Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:33])[NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[CH:30]=[CH:29][C:28](C=O)=[CH:27][CH:26]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:46]([O:51][CH3:52])([O:49][CH3:50])OC>CO>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16](=[O:33])[NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[CH:26]=[CH:27][C:28]([CH:46]([O:49][CH3:50])[O:51][CH3:52])=[CH:29][CH:30]=3)[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COC(OC)OC
Reactant: O=Cc1ccc(-c2ccccc2CNC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(OC)c1ccc(-c2ccccc2CNC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Yield: 93.1 %

Procedure:
To a vigorously stirred mixture of methanol (250 mL) containing aldehyde (S29) (17.0 g, 39.3 mmol) and p-toluenesulfonic acid monohydrate (0.75 g, 3.9 mmol) was added trimethyl orthoformate (17 mL, 160 mmol). After 1.5 h of moderate heating (flask equipped with short path to drive reaction forward), the reaction was quenched with a 1:1 mixture of saturated sodium bicarbonate and water (150 mL) and diluted with CH2Cl2 (200 mL). The aqueous layer was extracted with CH2Cl2 and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give a pale yellow solid (17.5 g, 36.6 mmol, 93%) which was used without further purification. 1H NMR (400 MHz, d6-DMSO): δ 7.88 (d, 2H, J=7.7 Hz), 7.79 (t, 1H, J=5.9 Hz), 7.68 (d, 2H, J=7.3 Hz), 7.43–7.30 (m, 11H), 7.19 (d, 1H, J=7.0 Hz), 5.40 (s, 1H), 4.29 (d, 2H, J=7.0 Hz), 4.20 (t, 1H, J=7.0 Hz), 4.11 (d, 2H, J=5.9 Hz), 3.25 (s, 6H). FAB/MS: 502 (M+Na+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][N:4]=[C:3]1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.C=O.[C:20]([O-])(=[O:22])C.[Na+].[OH-].[Na+]>C(O)(=O)C>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:20][OH:22])[N:4]=[C:3]1[C:8]1[CH:9]=[CH:10][C:11]([C:14]([F:16])([F:17])[F:15])=[CH:12][CH:13]=1
Reactant: CC(=O)[O-]
Reactant: Cc1cnc(-c2ccc(C(F)(F)F)cc2)n1C
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1c(CO)nc(-c2ccc(C(F)(F)F)cc2)n1C
Yield: 59.3 %

Procedure:
A mixture of 1,5-dimethyl-2-(4-trifluoromethylphenyl)imidazole (0.6 g), aqueous formaldehyde (3.5 ml of 36%), sodium acetate (0.6 g), and acetic acid (0.5 ml) was refluxed for 24 hours. The mixture was cooled, and concentrated sodium hydroxide added until the mixture was just: basic, keeping the temperature at about 10° C. The mixture was extracted with methylene chloride, and solvent removed from the organic layer under reduced pressure. The residue was flash-chromatographed on silica gel, eluting with methylene chloride containing methanol (97/3), to yield 0.4 g of 1,5-dimethyl-4-hydroxymethyl-2-(4-trifluoromethyl-phenyl)imidazole, m.p. 152° C.
Reaction SMILES: [CH:1]1([C:4]#[C:5][C:6]2[C:7]([NH2:26])=[N:8][C:9]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:11]=2)[CH2:3][CH2:2]1.CC(C)([O-])C.[K+]>C(O)(C)(C)C.O>[CH:1]1([C:4]2[NH:26][C:7]3=[N:8][C:9]([C:19]4[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=4)=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=4)[N:11]=[C:6]3[CH:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(-c2nc(N)c(C#CC3CC3)nc2-c2ccc(C)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1ccc(-c2nc3cc(C4CC4)[nH]c3nc2-c2ccc(C)cc2)cc1

Procedure:
3-(Cyclopropylethynyl)-5,6-di-p-tolylpyrazin-2-amine (step 4)(279 mg, 0.822 mmol) in tert-BuOH (10 ml) was treated with potassium tert-butoxide (184 mg, 1.644 mmol) and heated at reflux for 6 hours. The mixture was diluted with water and extracted with DCM (×3). The combined organic extracts were concentrated under reduced pressure and purification of the crude product by chromatography on silica eluting with 0-20% EtOAc in iso-hexane afforded the titled compound as a beige coloured solid;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]3)[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:13][CH2:14][N:15]([CH:18]3[CH2:22][CH2:21][NH:20][CH2:19]3)[CH2:16][CH2:17]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCN(C2CCNC2)CC1
Reaction time: 2 h

