Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.OC1C2N=NNC=2C=CC=1.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C.[C:49]([C:51]1[N:56]=[CH:55][C:54]([C:57]2[C:69]3[C:68]4[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=4)[N:62]([C:70]4[CH:78]=[CH:77][C:73]([C:74](O)=[O:75])=[C:72]([NH:79][CH2:80][CH2:81][CH2:82][OH:83])[CH:71]=4)[C:61]=3[CH:60]=[CH:59][CH:58]=2)=[CH:53][CH:52]=1)#[N:50]>CN(C)C=O.O>[C:49]([C:51]1[N:56]=[CH:55][C:54]([C:57]2[C:69]3[C:68]4[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=4)[N:62]([C:70]4[CH:78]=[CH:77][C:73]([C:74]([NH2:8])=[O:75])=[C:72]([NH:79][CH2:80][CH2:81][CH2:82][OH:83])[CH:71]=4)[C:61]=3[CH:60]=[CH:59][CH:58]=2)=[CH:53][CH:52]=1)#[N:50]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: N#Cc1ccc(-c2cccc3c2c2ccccc2n3-c2ccc(C(=O)O)c(NCCCO)c2)cn1
Agent: F[P-](F)(F)(F)(F)F
Agent: Oc1cccc2[nH]nnc12
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cccc3c2c2ccccc2n3-c2ccc(C(N)=O)c(NCCCO)c2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.4 %

Procedure:
260 mg of (1H-benzotriazol-1-yloxy)[tris(dimethylamino)]phosphonium hexafluorophosphate (BOP), 79 mg of hydroxybenzotriazole (HOBT), 41 mg (0.8 mmol) of ammonium chloride and 0.26 ml of diisopropylethylamine are successively added to a solution of 180 mg of 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(3-hydroxypropyl)amino]benzoic acid in 10 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 4 hours and then diluted with distilled water and extracted with ethyl acetate. The organic phase is subsequently washed with distilled water and a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a mixture of dichloromethane and methanol (96/4 by volume), and triturated in diisopropyl ether, so as to give 60 mg of 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(3-hydroxypropyl)amino]benzamide in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[CH2:7][CH2:8][CH:9]=[O:10].[C:15]([Mg]Br)#[CH:16].[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[CH2:7][CH2:8][CH:9]([OH:10])[C:15]#[CH:16]
Reactant: C#C[Mg]Br
Reactant: O=CCCc1sc2ccccc2c1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC(O)CCc1sc2ccccc2c1Cl
Reaction time: 1.5 h
Yield: 93.4 %

Procedure:
A solution of aldehyde 17 (2.11 g, 9.4 mmol) in 15 mL THF was added to a solution of ethynylmagnesium bromide (28.2 mL, 14.1 mmol, 0.5 M THF) at 0° C. After 1.5 h, saturated NH4Cl solution (75 mL) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined ethyl acetate solution was washed with brine (50 mL) and then was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (5-20% ethyl acetate/hexane) gave 2.20 g (8.78 mmol, 93%) of the alcohol (18).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[CH3:14][C:15]1[C@H:19]2[CH2:20][O:21][CH2:22][C@H:18]2[O:17][N:16]=1.B(F)(F)F.CCOCC.[Cl-].[NH4+]>C1(C)C=CC=CC=1.O1CCCC1.C(OCC)(=O)C.O>[F:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C@:15]1([CH3:14])[C@H:19]2[CH2:20][O:21][CH2:22][C@H:18]2[O:17][NH:16]1
Reactant: CC1=NO[C@@H]2COC[C@H]12
Reactant: Fc1ccccc1Br
Agent: FB(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C[C@]1(c2ccccc2F)NO[C@@H]2COC[C@@H]21
Temperature: -100 °C
Reaction time: 0.17 h
Yield: 85.7 %

