Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:5][CH:4]([C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[O:13]CC2C=CC=CC=2)[CH2:3]1.C(OC1C=CC(F)=CC=1C1CC(=O)C1)C1C=CC=CC=1.C(N(S(F)(F)F)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[F:21][C:2]1([F:1])[CH2:5][CH:4]([C:6]2[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=2[OH:13])[CH2:3]1
Reactant: Fc1ccc(OCc2ccccc2)c(C2CC(F)(F)C2)c1
Agent: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: O=C1CC(c2cc(F)ccc2OCc2ccccc2)C1
Solvent: ClCCl
Product: Oc1ccc(F)cc1C1CC(F)(F)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Synthesis of benzyl 2-(3,3-difluorocyclobutyl)-4-fluorophenyl ether (C20). A solution of 3-[2-(benzyloxy)-5-fluorophenyl]cyclobutanone (C19) (600 mg, 2.22 mmol) in dichloromethane (20 mL) cooled to −78° C. was treated with (diethylamino)sulfur trifluoride (753 mg, 4.44 mmol) over a period of 5 minutes. The mixture was stirred at −78° C. for 30 minutes, whereupon it was allowed to warm to room temperature and stirring was continued for 16 hours. The mixture was cooled to −78° C. and a saturated aqueous sodium bicarbonate solution (10 mL) was added. The mixture was allowed to warm to room temperature and additional saturated aqueous sodium bicarbonate solution (50 mL) was added, followed by extraction with dichloromethane (2×50 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL), dried over magnesium sulfate, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 25% ethyl acetate in heptanes) afforded the desired title compound as a colorless oil. Yield: 315 mg, 108 mmol, 48%. GCMS m/z 292 (M+). 1H NMR (400 MHz, CDCl3) δ 2.58-2.73 (m, 2H), 2.90-3.03 (m, 2H), 3.53-3.64 (m, 1H), 5.06 (s, 2H), 6.83-6.94 (m, 3H), 7.34-7.45 (m, 5H).
Reaction SMILES: CCN(C(C)C)C(C)C.[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][C:16](Cl)=[O:17].[Cl:19][C:20]1[C:29]([NH2:30])=[CH:28][C:27]2[C:22](=[CH:23][C:24]([C:31]([F:34])([F:33])[F:32])=[CH:25][CH:26]=2)[N:21]=1.CCCCCC.CC(=O)OCC>C(Cl)Cl>[Cl:19][C:20]1[C:29]([NH:30][C:16](=[O:17])[CH2:15][C:11]2[S:10][CH:14]=[CH:13][CH:12]=2)=[CH:28][C:27]2[C:22](=[CH:23][C:24]([C:31]([F:32])([F:34])[F:33])=[CH:25][CH:26]=2)[N:21]=1
Reactant: Nc1cc2ccc(C(F)(F)F)cc2nc1Cl
Reactant: O=C(Cl)Cc1cccs1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1cccs1)Nc1cc2ccc(C(F)(F)F)cc2nc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.5 %

Procedure:
373 μl (4 mmol) of DIPEA and 385 mg (2.4 mmol) of 2-(thiophen-2-yl)acetyl chloride were added in succession at 0° C. to a solution of 493 mg (2 mmol) of 2-chloro-7-(trifluoromethyl)quinolin-3-amine (VC05) in DCM (14 ml). After stirring for 16 h at RT, the mixture was diluted with DCM. It was then washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 19:1) of the residue yielded 321 mg (0.87 mmol, 44%) of N-(2-chloro-7-(trifluoromethyl)quinolin-3-yl)-2-(thiophen-2-yl)acetamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].[Br:32][C:33]1[C:34]([C:39](Cl)=[O:40])=[N:35][N:36]([CH3:38])[CH:37]=1>>[Br:32][C:33]1[C:34]([C:39]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][C:10]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]=[CH:12][CH:11]=3)=[C:2]([F:1])[CH:3]=2)=[O:40])=[N:35][N:36]([CH3:38])[CH:37]=1
Reactant: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCCCN1CCOCC1
Reactant: Cn1cc(Br)c(C(=O)Cl)n1
Product: COc1cc2c(Oc3ccc(NC(=O)c4nn(C)cc4Br)cc3F)ccnc2cc1OCCCN1CCOCC1

