Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH2:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11].[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:15]([O:1][O:14][C:6]1[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=1)[CH:17]1[O:19][CH2:18]1
Reactant: O
Reactant: COc1cc(O)cc(OC)c1OC
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1cc(OOCC2CO2)cc(OC)c1OC

Procedure:
In a suitable reaction vessel fitted with an attachment for the azeotropic separation of water, 18.4 g (0.1 mole) of 3,4,5-trimethoxyphenol are brought to the boil with 37 g (0.4 mole) of epichlorohydrin, followed by the dropwise addition over a period of 30 minutes of 10 g (0.1 mole) of 40% sodium hydroxide, the water being simultaneously removed azeotropically from the circuit. After the sodium hydroxide has been added, the mixture is left to react for 1 hour at boiling temperature, subsequently diluted with approximately 100 ml of toluene and the NaCl precipitated is filtered off. The filtrate is fractionated first under normal pressure and then in vacuo. The 3,4,5-trimethoxyphenoxy glycidyl ether is obtained as a colorless oil at b.p.1.0 =175°-180° C. Yield 19.2 g, corresponding to 80% of the theoretical, based on trimethoxyphenol.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:4]([CH3:9])=[N:5][O:6][C:7]=1[CH3:8].[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[Cl-:1].[CH3:9][C:4]1[C:3]([CH2:2][P+:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:7]([CH3:8])[O:6][N:5]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1noc(C)c1CCl
Solvent: Cc1ccccc1
Product: Cc1noc(C)c1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Cl-]

Procedure:
A solution of 59.6 g. (0.402 mole) of 4-chloromethyl-3,5-dimethylisoxazole, prepared as described above, and 116 g. (0.44 mole) of triphenylphosphine in 1 liter of toluene was heated at reflux under nitrogen for 6 hours. The resulting suspension was cooled and filtered. The filtrate was heated at reflux for an additional 20 hours. The precipitate was again removed by filtration and the combined solids were washed well with ether and benzene. The solvent was removed from the filtrate and the residue was taken up in 150 ml. of fresh toluene and refluxed for an additional 18 hours. Filtration as before gave another small quantity of solid. The combined solids were crystallized from ethanol-ether to give the desired phsophonium salt as a cream-white solid, m.p. 313°-316°.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.C(N(C(C)C)C(C)C)C.CN1CCCC1.Cl[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1.[CH3:36][NH:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(#N)C.O>[CH2:38]([N:37]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:1]2)=[O:35])=[CH:29][CH:28]=1)[CH3:36])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C=Nc1ccc(CCl)cc1
Reactant: c1ccc2c(c1)CNC2
Reactant: CNCc1ccccc1
Agent: CN1CCCC1
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1ccccc1)Cc1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A suspension of isoindoline (0.1 g, 0.839 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.219 ml, 1.259 mmol) in acetonitrile (2.80 ml) was treated with N-methylpyrrolidine (2.80 ml). The solution was cooled to 0° C. and 1-(chloromethyl)-4-isocyanatobenzene (0.155 g, 0.923 mmol) was added. After stirring for 2 hours at 0° C., the reaction was treated with a solution of N-methyl-1-phenylmethanamine (0.102 g, 0.839 mmol) in 0.5 mL acetonitrile. The reaction was stirred at 0° C. for 5 minutes and at ambient temperature for 30 minutes. The reaction was treated with water and the mixture was stirred for 4 hours. The suspension was filtered and the solid collected was washed with water and dried under vacuum to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.31 (s, 1H), 7.56-7.49 (m, 2H), 7.40-7.28 (m, 8H), 7.27-7.19 (m, 3H), 4.76 (bs, 4H), 3.47 (s, 2H), 3.43 (s, 2H), 2.06 (s, 3H); MS (ESI(+)) m/e 372 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(O[CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.C(O)C>CCCCCC>[CH2:23]([O:22][C:20]([C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][NH:4][C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[F:1])=[O:21])[CH3:24]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(F)cc1F
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)C(=CNc1ccc(F)cc1F)C(=O)OCC
Yield: 79.4 %

