylidene-1-(triphenylmethyl)piperidine (containing impurities) as a pale yellow amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][CH:17]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([NH:26][C:27]([C@@H:29]3[CH2:31][C@H:30]3[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:28])[CH:23]=2)[CH2:18]1>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][CH:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([NH:26][C:27]([C@@H:29]4[CH2:31][C@H:30]4[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:28])[CH:23]=3)[CH2:18]2)=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)[C@@H]1C[C@H]1C(=O)Nc1ccc2c(c1)CC(N)C2
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@@H]1C[C@H]1C(=O)Nc1ccc2c(c1)CC(NC(=O)c1nc(Cl)c(CC)[nH]1)C2
Yield: 93.7 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.23 g, 1.32 mmol), thionyl chloride (4 mL), ethyl trans(±)-2-[(2-amino-2,3-dihydro-1H-inden-5-yl)carbamoyl]cyclopropanecarboxylate obtained in Example (98a) (95 mg, 0.24 mmol) and pyridine (5 mL). Purification by silica gel column chromatography (elution solvent: hexane/ethyl acetate=1/2, 3/2, 1/0) gave 0.10 g of the title compound as a light yellow solid (92%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:22])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8].C[Li].C([Li])(C)(C)C.CN(C)[CH:32]=[O:33]>O1CCCC1.C(OCC)C.CCCCC>[Cl:22][C:5]1[CH:4]=[CH:3][C:2]([CH:32]=[O:33])=[CH:21][C:6]=1[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Br)ccc1Cl
Reactant: CN(C)C=O
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-bromo-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (3.25 g, Example 1a) in tetrahydrofuran (150 ml) was cooled to −78° C. under a nitrogen atmosphere. A solution of 1.4 M methyllithium in diethyl ether (6.1 ml) was added to this solution over 2 min. The mixture was stirred at −78° C. for 10 min., then a 1.7 M solution of tert-butyllithium in pentane (10.0 ml) was added dropwise. The mixture was stirred at −78° C. for a further 10 min., then dimethylformamide (1.0 ml) was added. The resulting solution was stirred at −78° C. for 30 min., quenched with saturated aqueous ammonium chloride solution (100 ml) and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the subtitled compound as a solid (2.76 g).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[CH:14][C:13]([N:16]([CH3:36])[C:17](=[O:35])[C:18]([C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=3)([CH3:20])[CH3:19])=[C:12]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=3[CH3:44])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2].[CH3:45][Si]([N-][Si](C)(C)C)(C)C.[K+].IC.C(OCC)(=O)C>O1CCCC1>[C:1]([N:4]([CH3:45])[C@@H:5]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[CH:14][C:13]([N:16]([CH3:36])[C:17](=[O:35])[C:18]([C:21]3[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[C:23]([C:31]([F:32])([F:33])[F:34])[CH:22]=3)([CH3:20])[CH3:19])=[C:12]([C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:38]=3[CH3:44])[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(=O)N[C@@H]1CCN(c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)C1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CCOC(C)=O
Product: CC(=O)N(C)[C@@H]1CCN(c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a solution of 146 mg (0.234 mmol) (R)—N-[6-(3-acetylamino-pyrrolidin-1-yl)-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-isobutyramide in 5 ml tetrahydrofuran were added dropwise at room temperature 0.31 ml (0.28 mmol) of a 0.91 N potassium bis(trimethylsilyl)amide solution in tetrahydrofuran. After stirring at room temperature for 30 min. 43 mg (30 mmol) iodomethane were added. The reaction mixture was stirred at room temperature for 18 h, followed by dilution with 10 ml ethyl acetate and washing with 10 ml saturated sodium carbonate solution. The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to give 130 mg (87%) of the title compound as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].Cl[CH2:16][CH2:17][N:18]1[C:27](=[O:28])[CH2:26][C:21]2([CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:20][C:19]1=[O:29]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][N:18]3[C:19](=[O:29])[CH2:20][C:21]4([CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:26][C:27]3=[O:28])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(N2CCNCC2)cc1F
Reactant: O=C1CC2(CCCC2)CC(=O)N1CCCl
Product: O=C1CC2(CCCC2)CC(=O)N1CCN1CCN(c2ccc(F)c(F)c2)CC1
Temperature: 165 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
A mixture of 1-(3,4-difluorophenyl)piperazine (21.5 mg, 0.109 mmol) and 8-(2-chloroethyl)-8-azaspiro[4.5]decane-7,9-dione(20 mg, 0.087 mmol) was heated with stirring at 165° C. for 1 hour. The residue was purified by preparative HPLC (see Example 8 for conditions), giving (after removal of the solvent) the title compound as a pale yellow oil (13.7 mg, 0.035 mmol, 40%): ESI-MS m/z 392 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCCC2=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CCCN1C1CNC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.3 %

