Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:13]=[CH:12][C:10](=[O:11])[NH:9][C:7]1=[O:8].[C:14]1([Si:20](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CO>N1C=CC=CC=1>[C:27]1([Si:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[CH:13]=[CH:12][C:10](=[O:11])[NH:9][C:7]2=[O:8])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=c1ccn(CCCCO)c(=O)[nH]1
Solvent: CO
Solvent: c1ccncc1
Product: O=c1ccn(CCCCO[Si](c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1

Procedure:
1-(4′-Hydroxybutyl)uracil (0.048 g, 0.26 mmol) was dissolved in dry pyridine (1.5 mL) and cooled in an ice-salt bath. A solution of triphenylsilyl chloride (0.099 g, 0.34 mmol) in dry pyridine (1.5 mL) was added drop-wise. The reaction mixture was kept at 0° C. under nitrogen for 2 h30. CH3OH (15 μL) was added and after 10 min the solution was concentrated on the rotary evaporator. The resultant crude transparent oil was purified by silica gel chromatography using a gradient elution of 0→3% CH3OH in CHCl3. The title compound was obtained as a white solid (0.085 g, 74%) from the fractions with Rf=0.50 (10% CH3OH/CHCl3).
Reaction SMILES: [NH2:1][C@H:2]([CH2:9]O)[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[BrH:11]>C(O)(=O)C.C(O)C>[Br:11][CH2:9][C@@H:2]([NH2:1])[CH2:3][C:4]1[NH:8][CH:7]=[N:6][CH:5]=1
Reactant: Br
Reactant: N[C@H](CO)Cc1c[nH]cn1
Solvent: CC(=O)O
Solvent: CCO
Product: N[C@H](CBr)Cc1cnc[nH]1
Temperature: 110 °C

Procedure:
900 mg (S)-histidinol (×2HCl) are dissolved in 20 mL HBr in acetic acid (32%) and heated to 110° C. in the microwave for 6 h. The solvent is eliminated in vacuo, the residue is dissolved in ethanol and again freed from the solvent in vacuo. This crude product is used in the next reaction step without further purification.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[CH:25][C:26]([N:29]5[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]5)=[N:27][CH:28]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].Cl>CO.O1CCOCC1>[N:29]1([C:26]2[N:27]=[CH:28][C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:1])([F:42])[F:43])=[O:6])[CH:13]=[CH:12][CH:11]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)=[CH:24][CH:25]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4ccc(N5CCNCC5)nc4)cnn23)c1

Procedure:
tert-Butyl 4-(5-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-imidazo[1,2-b]pyridazin-7-yl}pyridin-2-yl)piperazine-1-carboxylate (64 mg, 0.11 mmol) in methanol (0.5 mL) was treated with 4 N HCl in dioxane (0.4 mL) at r.t. for 1 h. The volatiles were removed under reduced pressure. The residue was dried in vacuum to afford the desired crude product which was used directly in next step without further purification. LCMS (M+H)+: m/z=497.1.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])[CH3:2].[CH2:20](O)[CH2:21][CH2:22][OH:23]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([C:3]1[CH:4]=[C:5]([C:6]2([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[O:23][CH2:22][CH2:21][CH2:20][O:7]2)[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[CH3:2]
Reactant: OCCCO
Reactant: CCc1cc(C(=O)c2ccccc2)ccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cc(C2(c3ccccc3)OCCCO2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 91.8 %

