Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:8]1[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:10](=[O:16])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]=O.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.[ClH:25]>CO>[ClH:25].[NH:1]([C:8]1[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][C:10](=[O:16])[C:9]=1[CH2:17][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=O
Reactant: CC1(C)CC(=O)C=C(Nc2ccccc2)C1
Reactant: C1COCCN1
Agent: Cl
Solvent: CO
Product: CC1(C)CC(=O)C(CN2CCOCC2)=C(Nc2ccccc2)C1
Reaction time: 1 h

Procedure:
2.15 Parts of 3-anilino-5,5-dimethyl-2-cyclohexen-1-one is dissolved in 10 volume parts of methanol under heating and, then, to the resulting solution are added 0.9 part of a 37 weight % aqueous solution of formaldehyde, 0.87 part of morpholine and 1.6 part of 20 weight % hydrochloric acid. The mixture is allowed to stand at room temperture for 1 hour, after which time the methanol is distilled off under reduced pressure, whereupon yellow crystals separate. The crystals are collected by filtration, washed with isopropyl ether and recrystallized from acetone. The procedure yields colorless scales of 3-anilino-5,5-dimethyl-2-morpholinomethyl-2-cyclohexen-1- one hydrochloride. Melting point: 172°-173° C
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[C:6]2[N:7]=1.[C:13]1(OC)C=CC=CC=1.[F:21][C:22]([F:29])([F:28])[S:23]([O:26]C)(=[O:25])=[O:24]>C(OCC)(=O)C>[F:21][C:22]([F:29])([F:28])[S:23]([O-:26])(=[O:25])=[O:24].[CH3:13][N:7]1[C:6]2=[CH:8][CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[NH+:4][CH:3]1[S:2][CH3:1]
Reactant: CSc1nc2cccccc-2n1
Reactant: COS(=O)(=O)C(F)(F)F
Reactant: COc1ccccc1
Solvent: CCOC(C)=O
Product: CSC1[NH+]=C2C=CC=CC=C2N1C
Product: O=S(=O)([O-])C(F)(F)F
Yield: 82 %

