Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:20][CH:19]2[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]3[C:16]([C:22]([NH:24][S:25]([CH:28]4[CH2:30][CH2:29]4)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]2=[O:21])[CH2:15]3)[CH2:3]1.[N:40]1[C:49]2[C:44](=[CH:45][C:46]([C:50](Cl)=[O:51])=[CH:47][CH:48]=2)[N:43]=[CH:42][CH:41]=1>>[N:40]1[C:49]2[C:44](=[CH:45][C:46]([C:50]([O:1][CH:2]3[CH2:20][CH:19]4[N:4]([C:5](=[O:39])[CH:6]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:13][CH:14]5[C:16]([C:22]([NH:24][S:25]([CH:28]6[CH2:30][CH2:29]6)(=[O:27])=[O:26])=[O:23])([NH:17][C:18]4=[O:21])[CH2:15]5)[CH2:3]3)=[O:51])=[CH:47][CH:48]=2)[N:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(O)CN2C1=O
Reactant: O=C(Cl)c1ccc2nccnc2c1
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(OC(=O)c3ccc4nccnc4c3)CN2C1=O
Yield: 37.6 %

Procedure:
Prepared by way of method I using 18-hydroxy-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]-nonadec-7-ene (100 mg, 0.176 mmol) and 6-quinoxalinecarbonyl chloride (68 mg, 0.35 mmol). The final trituration (diethyl ether/hexane) and filtration gave 48 mg (38%) of 18-(6-quinoxalinecarbonyloxy)-14-tert-butoxycarbonylamino-4-cyclopropylsulfonylaminocarbonyl-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]-nonadec-7-ene as a white powder: 98.5% pure (HPLC), MS m/z 723 (M−H)−, HRMS: calcd. 725.2969 and found 725.2947 (M+H)+, mp 158-160° C.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:16])[C:8]3[N:9]2[C:12](=[O:15])[NH:13][N:14]=3)=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[O:23]1[CH2:24][CH2:25][N:20]([C:2]2[CH:11]=[C:10]3[C:5]([NH:6][C:7](=[O:16])[C:8]4[N:9]3[C:12](=[O:15])[NH:13][N:14]=4)=[CH:4][C:3]=2[N+:17]([O-:19])=[O:18])[CH2:21][CH2:22]1
Reactant: C1COCCN1
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(F)cc2n2c(=O)[nH]nc12
Product: O=c1[nH]c2cc([N+](=O)[O-])c(N3CCOCC3)cc2n2c(=O)[nH]nc12

Procedure:
The title compound was prepared from 8-fluoro-7-nitro[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione and morpholine by a method analogous to the method described in example 11. M.p. 250° C. decomp.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]([CH:15]([CH3:17])[CH3:16])[C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:4][CH:3]=1.C([Li])CCC.C(O[B:27]1[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]1)(C)C.[Cl-].[NH4+]>C1COCC1>[C:10]([O:9][C:8](=[O:14])[N:7]([CH:15]([CH3:17])[CH3:16])[C:5]1[S:6][C:2]([B:27]2[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]2)=[CH:3][N:4]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CC(C)N(C(=O)OC(C)(C)C)c1ncc(Br)s1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)N(C(=O)OC(C)(C)C)c1ncc(B2OC(C)(C)C(C)(C)O2)s1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 48.6 %

Procedure:
A solution of tert-butyl 5-bromothiazol-2-yl(isopropyl)carbamate (Intermediate 43-1, 7.5 g, 23.3 mmol) in THF (50 mL) was treated with n-butyllithium (1.6 M in hexane, 21.8 mL, 34.88 mmol) dropwise at −78° C. The resulting solution was stirred at −78° C. for 10 min, then was treated dropwise with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.49 g, 34.9 mmol). The mixture was stirred at −78° C. for 2 h, then was warmed to rt and treated with 50% aqueous ammonium chloride (50 mL). The mixture was extracted with EtOAc (100 mL) and the organic layer was washed with water and brine, and dried and concentrated. The residue was slurried in hexane (30 mL) and the precipitate was collected by filtration, washed with hexane (20 mL) and dried to give tert-butyl-isopropyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate as a yellow solid (4.17 g, 48%). 1H NMR (400 MHz, chloroform-d) δ 7.95 (s, 1H) 5.37 (m, 1H) 1.60 (s, 9H) 1.44 (d, 6.7 Hz, 6H) 1.34 (s, 12H).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([C:20]3[NH:21][C:22]([C:25]4[S:26][CH:27]=[CH:28][N:29]=4)=[CH:23][CH:24]=3)[CH:17]=[C:16]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:15]=2)=[C:9]([F:36])[CH:8]=1)(=O)[CH3:2].C(N(CC)CC)C>C(#N)C>[F:36][C:9]1[CH:8]=[C:7]([C:6]2[O:37][C:1]([CH3:2])=[N:4][N:5]=2)[CH:12]=[CH:11][C:10]=1[O:13][C:14]1[CH:19]=[C:18]([C:20]2[NH:21][C:22]([C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[CH:23][CH:24]=2)[CH:17]=[C:16]([O:30][C@@H:31]([CH3:35])[CH2:32][O:33][CH3:34])[CH:15]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)NNC(C)=O)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2ccc(-c3nnc(C)o3)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 59.7 %