Procedure:
Q2 was prepared from 3-fluoro-4-[[6-methoxy-7-(3-morpholinopropoxy)-4-quinolyl]oxy]aniline and 4-bromo-1-methyl-1H-pyrazole-3-carbonyl chloride following the general procedure reported in Preparative Example 1 Step 3. 1H NMR (400 MHz, d4-MeOD, 300K) δ 2.20 (m, 2H), 2.73 (m, 4H), 2.81 (t, J=7.4 Hz, 2H), 3.80 (t, J=4.7 Hz, 4H), 4.02 (s, 3H), 4.05 (s, 3H), 4.29 (t, J=6.1 Hz, 2H), 6.54 (dd, J=5.4 Hz, J=1.0 Hz, 1H), 7.37 (t, J=9.0 Hz, 1H), 7.38 (s, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.68 (s, 1H), 7.86 (s, 1H), 7.95 (dd, J=12.9 Hz, J=2.4 Hz, 1H), 8.45 (d, J=5.4 Hz, 1H). MS (ES) C28H29BrFN5O5 requires: 614. Found: 614/616 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][C:4](=[O:7])[N:3]1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]#[N:19])=[CH:10][CH:9]=1.N[C@H](C(O)=O)C.C([O-])([O-])=O.[Na+].[Na+].[CH:32](=O)[C:33]1[C:34](=[CH:36][CH:37]=[CH:38][CH:39]=1)[OH:35]>O>[OH:35][C:34]1[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=1[CH:32]=[C:5]1[C:4](=[O:7])[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([C:18]#[N:19])=[CH:10][CH:9]=2)[C:2](=[O:1])[NH:6]1
Reactant: N#Cc1ccc(N2C(=O)CNC2=O)c2ccccc12
Reactant: O=Cc1ccccc1O
Agent: C[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(N2C(=O)NC(=Cc3ccccc3O)C2=O)c2ccccc12
Yield: 35.1 %

Procedure:
A mixture of compound 1C (150 mg, 0.6 mmol), alanine (53.1 mg, 0.6 mmol), and Na2CO3 (31.7 mg, 0.3 mmol) in water (1.4 mL) was treated with salicylaldehyde (0.11 mL, 0.94 mmol) and refluxed for 3.0 h. (Ref: Eur. J. Org. Chem. 1999, 2609-2621). The mixture was diluted with water (1 mL) and filtered, washing the yellow precipitates with water (2×2 mL). The yellow solids were triturated with ether (2 mL) and dried to give the title compound as a yellow solid (74.9 mg, 35.4%), mp 251-252° C. LC/MS m/z 356 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13]([C:23]([O:25]CC)=[O:24])=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[N:15]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].O.[OH-].[Li+].Cl>O1CCCC1.O>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13]([C:23]([OH:25])=[O:24])=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[N:15]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1sc(-c2ccnc(NC(C)=O)c2)nc1-c1ccccc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cc(-c2nc(-c3ccccc3Cl)c(C(=O)O)s2)ccn1
Reaction time: 18 h
Yield: 100.1 %

Procedure:
To a stirred solution of ethyl 2-[2-(acetylamino)pyridin-4-yl]-4-(2-chlorophenyl)-1,3-thiazole-5-carboxylate (0.249 g, 0.620 mmol) in tetrahydrofuran (1.670 mL) and water (0.100 mL) was added lithium hydroxide, monohydrate (0.037 g, 0.891 mmol) and stirred for 18 h. The mixture was acidified to pH 6 with aqueous 1N HCl (1.20 mL, 1.20 mmol) and extracted with EtOAc (10.0 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the crude product (0.232 g) as a yellow solid and used without further purification. LC/MS (AA) ES+ 374, 376. 1H NMR (400 MHz, d6 DMSO) δ: 10.75 (br s, 1H), 8.69 (br s, 1H), 8.47-8.46 (m, 0.5H), 8.06-8.04 (m, 0.5H), 7.65-7.64 (m, 0.5H), 7.58-7.44 (m, 5H), 7.06-7.99 (m, 0.5H), 2.12 (s, 3H).
Reaction SMILES: [CH3:1][C@@H:2]1[O:6][C:5](=[O:7])[CH:4]=[CH:3]1.[CH:8]1[O:9][CH:10]=[C:11]2[C:16]=1[CH2:15][CH2:14][CH2:13][CH2:12]2.C(Cl)Cl>CCOCC.Cl([O-])(=O)(=O)=O.[Li+]>[O:9]1[C@@H:10]2[C@H:4]3[C@H:3]([C@H:8]1[C:16]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=12)[C@H:2]([CH3:1])[O:6][C:5]3=[O:7]
Reactant: C[C@H]1C=CC(=O)O1
Reactant: c1occ2c1CCCC2
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@H]1OC(=O)[C@@H]2[C@@H]1[C@@H]1O[C@H]2C2=C1CCCC2
Temperature: 25 °C
Reaction time: 168 h
Yield: 58.2 %