Procedure:
25 g of 2-methylthiocycloheptimidazole was added to 100 ml of anisole and stirred under cooling with ice. Next, 28 g of methyl trifluoromethanesulfonate was dropwise added and stirred under cooling with ice. Further, everything was stirred for 2 hours and 30 minutes at room temperature, and then, 200 ml of ethyl acetate was added, and the crystals precipitated were separated by filtration and dried. 39.7 g of a colorless crystals was obtained.
Reaction SMILES: [C:1]1([C:7]2[CH:25]=[CH:24][C:10]3[O:11][C:12]4[CH:17]=[CH:16][C:15]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[CH:14][C:13]=4[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[B:31](OC)([O:34]C)[O:32]C.Cl>CCCCCC.C(OCC)(=O)C.O1CCCC1>[C:18]1([C:15]2[CH:16]=[C:17]([B:31]([OH:34])[OH:32])[C:12]3[O:11][C:10]4[CH:24]=[CH:25][C:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)=[CH:8][C:9]=4[C:13]=3[CH:14]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: c1ccc(-c2ccc3oc4ccc(-c5ccccc5)cc4c3c2)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1cc(-c2ccccc2)cc2c1oc1ccc(-c3ccccc3)cc12
Temperature: -80 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
In a 200 mL three-neck flask was put 2.4 g (7.5 mmol) of 2,8-diphenyldibenzofuran. The air in the flask was replaced with nitrogen. To this mixture was added 40 mL of tetrahydrofuran (THF), and this solution was cooled to −80° C. Then, 5.6 mL (9.0 mmol) of n-butyllithium (a 1.6 mol/L hexane solution) was dripped into this solution with a syringe. After that, this solution was stirred for 2 hours while its temperature was returned to room temperature. Then, this solution was again cooled to −80° C., and 1.7 mL (15 mmol) of trimethyl borate was added to this solution. This solution was stirred for 3 days while its temperature was returned to room temperature. After that, about 30 mL of diluted hydrochloric acid (1.0 mol/L) was added to this solution, followed by stirring for 1 hour. Then, the aqueous layer of this mixture was extracted with ethyl acetate, and the ethyl acetate solution and the organic layer were combined and washed with saturated brine. The organic layer was dried with magnesium sulfate. Then, this mixture was gravity filtered. The resulting filtrate was concentrated to give an oily substance, and a mixed solvent of ethyl acetate and hexane was added to the oily substance. The mixture was irradiated with ultrasonic waves, whereby a solid was precipitated. This solid was collected by suction filtration to give 2.2 g of a white powder in 82% □ yield, which was the substance to be produced.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([CH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1)[CH2:10][CH2:11][CH2:12][CH3:13].[Cl-].[NH4+]>C1COCC1>[CH2:9]([CH:14]1[CH2:19][CH2:18][C:17]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:16][CH2:15]1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: Brc1ccccc1
Reactant: CCCCCC1CCC(=O)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCC1CC=C(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 2,000 mL (inside volume) three-necked flask equipped with a reflux condenser, 700 mL of anhydrous THF and 27 g of magnesium shavings were charged, to which 160 g of bromobenzene were added dropwise at a speed to ensure continuous mild reflux. After the dropping was completed, the mixture was further stirred for 1 h. To the mixture, a solution of 170 g of 4-n-pentylcyclohexanone (available from Tokyo Chemical Industry Co., Ltd.) in 100 mL of THF was added at 50° C. The mixture was then refluxed for 2 h. The obtained reaction product liquid was cooled to room temperature, poured into an aqueous ammonium chloride solution and then extracted with benzene. The benzene solution was added with 1 g of p-toluenesulfonic acid and refluxed while removing water generated. When water was no longer distilled, the reaction mixture was cooled to room temperature, washed with an aqueous sodium hydrogen carbonate solution and then with an aqueous sodium chloride solution, dried and then concentrated. The residue was purified by silica gel column chromatography to obtain (4-n-pentylcyclohexenyl)benzene. The thus obtained product was dissolved in 1,000 mL of ethyl acetate and subjected to hydrogenation at 0.5 MPa using 2 g of 5% by mass-Pd/C as a catalyst. When a theoretical amount of hydrogen was consumed, the catalyst was separated by filtration. The resulting filtrate was concentrated to obtain 220 g of (4-n-pentylcyclohexyl)benzene. As a result of gas chromatographic analysis, it was confirmed that the (4-n-pentylcyclohexyl)benzene purity was 99.2% and the cis/trans molar ratio was 0.67.
Reaction SMILES: ClC1C(Cl)=CC=CC=1N1CCCN([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH:24]=[CH:25][C:26](=[O:30])[NH:27]3)=[CH:22][CH:21]=2)CC1.[Na+].[I-].[O:33]1[CH2:38][CH2:37][O:36][C:35]2[C:39]([N:43]3[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]3)=[CH:40][CH:41]=[CH:42][C:34]1=2.[C:49]([O-])([O-])=O.[K+].[K+]>CC#N>[O:33]1[CH2:38][CH2:37][O:36][C:35]2[C:39]([N:43]3[CH2:44][CH2:45][N:46]([CH2:49][CH2:16][CH2:17][CH2:18][O:19][C:20]4[CH:29]=[C:28]5[C:23]([CH:24]=[CH:25][C:26](=[O:30])[NH:27]5)=[CH:22][CH:21]=4)[CH2:47][CH2:48]3)=[CH:40][CH:41]=[CH:42][C:34]1=2
Reactant: O=c1ccc2ccc(OCCCN3CCCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Reactant: O=C([O-])[O-]
Reactant: c1cc2c(c(N3CCNCC3)c1)OCCO2
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5c4OCCO5)CC3)cc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.7 %