Procedure:
N′-Acetyl-3-fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}benzohydrazide (45 mg, 0.086 mmol) synthesized in Example (49a) was dissolved in acetonitrile (3.0 mL), and (methoxycarbonysulfamoyl)triethylammonium hydroxide (50 mg, 0.210 mmol) and triethylamine (0.05 mL, 0.359 mmol) were added, followed by stirring at 100° C. for 1 day under nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=80%-100%) to afford the desired compound (26 mg, yield 60%) as a colorless liquid.
Reaction SMILES: CS([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)=O.[CH3:15][NH:16][CH3:17]>C(O)C>[CH3:15][N:16]([CH3:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)CCCCCS(C)(=O)=O
Reactant: CNC
Solvent: CCO
Product: CCOC(=O)CCCCCN(C)C

Procedure:
Ethyl 6-(methanesulfonyl)hexanoate was allowed to react in a 5.6M solution of dimethylamine in ethanol (100 mL) for 17 hours. The solution was then concentrated in vacuo to dryness. The resulting bright orange paste was purified by column chromatography (column 5″L×2″W; eluted with a gradient of 100% dichloromethane→1%/0.25%→2%/0.5% MeOH/NH4OH in dichloromethane) to afford the product as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:37])[N:7]([C:14]1([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13])([O-])=O.[H][H]>C(O)C.[Ni]>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:37])[N:7]([C:14]1([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13]
Reactant: O=C1CCC(CCCCNC(=O)OCc2ccccc2)(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)C(=O)N1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: Nc1cccc2c1C(=O)N(C1(CCCCNC(=O)OCc3ccccc3)CCC(=O)NC1=O)C2=O
Reaction time: 1.5 h
Yield: 0 %

Procedure:
To a suspension of 5 (0.24 g, 0.472 mmol) in ethanol (15 mL) was added Raney Nickel (W.R. Grace and Co. Raney® 4200, slurry, in H2O) under argon. The mixture was subsequently saturated with hydrogen using a hydrogen balloon. After 1.5 h, the mixture was flushed with argon, filtered using EtOH and concentrated. Purification by flash chromatography (95:5 DCM:MeOH) afforded 6 (0.112 mg, 49%) as a bright yellow solid. Rf=0.38 (95:5 DCM:MeOH). 1H NMR (400 MHz, DMSO) δ 10.97 (s, 1H), 9.09 (s, 1H), 9.04 (s, 1H), 7.71-7.52 (m, 2H), 7.49-7.18 (m, 5H), 7.10 (m, 1H), 5.07-4.85 (m, 2H), 2.96 (m, 2H), 2.55 (m, 2H), 2.44 (m, 1H), 2.22 (m, 2H), 2.02 (m, 1H), 1.40 (m, 2H), 1.22 (m, 2H). MS (ESI) m/z calcd for C25H27N4O6 [M+H]+ 479.5. found 479.9.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][CH:20]([CH:26]([CH3:28])[CH3:27])[C:21]([N:23]([CH3:25])[CH3:24])=[O:22]>>[CH3:24][N:23]([CH3:25])[C:21]([CH:20]([NH:19][C:15]([C:7]1[CH:6]=[N:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH:26]([CH3:28])[CH3:27])=[O:22]
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)C(N)C(=O)N(C)C
Agent: Cl
Product: CC(C)C(NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1)C(=O)N(C)C

Procedure:
The title compound was synthesized in analogy to Example 69, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 80 mg, 0.34 mmol) and 2-amino-3,N,N-trimethyl-butyramide hydrochloride (CAN 1257848-66-0, 40.1 mg, 0.27 mmol) as starting materials and isolated (35 mg, 28.4%) as white solid; LC-MS (UV peak area, ESI) 93.77%, 361.0 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH2:5])[CH3:2].[CH3:10][C:11]([CH3:16])=[CH:12][C:13](Cl)=[O:14]>CCCCCC>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][NH:5][C:13](=[O:14])[CH:12]=[C:11]([CH3:16])[CH3:10])[CH3:2]
Reactant: CCCCC(CC)CN
Reactant: CC(C)=CC(=O)Cl
Solvent: CCCCCC
Product: CCCCC(CC)CNC(=O)C=C(C)C
Yield: 83.3 %