Procedure:
A suspension of 3-ethyl-4-nitro-benzophenone (11f) (20.0 g, 78.4 mmol), 1,3-propandiol (7.15 g, 94.0 mmol), p-toluenesulfonic acid monohydrate (50 mg) in toluene (300 mL) was refluxed using a Dean-Stark-trap for 24 hours. The Dean-Stark-trap was then replaced by a Soxhlet-extractor filled with molecular sieve and the mixture was refluxed for an additional 48 hours to achieve complete conversion. The reaction mixture was then cooled to ambient temperature, washed with an aqueous, saturated solution of NaHCO3 and concentrated in vacuo until crystallization started. The suspension was cooled for 0.5 hours in an ice bath and after which the crystalline product was filtered, washed with a small volume of hexane and air dried to give 22.48 g (72 mmol, 91.5%) compound 17 as yellow crystals.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.S(O[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]([CH3:35])[CH3:34])=[CH:29][CH:28]=1)(=O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[CH3:34][N:33]([CH3:35])[C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH2:25][N:2]([CH2:3][CH2:4][N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][O:8][C:7]3[CH:16]=[CH:17][CH:18]=[CH:19][C:6]2=3)[CH3:1])=[CH:28][CH:29]=1
Reactant: CN(C)c1ccc(CCOS(C)(=O)=O)cc1
Reactant: CNCCN1c2ccccc2COc2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CN(CCc1ccc(N(C)C)cc1)CCN1c2ccccc2COc2ccccc21
Temperature: 90 °C

Procedure:
5,11-Dihydro-5-[2-(N-methylamino)ethyl]dibenzo[b,e][1,4]oxazepine (254 mg, 1.00 mmol), 4-dimethylaminophenethyl mesylate (365 mg, 1.50 mmol), sodium carbonate (160 mg, 1.50 mmol) and sodium iodide (20 mg, 0.13 mmol) were added to acetonitrile (20 ml), and they were heated under reflux at 90° C. for 7 hours. The solvent was evaporated under reduced pressure. The obtained residue was distributed in ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with water and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography. The product was eluted with dichloromethane and then with dichloromethane and methanol (100:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain 5,11-dihydro-5-[2-[N-(4-dimethylaminophenethyl)-N-methylamino]ethyl]dibenzo[b,e][1,4]oxazepine in the form of a light yellow oil (184 mg, 46%).
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:28])[CH2:9][C:10]2[CH:15]=[C:14]([I:16])[C:13]([O:17][C:18]3[CH:23]=[C:22]([I:24])[C:21]([OH:25])=[C:20]([I:26])[CH:19]=3)=[C:12]([I:27])[CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:35]([CH:37]1[O:39][CH2:38]1)Br.CCOC(C)=O>O1CCOCC1>[CH:1]1([NH:7][C:8](=[O:28])[CH2:9][C:10]2[CH:15]=[C:14]([I:16])[C:13]([O:17][C:18]3[CH:23]=[C:22]([I:24])[C:21]([O:25][CH2:35][CH:37]4[CH2:38][O:39]4)=[C:20]([I:26])[CH:19]=3)=[C:12]([I:27])[CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC1CCCCC1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(Cc1cc(I)c(Oc2cc(I)c(OCC3CO3)c(I)c2)c(I)c1)NC1CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 4.8 %

Procedure:
Compound 4 (2.0 g, 2.1 mmol, 1.0 eq.) was dissolved in anhydrous dioxane (30 mL), then anhydrous Cs2CO3 (684 mg, 2.1 mmol, 1.0 eq.) was added and then epibromohydrin (1.8 mL, 21.0 mmol, 10.0 eq.) was added dropwise. The reaction medium was then slowly heated to reflux. The mixture was stirred during 12 hours upon reflux then cooled to room temperature. EtOAc (10 mL) was then poured and the precipitate was filtered. EtOH (20 mL) was then added to the solution and the precipitate was filtered off. The remaining solution was analyzed by TLC. The first precipitate was washed thoroughly with EtOAc (30 mL). The organic solution was then evaporated and purified by column chromatography using silica gel (DCM/hexanes 80/20). The product was further recrystallized to give N-cyclohexyl-2-(4-(3,5-diiodo-4-(oxiran-2-ylmethoxy)phenoxy)-3,5-diiodophenyl)acetamide (93 mg, 0.1 mmol) as a powder. The second filtrate and the remaining solution were revealed by TLC to be the starting material which did not react.
Reaction SMILES: [O:1]=[C:2]1[CH:5]([N:6]=[N+:7]=[N-:8])[CH:4]([CH2:9][CH2:10][C:11](=[O:14])[CH2:12][OH:13])[N:3]1[CH:15]([P:32]([O:37][CH2:38][CH3:39])([O:34][CH2:35][CH3:36])=[O:33])[C:16]([O:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].C(Cl)Cl.[CH3:43][S:44](Cl)(=[O:46])=[O:45].O=C1C(N=[N+]=[N-])C(CCC(=O)COS(C)(=O)=O)N1C(P(OCC)(OCC)=O)C([O-])=O>C(N(CC)CC)C>[O:1]=[C:2]1[CH:5]([N:6]=[N+:7]=[N-:8])[CH:4]([CH2:9][CH2:10][C:11](=[O:14])[CH2:12][O:13][S:44]([CH3:43])(=[O:46])=[O:45])[N:3]1[CH:15]([P:32]([O:34][CH2:35][CH3:36])([O:37][CH2:38][CH3:39])=[O:33])[C:16]([O:18][CH:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:17]
Reactant: CS(=O)(=O)Cl
Reactant: CCOP(=O)(OCC)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(N=[N+]=[N-])C1CCC(=O)CO
Agent: CCOP(=O)(OCC)C(C(=O)[O-])N1C(=O)C(N=[N+]=[N-])C1CCC(=O)COS(C)(=O)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)C(N=[N+]=[N-])C1CCC(=O)COS(C)(=O)=O
Reaction time: 0.03 h

