Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:18][CH3:19])=[CH:5][C:6]2[O:10][N:9]=[C:8]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:7]=2[CH:17]=1.[CH3:20][C:21]1[NH:22][C:23]2[C:28]([C:29]=1CCCS(C1C=CC=CC=1)(=O)=O)=[CH:27][CH:26]=[CH:25][CH:24]=2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][O:2][C:3]1[C:4]([O:18][CH3:19])=[CH:5][C:6]2[O:10][N:9]=[C:8]([CH:11]3[CH2:12][CH2:13][N:14]([C:29]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[NH:22][C:21]=4[CH3:20])[CH2:15][CH2:16]3)[C:7]=2[CH:17]=1
Reactant: Cc1[nH]c2ccccc2c1CCCS(=O)(=O)c1ccccc1
Reactant: COc1cc2onc(C3CCNCC3)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2onc(C3CCN(c4c(C)[nH]c5ccccc45)CC3)c2cc1OC
Temperature: 25 °C
Yield: 26.8 %

Procedure:
A stirred mixture of 5.0 g of 5,6-dimethoxy-3-(4-piperidyl)-1,2-benzisoxazole, 6.78 g of 2-methyl-3-(phenylsulfonylpropyl)indole, 120 ml of dimethylformamide and 15.0 g of anhydrous potassium carbonate was heated to 90° for 6 hrs and overnight at ambient temperature. The mixture was poured into water (300 ml) and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to yield a solid. The solid was purified by passing it through a silica gel column (20:1) and eluting it with dichloromethane-methanol (1%). Recrystallization two times from ethanol-water yielded 2.0 g (24%) of product, mp 176°-178°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[N:10])[CH:4]=1)#[N:2].C[O-].[Na+].[Cl-:14].[NH4+:15]>CO>[ClH:14].[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[C:9]([NH2:15])=[NH:10])#[N:2]
Reactant: [Cl-]
Reactant: [NH4+]
Reactant: N#Cc1cccc(C#N)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cl
Product: N#Cc1cccc(C(=N)N)c1

Procedure:
In analogy to Example 1 b), from 1,3-dicyanobenzene and sodium methylate in methanol followed by ammonium chloride there is obtained 3-cyano-benzamidine hydrochloride and therefrom with diethyl (2-methoxy-phenoxy)malonate there is obtained rac.-3-[5-(2-methoxy-phenoxy)-4,6-dioxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-benzonitrile as a white product. From this compound with PCl5 and POCl3 there is obtained 3-[4,6-dichloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-benzonitrile with a melting point of 155-156° from EtOAc. Reaction with 4-tert.-butylbenzenesulphonamide K yields 4-tert.-butyl-N-[6-chloro-2-(3-cyanophenyl)-5-(2-methoxyphenoxy)-pyrimidin-4-yl]-benzenesulphonamide.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][C:5]1[O:6][CH2:7][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:9]=1.CN(C)C1C=CC=CC=1.Cl[C:30]([N:32]=[C:33]=[O:34])=[O:31]>ClCCl>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]1[C:33](=[O:34])[NH:32][C:30](=[O:31])[N:9]2[CH:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:7][O:6][C:5]=12
Reactant: Fc1ccccc1CC1=NC(c2ccccc2)CO1
Reactant: O=C=NC(=O)Cl
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: O=c1[nH]c(=O)n2c(c1-c1ccccc1F)OCC2c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.4 %

Procedure:
To 2-(2-fluorobenzyl)-4-phenyloxazoline (0.250 g, 0.980 mmol) and N,N-dimethylaniline (0.134 g, 1.09 mmol) in dichloromethane (1.5 mL) at 0° C. was added dropwise chlorocarbonyl isocyanate (0.103 g, 0.980 mmol). The mixture was allowed to warm to room temperature and was stirred for 24 h. The solution was concentrated, dissolved in ethyl acetate (1 mL) and filtered through a short pad of silica gel, eluating with ethyl acetate (150 mL). Concentration gave green-yellow crystals (0.300 g) which were used immediately in the next step due. MS=325.1 ((M+H)+).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].COCCOC.[NH2:16][C:17]1[CH:22]=[N:21][CH:20]=[CH:19][N:18]=1>CCO>[CH2:7]([O:6][C:4]([C:3]1[N:16]=[C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]2[CH:2]=1)=[O:5])[CH3:8]