Procedure:
A mixture of 3-(2-oxopyrrolidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (320 mg, 1.33 mmol) and TFA (1.5 mL) in DCM (3 mL) was stirred at room temperature for 4 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH/DCM and eluted with 2M NH3/MeOH affording 1-Azetidin-3-ylpyrrolidin-2-one as a white solid (174 mg, 93%). 1H NMR (CDCl3, 300 MHz): γ 5.05 (m, 1H), 3.85-3.76 (m, 4H), 3.61 (m, 2H), 2.41 (m, 2H) and 2.07 (m, 2H)
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].C(O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:16][CH2:17][CH:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:24][CH:23]=3)[CH2:19][CH2:20]2)=[CH:13][CH:14]=1
Reactant: FC(F)(F)Oc1ccc(OC2CCN(c3ccc(OCc4ccccc4)cc3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(N2CCC(Oc3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Yield: 101.7 %

Procedure:
After 1-(4-Benzyloxyphenyl)-4-[4-(Trifluoromethoxy)phenoxy]piperidine (20.0 g) and ethyl alcohol (200 mL) was mixed and then (50% wet) 5 w/w % palladium on carbon (1 g) was added. The resulting mixture was stirred under 4 atms of atmosphere of hydrogen at 60-61° C. for 3 hr. The reaction mixture was then cooled to room temperature and was filtered to remove the catalyst followed by concentration in vacuo to give 16.2 g (99.5% yield) of an ivory crystal target compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:33])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][C:22]3[C:28]([C:29]([O:31]C)=O)=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:34]>CO>[C:29]([C:28]1[C:22]2[O:21][C:20]([C:17]3[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][N:11]([CH3:33])[C:9](=[O:10])[O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:19][CH:18]=3)=[N:24][C:23]=2[CH:25]=[CH:26][CH:27]=1)(=[O:31])[NH2:34]
Reactant: COC(=O)c1cccc2nc(-c3ccc(CCN(C)C(=O)OCc4ccccc4)cc3)oc12
Reactant: N
Solvent: CO
Product: CN(CCc1ccc(-c2nc3cccc(C(N)=O)c3o2)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 96 %

Procedure:
Methyl 2-(4-(2-((benzyloxycarbonyl)(methyl)amino)ethyl)phenyl)benzo[d]oxazole-7-carboxylate (150 mg, 0.34 mmol) was added to ammonia in methanol (5 ml) and the mixture was stirred at room temperature for 2 days. Evaporate the solvent to obtain benzyl 4-(7-carbamoylbenzo[d]oxazol-2-yl)phenethyl(methyl)carbamate as a white solid (140 mg, yield 96%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 2.84-2.91 (m, 5H), 3.52-3.56 (t, J=7 Hz, 2H), 4.96-5.05 (d, J=36 Hz, 2H), 7.28-7.42 (m, 6H), 7.47-7.51 (t, J=7.8 Hz, 2H), 7.80-7.82 (d, J=7.6 Hz, 1H), 7.85-7.87 (d, J=8 Hz, 2H), 7.94-7.96 (d, J=8 Hz, 1H), 8.18-8.2 (m, 2H); LC-MS (ESI) m/z: 430 (M+1)+.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[BrH:23]>O>[Br:23][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([N:16]([CH3:18])[CH3:17])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)C1CCN(c2ccc(N)cc2)CC1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CN(C)C(=O)C1CCN(c2ccc(Br)cc2)CC1
Reaction time: 0.5 h