Procedure:
Benzhydryl (2-oxo3-azido-4-[3-keto-4-hydroxybutyl]-N-azetidinyl)diethylphosphonoacetate, 251 mg., is treated at 0° under N2 in 22 ml. CH2Cl2 with 0.056 ml. methanesulfonyl chloride for 5 min., and then .100 ml. triethylamine is added. After 2 min. more at 0° and 30 min. at 25°, the solvent is evaporated and the product chromatographed by PLC, eluting with 10:3 CHCl3 -acetone, affording 197 mg. pure benzyhydryl (2-oxo-3-azido-4-[3-keto-4-methanesulfonyloxybutyl]-N-azetidinyl)diethylphosphonoacetate. NMR (δ, CDCl3): 1.24 m, POCH2CH3 ; 2.0-2.5 m, CH2CH2 ; 3.14 s, CH3SO2 ; 3.8-4.4 m, POCH2CH3 ; 4.71 s, COCH2OSO2Me; 5.09 d, J=22, CHP; 6.93 s, CHφ2 ; 7.36 s, Ar. IR (μ, film): 4.73, azido; 5.64, β-lactam; 5.72, ester.
Reaction SMILES: [NH2-].[Na+].N.[CH3:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2.[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCOCC>[CH2:14]([N:10]1[C:11]2[C:7](=[CH:6][C:5]([CH3:4])=[CH:13][CH:12]=2)[CH:8]=[CH:9]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccc2[nH]ccc2c1
Agent: N
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Product: Cc1ccc2c(ccn2Cc2ccccc2)c1
Reaction time: 1.5 h
Yield: 52.7 %

Procedure:
To a stirred mixture of sodium amide (prepared from 0.9 g 39.13 mmoles of sodium) and ca 100 ml of liquid ammonia was added a solution of 5.08 g (38.73 mmoles) of 5-methylindole in 100 ml of ether during 5 minutes. The mixture was stirred for 1.5 hours. Then a solution of 5.15 g (40.68 mmoles) of benzyl chloride in 100 ml of ether was added during 10 minutes. The mixture was stirred for two hours. The ammonia was allowed to evaporate overnight. The inside of the flask was washed down with MeOH. Then 150 ml of H2O was added. The layers were separated. The aqueous layer was extracted with 100 ml of ether. The combined ether phases were washed with 50 ml of brine and dried over MgSO4. Evaporation of the solvent left 9.41 g of oil. The oil was chromatographed on a 700 g column of silica gel. The column was eluted with 30% CH 2 Cl2 -Skellysolve B and 200 ml fractions were collected. The fractions were assayed by silica gel tlc (2×8") (25% CH2Cl2 -Skellysolve B). Fractions 12-17 were combined giving 4.52 g (53%) of 1-benzyl-5-methylindole as a yellow-green oil.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]([OH:16])=O)=[N:6]1.S(Cl)(Cl)=O.[NH2:25][C:26]1[C:31]([C:32]#[N:33])=[CH:30][N:29]=[CH:28][N:27]=1>N1C=CC=CC=1>[C:32]([C:31]1[C:26]([NH:25][C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=3[F:1])[N:6]=2)=[O:16])=[N:27][CH:28]=[N:29][CH:30]=1)#[N:33]
Reactant: O=C(O)c1nn(Cc2ccccc2F)c2ncccc12
Reactant: N#Cc1cncnc1N
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: N#Cc1cncnc1NC(=O)c1nn(Cc2ccccc2F)c2ncccc12
Temperature: 25 °C
Reaction time: 7 h