Reactant: CCOC(=O)C(=O)CBr
Reactant: Nc1cnccn1
Solvent: CCO
Solvent: COCCOC
Product: CCOC(=O)c1cn2ccncc2n1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Ethyl bromopyruvate (62.9 g) was added to the DME (258 mL) solution of 2-aminopyrazine (24.8 g) at room temperature and stirred for 2.5 h. The reaction mixture was cooled to 0° C. and stirred for 30 min to afford a pale brown precipitate. The precipitate was filtered and washed with Et2O to give pale brown crystals. The suspension of the precipitate (66.1 g) in EtOH (1.29 L) was heated at reflux temperature to turn to clear solution. After refluxing for 2 h, the reaction mixture was concentrated under reduced pressure, then mixed with CHCl3 and saturated NaHCO3aq. The mixture was filtered through a pad of Celite and the separated organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with CHCl3-MeOH (99/1˜97/3), and collected fractions were concentrated under reduced pressure followed by recrystallization from CHCl3-Et2O. The titled compound was obtained as pale pink crystals. Yield: 10.9 g, 22%).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]>C1(C)C=CC=CC=1>[OH:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:12]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCCCCO
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCCCCO
Yield: 85.7 %

Procedure:
Step 1. A mixture of phthalic anhydride (1.48 g, 10 mmol) and 5-amino-1-pentanol (1.03 g, 10 mmol) in toluene (20 ml) was heated under reflux overnight. The solvent was removed under vacuum, and the residue was purified by chromatography to afford N-(5-hydroxypentyl)phthalimide (2.00 g, 88%) as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 1.37-1.48 (m, 2H), 1.56-1.67 (m, 2H), 1.67-1.79 (m, 2H), 3.64 (t, J=6.5 Hz, 2H), 3.70 (t, J=7.5 Hz, 2H), 7.66-7.76 (m, 2H), 7.80-7.99 (m, 2H). Step 2. Diisopropyl azodicarboxylate (0.69 ml, 3.51 mmol) was added dropwise to a mixture of OZ288 (0.50 g, 1.4 mmol), N-(5-hydroxypentyl)phthalimide (0.65 g, 2.79 mmol), triphenylphosphine (0.92 g, 3.51 mmol), and triethylamine (0.5 ml, 3.51 mmol) in THF (50 ml) at 0° C. under N2 atmosphere. The resulting mixture was stirred at rt for 24 h. After removal of the solvent, the crude product was purified by crystallization from EtOH to afford the desired phenol ether (0.35 g, 44%) as a colorless solid. mp 115-116° C.; 1H NMR (500 MHz, CDCl3) δ 1.46-2.08 (m, 28H), 2.43-2.53 (m, 1H), 3.71 (t, J=7.0 Hz, 2H), 3.92 (t, J=6.5 Hz, 2H), 6.79 (d, J=9.0 Hz, 2H), 7.09 (d, J=9.0 Hz, 2H), 7.67-7.75 (m, 2H), 7.80-7.99 (m, 2H); 13C NMR (125.7 MHz, CDCl3) δ 23.42, 26.49, 26.89, 28.33, 28.85, 31.65, 34.76, 34.81, 36.41, 36.81, 37.85, 42.05, 67.55, 108.46, 111.34, 114.34, 123.18, 127.56, 132.15, 133.86, 138.20, 157.34, 168.43. Step 3. A mixture of the above phenol ether (0.30 g, 0.53 mmol) and hydrazine monohydrate (1 ml) in chloroform (30 ml) and methanol (3 ml) was heated at 50° C. for 24 h. After the reaction mixture was cooled to rt and filtered to the remove a solid by-product, the filtrate was washed with water (2×10 ml) and brine (10 ml), dried over MgSO4, filtered, and concentrated. The residue was dissolved in CH2Cl2 (5 ml) and a solution of methanesulfonic acid (0.05 g, 0.52 mmol) in ethyl acetate (20 ml) was added. The precipitate was collected by filtration to afford trioxolane OZ498 (0.19 g, 68%) as a colorless solid. mp 155-156° C.; 1H NMR (500 MHz, DMSO-d6) δ 1.38-1.98 (m, 28H), 2.30 (brs, 3H), 2.50-2.59 (m, 1H), 2.76-2.85 (m, 2H), 3.92 (t, J=6.3 Hz, 2H), 6.83 (d, J=8.8 Hz, 2H), 7.11 (d, =8.3 Hz, 2H), 7.63 (brs, 3H); 13C NMR (125.7 MHz, DMSO-d6) δ 22.72, 25.98, 26.39, 26.90, 28.35, 31.49, 34.28, 34.44, 35.96, 36.25, 38.97, 40.86, 67.22, 108.32, 110.71, 114.44, 127.58, 138.04, 157.08. Anal. Calcd for C28H43NO7S: C, 62.54; H, 8.06; N, 2.60. Found: C, 62.55; H, 7.93; N, 2.76.