Procedure:
Into an appropriate reactor fitted with warming, cooling and stirring means, were poured 152.5 ml (1.5 mol) of 2,4-difluoroaniline and 425 ml (2.1 mol) of diethyl ethoxymethylenemalonate. The mixture was warmed at 90° to 100° C. for about three hours with evacuation of ethanol appearing in the condensation. This led to a solid product which was treated with hexane, washed, crystallized from hexane and dried to give 356.5 g (yield 79.5%) of 1-(2,2-diethoxycarbonyl-vinylamino)-2,4-difluoro-benzene. Elemental analysis of the product showed a good correspondence with the formula C14H15NO4F2. 350 g (1.17 mol) of this product were poured into a reactor with 1 liter of diphenyloxide. The mixture was refluxed at 265°-270° C. for 11/2 hours with a subsequent evacuation of the ethanol produced during the cyclisation. After cooling to ambient temperature, there was obtained a residue which was treated with benzene and then with hexane, dried and recrystallized from methanol. This gave 239 g (yiel 80.7%) of 1,4-dihydro-3-ethoxycarbonyl-6,8-difluoro-4-oxo-quinoline, elemental analysis of which showed a good correspondence with the formula C12H9NO3F2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)C(C)C)C.[CH3:52][NH:53][CH2:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=1>ClCCl>[C:1]([O:5][C:6](=[O:7])[N:8]([CH3:9])[C@@H:10]([C:11](=[O:13])[N:53]([CH3:52])[CH2:54][CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNCCc1ccccn1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCc1ccccn1)C(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
(2R)-2-(N-(tert-Butoxycarbonyl)-N-methylamino)-3-phenylpropionic acid (11.2 g, 40 mmol), 1-hydroxy-7-azabenzotriazole (5.4 g, 40 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (7.7 g, 40 mmol) were dissolved in dichloromethane (100 mL). The reaction mixture was stirred for 15 min. Ethyidiisopropylamine (6.85 mL, 40 mmol) and 2-(2-methylaminoethyl)pyridine (5.54 mL, 40 mmol) were added. The reaction mixture was stirred for 16 h. The reaction mixture was washed with sat. aqueous sodium hydrogen carbonate solution (3×150 mL). The organic layer was dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (400 g), using ethyl acetate as eluent, to give 10.9 g of N-methyl-N{(1R)-1-[N-methyl-N-(2-(2-pyridyl)ethyl)carbamoyl]-2-phenylethyl}carbamic acid tert-butyl ester.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[OH:17])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:18]1([CH:16]([OH:17])[CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(O)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC(CCC1CCNCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 117.4 %

Procedure:
To a solution of 1.48 g (4.66 mmol) of 1-t-butoxycarbonyl-4-(3-phenyl-3-hydroxypropyl)piperidine in 8 mL of CH2Cl2 at rt was added 2 mL of trifluoroacetic acid. After stirring for 2 h at rt, the reaction mixture was poured into 100 mL of sat'd NaHCO3 solution and extracted with CH2Cl2. The combined organic fractions were dried over MgSO4, filtered and the filtrate was concentrated to give 1.2 g of the title compound.
Reaction SMILES: N1(C2C=CC(CC3[C:12]([O:24]C)=NC4C(C=3Cl)=CC(Br)=CC=4C)=CC=2)C=CC=N1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[N:43]=[C:42](Cl)[C:41]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([S:55]([CH3:58])(=[O:57])=[O:56])=[CH:51][CH:50]=2)=[C:40]3[Cl:59])=[O:36])=[CH:31][CH:30]=1.N1(C2C=CC(CC3C(OC)=NC4C(C=3Cl)=CC(Br)=CC=4)=CC=2)C=CC=N1>>[Cl:59][C:40]1[C:39]2[C:44](=[CH:45][CH:46]=[C:37]([C:35]([C:32]3[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=3)=[O:36])[CH:38]=2)[N:43]=[C:42]([O:24][CH3:12])[C:41]=1[CH2:48][C:49]1[CH:50]=[CH:51][C:52]([S:55]([CH3:58])(=[O:57])=[O:56])=[CH:53][CH:54]=1
Reactant: CS(=O)(=O)c1ccc(Cc2c(Cl)nc3ccc(C(=O)c4ccc(Cl)cc4)cc3c2Cl)cc1
Reactant: COc1nc2c(C)cc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Product: COc1nc2ccc(C(=O)c3ccc(Cl)cc3)cc2c(Cl)c1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
The title compound was prepared by substituting 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloroquinoline (Intermediate 6: step c) with (4-chlorophenyl)(2,4-dichloro-3-(4-(methylsulfonyl)benzyl)quinolin-6-yl)methanone (Intermediate 22: step a) then following the procedure described for the preparation of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxyquinoline (Intermediate 16).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([F:12])=[CH:5][C:3]=1[NH2:4].[CH3:13][C:14]([CH3:23])([C:21]#[CH:22])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CCN(CC)CC.C(OCC)(=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:19]([O:18][C:16](=[O:17])[CH2:15][C:14]([CH3:23])([CH3:13])[C:21]#[C:22][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([F:12])=[CH:5][C:3]=1[NH2:4])[CH3:20]
Reactant: C#CC(C)(C)CC(=O)OCC
Reactant: Nc1cc(F)c([N+](=O)[O-])cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(C)(C)C#Cc1cc([N+](=O)[O-])c(F)cc1N
Temperature: 70 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
To a solution of 2-bromo-5-fluoro-4-nitroaniline (45.7 g, 0.19 mol) and ethyl 3,3-dimethylpent-4-ynoate (88.3 g, 0.57 mol) in Et3N (700 mL) was added Pd(PPh3)2Cl2 (13.8 g, 0.02 mol) and CuI (3.6 g, 0.02 mol) under N2. The reaction mixture was stirred at 70° C. for 8 hours. The reaction mixture was diluted with 500 mL of ethyl acetate and 1500 mL of water. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (500 mL×3), the combined organic layers were washed with brine and dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 10:1) to give ethyl-5-(2-amino-4-fluoro-5-nitrophenyl)-3,3-dimethylpent-4-ynoate (34.5 g, 57%). 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J=8.1 Hz, 1 H), 6.36 (d, J=13.2 Hz, 1 H), 5.60 (brs, 2 H), 4.16 (q, J=7.2 Hz, 2 H), 2.51 (s, 2 H), 1.40 (s, 6 H), 1.28 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc2ccccc2n1
Reactant: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCNCC1
Product: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCN(c2ccc3ccccc3n2)CC1
Yield: 18.1 %