Procedure:
tert-butyl 3-(4-{[(3,4-dichlorophenyl)amino]carbonyl}piperazin-1-yl)pyrrolidine-1-carboxylate (690 mg, 1.6 mmol) was dissolved in dichloromethane (50 ml) at room temperature. Trifluoroacetic acid (3 ml) was added and the mixture left to stir for 2 hours then concentrated in vacuo.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Li]CCCC.[Si:14]([O:21][CH2:22][C:23](=[O:25])[CH3:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:23]([OH:25])([CH3:24])[CH2:22][O:21][Si:14]([C:17]([CH3:19])([CH3:18])[CH3:20])([CH3:15])[CH3:16])=[N:3][CH:4]=1
Reactant: CC(=O)CO[Si](C)(C)C(C)(C)C
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(O)(CO[Si](C)(C)C(C)(C)C)c1ccc(Br)cn1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
For a literature procedure to carry out a selective mono-lithiation of 2,5-dibromopyridine, see: Wang, X.; Rabbat, P.; O'Shea, P.; Tillyer, R.; Grabowski, E. J. J.; Reider, P. J. Tetrahedron Lett. 2000, 41, 4335-4338. n-BuLi (3.17 mL, 5.07 mmol) was added to 2,5-dibromopyridine (1.00 g, 4.22 mmol) in toluene (49.7 mL) at −78° C. and stirred for 2 hours at −78° C. 1-{[tert-Butyl(dimethyl)silyl]oxy}propan-2-one (1.22 mL, 6.33 mmol) was added dropwise to the reaction mixture over 15 minutes. Upon addition, the reaction mixture was warmed to room temperature overnight. The reaction mixture was quenched with a saturated aqueous NH4Cl (2.00 mL) and the solvent was removed under reduced pressure. The resultant residue was diluted with dichloromethane (20.0 mL) and was partitioned with a saturated aqueous solution of NH4Cl (20.0 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure and purified by silica gel chromatography (ethyl acetate/hexanes) to yield 2-(5-bromopyridin-2-yl)-1-{[tert-butyl(dimethyl)silyl]oxy}propan-2-ol. MS APCI calc'd for C14H25BrNO2Si [M+H]+ 346. found 346 and 348.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.Cl[Si](C)(C)[CH3:15]>CO>[Br:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH3:15])=[O:11])=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1ccc(CBr)cc1
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)Cc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 434.3 %

Procedure:
To a stirred suspension of 2-(4-(bromomethyl)phenyl)acetic acid (5.00 g, 21.8 mmol, 1.0 eq.) in methanol (75 mL) was added chlorotrimethylsilane (0.64 mL, 5.02 mmol, 0.23 eq.) at room temperature. The resulting mixture was stirred at room temperature for 2 hr, at which time the reaction was a clear colorless solution. The volatile material was removed under reduced pressure, the residue dissolved in methanol (25 mL), and the volatile material was removed under reduced pressure. This process was repeated two additional times to afford methyl 2-(4-(bromomethyl)phenyl)acetate as an orange solid (5.30 g, quantitative yield). 1H NMR (CDCl3, 500 MHz) δ 7.37-7.33 (m, 2H), 7.26-7.24 (m, 2H), 4.48 (s, 2H), 3.69 (s, 3H), 3.62 (s, 2H). [Lit. J. Med. Chem. 2009, 52, 1180-9.]
Reaction SMILES: CN(C1C=CC=CN=1)C.Cl.CN(CCCN=C=NCC)C.[CH2:22]([N:24]1[CH:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:27](=[O:35])[N:26]([C:36]([CH3:41])([CH3:40])[C:37]([OH:39])=O)[CH2:25]1)[CH3:23].[Cl:42][C:43]1[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][C:44]=1[NH2:45]>ClCCl.O>[Cl:42][C:43]1[C:49]([Cl:50])=[CH:48][CH:47]=[CH:46][C:44]=1[NH:45][C:37](=[O:39])[C:36]([N:26]1[C:27](=[O:35])[CH:28]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:24]([CH2:22][CH3:23])[CH2:25]1)([CH3:41])[CH3:40]
Reactant: Nc1cccc(Cl)c1Cl
Reactant: CCN1CN(C(C)(C)C(=O)O)C(=O)C1c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCN1CN(C(C)(C)C(=O)Nc2cccc(Cl)c2Cl)C(=O)C1c1ccccc1
Reaction time: 0.25 h
Yield: 21.9 %