Procedure:
At RT, 39.4 g (145 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (preparation described in US2010/004235, page 27) were initially charged, and then thionyl chloride (370 ml) was added. The suspension was heated to reflux for 2 h and the now clear solution was concentrated under reduced pressure. 100 mg (0.345 mmol) of the acid chloride thus prepared were initially charged in pyridine (1.0 ml) and then 41.5 mg (0.345 mmol) of 4-amino-5-cyanopyrimidine were added in portions. The mixture was stirred at RT for 7 h and then left to stand overnight. Subsequently, volatile constituents were removed under high vacuum, the residue was separated by means of preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid gradient) and the product fractions were concentrated. This gave 30 mg (23% of theory) of the title compound in solid form.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.[N:13]1([C:18]2[CH:19]=[C:20]([C@@H:24]([NH2:26])[CH3:25])[CH:21]=[CH:22][CH:23]=2)[CH:17]=[CH:16][N:15]=[CH:14]1>>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([NH:26][C@H:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[CH:19]=1)[CH3:25])=[O:8]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: C[C@H](N)c1cccc(-n2ccnc2)c1
Product: C[C@H](NC(=O)C=Cc1ccccc1F)c1cccc(-n2ccnc2)c1

Procedure:
The title compound was prepared from 2-fluorocinnamic acid and (S)-1-(3-imidazol-1-yl-phenyl)-ethylamine following the general procedures as described for Example 1.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH:24]1[CH2:31][CH2:30][CH2:29][C@H:25]1[C:26]([NH2:28])=[O:27].CO>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([N:24]5[CH2:31][CH2:30][CH2:29][C@H:25]5[C:26]([NH2:28])=[O:27])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Solvent: CO
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCC[C@H]3C(N)=O)cc1OCC2
Yield: 44 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and L-prolinamide, were reacted and the crude product subjected to flash chromatography (SiO2, gradient 0 to 8% methanol in DCM) then recrystallisation from methanol to give 338 as a white solid (115 mg, 44%). LCMS: RT=2.48 min, [M+H]+409. 1H NMR 400 MHz (DMSO-d6) δ: 9.06 (1 H, s), 7.88 (1 H, s), 7.83 (1 H, s), 7.33 (1 H, br), 6.92 (1 H, br), 5.97-5.96 (1 H, m), 5.94 (1 H, s), 4.53-4.45 (4 H, m), 4.30 (1 H, d, J=8.51 Hz), 3.59 (1 H, s), 3.37 (1 H, d, J=9.93 Hz), 2.18 (1 H, m), 1.95 (3 H, m), 1.47 (6 H, dd, J=6.59, 3.43 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11](=[O:13])[CH3:12].C[O:15][C:16]1C=CC=C[C:17]=1C1CC(=O)CC(=O)C1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:17][C:16](=[O:15])[CH2:12][C:11](=[O:13])[CH2:10]1
Reactant: CC(=O)C=Cc1ccc(F)cc1Br
Reactant: COc1ccccc1C1CC(=O)CC(=O)C1
Product: O=C1CC(=O)CC(c2ccc(F)cc2Br)C1