Procedure:
A mixture of intermediate 15 (70 mg, 0.24 mmol) and NaI (70 mg, 0.48 mmol) in CH3CN was heated to reflux for 30 min and then cooled to rt. Intermediate 61 (78 mg, 0.36 mmol) and anhydrous K2CO3 (162 mg, 0.96 mmol) were added to the mixture. The resulting mixture was heated to reflux and stirred for 4 h. Precipitated crystals were filtered off and the filtrate was evaporated under reduced pressure. The residue was extracted with EtOA. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=30:1) to give 7-(4-(4-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)piperazin-1-yl)butoxy)quinolin-2(1H)-one (compound 42) (52 mg, 50%). 1H NMR (300 MHz, CDCl3): δ 11.65 (brs, 1H), 7.72 (d, J=9.6 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 6.82-6.75 (m, 3H), 6.61-6.52 (m, 3H), 4.33-4.26 (m, 4H), 4.12-4.08 (m, 2H), 3.12 (br, 4H), 2.70 (br, 4H), 2.52 (br, 2H), 2.04-1.68 (m, 6H). HPLC: 99%, RT 2.167 min. MS (ESI) m/z 436.0 [M+H]+.
Reaction SMILES: N1C=CN=C1.[NH:6]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:7]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([NH2:18])=O)=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9].O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:16]([C@@H:15]1[CH2:19][CH2:20][CH2:21][N:14]1[C:12](=[O:13])[C@H:7]([C@H:8]([CH2:10][CH3:11])[CH3:9])[NH:6][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])#[N:18]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(N)=O
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C#N
Reaction time: 1 h
Yield: 94 %

Procedure:
Imidazole (84 mg, 1.24 mmol) was added to a solution of BocIleProNH2 in dry pyridine (10 cm3), under a nitrogen atmosphere. The solution was cooled to -35° C., before the dropwise addition of POCl3 (0.25 cm3, 2.48 mmol). The reaction was stirred at -30° C. to -20° C. for 60 min. The solution was then evaporated and the crude residue subjected to column chromatography (silica gel) to yield 180 mg (94%) of 2-(S)-cyano-1-[N-(t-butoxycarbonyl)isoleucyl]pyrrolidine as a colourless oil.
Reaction SMILES: [NH2:1][C:2](=[O:27])[CH:3]([CH3:26])[C@H:4]([NH:18]C(=O)OC(C)(C)C)[C:5]1[NH:9][C:8]2[CH:10]=[CH:11][C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:13][C:7]=2[N:6]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:18][C@H:4]([C:5]1[NH:9][C:8]2[CH:10]=[CH:11][C:12]([C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:13][C:7]=2[N:6]=1)[C@@H:3]([CH3:26])[C:2]([NH2:1])=[O:27]
Reactant: CC(C(N)=O)[C@H](NC(=O)OC(C)(C)C)c1nc2cc(C(C)(C)C)ccc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](C(N)=O)[C@H](N)c1nc2cc(C(C)(C)C)ccc2[nH]1

Procedure:
A solution of tert-butyl [(1S)-3-amino-1-(5-tert-butyl-1H-benzimidazol-2-yl)-2-methyl-3-oxopropyl]carbamate (Preparation 29, 3.07 g, 8.2 mmol) in DCM (50 mL) and TFA (10 mL) was stirred at room temperature for 3 hours before concentrating in vacuo. Saturated aqueous NaHCO3 solution (100 mL) was added and the product extracted with 2-MeTHF (4×100 mL). The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified using reverse phase column chromatography eluting with 0-40% acetonitrile in water. The resulting solid was dissolved in MeCN (40 mL) at 50° C. and methanol added before allowing the solution to cool. The resulting white precipitate was collected, dried, and further triturated with EtOAc (5 mL) twice to afford a white solid as the desired (2R,3S) diastereomer.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[CH:8]=[CH:7]2.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: [H][H]
Reactant: Cc1cccc2ccc(=O)oc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cccc2c1OC(=O)CC2
Reaction time: 5 h
Yield: 88.4 %