Procedure:
A solution of 1-bromo-2-fluorobenzene (31.1 g, 178 mmol) in a mixture of toluene (750 ml) and tetrahydrofuran (75 ml) was cooled to −100° C. Within 10 minutes a solution of n-butyllithium (1.6 M in hexane; 100 ml, 160 mmol) was added dropwise at a rate so that temperature could be maintained between −95 and −102° C. After 10 minutes stirring at −100° C. a mixture of (3aS,6aS)-rel-3-methyl-3a,4,6,6a-tetrahydrofuro[3,4-d]isoxazole (11.3 g, 88.9 mmol) and boron trifluoride diethyl etherate (25.2 g, 178 mmol) in a mixture of toluene (75 ml) and tetrahydrofuran (14 ml) was added within 3-5 minutes keeping the temperature below −94° C. The reaction mixture was stirred additional 10 minutes at −95 to −102° C. For the workup, a saturated solution of ammonium chloride (60 ml), water (100 ml) and ethyl acetate (200 ml) were added and the reaction mixture was left to warm to 0° C. The layers were separated and the aqueous layer was extracted once more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate and evaporated at reduced pressure. The crude product was purified by chromatography using a gradient of heptane and ethyl acetate=100:0 to 0:100 as the eluent. The (3S,3aS,6aS)-rel-3-(2-fluoro-phenyl)-3-methyl-hexahydro-furo[3,4-d]isoxazole (17 g, 81% yield) was obtained as an off-white solid. MS (ISP): m/z=224.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)=[CH:11][C:10]=1/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pt]=O.C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)/C=C/c1cc(-c2ccc(OC(F)(F)F)cc2)ccc1OCc1ccccc1
Agent: O=[Pt]
Solvent: CCO
Product: O=C(O)CCc1cc(-c2ccc(OC(F)(F)F)cc2)ccc1OCc1ccccc1
Reaction time: 1 h
Yield: 77.7 %

Procedure:
A mixture of (E)-3-[4-benzyloxy-4′-(trifluoromethoxy)biphenyl-3-yl]propenoic acid (compound No. 2; 100 mg, 0.241 mmol), platinum oxide (5 mg) and ethanol (10 ml) was stirred for 1 hour under hydrogen atmosphere. The reaction mixture was filtered through celite. The residue obtained by concentration of the filtrate under reduced pressure was washed with methanol under suspension to give the title compound (78 mg, 78.0%) as a white solid.
Reaction SMILES: Cl.Cl.[OH:3][C@@H:4]1[CH2:11][N:10]([CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH:17]([CH3:21])[C:16]2=[O:22])[CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.[Cl:23][C:24]1[CH:34]=[CH:33][C:27]([CH:28]=[CH:29][C:30](O)=[O:31])=[CH:26][C:25]=1[F:35].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:23][C:24]1[CH:34]=[CH:33][C:27](/[CH:28]=[CH:29]/[C:30]([N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][N:10]3[CH2:9][CH2:8][C:5]4([CH2:6][CH2:7]4)[C@H:4]([OH:3])[CH2:11]3)[C:16](=[O:22])[CH:17]2[CH3:21])=[O:31])=[CH:26][C:25]=1[F:35]
Reactant: O=C(O)C=Cc1ccc(Cl)c(F)c1
Reactant: CC1NCCN(CCCN2CCC3(CC3)[C@H](O)C2)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1C(=O)N(CCCN2CCC3(CC3)[C@H](O)C2)CCN1C(=O)/C=C/c1ccc(Cl)c(F)c1
Reaction time: 1 h