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[NH2:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[C:9]#[N:10].[C:15]([CH2:18][C:19](=O)[CH3:20])(=[O:17])[CH3:16]>>[NH2:10][C:9]1[C:8]2[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:6]=[C:19]([CH3:20])[C:18]=1[C:15](=[O:17])[CH3:16]
Reactant: CC(=O)CC(C)=O
Reactant: N#Cc1ccccc1N
Agent: Cl[Sn](Cl)(Cl)Cl
Product: CC(=O)c1c(C)nc2ccccc2c1N

Procedure:
1-(4-Amino-2-methylquinolin-3-yl)ethanone was prepared analogously to Intermediate 2a, Example 6, by tin tetrachloride-promoted reaction of 2-aminobenzonitrile and acetyl acetone in a manner known from the literature (Tetrahedron 51:12277 (1995)).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[N:7]=[C:8]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH3:16])=[CH:11]2.CC1(C)C(C)(C)OB([C:46]2[CH:51]=[CH:50][C:49]([CH2:52][C:53]([O:55][CH2:56][CH2:57][F:58])=[O:54])=[CH:48][CH:47]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:32]([O:31][C:30]([NH:29][C:8]1[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:25])([CH3:27])[CH3:26])([CH3:22])[CH3:23])[CH2:14][CH2:15][CH3:16])=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([C:46]3[CH:47]=[CH:48][C:49]([CH2:52][C:53]([O:55][CH2:56][CH2:57][F:58])=[O:54])=[CH:50][CH:51]=3)=[CH:37][C:6]=2[N:7]=1)=[O:36])([CH3:33])([CH3:34])[CH3:35]
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Reactant: CC1(C)OB(c2ccc(CC(=O)OCCF)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(-c3ccc(CC(=O)OCCF)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Temperature: 100 °C

Procedure:
tert-butyl (1E,4E)-8-bromo-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate, 2-fluoroethyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (1.5 equiv), tetrakis(triphenylphosphine)palladium(0), 2M aqueous potassium carbonate (3 equiv) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) afforded 2-fluoroethyl 2-(4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)[CH2:4][CH2:3]1.[CH2:36]([O:38][C:39](=[O:45])[C:40](=[N+]=[N-])[CH2:41][CH3:42])[CH3:37].O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([C@H:5]3[CH2:6][CH2:7][C@H:2]([O:1][CH:40]([CH2:41][CH3:42])[C:39]([O:38][CH2:36][CH3:37])=[O:45])[CH2:3][CH2:4]3)[C:9]3[N:10]([N:33]=[CH:34][N:35]=3)[C:11]=2[CH2:30][CH2:31][CH3:32])=[CH:17][CH:18]=1)#[N:29]
Reactant: CCOC(=O)C(CC)=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(CC)C(=O)OCC)CC2)c2ncnn12
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.87 g), rhodium(II) acetate (dimer) (0.0084 g) and toluene (10 mL) was heated to 80° C. under an argon atmosphere, a solution of 2-diazobutyric acid ethyl ester (1.0 g) in toluene (10 mL) was added dropwise, and the mixture was stirred at 80° C. for 30 min. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.78 g, 71%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C:5]([CH3:33])([O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][CH:27]=[CH:26]2)[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)O)[CH3:2].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClC(Cl)C.CCOCC>[CH2:1]([O:3][C:4](=[O:34])[C:5]([CH3:33])([O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][CH:27]=[CH:26]2)[CH2:6][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Oc1ccc2ncccc2c1)C(O)c1ccc(OCc2ccccc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: CC(Cl)Cl