Procedure:
To a solution of 8-Methyl coumarin (16.2 gm) in Ethyl acetate (160 ml), 10% w/w Palladium-charcoal (1.62 gm) was added. Hydrogenation was carried out for 5 hours at 55-60° C. in an autoclave at 240-250 psi. using Hydrogen gas. The reaction mixture was filtered through hyflow bed and distilled under vacuum to give a 14.5 gm of title compound as a white solid.
Reaction SMILES: [C:1]([O:8][C@@H:9]1[C@@H:23]([OH:24])[C@@H:22]([OH:25])[C@@H:21]([CH3:26])[O:20][C@@H:10]1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].C([Sn](=O)CCCC)CCC.[CH2:37](Br)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1(C)C=CC=CC=1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:37]([O:24][C@H:23]1[C@@H:22]([OH:25])[C@@H:21]([CH3:26])[O:20][C@H:10]([O:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[C@@H:9]1[O:8][C:1](=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COc1ccc(O[C@H]2O[C@H](C)[C@H](O)[C@H](O)[C@H]2OC(=O)CCC(C)=O)cc1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCCC[Sn](=O)CCCC
Agent: [I-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(O[C@H]2O[C@H](C)[C@H](O)[C@H](OCc3ccccc3)[C@H]2OC(=O)CCC(C)=O)cc1
Temperature: 60 °C

Procedure:
4-Methoxyphenyl 2-O-levulinoyl-α-D-fucopyranoside (2.37 g, 6.46 mmol) and dibutyl tin oxide (1.61 g, 6.46 mmol) are dissolved in 70 mL of toluene. The mixture was refluxed with a Dean-Stark trap for 2.5 h. Then it was cooled to 60° C., benzylbromide and tetrabutylammonium iodide were added and refluxed for 2 h. After cooling to room temperature the reaction mixture was diluted with water and extracted 3 times with EtOAc, dried over Na2SO4 and concentrated. The crude product was purified by column chromatography (3:2 hexane/EtOAc) yielding 2.82 g (95%, 2 steps) of 6 as a colorless oil: [α]D: +140.8 (c=0.35, CHCl3). IR (thin film, CHCl3): 3015, 1739, 1713, 1503, 1362, 1050 cm−1. 1H NMR (CDCl3, 300 MHz) δ 1.29 (d, J=6.6 Hz, 3H), 2.14 (s, 3H), 2.62 (m, 3H), 2.72 (m, 2H), 3.76 (s, 3H), 3.92 (s, 1H), 4.09 (m, 2H), 4.74 (s, 2H), 5.28 (dd, J=10.2 Hz J=3.9 Hz, 1H), 5.50 (m, 1H), 6.82 (d, J=9.0 Hz, 2H), 6.98 (d, J=9.0 Hz, 2H), 7.33 (m, 5H). 13C NMR (CDCl3, 75 MHz) 16.2, 28.1, 29.9, 37.9, 55.7, 66.2, 69.8, 70.0, 72.4, 75.6, 96.2, 114.5, 118.0, 118.2, 127.6, 127.7, 127.9, 128.5, 137.7, 150.7, 155.0, 172.0, 206.0. MALDI-HRMS: m/z [M+Na]+ calcd 481.1833, obsd 481.1824.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:17][CH2:16]3)[N:10]=2)=[CH:5][CH:4]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH2:34][CH2:35][NH:36][CH2:37][CH:38]=2)=[CH:29][CH:28]=1>>[ClH:1].[ClH:1].[CH:21]1([N:18]2[CH2:17][CH2:16][CH:15]([CH2:14][C:11]3[N:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][N:36]5[CH2:35][CH:34]=[C:33]([C:30]6[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=6)[CH2:38][CH2:37]5)=[CH:4][CH:5]=4)[O:13][N:12]=3)[CH2:20][CH2:19]2)[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: ClCc1ccc(-c2nc(CC3CCN(C4CCCC4)CC3)no2)cc1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Product: Cl
Product: Fc1ccc(C2=CCN(Cc3ccc(-c4nc(CC5CCN(C6CCCC6)CC5)no4)cc3)CC2)cc1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 23, starting from 4-[5-(4-chloromethylphenyl)[1,2,4]oxadiazol-3-ylmethyl]-1-cyclopentylpiperidine and 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine. HPLC: Rt=11.63 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:16][CH:17]1[CH2:21][CH2:20]S[CH2:18]1.ClC1C=C(C=CC=1)C(OO)=O.[S:33]([O-:36])([O-])=[O:34].[Na+].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:16][CH:17]1[CH2:21][CH2:20][S:33](=[O:36])(=[O:34])[CH2:18]1
Reactant: CCOC(=O)c1cc(Br)cc2c(CC3CCSC3)c[nH]c12
Reactant: O=S([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)cc2c(CC3CCS(=O)(=O)C3)c[nH]c12
Reaction time: 5 h
Yield: 42.56 %