Procedure:
The title compound was prepared from 4-(2-bromo-4-fluoro-phenyl)-but-3-en-2-one (34 g, 142 mmol), stage 1, following the procedure describing the synthesis of 5-(2-methoxy-phenyl)-cyclohexane-1,3-dione (example 1/a stage 2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C:14]([CH2:18][C:19]([OH:21])=O)([CH3:17])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][C:14]([CH3:17])([CH2:18][C:19](=[O:21])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: Nc1ccccc1
Reactant: CC1(CC(=O)O)CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: CC1(CC(=O)Nc2ccccc2)CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 74.2 %

Procedure:
A procedure similar to that described in Example 52 was carried out with 9-bromo-5-carboxymethyl-5-methyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (100 mg, 0.28 mmol) and aniline (28 μL, 0.31 mmol) to give 89 mg of the title compound (73%): mp 155°~162° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ812.00 (s, 1H), 9.92 (s, 1H), 7.46 (d, 2H, J=8 Hz), 7.23 (t, 2H, J=8 Hz), 7.14 (bs, 2H), 6.99 (t, 1H, J=8 Hz), 3.63 (d, 1H, J=15 Hz), 2.90 (d, 1H, J=15 Hz), 2.80~2.90 (m, 2H), 2.25~2.40 (m, 1H), 1.85~2.00 (m, 1H), 1.68 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:12]=[C:11]([C:20]([OH:22])=O)[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C2N(C3C=NC=CC=3)N=C(C([N:44]3[CH2:49][CH2:48][NH:47][C:46](=[O:50])[CH2:45]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[N:12]=[C:11]([C:20]([N:44]3[CH2:49][CH2:48][NH:47][C:46](=[O:50])[CH2:45]3)=[O:22])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Br)c2)n(-c2cccnc2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3cccnc3)n2)CCN1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Br)c3)n(-c3cccnc3)n2)CCN1

Procedure:
50 mg (0.14 mmol) of the compound of Example 32A is reacted analogously to the synthesis of the compound of Example 4 with 15 mg (0.15 mmol) of 2-oxopiperazine. 59 mg (96% of theory) of the title compound is obtained.
Reaction SMILES: OO[S:3]([O-:5])=O.[K+].[OH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[NH:14][C:15]1S[C:17]2[CH:23]=[C:22]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([C:31]([NH:33][CH3:34])=[O:32])[CH:26]=3)[CH:21]=[CH:20][C:18]=2[N:19]=1>O.CO>[OH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[NH:14][C:15]1[S:3](=[O:5])[C:20]2[CH:21]=[C:22]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([C:31]([NH:33][CH3:34])=[O:32])[CH:26]=3)[CH:23]=[CH:17][C:18]=2[N:19]=1
Reactant: O=S([O-])OO
Reactant: CNC(=O)c1cc(Oc2ccc3nc(N[C@@H]4CCCC[C@H]4O)sc3c2)ccn1
Agent: [K+]
Solvent: O
Solvent: CO
Product: CNC(=O)c1cc(Oc2ccc3c(c2)S(=O)C(N[C@@H]2CCCC[C@H]2O)=N3)ccn1
Reaction time: 23 h

Procedure:
A solution of OXONE® (KHSO5, 380 mg, mmol) in water (4 ml) was added dropwise to a solution of 4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (25 mg, mmol) in methanol (4 ml) at rt. After stirring for 23 hours the suspension is diluted with water (50 ml) and extracted with ethyl acetate (2×10 ml). The combined organic layers were washed with brine, concentrated, and purified by prep HPLC to yield the title compound as white solid. Yield: 2.4 mg. ES/MS m/z 415.1 (MH+), Rt=1.81 min.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1.C(N(CC)CC)C.[Cl:21][C:22]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>ClCCl>[Cl:21][C:22]1[C:30]([C:31]([F:33])([F:34])[F:32])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([N:9]1[CH2:8][CH2:7][N:6]2[CH:11]=[C:3]([C:2]([F:12])([F:1])[F:13])[N:4]=[C:5]2[CH2:10]1)=[O:25]
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2cc(C(F)(F)F)nc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.5 %