Procedure:
To a solution of crude 1-[3-((S)-4-hydroxy-6-aza-spiro[2,5]oct-6-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride (example 38; 0.03 g, 0.1 mmol) in N,N-dimethylformamide (0.8 ml) was added 4-chloro-3-fluorocinnamic acid (0.02 g, 0.1 mmol), triethylamine (0.05 ml, 0.4 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (0.04 g, 0.1 mmol) and the reaction shaken for 1 h, after which time the reaction mixture was directly purified by preparative HPLC. This afforded the titled product as a colorless gum. MS (ISP)=464.3 (M+H)+.
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:9].[C:20](=[O:58])([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[O:21][C:22]1[C:27]([O:28][CH3:29])=[CH:26][C:25]([C@H:30]2[C@@H:42]3[C:43](=[O:46])[O:44][CH2:45][C@H:41]3[C@H:40]([OH:47])[C:39]3[C:31]2=[CH:32][C:33]2[O:37][CH2:36][O:35][C:34]=2[CH:38]=3)=[CH:24][C:23]=1[O:48][CH3:49].O>ClCCl>[C:8](=[O:9])([O:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)[O:47][C@H:40]1[C@@H:41]2[CH2:45][O:44][C:43](=[O:46])[C@H:42]2[C@H:30]([C:25]2[CH:24]=[C:23]([O:48][CH3:49])[C:22]([O:21][C:20]([O:50][CH2:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[O:58])=[C:27]([O:28][CH3:29])[CH:26]=2)[C:31]2[C:39]1=[CH:38][C:34]1[O:35][CH2:36][O:37][C:33]=1[CH:32]=2
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@@H](O)[C@@H]3COC(=O)[C@@H]23)OCO4)cc(OC)c1OC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COc1cc([C@@H]2c3cc4c(cc3[C@@H](OC(=O)Oc3ccc([N+](=O)[O-])cc3)[C@@H]3COC(=O)[C@@H]23)OCO4)cc(OC)c1OC(=O)OCc1ccccc1
Reaction time: 0.75 h

Procedure:
0.155 ml of anhydrous pyridine is added to a solution of 1.71 mmol of p-nitrophenyl chloroformate in 5 ml of anhydrous dichloromethane. A white precipitate is formed in the reaction mixture. A solution of 0.502 mmol of the compound obtained in Step 1 in 5 ml of dichloromethane is then added dropwise under argon. Stirring is carried out for 45 minutes at ambient temperature, then 15 ml of water are poured into the reaction mixture. The organic phase is washed with water, dried over MgSO4, filtered and concentrated under recued pressure. Chromatography on silica gel (cyclohexane/ethyl acetate: 4/1) enables the expected product to be isolated.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[NH:9])[NH:7][OH:8])=[C:4]([F:12])[CH:3]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[C:14]#[CH:15]>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[NH:9])[NH:7][O:8][CH:15]=[CH:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])=[C:4]([F:12])[CH:3]=1
Reactant: C#CC(=O)OCC
Reactant: N=C(NO)c1ccc(Br)cc1F
Product: CCOC(=O)C=CONC(=N)c1ccc(Br)cc1F

Procedure:
Scheme 10 shows the synthesis of 9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine III from 4-bromo-2-fluorobenzonitrile 11. Addition of hydroxylamine to the nitrile of 11 gave 4-bromo-2-fluoro-N-hydroxybenzimidamide 24. Michael addition of 24 to ethyl propiolate gave ethyl 3-(4-bromo-2-fluorobenzimidamidooxy)acrylate 25. Heating 25 in a high-boiling solvent such as toluene, xylene, ethylbenzene, or diphenyl oxide gave cyclized imidazole, ethyl 2-(4-bromo-2-fluorophenyl)-1H-imidazole-4-carboxylate 26, along with by-product pyrimidine, 2-(4-bromo-2-fluorophenyl)pyrimidin-4-ol. Alternatively, 25 can be cyclized to 26 with catalytic Lewis acids such as Cu(I) or Cu(II) salts. Alkylation of 26 with a 2-hydroxyethylation reagent, such as 1,3-dioxolan-2-one, in a base, such as N-methylimidazole or cesium carbonate, gave ethyl 2-(4-bromo-2-fluorophenyl)-1-(2-hydroxyethyl)-1H-imidazole-4-carboxylate 27. Ring-cyclization of 27 with an aqueous basic reagent, such as potassium hydroxide, lithium hydroxide, and methyl tributylammonium hydrochloride, gave 9-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxylic acid 28. Addition of acetamidine to 28 with triphenylphosphine gave 9-bromo-N-(1-iminoethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide 29. Ring-cyclization of 29 with isopropylhydrazine hydrochloride 4 in acetic acid gave 9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine III.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([CH:21]3[CH2:24][N:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH2:22]3)[N:17]=2)[CH2:11][C:12]([O:14]C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[Li].O.Cl>O1CCOCC1.O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:16]2[O:20][N:19]=[C:18]([CH:21]3[CH2:22][N:23]([S:25]([CH3:28])(=[O:26])=[O:27])[CH2:24]3)[N:17]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C2CN(S(C)(=O)=O)C2)no1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CC(c2noc([C@H](CCCC3CCCCC3)CC(=O)O)n2)C1
Temperature: 25 °C
Reaction time: 2.25 h
Yield: 88.7 %