Procedure:
To 224.0 mg(2.28 mmol) of (S)-5-methyl-2(5H)-furanone were added 557.9 mg(1.5 equivalents) of 4,5,6,7-tetrahydroisobenzofuran in 2 ml of dehydrated ether solution and 1.06 g of lithium perchlorate, and, after flushing with argon, the mixture was stirred for 168 hours at room temperature. The reaction mixture was poured into 20 ml of water, which was extracted with methylene chloride(10 ml×3). The organic layer was dried over anhydrous magnesium sulfate, filtered and solvent was distilled off under reduced pressure. The residue was purified by means of silica gel column chromatography(methylene chloride, then methylene chloride:ethyl acetete=10:1) to obtain 292.2 mg of (3S, 3aS, 4S, 9R, 9aR)-4,9-epoxy-3-methyl-3a,4,5,6,7,8,9,9a-octahydronaphtho[2,3-c]furan-1(3H)-one (yield 58%).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10][C:11]1[C:12]([NH2:18])=[N:13][CH:14]=[C:15]([Br:17])[CH:16]=1)=O.[H-].[Na+]>CS(C)=O.O>[Br:17][C:15]1[CH:14]=[N:13][C:12]2[NH:18][C:3](=[O:2])[C@H:5]3[N:6]([CH2:7][CH2:8][CH2:9]3)[CH2:10][C:11]=2[CH:16]=1
Reactant: COC(=O)[C@@H]1CCCN1Cc1cc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1Nc2ncc(Br)cc2CN2CCC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
A solution of (S)-1-(2-amino-5-bromo-pyridin-3-ylmethyl)pyrrolidine-2-carboxylic acid methyl ester (3.66 g, 11.6 mmol) in DMSO (120 mL) was treated with NaH (60% dispersion in mineral oil, 0.47 g, 11.7 mmol). After stirring at room temperature for 4 h, the mixture was diluted with H2O (2500 mL) and extracted with EtOAc (5×150 mL). The combined organic layers were washed with H2O (4×100 mL) and brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo. Purification by flash column chromatography (silica gel, CH2Cl2,/MeOH, 99:1) gave the title compound (2.75 g, 84%) as an off-white solid: MS (ESI) m/e 282 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[O:11]1[CH2:15][CH2:14][CH:13]([NH2:16])[CH2:12]1>>[NH2:1][C:2]1[CH:9]=[C:8]([NH:16][CH:13]2[CH2:14][CH2:15][O:11][CH2:12]2)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: NC1CCOC1
Product: N#Cc1cnc(N)cc1NC1CCOC1

Procedure:
From intermediate 21 and racemic tetrahydrofuran-3-amine, reacted in an analogous manner to the preparation of intermediate 49. (UPLC-MS 3) tR 0.32 min; ESI-MS 205.1 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[C:13](Cl)[CH:12]=[CH:11][N:10]=1.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[Cl:8][C:9]1[CH:14]=[C:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:12]=[CH:11][N:10]=1
Reactant: C1COCCN1
Reactant: Clc1ccnc(Cl)c1
Solvent: CCN(CC)CC
Product: Clc1cc(N2CCOCC2)ccn1
Temperature: 25 °C
Reaction time: 45 h