Procedure:
In 20 ml of n-hexane was dissolved 1.40 g (0.011 mol) of 2-ethylhexylamine. With stirring, 1.20 g (0.01 mol) of β-methylcrotonyl chloride was added to the solution. After reaction, the reaction mixture was washed first with diluted hydrochloric acid and then with 10% sodium hydroxide solution and subsequently dried with sodium sulfate. The solvent was distilled off and the residue was further distilled in vacuum. A fraction having a boiling point of 133°-134° C./l mmHg was collected, obtaining 1.76 g of N-(2-ethylhexyl)-β-methylcrotonamide as an oil (yield: 82.3%). Usual analysis was carried out to identify the compound. The results are shown below.
Reaction SMILES: [CH2:1]([O:3][Si:4]([O:13][CH2:14][CH3:15])([CH2:11]I)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2].[K].[NH:17]1[CH:21]=[N:20][CH:19]=[N:18]1>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O>[CH2:1]([O:3][Si:4]([O:13][CH2:14][CH3:15])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:11][N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)[CH3:2]
Reactant: CCO[Si](CI)(OCC)c1ccccc1
Reactant: c1nc[nH]n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K]
Solvent: O
Solvent: Cc1ccccc1
Product: CCO[Si](Cn1cncn1)(OCC)c1ccccc1
Yield: 78.1 %

Procedure:
A mixture of 4.0 g (0.012 mol) of diethoxy(iodomethyl)phenylsilane, 1.5 g (0.014 mol) of 1,2,4-triazole potassium salt, and 0.5 g (0.14 mmol) of tetrabutylammonium hydrogen sulfate in 10 ml of toluene was stirred and warmed to 100°-110° C. for 5 hours, cooled, diluted with water, and extracted with methylene chloride. The methylene chloride solution was washed with brine, dried over magnesium sulfate, and evaporated to leave 2.6 g (79%) of the title compound as a pale brown oil: nD19 1.5543; ir (neat) 2980, 1590, 1505, 1430, 1270 cm-1 ; nmr (CDCl3) 1.2 (6H, t, J=7), 3.8 (4H, q, J=7), 3.9 (2H, s), 7.2-7.7 (5H, m), 7.8 (s, 1H) and 8.0 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:39][CH2:38][NH:37][C:36](=[O:40])[CH2:35]2)[CH2:31]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:30]4[CH2:31][CH:32]([N:34]5[CH2:39][CH2:38][NH:37][C:36](=[O:40])[CH2:35]5)[CH2:33]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: O=C1CN(C2CNC2)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC(N4CCNC(=O)C4)C3)n(C)c2n1
Reaction time: 16 h

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.26 mmol), 4-azetidin-3-ylpiperazin-2-one (44 mg, 0.28 mmol) and 4 Å powdered molecular sieves (250 mg) in MeOH (2 mL) and DCE (5 mL) was stirred at room temperature for 2 h before the addition of sodium triacetoxyborohydride (108 mg, 0.51 mmol). The reaction mixture was stirred for 16 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-7%). The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 514 as a yellow foam (42 mg, 31%). LCMS (Method I): RT 2.28 min [M+H]+ 531.2. 1H NMR (CDCl3, 400 MHz): δ 8.02-7.97 (m, 1 H); 7.79-7.74 (m, 1 H); 7.31-7.24 (m, 2 H); 5.93 (bs, 1 H); 4.35 (m, 4 H); 3.94 (s, 2 H); 3.94-3.80 (m, 7 H); 3.66 (bs, 2 H); 3.43-3.33 (m, 4 H); 3.21 (s, 3 H); 3.06 (s, 2 H); 2.58 (t, J=5.37 Hz, 2 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]3[S:20][C:19]4[N:21]=[CH:22][CH:23]=[N:24][C:18]=4[N:17]([CH2:25][O:26][CH3:27])[C:16]=3[CH:28]=1)[CH:5]=[N:6]2.[CH2:29]([O:31][C:32]([Sn](CCCC)(CCCC)CCCC)=[CH2:33])[CH3:30]>CN(C)C=O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:32]([O:31][C:29]([C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]3[S:20][C:19]4[N:21]=[CH:22][CH:23]=[N:24][C:18]=4[N:17]([CH2:25][O:26][CH3:27])[C:16]=3[CH:28]=1)[CH:5]=[N:6]2)=[CH2:30])[CH3:33]
Reactant: COCN1c2cc(Cn3cnc4ncnc(Cl)c43)ccc2Sc2nccnc21
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=C(OCC)c1ncnc2ncn(Cc3ccc4c(c3)N(COC)c3nccnc3S4)c12
Temperature: 80 °C