Procedure:
Dimethylaminopyridine (50 mg) and dimethylaminopropylethylcarbodiimide hydrochloride (0.5 g) were added to a solution of 2-(1-ethyl-5-phenylimidazolidin-4-on-3-yl)isobutyric acid (0.6 g) prepared according to Example 8 in dichloromethane (15 mL) at 0° C. After stirring for 15 minutes at 0° C. to room temperature, 2,3-dichloroaniline (0.4 g) was added and the mixture was stirred overnight at room temperature. The reaction solution was poured into water whose pH was 2, and the mixture was extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the resulting crude product was purified by thin-layer chromatography (silica gel, ethyl acetate/n-hexane=2/3) to give 0.2 g of the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][C:7]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][Cl:3])=[CH:8][C:7]=1[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(F)c(Oc2ccccc2)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Fc1ccc(CCl)cc1Oc1ccccc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 481.6 %

Procedure:
To a stirred solution of 12.6 grams (0.106 mole) of thionyl chloride and one drop (catalyst) of pyridine in 25 mL of toluene was added dropwise a solution of 19.5 grams (0.088 mole) of 4-fluoro-3-phenoxyphenylmethanol in 30 mL of toluene at such a rate as to maintain the reaction mixture temperature at 25°-35° C. Upon completion of the 45 minute addition time, the reaction mixture was warmed to 45° C. where it was stirred during a one hour period. After this time the reaction mixture was cooled, and the excess thionyl chloride was removed under reduced pressure. The residue, 23.5 grams of a semi-solid mixture, was combined with 114.2 grams of the same material from a previous reaction. The combination was distilled under reduced pressure yielding 100.3 grams of 4-fluoro-3-phenoxyphenylmethyl chloride; b.p. 98°-105° C./0.025-0.055 mm. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1.[NH2:19][C:20]1[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=1[C:22]([NH:24][CH2:25][CH:26]1[CH2:28][CH2:27]1)=[O:23].CCN(CC)CC>CC(O)C>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[N:3]=[C:2]2[NH:19][C:20]1[CH:32]=[CH:31][CH:30]=[CH:29][C:21]=1[C:22]([NH:24][CH2:25][CH:26]1[CH2:28][CH2:27]1)=[O:23]
Reactant: Nc1ccccc1C(=O)NCC1CC1
Reactant: Clc1ccc2nc(-c3cccnc3)nc(Cl)c2c1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=C(NCC1CC1)c1ccccc1Nc1nc(-c2cccnc2)nc2ccc(Cl)cc12
Temperature: 25 °C

Procedure:
A 100 mL round bottom flask was charged with 4,6-dichloro-2-(pyridin-3-yl)quinazoline (synthesized as described in Scheme 1 and 4, substituting 5-chloro-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid) (150 mg, 0.54 mmol) and 2-amino-N-(cyclopropylmethyl)benzamide) (310 mg, 1.63 mmol) and anhydrous i-PrOH (20 mL) was added and refluxed for 3 h. The reaction mixture was cooled to room temperature and Et3N (3 eq) was added. The solvent was removed in vacuo. To the crude product was added a water-methanol mixture (5:1, 50 mL), and then sonicated for 5 min. The solidified compound was collected by filtration, and the solid was recrystallized from hot methanol and washed with water. The product was dried at 50° C. to give 2-(6-chloro-2-(pyridin-3-yl)quinazolin-4-ylamino)-N-(cyclopropylmethyl)benzamide as a colorless cotton (220 mg, 94%). The structure was confirmed by NMR and elemental analysis. 1H NMR (Bruker 300 MHz, DMSO-d6) ppm 0.20-0.98 (m, 5H), 3.07-3.21 (m, 2H), 7.24-8.26 (m, 7H), 8.68-9.55 (m, 5H), 12.22 (s, 1H). CHN Calcd. C, 67.05; H, 4.69; N, 16.29. Found C, 67.15; H, 4.89; N, 16.25
Reaction SMILES: [CH:1]([O:3][CH2:4][CH:5]([CH3:7])[CH3:6])=[CH2:2].[C:8]([O:13][CH2:14][CH:15]([CH3:17])[CH3:16])(=[O:12])[C@@H:9]([CH3:11])[OH:10]>P(Cl)(Cl)(Cl)=O.C(OCC)(=O)C>[CH2:4]([O:3][CH:1]([O:10][C@H:9]([CH3:11])[C:8]([O:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[O:12])[CH3:2])[CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)COC(=O)[C@@H](C)O
Reactant: C=COCC(C)C
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)COC(=O)[C@@H](C)OC(C)OCC(C)C
Temperature: 25 °C
Yield: 86.7 %