Procedure:
To a solution of triethylamine (1.0 equiv.) and 2,4-dichloropyridine (1.0 equiv.) at RT was added morpholine (1.0 equiv) in one portion, the resulting mixture was then stirred at RT for 45 hr. LCMS analysis indicated the formation of the desired product (M+H=199, Rt=0.29 min, major) and the undesired isomer (M+H=199, Rt=0.33 min, minor). The reaction mixture was concentrated in vacuo and purified via ISCO to yield 4-(2-chloropyridin-4-yl)morpholine as a light brown solid (28%). LCMS (m/z) (M+H)=299.0, Rt=0.29 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 3.18-3.37 (m, 4H) 3.72-3.91 (m, 4H) 6.51-6.61 (m, 1H) 6.61-6.69 (m, 1H) 8.05 (d, J=6.26 Hz, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([OH:26])=O)=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][C:32]([C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38])([F:34])[CH3:33].CCN(C(C)C)C(C)C>C1C=CC=CC=1.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:38][C:37]3[CH:39]=[CH:40][CH:41]=[C:35]([C:32]([F:31])([F:34])[CH3:33])[CH:36]=3)=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: CC(F)(F)c1cccc(N)c1
Reactant: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)O)c3c(c2[nH]1)CC(C)(C)O3
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)Nc3cccc(C(C)(F)F)c3)c3c(c2[nH]1)CC(C)(C)O3
Yield: 4.4 %

Procedure:
The title compound was prepared by following the procedure described for Example-108 using 2-[(2-chloro-6-methylphenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-35, 0.200 g, 0.537 mmol), thionyl chloride (2.0 mL), 3-(1,1-difluoroethyl)aniline (Intermediate-39, 0.088 g, 0.537 mmol), THF (5.0 mL) and DIPEA (3.0 mL), benzene (2 mL). The obtained crude product was purified by column chromatography on neutral alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.012 g of the desired product. 1HNMR (DMSO-d6): δ 1.57 (s, 6H), 1.97 (s, 3H), 2.24 (s, 3H), 3.11 (s, 2H), 7.25-7.32 (m, 3H), 7.41-7.49 (m, 3H), 7.61 (d, J=7.8 Hz, 1H), 8.07 (s, 1H), 9.05 (m, 1H), 9.87 (s, 1H), 10.95 (s, 1H); MS [M−H]−: 513.42.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][CH:13]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[I:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[O:10][C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][CH:13]=1
Reactant: Cc1cc(O)c(I)cc1C
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc(C)c(C)cc3I)c2cc1OC
Temperature: 130 °C
Reaction time: 4 h
Yield: 57.6 %

Procedure:
2-Iodo-4,5-dimethylphenol (447 mg), 4-chloro-6,7-dimethoxyquinoline (466 mg), and 4-dimethylaminopyridine (539 mg) were suspended in o-dichlorobenzene (20 ml), and the mixture was stirred at 130° C. for 4 hr. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography using acetone-chloroform to give the title compound (452 mg, yield 50%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:10]([C:11]([OH:13])=O)[CH2:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7]1)=[O:5])[CH3:2].C(N(CC)C(C)C)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Cl:45][C:46]1[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=1>C(#N)C>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:10]([C:11](=[O:13])[NH:50][C:49]2[CH:51]=[CH:52][C:46]([Cl:45])=[CH:47][CH:48]=2)[CH2:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)O
Reactant: Nc1ccc(Cl)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 7a (1 g; 3.48 mmol) is suspended in acetonitrile (7 ml) and N,N-diisopropyl ethyl amin (1.22 ml; 6.96 mmol) is added at 25° C. BOP-Cl (1.772 g; 6.96 mmol) is added as a solid and after stirring for 30 min at 25° C. 4-chloroaniline (0.444 g; 3.48 mmol) is added to the reaction mixture. The mixture is stirred for 18 h at 25° C., evaporated to dryness and dissolved in ethyl acetate (100 ml). The organic phase is washed with saturated aquous Na2CO3 solution (100 ml), 2 N HCl (50 ml), water and brine and dried over Na2SO4. The organic phase is filtered and the filtrate is evaporated to dryness. The crude product is purified by silica gel chromatography. Yield: 0.5 g (36.2%), ESI-MS: m/z=395 [M−H]−, Cl-pattern
Reaction SMILES: C([Li])CCC.[O:6]1[C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)OCC1.[C:16]1([C:22]2[N:31]=[C:30]([C:32](OCC)=[O:33])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CCCCCC.O1CCCC1>[C:16]1([C:22]2[N:31]=[C:30]([C:32]([N:13]3[CH2:12][CH2:11][C:10](=[O:6])[CH2:15][CH2:14]3)=[O:33])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2)nc2ccccc12
Reactant: C1CC2(CCN1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: O=C1CCN(C(=O)c2nc(-c3ccccc3)nc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 1.6M solution of butyllithium in hexane (37 ml) is added, under a nitrogen atmosphere and at 0° C., to 1,4-dioxa-8-azaspiro[4,5]decane (7.5 ml) in anhydrous tetrahydrofuran (30 ml). After 30 minutes, a solution of ethyl 2-phenylquinazoline-4-carboxylate (8 g) in anhydrous tetrahydrofuran (30 ml) is added. After 2 hours at ambient temperature, water is added and the mixture is extracted with methylene chloride. The organic phase is washed with water, dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue is taken up in acetone (100 ml) and concentrated hydrochloric acid (20 ml) and the mixture is stirred for 5 hours at ambient temperature.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:20](C1C=CC(CC2C=CC([N+]([O-])=O)=CC=2)=CC=1)([O-])=[O:21].[N+](C1C=CC(C(C2C=CC([N+]([O-])=O)=CC=2)=O)=CC=1)([O-])=O>O.C(O)(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[N:20][OH:21])[C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Cc2ccc([N+](=O)[O-])cc2)cc1
Agent: O=C(c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(C(=NO)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C