Procedure:
Using the procedure from Example 7A, Step 7E, 4-[(3,4-dichlorophenyl)sulfonyl]piperidine (150 mg, 0.51 mmol) was reacted with 2-chloroquinoline (328 mg, 2.0 mmol) to afford the title compound (39 mg), a white solid, in 18% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18]>>[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:10]([C:11]2[CH:16]=[N:15][CH:14]=[N:13][CH:12]=2)[C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1ccc(Nc2cncnc2)cc1
Product: O=[N+]([O-])c1ccc(CN(c2ccc([N+](=O)[O-])cc2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[(4-nitrophenyl)amino]pyrimidine and 4-nitrobenzyl bromide
Reaction SMILES: [CH2:1]([N:8]([CH3:25])[C:9]1[CH:14]=[C:13]([CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:12]=[CH:11][C:10]=1[N+:22]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([N:8]([CH3:25])[C:9]1[C:10]([NH2:22])=[CH:11][CH:12]=[C:13]([CH2:15][N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)c1cc(CN2CCOCC2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)c1cc(CN2CCOCC2)ccc1N
Yield: 102.6 %

Procedure:
A mixture of N-benzyl-N-methyl-5-(4-morpholinylmethyl)-2-nitroaniline (3.3 g, 9.7 mmol) and 10% palladium charcoal (0.25 g) in ethyl acetate (100 mL) is hydrogenated (50 psi initial hydrogen pressure) until HPLC shows that reaction is complete (40 min). The solvent is evaporated to give 3.1 g of the title compound as an oil.
Reaction SMILES: [CH:1]1([CH2:10][CH2:11]O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C([Br:16])C=C>C(#N)C>[CH:1]1([CH2:10][CH2:11][Br:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: C=CCBr
Reactant: OCCC1CCc2ccccc21
Solvent: CC#N
Product: BrCCC1CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
N,N-Carbonyl diimidazole (2.0 g, 12.3 mmol) was added to a solution of 2-indanylethanol (2.0 g, 12.3 mmol) in acetonitrile. The reaction mixture was stirred at room temperature for 1 h and allyl bromide (8.93 g, 73.8 mmol) was added. The reaction mixture was heated to 70° C. for 24 h and was poured onto water. The aqueous solution was extracted with Et2O and the organic solution was washed with water (1×) followed by brine (1×). The organic solution was dried over MgSO4, filtered, and concentrated to afford the title compound (2.54 g). 1H NMR (400 MHz, CDCl3) δ 7.10-7.25 (m, 4H), 3.48 (t, 2H), 3.11 (m, 2H), 2.63 (m, 3H), 2.07 (m, 2H).
Reaction SMILES: C[C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[CH2:7]([O:15][C:16](=[O:19])[CH2:17][Br:18])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:20](OCC)C>>[Br-:18].[CH3:20][NH+:6]1[CH:5]=[CH:4][N:3]([CH2:17][C:16](=[O:19])[O:15][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:2]1
Reactant: CCOCC
Reactant: Cc1ncc[nH]1
Reactant: CCCCCCCCOC(=O)CBr
Product: CCCCCCCCOC(=O)CN1C=C[NH+](C)C1
Product: [Br-]