Procedure:
24.0 g of dehydrated isobutyl vinyl ether was dropwise added to a mixture of 32.7 g of isobutyl (R)-(+)-lactate and 0.3 g of phosphorus oxychloride which was being stirred at room temperature, so that the internal temperature of the reaction system could be kept at 40° C. or less. Then, the resulting mixture was stirred at room temperature overnight. After the reaction, thereto was added 200 ml of ethyl acetate, followed by washing with a saturated aqueous sodium hydrogen carbonate solution, water and a saturated aqueous sodium chloride solution in this order. The washed material was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove the solvent. The resulting concentrate was subjected to distillation to obtain 47.8 g (yield: 96.9%) of an oily title compound (diastereomixture).
Reaction SMILES: [Cl:1][C:2]1[C:20]([NH:21][C:22](=[O:35])[CH2:23][N:24]2[C:28](=[O:29])[C:27]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]3[C:25]2=[O:34])=[CH:19][CH:18]=[C:17]([Cl:36])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2.[CH3:37]N(C)C=O.[H-].[Na+].CI>O>[Cl:1][C:2]1[C:20]([N:21]([C:22](=[O:35])[CH2:23][N:24]2[C:25](=[O:34])[C:26]3=[CH:33][CH:32]=[CH:31][CH:30]=[C:27]3[C:28]2=[O:29])[CH3:37])=[CH:19][CH:18]=[C:17]([Cl:36])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(NC(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Reaction time: 0.5 h

Procedure:
To a mixture of 8-[2,6-dichloro-3-(phthalimidoacetylamino)benzyloxy]-2-methylquinoline (4.44 g) and N,N-dimethylformamide (44 ml) was added sodium hydride (60% in oil, 375 mg) in an ice-water bath. After stirring for 30 minutes in an ice-water bath, methyl iodide (0.6 ml) was added thereto and the mixture was stirred at ambient temperature for 1 hour. To this mixture was added, water (88 ml) in an ice-water bath and the mixture was stirred at the same temperature for 1.5 hours. The precipitate was collected by vacuum filtration and washed with water and methanol to give 8-[2,6-dichloro-3-[N-(phthalimidoacetyl)-N-methylamino]benzyloxy]-2-methylquinoline (3.99 g) as a yellow powder.
Reaction SMILES: C[CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[O:9][C:10]([C:17]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([N:26]4[CH2:31][CH2:30][N:29](CC5C=C(C=CC=5)C(OC)=O)[C:28](=O)[CH2:27]4)=[N:24][CH:25]=3)=[O:18])=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)[CH2:3]1.[Cl:44][C:45]1[CH:50]=[C:49]([Cl:51])[CH:48]=[C:47]([Cl:52])[C:46]=1[S:53](Cl)(=[O:55])=[O:54]>>[N:4]1([C:8]2[O:9][C:10]([C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([N:26]4[CH2:31][CH2:30][N:29]([S:53]([C:46]5[C:47]([Cl:52])=[CH:48][C:49]([Cl:51])=[CH:50][C:45]=5[Cl:44])(=[O:55])=[O:54])[CH2:28][CH2:27]4)=[CH:22][CH:21]=3)=[O:18])=[C:11]([C:13]([F:14])([F:16])[F:15])[N:12]=2)[CH2:3][CH2:2][CH2:7][CH2:6][CH2:5]1
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Cl)cc1Cl
Reactant: COC(=O)c1cccc(CN2CCN(c3ccc(NC(=O)c4oc(N5CCCC(C)C5)nc4C(F)(F)F)cn3)CC2=O)c1
Product: O=C(Nc1ccc(N2CCN(S(=O)(=O)c3c(Cl)cc(Cl)cc3Cl)CC2)nc1)c1oc(N2CCCCC2)nc1C(F)(F)F