Procedure:
To a solution of 0.9 g of 8-(6-chloropurin-7-ylmethyl)-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine in N,N-dimethylformamide (15 ml) were added in a nitrogen atmosphere 1.03 g of 1-ethoxyvinyl-tri-n-butyltin (IV) and 0.015 g of bis(triphenylphosphine) palladium (II) chloride. After degassing, the mixture was heated to 80° C. for 20 hours. Then the insoluble matters were removed by filtering through celite. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 0.77 g of the title compound as yellow crystals.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15]([C:17]([O:19]CC)=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C([Li])CCC>CCCCCC.O1CCCC1>[C:1]1([C:7]2[N:16]=[C:15]([C:17]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Reactant: C1CCNC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(c1nc(-c2ccccc2)nc2ccccc12)N1CCCC1

Procedure:
The procedure of Example 24 is followed using ehtyl 2-phenylquinazoline-4-carboxylate (3 g), pyrrolidine (3 ml), a 1.6M solution of butyllithium in hexane (15 ml) and tetrahydrofuran (25 ml) as the starting materials. After recrystallisation from ethanol, 1-[(2-phenylquinazolin-4-yl)-carbonyl]-pyrrolidine (2.1 g), melting at 153° C., is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[C:4]([CH3:9])=[CH:5][C:6]=1[C:7]#[N:8].[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(O)(=O)C>[C:7]([C:6]1[CH:5]=[C:4]([CH3:9])[N:3]([C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[C:2]=1[NH:1][C:19](=[O:21])[CH3:20])#[N:8]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(C)c(-n2c(C)cc(C#N)c2N)c(C)c1
Solvent: CC(=O)O
Product: CC(=O)Nc1c(C#N)cc(C)n1-c1c(C)cc(C)cc1C
Temperature: 25 °C
Yield: 112.7 %

Procedure:
A mixture of compound (3) (25.3 g, 0.106 mol) and acetic anhydride (11.0 mL, 0.117 mol) were refluxed in acetic acid (25 mL) for 45 minutes, cooled to room temperature, poured onto crushed ice and extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate, dried, and concentrated to give 33.6 g (100%) of compound (4) as a yellow foam.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[C:14](C)[C:13](O)=[C:12](CC)[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:20][C:21]([F:36])([F:35])[C:22]1[CH:34]=[CH:33][C:25]([C:26]([NH:28][CH2:29][CH2:30][CH2:31][OH:32])=[O:27])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[C:1]([O:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[O:32][CH2:31][CH2:30][CH2:29][NH:28][C:26](=[O:27])[C:25]1[CH:33]=[CH:34][C:22]([C:21]([F:35])([F:36])[F:20])=[CH:23][CH:24]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCCO)c1ccc(C(F)(F)F)cc1
Reactant: CCc1cc(OC(=O)c2ccccc2)cc(C)c1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NCCCOc1ccccc1OC(=O)c1ccccc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a mixture of 0.5 g of crude 3-ethyl-4-hydroxy-5-methylphenyl benzoate, 0.48 g of 3-(4-(trifluoromethyl)benzamido)propan-1-ol, 0.54 g of triphenylphosphine and 10 ml of tetrahydrofuran was added dropwise a solution of 0.41 g of diisopropylazodicarboxylate dissolved in 2 ml of tetrahydrofuran, while stirring at room temperature. After stirring at room temperature for 24 hours, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.87 g of 3-ethyl-5-methyl-4-(3-(4-(trifluromethyl)benzamido)propyloxyphenyl benzoate (90% yield).
Reaction SMILES: C([O:8][C:9]([CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:21](=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:17]=2)[CH2:12]1)=[O:10])C1C=CC=CC=1.[H][H]>[Pd].C1COCC1>[C:21]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([C:9]([OH:10])=[O:8])[CH2:20][CH2:19]2)(=[O:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCC(=O)c1ccc2c(c1)CCC(C(=O)OCc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCC(=O)c1ccc2c(c1)CCC(C(=O)O)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 111.1 %