Procedure:
A solution of methyl(3R)-6-cyclohexyl-3-{3-[1-(methylsulfonyl)-3-azetidinyl]-1,2,4-oxadiazol-5-yl}hexanoate (preparation 38) (780 mg, 1.05 mmol) in dioxan (20 ml) and H2O (10 ml) was treated with LiOH.H2O (218 mg, 5.2 mmol) and stirred at room temperature for 2.25 hours. The reaction mixture was acidified with 2M HCl (20 ml) and extracted with EtOAc. The organic extract was washed with H2O and the solvent was removed under reduced pressure. The oil was purified on a silica column eluting with a solvent gradient of DCM:MeOH:AcOH (100:0:0) gradually changing to (90:10:1) to afford a colourless oil which solidified on standing. The solid was triturated with pentane, filtered off and dried under reduced pressure to afford the title compound as a white solid (372 mg, 78%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1.[C:13]1([O:19][CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:16]2[CH:17]=[CH:18][C:13]([O:19][CH3:20])=[CH:14][CH:15]=2)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1
Reactant: COc1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Product: COc1ccc(S(=O)(=O)c2ccc(Br)cc2F)cc1

Procedure:
The subtitle compound was prepared by the method of example 9 step (i) using 4-bromo-2-fluorobenzenesulfonyl chloride and anisole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:22][NH2:23])([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1.[OH-].[Na+]>ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([CH2:22][NH:23][C:36](=[O:37])[C:35]2[CH:39]=[CH:40][C:32]([Cl:31])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(CN)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NC1(CNC(=O)c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.1 %