Procedure:
Compound 152 was prepared by the general procedure for compound 8, by using compound C-3 and 2,4,6-trichlorophenylsulfonyl chloride as the starting materials. LCMS (ESI) Rt=4.56 min, [M+1]+ 669.4.
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][CH:38]=[C:39]([CH:42]=2)[C:40]#[N:41])O1>>[C:40]([C:39]1[CH:42]=[C:35]([C:2]2[C:3]([N:22]([CH2:24][CH2:25][OH:26])[CH3:23])=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)[CH:36]=[N:37][CH:38]=1)#[N:41]
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Reactant: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Product: CN(CCO)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cncc(C#N)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 151 using 5-bromo-6-((2-hydroxyethyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 151.1) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile to afford a yellow wax. UPLC-MS (Condition 3) tR=1.02 min, m/z=458.3 [M+H]+, m/z=456.3 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.69 (s, 3H) 3.47 (t, J=5.38 Hz, 2H) 3.56 (t, J=6.11 Hz, 2H) 4.34-4.84 (m, 1H) 7.36 (d, J=8.31 Hz, 2H) 7.79-7.90 (m, 2H) 8.14 (d, J=2.45 Hz, 1H) 8.45 (t, J=2.08 Hz, 1H) 8.77 (d, J=2.20 Hz, 1H) 9.00 (dd, J=7.21, 2.08 Hz, 2H) 10.21 (s, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][C:16]#[CH:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[CH3:23][O:24][CH2:25][O:26][C:27]1[CH:36]=[C:35]2[C:30]([C:31](=[O:48])[C:32]([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][O:46][CH3:47])=[CH:40][CH:39]=3)([CH3:37])[CH2:33][S:34]2)=[CH:29][CH:28]=1.[Cl-].[NH4+]>O1CCCC1>[Si:1]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][C:16]#[C:17][C:31]1([OH:48])[C:30]2[C:35](=[CH:36][C:27]([O:26][CH2:25][O:24][CH3:23])=[CH:28][CH:29]=2)[S:34][CH2:33][C:32]1([C:38]1[CH:39]=[CH:40][C:41]([O:44][CH2:45][O:46][CH3:47])=[CH:42][CH:43]=1)[CH3:37])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2=O)cc1
Reactant: C#CCOCCOCCO[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCOc1ccc(C2(C)CSc3cc(OCOC)ccc3C2(O)C#CCOCCOCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
To a solution of 9-(t-butyldimethylsilyloxy)-4,7-dioxa-1-nonyne (1.03 g, 4.01 mmol) in dry tetrahydrofuran (10 ml) was added dropwise -n-butyl lithium (2.3 ml, 3.74 mmol, 1.63 mole/l in tetrahydrofuran) at −78° C., which was then stirred at −20° C. for 1 hour. Then, to this reaction mixture was added 7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylthiochroman-4-one (1.0 g, 2.67 mmol) dissolved in tetrahydrofuran (10 ml) at the same temperature for 30 min, and the resulting mixture was stirred at −10° C. (for 24 hours. After the reaction was completed, saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane:ethyl acetate=4:1) to give the title compound (1.15 g, yield: 68%) as a colorless oil.
Reaction SMILES: Cl.[CH2:2]([NH2:6])[CH2:3][C:4]#[CH:5].C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>ClCCl.Cl>[CH2:2]([NH:6][S:15]([CH3:14])(=[O:17])=[O:16])[CH2:3][C:4]#[CH:5]
Reactant: C#CCCN
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCCNS(C)(=O)=O
Reaction time: 3 h