Product: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc2ncccc2c1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a LDA solution (42 mL, 1.5 M solution in THF) in 65 mL of dry THF at −78° C., a solution of 2-(quinolin-6-yloxy)-propionic acid ethyl ester (8.61 g, 0.035 mol) in 65 mL of dry THF was cannulated in. The resulting solution is allowed to stand at −78° C. for 3 min. Solid 4-benzyloxy-benzaldehyde (6.71 g, 0.032 mol) was added and resulting mixture was allowed to stand at −78° C. for 5 min until all solid dissovled in the solution. Reaction was then quenched with AcOH (6.03 mL, 0.105 mol) in 60 mL of THF at −78° C. The mixture was then diluted with Et2O and washed with sat'NH4Cl, water and brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by chromatography to give 3-(4-benzyloxy-phenyl)-3-hydroxy-2-methyl-2-(quinolin-6-yloxy)-propionic acid ethyl ester in 86% yield. A of solution of 2.75 g of give 3-(4-benzyloxy-phenyl)-3-hydroxy-2-methyl-2-(quinolin-6-yloxy)-propionic acid ethyl ester (6.01 mmol), trifluoroacetic acid (2.8 mL, 36.1 mmol), triethylsilane (5.8 mL, 36.1 mmol) in 80 mL of dichloroethane was heated to reflux for 50 h. The mixture was cooled to r.t. and diluted with Et2O and washed with sat' NaHCO3, water and brine. Organic layer was dried over Mg SO4, filtered and concentrated. Residue was purified by chromatography (5% MeOH in CH2Cl2) to give 86% of title compound as light yellow oil. 1H NMR (400 MHz, CDCl3) δδ8.78 (dd, 1H, J=4.4, 1.6 Hz), 8.00 (d, 1H, J=9.2 Hz), 7.98 (d, 1H, J=8.8 Hz), 7.45-7.32 (m, 7H), 7.19 (d, 2H, J=8.8 Hz), 7.04 (d, 1H, J=3.2 Hz), 6.93 (d, 2H, J=8.8 Hz), 5.06 (s, 2H), 4.23 (q, 2H, J=7.1 Hz), 3.38, 3.18 (ABq, 2H, J=13.8 Hz), 1.53 (s, 3H), 1.19 (t, 3H, J=7.1 Hz). MS (ES+) m/z mass calcd for C28H28O4 (m+1) 442, found 442.
Reaction SMILES: Cl.[CH:2]([NH:5][NH2:6])([CH3:4])[CH3:3].[CH2:7]([O:14][C:15](=[O:21])[NH:16][CH2:17][CH2:18][CH:19]=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCN(CC)CC.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]=[C:37]([N+]([O-])=O)[CH2:38][CH:39]2[O:43][CH2:42][CH2:41][O:40]2)=[CH:32][CH:31]=1>C(O)(C)C>[CH2:7]([O:14][C:15](=[O:21])[NH:16][CH2:17][CH2:18][C:19]1[C:37]([CH2:38][CH:39]2[O:43][CH2:42][CH2:41][O:40]2)=[C:36]([C:33]2[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=2)[N:5]([CH:2]([CH3:4])[CH3:3])[N:6]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)NN
Reactant: O=[N+]([O-])C(=Cc1ccc(F)cc1)CC1OCCO1
Reactant: O=CCCNC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC(C)n1nc(CCNC(=O)OCc2ccccc2)c(CC2OCCO2)c1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A solution of isopropylhydrazine hydrochloride (1.06 g, 9.6 mmol), (3-oxo-propyl)-carbamic acid benzyl ester (2.0 g, 9.6 mmol), and Et3N (3.9 g, 38.4 mmol) in isopropanol (30 mL) was heated to reflux. After 3 h, the solution was treated with 2-[3-(4-fluoro-phenyl)-2-nitro-allyl]-[1,3]dioxolane (2.2 g, 8.7 mmol) and stirred at 60° C. for 18 h. The mixture was cooled to rt and concentrated. The residue was partitioned between EtOAc and water. The organic layer was separated, dried (MgSO4), and concentrated. Purification by FCC gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[C:4]([NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>FC(F)(F)C1C=CC=CC=1>[F:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:3]=1[C:4]1[O:9][C:8]([O:10][CH2:11][CH3:12])=[C:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]=1