Procedure:
The title compound was prepared by modification of procedures previously reported in the literature (Chapman and Fidler (1936) J. Chem. Soc, 448; Kulin and Leffek (1973) Can. J. Chem., 51: 687). A solution of chromic anhydride (20 g, 200 mmol) in 125 ml of H2O was added dropwise over 4 hours, to a suspension of bis(4-nitrophenyl)methane (25 g, 97 mmol) in 300 ml of acetic acid heated to reflux. The reaction mixture was heated at reflux for 1 hour, cooled to room temperature, and poured into water. The solid was collected by filtration, washed with H2O, 5% sodium bicarbonate, H2O , and air-dryed to provide a 1:1 mixture of bis(4-nitrophenyl)methane/4,4'-dinitrobenzophenone via 1H NMR. This material was oxidized with a second portion of chromic anhydride (20 g, 200 mmol), followed by an identical work-up procedure to provide the crude product. Trituration with 200 ml of benzene heated to reflux for 16 hours provided 4,4'-dinitrobenzophenone (20.8 g, 79%) as a yellow powder.
Reaction SMILES: ClC(OCC)=O.C(Cl)(Cl)Cl.[CH2:11]([C:14]1([C:23]([C:26]([OH:28])=[O:27])([CH3:25])[CH3:24])[C:19](=[O:20])[NH:18][C:17](=[O:21])[NH:16][C:15]1=[O:22])[CH:12]=[CH2:13].[CH:29]1[C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=[C:31](O)[CH:30]=1>ClCCl.C(N(CC)CC)C>[CH2:11]([C:14]1([C:23]([C:26]([O:28][C:31]2[CH:30]=[CH:29][C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=2)=[O:27])([CH3:24])[CH3:25])[C:19](=[O:20])[NH:18][C:17](=[O:21])[NH:16][C:15]1=[O:22])[CH:12]=[CH2:13]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: C=CCC1(C(C)(C)C(=O)O)C(=O)NC(=O)NC1=O
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC1(C(C)(C)C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)NC(=O)NC1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 2.19 g. of ethyl chloroformate in 90 ml. of chloroform was added to a solution of 5.08 g. of "allonalcarboxylic acid" [5-allyl-5-(1-carboxyisopropyl)barbituric acid] and 2.02 g. of triethylamine in 100 ml. of dichloromethane, cooled to 0°-5°, and the mixture was stirred at room temperature for 5 hours. p-Nitrophenol (3.06 g.) was added and the mixture was stirred at room temperature for 14 hours. The reaction mixture was washed with saturated sodium carbonate solution (3 × 25 ml.), and water until the workings were neutral, dried over anhydrous sodium sulfate and filtered. Evaporation of the filtrate under reduced pressure gave 4.7 g. of an oil. Crystallization from a mixture of ether-heptane (1:1) gave 2.2 g. of the ester, m.p. 140°-141°.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[Cl:29][C:30]1[N:35]=[C:34](Cl)[N:33]=[CH:32][N:31]=1>C(O)(C)C>[Cl:29][C:30]1[N:35]=[C:34]([N:13]2[CH2:14][CH2:15][CH:10]([O:9][CH2:8][C:7]3[CH:16]=[CH:17][C:4]([O:3][C:2]([F:18])([F:1])[F:19])=[CH:5][CH:6]=3)[CH2:11][CH2:12]2)[N:33]=[CH:32][N:31]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: FC(F)(F)Oc1ccc(COC2CCNCC2)cc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)Oc1ccc(COC2CCN(c3ncnc(Cl)n3)CC2)cc1
Temperature: 80 °C
Yield: 25.7 %