Procedure:
To a solution of ethyl 5-bromo-3-(tetrahydro-3-thienylmethyl)-1H-indole-7-carboxylate (7.61 g, 20.73 mmol) in dichloromethane (150 mL) was added portionwise 3-chlorobenzoperoxoic acid (10.69 g, 62.19 mmol) at room temperature. The resulting solution was stirred for 5 h. Sodium sulfite was added, and the mixture was washed with water, extracted with DCM (3×100 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by column on sillal gel (petroleum:ethyl acetate=10:1 to 5:1 to 2:1), giving 3.52 g (42.56%) of the title compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:9]=[N:10][N:11]([C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]=2)[CH:12]=1)(=O)=O.[F:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][NH:27][CH3:28])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][N:27]([CH3:28])[CH2:6][CH2:7][C:8]2[CH:9]=[N:10][N:11]([C:13]3[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]=3)[CH:12]=2)=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)OCCc1cnn(-c2cc(C#N)ccn2)c1
Reactant: CNCc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCc1cnn(-c2cc(C#N)ccn2)c1)Cc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To a mixture of 2-[1-(4-cyanopyridin-2-yl)pyrazol-4-yl]ethyl methanesulfonate (476 mg, 1.6 mmol) and (4-fluoro-benzyl)-methyl-amine (444 mg, 3.2 mmol) in ACN (30 mL) at rt was added K2CO3 (4.5 g, 32 mmol) and KI (1.0 g, 6.2 mmol. The reaction mixture was heated to 80° C. and stirred overnight. Filtered, solvent removed and purified by prep-HPLC to give the title compound (270 mg, 50%). [M+H] Calc'd for C19H18FN5, 336; Found, 336.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].[Li]CCCC.CCCCCC.BrC(C)=C.COCN[C:27]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][N:33]=[C:32]2[NH:39][C:40]1[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[CH:49]=2)=[C:42]([Cl:55])[CH:41]=1)=[O:28].Cl>O1CCCC1>[Cl:55][C:42]1[CH:41]=[C:40]([NH:39][C:32]2[C:31]3[C:36](=[CH:37][CH:38]=[C:29]([C:27](=[O:28])[C:2]#[C:1][CH3:3])[CH:30]=3)[N:35]=[CH:34][N:33]=2)[CH:45]=[CH:44][C:43]=1[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[CH:49]=1
Reactant: CC(C)NC(C)C
Reactant: COCNC(=O)c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Agent: C=C(C)Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC#CC(=O)c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4.22 ml of N,N-diisopropylamine in tetrahydrofuran (25 ml) cooled to −78° C. was added dropwise 18.8 ml of 1.6 mol/L n-BuLi hexane solution. After completion of addition, a temperature was elevated to 0° C., and the mixture was stirred at 0° C. for 20 minutes, and cooled again to −78° C. 1.33 ml of 2-bromo-1-propene in tetrahydrofuran (25 ml) was added, and the mixture was stirred at −78° C. for 2 hours. To the mixture was added dropwise a solution of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-quinazoline-6-carboxylic acid methoxy methyl amide (XI-1, 2.33 g) in tetrahydrofuran (50 ml) and, after completion of addition, a temperature was elevated to 0° C., followed by stirring for 3 hours. After completion of the reaction, the reaction mixture was poured into ice water, neutralized with 2 mol/L hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, the filtrate was concentrated, and the resulting crystalline residue was washed with methylene chloride to obtain 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-oxo-2-butyn-1-yl)quinazoline (VII-4, 1.71 g) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:20])[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:20])[CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2ccc(F)c(F)c2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1(c2ccc(F)c(F)c2)CNC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.5 %

Procedure:
A mixture of tert-butyl 3-(3,4-difluorophenyl)-3-hydroxyazetidine-1-carboxylate (1.06 g, 3.72 mmol) and trifluoroacetic acid (3 ml) in dichloromethane (30 ml) was stirred at ambient temperature for 1.5 h. The solvent was evaporated and the crude product was purified on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine, 4:1) to give the title compound (0.52 g). MS m/z (rel. intensity, 70 eV) 185 (M+, 1), 156 (50), 141 (bp), 127 (58), 114 (90).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:15]O>>[CH3:15][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[Cl:1]
Reactant: CO
Reactant: O=C(O)c1cccnc1Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 89 %