Reactant: CCOC(=O)C(NC(=O)c1c(F)cccc1F)C(=O)OCC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: FC(F)(F)c1ccccc1
Product: CCOC(=O)c1nc(-c2c(F)cccc2F)oc1OCC
Yield: 44.7 %

Procedure:
A solution of diethyl 2-(2,6-difluorobenzamido)malonate (5.00 g, 15.9 mmol) in trifluorotoluene (16 mL) and trifluoroacetic anhydride (8.33 mL, 129.7 mmol) was heated in the microwave at 160° C. for 5 minutes. The solvent was removed in vacuo and the residue purified by silica gel column chromatography using a gradient of 0-90% EtOAc in hexanes to afford ethyl 2-(2,6-difluorophenyl)-5-ethoxyoxazole-4-carboxylate (2.11 g, 7.1 mmol, 45%) as a white solid which was used without further purification. 1H NMR (CDCl3) δ 1.39 (3H, t), 1.53 (3H, t), 4.39 (2H, q), 4.58 (2H, q), 7.02 (2H, t), 7.41 (1H, m).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:15][O-:16].[Na+]>CO>[CH3:15][O:16][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1ccc2ccnc(Cl)c2c1
Agent: [Na+]
Solvent: CO
Product: COc1nccc2ccc([N+](=O)[O-])cc12
Yield: 81 %

Procedure:
To a suspension of 1-chloro-7-nitroisoquinoline (670 mg, 3.21 mmol) obtained in Preparation Example 1-5, Step 4 in methanol (100 ml) was added a 1M solution (6.5 ml, 6.5 mmol) of sodium methoxide. The mixture was refluxed under heating for 3 hr and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:acetone=30:1) to give 1-methoxy-7-nitroisoquinoline (530 mg, 81%).
Reaction SMILES: C[Si](C)(C)[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])[F:5].[F-].[K+].CN1CCN(C)C1=O.[F:22][C:23]1[CH:24]=[C:25]([Br:30])[CH:26]=[CH:27][C:28]=1I>CN(C)C=O.[Cu]Br>[F:22][C:23]1[CH:24]=[C:25]([Br:30])[CH:26]=[CH:27][C:28]=1[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])[F:5]
Reactant: Fc1cc(Br)ccc1I
Reactant: C[Si](C)(C)C(F)(F)C(F)(F)F
Agent: [Cu]Br
Agent: [F-]
Agent: [K+]
Solvent: CN1CCN(C)C1=O
Solvent: CN(C)C=O
Product: Fc1cc(Br)ccc1C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
13.2 g (91.9 mmol) of copper(I) bromide were cooled to −5° C. in 80 ml of dry N,N-dimethylformamide. Under nitrogen, 14.7 g (76.7 mmol) of trimethyl-(pentafluoroethyl)silane were added. 4.45 g (76.7 mmol) of potassium fluoride (spray-dried) were added in portions over the course of 30 minutes at a rate such that the internal temperature remained below 0° C. The mixture was stirred at 0° C. for 1 hour and was then warmed to 20° C. over the course of 12 hours. Thereafter 10 ml of dry 1,3-dimethyl-2-imidazolidinone and 22 g (73.1 mmol) of 3-fluoro-4-iodo-bromobenzene were added. The contents were stirred at 75° C. for 14 hours. Then all of the volatile constituents were distilled off to dryness, the distillate being collected in a cold trap cooled with liquid nitrogen. The distillate was subsequently warmed to 20° C. and dissolved in 500 ml of diethyl ether. This solution was washed with four times 100 ml of water and then with two times 100 ml of saturated aqueous NaCl solution. The organic phase was then dried, and the solvent was removed on a Vigreux column. Subsequent distillation of the residue on a Vigreux column gave 16.1 g of product (boiling point: 86-87° C. (75 mmHg)) with a purity of 99% by weight.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1.[Cl:10][C:11]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=1[C:13](Cl)=[O:14].Cl>ClCCl>[Cl:10][C:11]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:12]=1[C:13]([C:6]1[NH:5][CH:9]=[CH:8][CH:7]=1)=[O:14]
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Reactant: c1cc[nH]c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc[nH]1)c1cc(Cl)ccc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