Procedure:
2-(Trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (1.06 g, 5.55 mmol, Intermediate 4) and triethylamine (0.850 ml, 6.10 mmol) were dissolved in dichloromethane (DCM) (25 ml). 2-chloro-3-(trifluoromethyl)benzoyl chloride (1.348 g, 5.55 mmol) was added and the mixture stirred at room temperature for 24 h. The solvents were removed in vacuo and the solid partitioned between dichloromethane (100 ml) and saturated sodium bicarbonate solution (50 ml). The aqueous phase was extracted with dichloromethane (3×50 ml), the combine organic extracts were dried over anhydrous sodium sulfate and then concentrated to afford 7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (2.22 g, 5.58 mmol, 101% yield).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[CH3:2].CON(C)[C:19](=[O:31])[CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:14]([N:3]([CH2:1][CH3:2])[C:4](=[O:13])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]=1[C:19](=[O:31])[CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:15]
Reactant: CON(C)C(=O)CCCCOc1ccccc1
Reactant: CCN(CC)C(=O)Oc1ccc(C)cc1
Product: CCN(CC)C(=O)Oc1ccc(C)cc1C(=O)CCCCOc1ccccc1

Procedure:
The title compound was prepared from 4-methylphenyl diethylcarbamate and N-methoxy-N-methyl-5-phenoxypentanamide following the same procedure used in Example F.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[N:18]=[C:19](/[CH:22]=[CH:23]/[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:20][CH:21]=2)=[CH:11][CH:10]=1)(=O)=O.[NH:30]1[CH:34]=[N:33][N:32]=[N:31]1>>[C:24]1(/[CH:23]=[CH:22]/[C:19]2[O:20][CH:21]=[C:17]([CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][N:31]4[N:32]=[N:33][CH:34]=[N:30]4)=[CH:10][CH:11]=3)[N:18]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: c1nnn[nH]1
Reactant: CS(=O)(=O)OCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Product: C(=C/c1nc(COc2ccc(CCCn3ncnn3)cc2)co1)\c1ccccc1
Yield: 41 %

Procedure:
In substantially the same manner as in Working Example 33, 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl methanesulfonate was allowed to react with tetrazole, and the reaction mixture was subjected to extraction. The extract was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane (1:1, v/v), 2-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-2H-tetrazole was obtained. The yield was 41%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 97-98° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)/[CH:7]=[N:8]/[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])([O-:3])=[O:2].C(N(CC)CC)C>ClCCl.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-]>[N+:1]([C:4]1[CH:5]=[C:6]([C@H:7]2[C@@H:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][CH2:9][NH:8]2)[CH:16]=[CH:17][CH:18]=1)([O-:3])=[O:2]
Reactant: COC(=O)CCC/N=C/c1cccc([N+](=O)[O-])c1
Agent: [Ti+4]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CCN[C@H]1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
To the imine 15A (1.0 g, 2.84 mmol) and triethylamine (0.39 mL, 2.84 mmol) in dichloromethane (50 mL) at −10° C. was added titanium chloride (11.3 mL, 1.0 M in dichloromethane) dropwise under argon. The reaction was stirred at rt for 4 h and then quenched with saturated potassium carbonate. The mixture was filtered through celite and the aqueous layer was extracted with dichloromethane (2×). The organic extracts were combined, washed with brine and dried over sodium sulfate. The solvent was evaporated and the crude residue was purified by preparative HPLC equipped with a YMC ODS S5 (30×100 mm) column. The separation was performed using a linear gradient (solvent A: 10% acetonitrile-90% water-0.1% TFA; solvent B: 90% acetonitrile-90% water-0.1% TFA; 0 to 100% B in 12 min with a flow rate of 40 mL/min to give 0.32 g of 15B as a solid. 1H NMR (400 MHz, Methanol-d4) δ ppm 2.53 (m, 2H) 3.47 (s, 3H) 3.62 (m, 1H) 3.79 (m, 2H) 5.14 (d, J=6.85 Hz, 1H) 7.76 (m, 2H) 8.33 (m, 2H).