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Methyl imidazol (18.1 g) in 20 ml diethyl ether is added drop wise to a stirred mixture of Octyl-2-bromoacetate (55.7 g) and diethyl ether (200 ml) and cooled to 0° C. in an ice bath. The mixture is stirred overnight to yield a two phase mixture. The top ether layer is decanted and the product is stirred in 100 ml of fresh diethyl ether for 10 minutes. The ether layer is again decanted. The product is washed in this manner 5 times to yield, after drying under vacuum, the product as a white waxy solid.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[O:8][B:7]([OH:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:14]=O.[NH2:16][OH:17].Cl.CC([O-])=O.[Na+]>C1COCC1.O>[F:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[O:8][B:7]([OH:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH:14]=[N:16][OH:17]
Reactant: NO
Reactant: CC1(C)OB(O)c2ccc(C=O)c(F)c21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OB(O)c2ccc(C=NO)c(F)c21
Reaction time: 2 h

Procedure:
To a solution of 4-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde (136 mg, 0.7 mmol) and NH2OH.HCl (58.5 mg, 0.84 mmol) in THF (4 mL) and H2O (1 mL) at rt was added NaOAc (80.5 mg, 0.98 mmol). The reaction mixture was stirred for 2 h and diluted with H2O. The mixture was extracted three times with ethyl acetate and the organic layer was separated. The organic solution was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give crude compound 4-fluoro-1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbaldehyde oxime as a light yellow solid. It was used in next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:6]([CH2:7][O:8][CH2:9][CH:10]=[CH2:11])=[C:5]([N+:16]([O-:18])=[O:17])[CH:4]=1.[CH3:19][O:20][SiH:21]([O:24][CH3:25])[O:22][CH3:23]>[H+].[H+].O.O.O.O.O.O.Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH3:19][O:20][Si:21]([O:24][CH3:25])([O:22][CH3:23])[CH2:11][CH2:10][CH2:9][O:8][CH2:7][C:6]1[CH:12]=[C:13]([O:14][CH3:15])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:16]([O-:18])=[O:17]
Reactant: CO[SiH](OC)OC
Reactant: C=CCOCc1cc(OC)c(OC)cc1[N+](=O)[O-]
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: O
Product: COc1cc(COCCC[Si](OC)(OC)OC)c([N+](=O)[O-])cc1OC
Temperature: 37 °C
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
A 30-ml eggplant type flask was purged with nitrogen, and charged with 1.5 g (5.9 mmol) of allyl 4,5-dimethoxy-2-nitrobenzyl ether, 0.865 g (7.1 mmol) of trimethoxysilane, and an infinitesimal amount of hydrogen hexachloroplatinate(IV) hexahydrate (H2PtCl6·6H2O), followed by stirring at 37° C. for 30 minutes. Thereafter, the bath temperature was raised to 100° C., and the reaction was completed in 2 hours. The reaction mixture was purified by silica gel column chromatography using a medium-pressure column. Using a mixture of hexane, ethyl acetate and tetramethoxysilane (in a volume ratio of 100:20:1) as the eluent, 0.95 g (2.53 mmol) of the desired product was obtained in a 43% yield. Its Rf value (for the aforesaid eluent) was 0.19.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:6]([C:12]1[CH:26]=[CH:25][C:15]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][CH:13]=1)=[N:7]2.[NH2:33][NH2:34]>O1CCOCC1>[NH:33]([C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:6]([C:12]1[CH:26]=[CH:25][C:15]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][CH:13]=1)=[N:7]2)[NH2:34]
Reactant: NN
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2nc3ccnc(Cl)c3cc2-c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc3ccnc(NN)c3cc2-c2ccccc2)cc1
Temperature: 100 °C