200 mL of dichloromethane was poured into a 1 L three-necked flask equipped with a stirrer, thermometer, dropping funnel, and nitrogen inlet tube, cooled to 0° C. using a salt-ice bath, and then 80.4 g (0.6 mol) of aluminum chloride and 40.3 g (0.6 mol) of pyrrole were added. Next, 104.7 g (0.50 mol) of 2,5-dichlorobenzoyl chloride dissolved in 100 mL of dichloromethane was slowly added dropwise using a dropping funnel. After completing the addition, the reactant was stirred for 3 hours while maintained at 5° C. to 10° C. using the salt-ice bath. After confirming the disappearance of raw materials by way of thin-layer chromatography, the reaction liquid was gradually added to 1 L of 2 N HCl, and excessive aluminum chloride was dissolved and removed. The organic layer was washed using 5% sodium bicarbonate water, water, and a sodium chloride solution, and the organic layer was dried using magnesium sulfate, and then the solvent was removed by an evaporator. The approximate yield amount was 120 g. The crude product was recrystallized from hexane/ethyl acetate to obtain the intended product in an amount of 95 g and at a yield of 79% as a milky white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH3:15])[C:6]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[N:7][CH:8]=1.[N-:16]=[N+:17]=[N-:18].[Na+].O>CC(N(C)C)=O>[N:16]([CH2:2][C:3]1[CH:4]=[C:5]([CH3:15])[C:6]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[N:7][CH:8]=1)=[N+:17]=[N-:18]
Reactant: Cc1cc(CCl)cnc1OCC(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(CN=[N+]=[N-])cnc1OCC(F)(F)F
Temperature: 90 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
A mixture of 5-(chloromethyl)-3-methyl-2-(2,2,2-trifluoroethoxy)pyridine (0.75 g, 3.15 mmol, Step-3) and sodium azide (0.41 g, 6.29 mmol) in DMA (8 mL) is stirred at 90° C. for 2 hours. The reaction mixture is poured into water (50 mL), and extracted with n-hexane/EtOAc (1:10, 50 mL). The organic layer is washed with water (50 mL) and dried over sodium sulfate. After filtration, the organic fraction is concentrated in vacuo to give 0.77 g (>99% yield) of the title compound as colorless oil. This material is used for the next reaction (Step-5) without further purification.
Reaction SMILES: P(=O)([O-])OC(CC)(CC)[C:4]#[N:5].[CH3:12][O-].[Na+].[CH2:15]([N:19]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[S:20]1(=[O:22])=[O:21])[C:16]([CH3:18])=O>CN(C)C=O>[O:21]=[S:20]1(=[O:22])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=2[C:29](=[O:30])[N:19]1[CH2:15][C:16]([CH3:12])=[CH:18][C:4]#[N:5]
Reactant: CC(=O)CN1C(=O)c2ccccc2S1(=O)=O
Reactant: CCC(C#N)(CC)O[PH](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=CC#N)CN1C(=O)c2ccccc2S1(=O)=O
Temperature: 34 °C
Yield: 23 %

Procedure:
7.4 g (42 millimoles) of diethylcyanomethyl phosphonate and 6.8 g (38 millimoles) of 30% strength sodium methylate were simultaneously added dropwise to 10.0 g (42 millimoles) of N-acetonylsaccharin in 200 ml of dimethylformamide, while stirring thoroughly, the temperature increasing to 34° C. The reaction mixture was stirred for a further hour at room temperature, after which the contents of the flask were poured onto ice-water and extracted three times with methylene chloride, the organic phase was dried and evaporated down under reduced pressure, and the crude product was recrystallized from ethanol to give 2.5 g (23%) of 3-(2,3-dihydro-1,1-dioxido-3-oxo-1,2-benzisothiazol-2-yl)-1-cyano-2-methylprop-1-ene of melting point 118°-121° C.