Procedure:
To a suspension of 2-chloronicotinic acid 3 (15.8 g, 0.1 mol) in 100 ml of dry MeOH at 0° C. was added thionyl chloride (17.8 g, 0.15 mol) dropwise. The reaction was then slowly warmed to room temperature and stirred for 2 days. The solvent was then removed via vacuum and the residue was dissolved in sat. NaHCO3. The resulted basic solution was then extracted with EtOAc (3×100 ml). The combined organic phases were washed with brine, dried with NaSO4, concentrated via vacuum to give 2-chloronicotinic methyl ester 4(15.3 g, 89%) as an oil: 1H NMR (CDCl3, 300 MHZ) δ 8.52 (dd, J=1.8, 4.5 Hz, 1H), δ 8.19 (dd, J=2.1, 7.8 Hz, 1H), δ 7.38 (dd, J=4.8, 7.8 Hz, 1H), δ 3.97 (s, 3H)
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([NH:12][C:13](=[O:15])[CH3:14])=[CH:7][C:6]=1[CH3:16])=O.[NH2:17][C:18]([NH2:20])=[S:19].CCO>C1(C)C=CC=CC=1>[NH2:20][C:18]1[S:19][CH:2]=[C:3]([C:5]2[C:10]([CH3:11])=[CH:9][C:8]([NH:12][C:13](=[O:15])[CH3:14])=[CH:7][C:6]=2[CH3:16])[N:17]=1
Reactant: NC(N)=S
Reactant: CC(=O)Nc1cc(C)c(C(=O)CCl)c(C)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(=O)Nc1cc(C)c(-c2csc(N)n2)c(C)c1
Yield: 86.2 %

Procedure:
A solution of compound N-(4-(2-chloroacetyl)-3,5-dimethylphenyl)acetamide (3.4 g, 14.2 mmol), thiourea (1.79 g, 23.6 mmol) and KI (150 mg) in toluene (50 mL) and 95% EtOH (50 mL) was refluxed overnight. After the solvent was distilled off, the residue was dissolved in EtOAc (600 mL) and washed with saturated Na2CO3 solution and brine successively, and dried over Na2SO4. After removal of solvent, the residue was subjected to column chromatography (silica gel, EtOAc:NH4OH=100:0.5) to furnish N-(4-(2-aminothiazol-4-yl)-3,5-dimethylphenyl)acetamide (3.2 g, 86.1% yield).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:6][CH:5]=1)=[C:2]=[S:3].[H-].[Na+].[C:18]([CH:21]([CH2:27][CH2:28][C:29]([O:31]CC)=O)[C:22](OCC)=[O:23])(=[NH:20])[NH2:19].Cl>CN(C)C=O>[S:3]=[C:2]1[NH:19][C:18]2[NH:20][C:29](=[O:31])[CH2:28][CH2:27][C:21]=2[C:22](=[O:23])[N:1]1[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]([F:13])([F:15])[F:14])=[CH:8][CH:9]=1
Reactant: FC(F)(F)COc1ccc(N=C=S)cc1
Reactant: CCOC(=O)CCC(C(=N)N)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2c([nH]c(=S)n(-c3ccc(OCC(F)(F)F)cc3)c2=O)N1
Reaction time: 0.08 h
Yield: 26.6 %

Procedure:
To a solution of 1-isothiocyanato-4-(2,2,2-trifluoroethoxy)benzene (1.77 g) in N,N-dimethylformamide (25 mL) was added sodium hydride (60% in oil, 0.478 g) under ice-cooling. The reaction mixture was stirred for 5 min under ice-cooling, diethyl 2-carbamimidoylpentane-1,5-dioate (2.5 g) was added thereto, and the mixture was stirred for 30 min under ice-cooling. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (25 mL), sodium ethoxide (20% ethanol solution, 10.6 mL) was added thereto, and the mixture was stirred for 30 min. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.75 g).