Procedure:
A solution of 1-(4-aminophenyl)-N,N-dimethylpiperidine-4-carboxamide (4.2 g, 16.98 mmol) in 25 mL HBr in 20 mL of water was added a solution of NaNO2 (1.17 g, 16.98 mmol) in water (2 mL) slowly. The mixture was stirred at −10° C.˜0° C. for 30 minutes, and added dropwise to a solution of CuBr (1.34 g, 9.34 mmol) in 12 mL HBr in water (10 mL). Then the mixture was stirred at reflux for 2 hours. The mixture was partitioned between 2N NaOH and EA, washed with EA, dried over Na2SO4. The volatiles were removed in vacuo, and the residue was purified by chromatography with PE/EA (15:1˜2:1) to give 2.5 g of 1-(4-bromophenyl)-N,N-dimethylpiperidine-4-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[NH:12][C@H:11]([C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.Br[CH2:18][C:19]([C:21]1[CH:22]=[N:23][C:24]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)=[N:25][CH:26]=1)=[O:20]>>[Cl:1][C:2]1[N:3]=[C:4]2[N:12]([CH2:18][C:19]([C:21]3[CH:26]=[N:25][C:24]([O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)=[N:23][CH:22]=3)=[O:20])[C@H:11]([C:13]([F:14])([F:15])[F:16])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: O=c1cc(Cl)nc2n1CC[C@@H](C(F)(F)F)N2
Reactant: O=C(CBr)c1cnc(OCC2CC2)nc1
Product: O=C(CN1c2nc(Cl)cc(=O)n2CC[C@H]1C(F)(F)F)c1cnc(OCC2CC2)nc1

Procedure:
180 mg (0.71 mmol) of (8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 211.66 mg (0.78 mmol) of 2-bromo-1-(2-cyclopropylmethoxypyrimidin-5-yl)ethanone were used in the reaction. After purification by chromatography on silica gel (eluent: 80/20 DCM/MeOH), 160 mg of (8S)-2-chloro-9-[2-(2-cyclopropylmethoxypyrimidin-5-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics of which are as follows:
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[CH2:4][CH2:5][CH2:6][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[NH2:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O.C1COCC1.O>[CH2:25]([O:24][C:22]([NH:8][C@H:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:6][CH2:5][CH2:4][C:3]([F:13])([F:14])[F:2])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)[C@@H](N)CCCC(F)(F)F
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCCC(F)(F)F)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3.77 g (14.4 mmol, purity about 90%) of rac-methyl 6,6,6-trifluoronorleucinate hydrochloride Example 99A were initially charged in 212 ml of water/THF (8:1), and 6.17 g (44.6 mmol) of potassium carbonate were added. The reaction mixture was cooled to 0° C., 2.68 ml (15.8 mmol) of benzyl chloroformate were slowly added dropwise and the mixture was then stirred at RT overnight. The mixture was diluted with 100 ml of water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered off and concentrated. The residue was purified by silica gel chromatography (cyclohexane/ethyl acetate 4:1). This gave 3.64 g (76% of theory, purity 100%) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16]C)[CH:14]=2)[CH2:9][CH2:8][CH:7]1[NH:18][C:19](=[O:23])[O:20][CH2:21][CH3:22].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[CH2:9][CH2:8][CH:7]1[NH:18][C:19](=[O:23])[O:20][CH2:21][CH3:22]
Reactant: CCOC(=O)NC1CCc2ccc(OC)cc2C1Cc1ccc(Cl)c(Cl)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)NC1CCc2ccc(O)cc2C1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Ethyl 1-(3,4-dichlorobenzyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (2.1 g, 5.14 mmol) was dissolved in CH2Cl2 (50 ml) and BBr3 (3.87 g, 15.4 mmol) was added at −10° C. The reaction mixture was slowly warmed to RT and stirred for 2 h. The reaction mixture was added to ice water and extracted with CH2Cl2. The organic layer was washed with NaHCO3 solution and NaCl solution, then dried on MgSO4 and the solvent was removed. The product was obtained as a brown oil (2.05 g, 5.14 mmol, 100%).