Procedure:
To a stirred solution of 16-1 (6.8 g, 15.2 mMol) in anhydrous 1,4-dioxane (20 mL) was added hydrazine (10.8 mL, 343 mMol). The solution was heated to 100° C. in a microwave reactor for 5 minutes. The solvent was removed in vacuo and the crude residue was taken up in ethyl acetate and washed with aqueous NaHCO3 solution followed by brine. The organic layer was dried with MgSO4, filtered and concentrated in vacuo to yield 16-2 as an orange solid. LC/MS (M+1) calculated: 442.5; observed: 442.2
Reaction SMILES: [NH2:1][C:2]1[C:7]([S:8]([NH:11][C:12]2[CH:13]=[N:14][C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>ClCCCl>[CH3:19][O:18][C:16]1[CH:17]=[C:12]([N:11]2[C:22](=[O:23])[NH:1][C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[S:8]2(=[O:10])=[O:9])[CH:13]=[N:14][C:15]=1[O:20][CH3:21]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(NS(=O)(=O)c2cccnc2N)cnc1OC
Solvent: ClCCCl
Product: COc1cc(N2C(=O)Nc3ncccc3S2(=O)=O)cnc1OC
Yield: 64.6 %

Procedure:
The title compound (1.4 g, 4.16 mmol) was prepared from 2-amino-N-(5,6-dimethoxypyridin-3-yl)pyridine-3-sulfonamide (2.0 g, 6.44 mmol) and 1,1′-carbonyldiimidazole (3.13 g, 19.3 mmol) in 1,2-dichloroethane (15 mL) at 90° C. for 16 h using the methods of (IntA14) step 3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:16][C:17]2[N:22]=[C:21]([C:23](OCC)=[O:24])[CH:20]=[C:19]([CH2:28][O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[N:18]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[N:11][CH:10]=1.[H-].C([Al+]CC(C)C)C(C)C.CO.O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:16][C:17]2[N:22]=[C:21]([CH:23]=[O:24])[CH:20]=[C:19]([CH2:28][O:29][CH2:30][C:31]([F:34])([F:33])[F:32])[N:18]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[N:11][CH:10]=1
Reactant: CCOC(=O)c1cc(COCC(F)(F)F)nc(Nc2ccc(-c3cnnc(C)c3)c(OC)c2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COc1cc(Nc2nc(C=O)cc(COCC(F)(F)F)n2)ccc1-c1cnnc(C)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Ethyl 2-(3-methoxy-4-(6-methylpyridazin-4-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)-pyrimidine-4-carboxylate (595 mg, 1.25 mmol) was dissolved in dichloromethane (25 mL) under nitrogen atmosphere and cooled at −78° C. Diisobutyl aluminum hydride (1 M in hexane, 4.36 mL, 4.36 mmol) was added over 10 min. After 1 h diisobutyl aluminum hydride (1 M in hexane, 1.4 mL) was added and the mixture was stirred for 2 h. MeOH (3 mL) was added and the mixture was let to rt. Water (5 mL) was added. The slurry was stirred for 20 min and filtrated through a plug of diatomeous earth. The filter plug was washed with 10% MeOH in DCM. The phases were separated and the aqueous phase was extracted with DCM. The combined organic layer was dried over sodium sulfate, filtered and concentrated onto silica. The residue was purified by column chromatography on silica eluting with a gradient of methanol in dichloromethane to give the title compound as a solid, 270 mg (50%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14]C(=O)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[CH:20]([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])C.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>C(O)C>[CH2:25]([O:24][C:20]1([O:21][CH2:22][CH3:23])[CH2:12][CH2:11][CH:10]([CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:15][CH2:14]1)[CH3:26]
Reactant: CCOC(OCC)OCC
Reactant: O=C1CCC(COCc2ccccc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC1(OCC)CCC(COCc2ccccc2)CC1

Procedure:
4-Benzyloxymethylcyclohexanone (168 g, 0.77 mol) is dissolved in ethanol (2000 mL), and then triethylorthoformate (350 mL) and p-toluenesulfonic acid (13.3 g) are added. The resulting mixture is stirred and refluxed for 6 hours. After addition of triethylamine (10.5 mL) at room temperature, the mixture is concentrated (500 mL). After addition of sat. NaHCO3 aq., the resulting mixture is extracted with EtOAc. The water layer is extracted with EtOAc and the combined organic layer is washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The crude mixture is purified by short pad silica gel column chromatography to afford (4,4-diethoxycyclohexylmethoxymethyl)benzene.