Procedure:
To a solution of 4-aminomethyl-4-tert-butoxycarbonylamino-piperidine-1-carboxylic acid tert-butyl ester (12.2 mg, 0.037 mmol) and triethylamine (16 μL, 0.12 mmol) in dry dichloromethane (4 mL) was added 4-chlorobenzoyl chloride (5 μL, 0.037 mmol). After stirring for 18 hours at room temperature, the reaction mixture was partionated between dichloromethane (2 mL) and water (1 mL) with 10% aqueous sodium hydroxide (0.1 mL). The two layers were separated and the aqueous phase was further extracted with dichloromethane (2 mL). The combined organic layers were dried (Mg2SO4), filtered and concentrated. Preparative TLC, eluting with 10% methanol-dichloromethane, gave 4-tert-butoxycarbonylamino-4-[(4-chloro-benzoylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (6 mg, 0.013 mmol, 35%). LC-MS (LCT2) m/z 490 [M+Na+], Rt 8.20 min.
Reaction SMILES: [CH3:1][C:2](=[CH2:30])[CH2:3][C@@:4]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]2)[CH2:6][CH2:5]1.C1C=C(Cl)C=C(C(OO)=[O:39])C=1>ClCCl>[CH3:30][C:2]1([CH2:3][C@@:4]2([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:9][C:8](=[O:10])[N:7]([C@H:11]3[CH2:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:12]3)[CH2:6][CH2:5]2)[CH2:1][O:39]1
Reactant: C=C(C)C[C@]1(c2ccccc2)CCN([C@H]2CCCN(C(=O)OC(C)(C)C)C2)C(=O)O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H](N2CC[C@](CC3(C)CO3)(c3ccccc3)OC2=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
To a solution of (S)-tert-butyl 3-((R)-6-(2-methylallyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)piperidine-1-carboxylate (2.98 g, 7.2 mmol) in dichloromethane (200 mL) was added m-CPBA (77% maximum, 3.3 g, 2 equiv). The mixture was stirred 3 h at rt before being diluted by dichloromethane (150 mL), washed by 5% NaOH solution (2×40 mL), 30% aq sodium thiosulfate solution (30 mL), satd aq NaHCO3 (30 mL), 30% aq sodium thiosulfate solution (30 mL), satd aq NaHCO3 (30 mL), brine (30 mL), and dried over Na2SO4. Filtration and concentration gave crude (3S)-tert-butyl 3-((6S)-6-((2-methyloxiran-2-yl)methyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)piperidine-1-carboxylate (2.98 g 93% yield) which was used for next steps without further purification. LC-MS Method 1 tR=1.68 min., m/z 431 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[NH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[F:26][C:15]([F:14])([F:25])[C:16]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[N:18]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[NH:12][C:11](=[O:13])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[N:17]=1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Reactant: O=C1CCC(c2ccc(Br)cc2)N1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1CCC(c2ccc(-n3nc(C(F)(F)F)c4c3CCCC4)cc2)N1
Temperature: 190 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-(4-bromophenyl)-2-pyrrolidinone (81 mg, 0.34 mmol; preparation described in WO00/21958), 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (64 mg, 0.34 mmol) N,N-dimethylglycine (20 mol %, 7 mg, 0.07 mmol), copper (I) iodide (10 mol %, 6.5 mg, 0.034 mmol) and potassium carbonate (0.7 mmol, 97 mg) in dimethylsulfoxide (2 ml) was stirred at 190° C. in a microwave reactor for 30 minutes. The reaction mix was cooled and partitioned between dichloromethane (5 ml) and water (5 ml). The organic layer was added to a 5 g isolute silica sep-pak column and eluted with ethyl acetate. The solvent was removed under reduced pressure to give a dark oil (161 mg) which was further purified by mass directed auto-prep (MDAP) to give the title compound as a yellow oil (17 mg, 14%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[C:20]([C:22]1([OH:27])[CH2:26][CH2:25][O:24][CH2:23]1)#[CH:21]>CN(C)C=O.C(N(CC)CC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6]([C:21]#[C:20][C:22]1([OH:27])[CH2:26][CH2:25][O:24][CH2:23]1)[N:5]=2
Reactant: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(Cl)nc21
Reactant: C#CC1(O)CCOC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(C#CC3(O)CCOC3)nc21

Procedure:
A suspension of 0.3 g (2.24 mmol) of 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxamide in 17 ml of a dimethylformamide/triethylamine mixture (V/V; 2/1) is placed in a 10 ml microwave tube. This suspension is sparged with argon for 10 minutes and then 0.319 g (2.79 mmol) of (±)-3-ethynyltetrahydro-3-furanol, 0.043 g of CuI (0.23 mmol) and 0.079 g of bis(triphenylphosphine) palladium(II)dichloride (0.11 mmol) are successively added.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[N:7]1[C:12]2[NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[C:16](=[O:18])[NH:17][C:11]=2[CH:10]=[CH:9][CH:8]=1>O1CCOCC1>[Cl:1][CH2:2][CH2:3][C:4]([N:13]1[C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16](=[O:18])[NH:17][C:11]2[CH:10]=[CH:9][CH:8]=[N:7][C:12]1=2)=[O:5]
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Reactant: O=C(Cl)CCCl
Solvent: C1COCCO1
Product: O=C1Nc2cccnc2N(C(=O)CCCl)c2ccccc21