Procedure:
50 mL of a THF solution containing 3.79 g (8.69 mmol) of 6-decanoyl-1,2,3,4-tetrahydro-2-naphthalenecarboxylic acid benzyl ester and 0.43 g of 5% palladium/carbon was placed in a hydrogen atmosphere, using a baloon, and was stirred at room temperature for 24 hours. The reaction mixture was filtered and by concentrating the filtrate, there was obtained 3.19 g of 6-decanoyl-1,2,3,4-tetrahydro-2-naphthalenecarboxylic acid. The yield was 100%.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=3)=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:30](Cl)=[O:31]>C(Cl)Cl>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:30]([N:4]2[C:5]3[CH:10]=[C:9]([C:11]4[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=4)[CH:8]=[CH:7][C:6]=3[O:1][CH2:2][CH2:3]2)=[O:31])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: O=C1CCC(c2ccc3c(c2)NCCO3)=NN1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCOc3ccc(C4=NNC(=O)CC4)cc32)cc1OC

Procedure:
6-(3,4-Dihydro-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-one was dissolved in methylene chloride and 1.1 equivalent of triethylamine. 1.1 equivalent of 3,4-dimethoxybenzoylchloride was added and the mixture heated at reflux for four hours. The solution was washed with sodium bicarbonate solution and then evaporated to dryness. The residue was chromatographed on silica gel eluting with 1:1 ethyl acetate:ethyl ether. The title compound was collected as white needles, mp 207°-208° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[OH:12].[C:13](O)(=[O:20])[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:3]([OH:12])[CH:4]=1)([CH3:9])([CH3:11])[CH3:10]
Reactant: O=C(O)c1ccncc1
Reactant: CC(C)(C)c1ccc(N)c(O)c1
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)c1ccc(NC(=O)c2ccncc2)c(O)c1
Temperature: 80 °C
Yield: 51.9 %

Procedure:
A mixture of 1.44 g of 2-amino-5-tert-butylphenol, 1.07 g of isonicotinic acid, 2.17 g of WSC and 15 ml of pyridine was stirred while heating at 80° C. for five hours. The reaction mixture was cooled to room temperature, and then water was poured. Precipitated solid was filtered and washed with water and diethyl ether to give 1.22 g of N-(4-tert-butyl-2-hydroxyphenyl)isonicotinamide.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][N:9]1[CH:14]2[CH2:15][CH2:16][CH:10]1[CH2:11][CH:12]([N:17]1[C:30]3[CH:29]=[CH:28][C:27]([C:31](O)=[O:32])=[CH:26][C:25]=3[O:24][C:23]3[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:58]([N:60](CC)[CH2:61][CH3:62])[CH3:59]>CN(C=O)C>[CH2:58]([N:60]([CH2:61][CH3:62])[C:31]([C:27]1[CH:28]=[CH:29][C:30]2[N:17]([CH:12]3[CH2:13][CH:14]4[N:9]([CH3:8])[CH:10]([CH2:16][CH2:15]4)[CH2:11]3)[C:18]3[C:23]([O:24][C:25]=2[CH:26]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:32])[CH3:59]
Reactant: CN1C2CCC1CC(N1c3ccccc3Oc3cc(C(=O)O)ccc31)C2
Reactant: CCN(CC)CC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1N2C1CC2CCC(C1)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a solution of the TFA salt of 10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic acid 3a (65 mg, 0.14 mmol) and HBTU (64 mg; 0.17 mmol) in DMF (2 mL) was added triethylamine (69 μL, 0.43 mmol). The mixture was stirred for 1 hr at rt, and purified without prior quenching via reverse phase HPLC (eluent gradient: acetonitrile in water containing 0.1% TFA) to yield 44.4 mg (61%) of title compound 10-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)-10H-phenoxazine-3-carboxylic acid diethylamide, 4a as a TFA salt. MS m/z (MH+) 406.2.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=2)[N:19]=4)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(Cl)Cl>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[CH:31]([N:27]1[C:26]([C:20]2[N:19]=[C:18]3[N:22]([CH2:23][CH2:24][O:25][C:16]4[CH:15]=[C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:35]=[CH:34][C:17]=43)[CH:21]=2)=[N:30][CH:29]=[N:28]1)([CH3:33])[CH3:32]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc1OCC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.2 g, 2.51 mmol) in DCM (12 mL) was added TFA (8 mL) and the reaction mixture stirred at RT for 1 h. The reaction mixture was concentrated in vacuo, the residue tirutrated in diethyl ether to give 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetic acid salt as a grey solid (1.34 g, 100%). LCMS: RT=2.88 min, M+H+=379