Procedure:
To a 5-10° C. solution of tert-butyl but-3-yn-1-ylcarbamate (115 g, 0.675 mol) in dichloromethane (500 mL) was added 4N hydrochloric acid in dioxane (650 mL, 2.60 mol). After 3 hours at ambient temperature, the reaction mixture was concentrated in vacuo. The residue was washed with dichloromethane, then with diethyl ether, and then dried in vacuo to afford but-3-yn-1-amine hydrochloride as an intermediate. To a −5 to −10° C. solution of but-3-yn-1-amine hydrochloride and triethylamine (206 mL, 1.47 mol) in dichloromethane (500 mL) was added methanesulfonyl chloride (68.4 mL, 0.88 mol). After 3 hours at ambient temperature, the reaction mixture was diluted with 1N hydrochloric acid (150 mL). The organics were separated, washed with saturated aqueous sodium bicarbonate (150 mL) and with brine, then dried over magnesium sulfate, filtered, and concentrated in vacuo to afford N-but-3-yn-1-ylmethanesulfonamide.
Reaction SMILES: [OH:1][N:2]=[C:3]([Br:5])Br.[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.CC(=O)OCC>[Br:5][C:3]1[N:11]=[C:10]([C:9]2[CH:12]=[CH:13][CH:14]=[C:7]([Cl:6])[CH:8]=2)[O:1][N:2]=1
Reactant: ON=C(Br)Br
Reactant: N#Cc1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Clc1cccc(-c2nc(Br)no2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Hydroxycarbonimidic dibromide (2.21 g, 10.89 mmol) was added portionwise over 1 h 20 min to a mixture of 3-chlorobenzonitrile (3.00 g, 21.29 mmol) and NaHCO3 (2.9 g, 34.87 mmol) in toluene (3 ml) at 90° C. Stirring was continued for 3 h and then the reaction mixture was cooled to r.t., diluted with EA and washed with water. The organic phase was dried and concentrated. A mixture of 3-chlorobenzonitrile and 3-bromo-5-(3-chlorophenyl)-1,2,4-oxadiazole was obtained after flash chromatography (hex/EA 10:1). 1.0 g of the mixture was dissolved in MeNH2 (4 ml, 8.5 M in EtOH) and heated in a microwave reactor for 30 min at 60° C. The volatiles were removed under reduced pressure and the residue was dissolved in water and extracted with CHCl3. The organic phase was dried and concentrated. Recrystallization from EA gave 137 mg of the title compound. 1H NMR: 3.00 (d, 3 H) 4.35 (bs, 1 H) 7.43 (t, 1 H) 7.50-7.55 (m, 1 H) 7.92 (d, 1 H) 8.03 (s, 1 H)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][OH:4].[CH3:5][O:6][C:7]1[CH:26]=[CH:25][CH:24]=[CH:23][C:8]=1[C:9](Cl)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O>N1C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:26]=[CH:25][CH:24]=[CH:23][C:8]=1[C:9]([O:4][CH2:3][CH2:2][Cl:1])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccccc1C(Cl)(c1ccccc1)c1ccccc1
Reactant: OCCCl
Solvent: O
Solvent: c1ccncc1
Product: COc1ccccc1C(OCCCl)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
2-Chloroethanol (4.02 ml, 60 mmol) and monomethoxytrityl chloride (9.2643 g, 30 mmol) were stirred in pyridine (150 ml) at room temperature for 3 hours. Cold water (15 ml) was added to the reaction solution and the mixture was stirred for 30 minutes, and the reaction mixture was extracted with chloroform (500 ml) and washed with water (200 ml ×3 times). The organic layer was dried with anhydrous magnesium sulfate. The magnesium sulfate was removed by filtration and the filtrate was distilled under a reduced pressure. n-Hexane (100 ml) was added to the residue to effect crystallization, and thus 9.6307 g (yield=91%) of 2-chloroethyl monomethoxytrityl ether <1> was obtained.
Reaction SMILES: [OH:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.C(O)C>ClCCl>[OH:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([O:5][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([O:10][CH3:9])=[CH:12][CH:13]=1)=[O:4]
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)[C@H](O)C(=O)O
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(COC(=O)[C@@H](O)C(C)C)cc1

Procedure:
2-hydroxy-3-methyl-(S)-(+)-butyric acid (1.77 g) was esterified by alkylation with 4-methoxybenzyl chloride by the method described in Example A-I-1, step a. The title compound (3.10 g) was obtained after silica gel column chromatography (0, 1, 2% ethanol in dichloromethane). Rf (2%MeOH/CHCl3) 0.50.