Procedure:
Equimolar amounts of 3-chloropropionyl chloride and 5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one in solution in dioxane were reacted to obtain 11-(3-chloropropionyl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one which melted at 216°-218° C. with decomposition.
Reaction SMILES: [C@@H:1]12[CH2:6][C@@H:5]1[CH2:4][C@H:3]([C:7]([NH:9][C:10]1([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=3)[CH2:12][CH2:11]1)=[O:8])[NH:2]2.CC#N.[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1>>[F:26][C:27]([F:36])([F:37])[C:28]1[CH:35]=[CH:34][C:31]([CH2:32][N:2]2[C@@H:3]([C:7]([NH:9][C:10]3([C:13]4[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=4)[CH2:11][CH2:12]3)=[O:8])[CH2:4][C@@H:5]3[C@H:1]2[CH2:6]3)=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(C2(NC(=O)[C@H]3C[C@H]4C[C@H]4N3)CC2)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Solvent: CC#N
Product: COC(=O)c1ccc(C2(NC(=O)[C@H]3C[C@H]4C[C@H]4N3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.2 %

Procedure:
To a solution of methyl 4-(1-((1R,3R,5R)-2-azabicyclo[3.1.0]hexane-3-carboxamido)cyclopropyl)benzoate (D104) (1.7 g, 5.7 mmol) in MeCN (80 ml) Cs2CO3 (2.8 g, 8.5 mmol) and 4-(trifloromethyl)benzylbromide (1.6 g, 6.8 mmol) were added and the resulting mixture was stirred at RT for 4 hrs. Solvent was evaporated and the residue was loaded on a SNAP-Si cartridge (100 g), eluted with a mixture DCM/AcOEt from 10/0 to DCM/AcOEt 9/1. Collected fractions after solvent evaporation afforded the title compound (D147) (2.41 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:19][CH3:20])[N:7]=[C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:9]=1)=O.[AlH4-].[Li+].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:19]([N:6]1[C:5]([CH:3]=[O:2])=[CH:9][C:8]([NH:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)=[N:7]1)[CH3:20]
Reactant: CCn1nc(NCc2ccc(F)cc2)cc1C(=O)OC
Agent: O=S(=O)([O-])[O-]
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCn1nc(NCc2ccc(F)cc2)cc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carboxylic acid methyl ester (529, 1.00 g, 3.61 mol) in tetrahydrofuran (70.0 mL) under an atmosphere of nitrogen at room temperature, lithium tetrahydroaluminate (1.00 M of in tetrahydrofuran, 10.00 mL) was slowly added. The reaction was stirred at room temperature overnight, followed by slowly adding sodium sulfate decahydrate (15.0 g). After 2 hours, the reaction was filtered, concentrated and purified with silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a yellow oil (530, 0.16 g, 18%). MS (ESI) [M+H+]+=248.2.
Reaction SMILES: [C:1]1([C:7]2[CH:17]=[CH:16][C:10]([CH2:11][C:12](=[CH2:15])[CH2:13]Cl)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][CH:19]1[CH2:24][CH:23]([CH3:25])[CH2:22][NH:21][CH2:20]1.[OH-].[Na+]>>[C:1]1([C:7]2[CH:17]=[CH:16][C:10]([CH2:11][C:12](=[CH2:15])[CH2:13][N:21]3[CH2:22][CH:23]([CH3:25])[CH2:24][CH:19]([CH3:18])[CH2:20]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1CNCC(C)C1
Reactant: C=C(CCl)Cc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: C=C(Cc1ccc(-c2ccccc2)cc1)CN1CC(C)CC(C)C1
Temperature: 120 °C

Procedure:
A mixture of 2-[(4-phenyl)benzyl]-2-propenyl chloride (4 g.), synthesized by method utilized in Example 1, and 3,5-dimethylpiperidine (3.7 g.) was heated at 120° C. for five hours. The mixture was cooled to room temperature and neutralized with 25% aqueous sodium hydroxide (15 ml.). The mixture was extracted with toluene, dried over sodium sulfate and evaporated to give an oil which partially solidified on standing. The product was triturated with petroleum ether, having a boiling point range of 30° C. to 60° C., and the insoluble material was removed by filtration. The filtrate was evaporated under reduced pressure to yield 1-[2-[(4-phenyl)benzyl]-2-propenyl]-3,5-dimethylpiperidine in a yield of 4.9 grams.