Procedure:
To a solution of 4-(4-(trifluoromethoxy)benzyloxy)piperidine (2.2 g, 8.00 mmol) in isopropanol (25 mL, 3 mL/mmol) was added DIPEA (3.6 mL, 0.02 mol) and 2,4-dichloro-1,3,5-triazine (1.2 g, 8.00 mmol) and the reaction was heated at 80° C. for 2 h. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×40 mL). The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 2-chloro-4-(4-((4-(trifluoromethoxy)benzyl)oxy)piperidin-1-yl)-1,3,5-triazine (800 mg, 57%) as a solid. Observed mass (M+1): 389.0.
Reaction SMILES: FC1C=CC(CN)=CC=1.[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH2:14][NH2:15].[CH2:20]([N:27]1[CH2:31][CH2:30][N:29]([C:32]2[S:33][C:34]([C:38](O)=[O:39])=[C:35]([CH3:37])[N:36]=2)[C:28]1=[O:41])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([N:27]1[CH2:31][CH2:30][N:29]([C:32]2[S:33][C:34]([C:38]([NH:15][CH2:14][C:13]3[CH:16]=[CH:17][C:18]([F:19])=[C:11]([F:10])[CH:12]=3)=[O:39])=[C:35]([CH3:37])[N:36]=2)[C:28]1=[O:41])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NCc1ccc(F)c(F)c1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Agent: NCc1ccc(F)cc1
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)NCc1ccc(F)c(F)c1
Yield: 43 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 4-fluorobenzylamine with 3,4-difluorobenzylamine to react with 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white powder in 43% yield: mp 152-153° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.36-7.00 (m, 8H), 6.05 (s, 1H), 4.49 (d, J=5.7 Hz, 2H), 4.45 (s, 2H), 4.05 (t, J=8.4 Hz, 2H), 3.44 (t, J=8.4 Hz, 2H), 2.58 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.5, 157.3, 155.3, 153.6, 152.0, 148.6, 135.2, 128.9, 128.2, 128.1, 123.6, 117.5, 116.8, 116.7, 116.6, 47.9, 42.9, 42.0, 41.6, 17.2; MS (ES+) m/z 443.0 (M+1).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]2[C:21]([CH:22]=O)=[CH:20][C:11]3[C:12]([N:15]4[CH:19]=[N:18][CH:17]=[N:16]4)=[N:13][O:14][C:10]=3[C:9]=2[F:24])[CH2:5][C@@H:4]([CH3:25])[O:3]1.[NH:26]1[C:31](=[O:32])[CH2:30][C:29](=[O:33])[NH:28][C:27]1=[O:34]>CS(C)=O>[F:24][C:9]1[C:10]2[O:14][N:13]=[C:12]([N:15]3[CH:19]=[N:18][CH:17]=[N:16]3)[C:11]=2[CH:20]=[C:21]2[C:8]=1[N:6]1[CH2:5][C@@H:4]([CH3:25])[O:3][C@@H:2]([CH3:1])[C@@H:7]1[C:30]1([C:29](=[O:33])[NH:28][C:27](=[O:34])[NH:26][C:31]1=[O:32])[CH2:22]2
Reactant: C[C@@H]1CN(c2c(C=O)cc3c(-n4cncn4)noc3c2F)C[C@@H](C)O1
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CS(C)=O
Product: C[C@@H]1CN2c3c(cc4c(-n5cncn5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 150 °C
Yield: 43.9 %

Procedure:
A mixture of 6-((2R,6R)-2,6-dimethylmorpholino)-7-fluoro-3-(1H-1,2,4-triazol-1-yl)benzo[d]isoxazole-5-carbaldehyde (Intermediate 574, 500 mg, 1.45 mmol) and pyrimidine-2,4,6(1H,3H,5H)-trione (185 mg, 1.45 mmol) in DMSO (6 ml) was heated at 150° C. for 2 hours in a microwave reactor. The reaction mixture was purified by Super Critical Fluid chromatography on a Chiralpac IC column with a 35% MeOH, 65% CO2 mobile phase to give 290 mg of product as a solid as the first eluting compound.