Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:22]=3[O:21][CH3:20])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15]
Reactant: COc1ccc(C)cc1B(O)O
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(I)c(F)ccc12
Product: COc1ccc(C)cc1-c1c(F)ccc2c(N)c(C(=O)NC3CC3)nnc12
Yield: 76.2 %

Procedure:
Using Method A, 4-amino-7-fluoro-8-iodo-N-cyclopropyl-cinnoline-3-carboxamide (178 mg, 0.48 mmol) and 2-methoxy-5-methylphenylboronic acid (160 mg, 0.96 mmol) were reacted. After purification the title compound (134 mg, 76% yield) was obtained as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.98 (d, J=4.8 Hz, 1H), 8.50 (a dd, J=5.5, 9.3 Hz, 1H), 7.71 (t, J=9.1 Hz, 1H), 7.23 (m, 1H), 7.106(s, 1H), 7.02 (d, J=8.4 Hz, 1H), 3.60 (s, 3H), 2.95 (m, 1H), 2.28 (s, 3H), 0.67 (m, 4H). MS APCI, m/z=367.
Reaction SMILES: [CH:1]([C:3]([CH3:5])=[O:4])=[CH2:2].[OH-].[Na+].[O:8]=[C:9]([CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[C:10]([O:12]CC)=[O:11].Cl>C(O)C>[OH:8][C:9]1([C:10]([OH:12])=[O:11])[CH2:5][C:3](=[O:4])[CH2:1][CH2:2][C:15]1([CH3:16])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(=O)C(C)c1ccccc1
Reactant: C=CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(c2ccccc2)CCC(=O)CC1(O)C(=O)O
Temperature: 20 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
3.5 cm3 (39 mmol) of methyl vinyl ketone and 72 cm3 (71.5 mmol) of a normal aqueous sodium hydroxide solution were successively added to a solution, cooled to the region of 7° C., of 6.7 g (32.5 mmol) of ethyl (RS)-2-oxo-3-phenylbutyrate in 68 cm3 of ethanol and then the reaction mixture was stirred at a temperature in the region of 20° C. for two hours. The reaction mixture was cooled to 15° C. and 72 cm3 of a normal aqueous hydrochloric acid solution were added. After concentrating the ethanol, the precipitate formed was filtered off, washed with water and then dried at 50° C. 4.4 g (50%) of (1RS,2RS)-1-hydroxy-2-methyl-5-oxo-2-phenylcyclohexane-1-carboxylic acid were thus obtained in the form of a beige powder, the characteristics of which were as follows:
Reaction SMILES: [CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:24]=[CH:23][N:22](OCC[Si](C)(C)C)[C:17]=4[N:18]=[C:19](C)[N:20]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[CH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33]>C(Cl)Cl>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:24]=[CH:23][NH:22][C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[CH:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C#CCC(C1CCCC1)n1cc(-c2nc(C)nc3c2ccn3OCC[Si](C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C#CCC(C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 1 h
Yield: 60 %

Procedure:
A solution of 4-[1-(1-cyclopentylbut-3-yn-1-yl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]-methyl-7H-pyrrolo[2,3-d]pyrimidine (52 mg, 0.12 mmol) in DCM (3 mL) and TFA (1 mL) was stirred for 2 hours. The solvents were removed in vacuo. The resulting residue was dissolved in THF (3 mL) and 6N NaOH (2 mL) was added. After stirring for 1 hour, the mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) afforded product (30 mg, 60%).
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[N:9][C:10]([CH3:16])([CH3:15])[C:11](=[O:14])[N:12]([CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[N:24]=C=O.BrC1C2C(C3C=CC=CC=3Cl)=NC(C)(C)C(=O)N(C)C=2C=CC=1NC(NCCO)=O>CC(C)=O.CCOCC>[NH2:24][C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH3:13])[C:11](=[O:14])[C:10]([CH3:16])([CH3:15])[N:9]=[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:7]=2[C:2]=1[Br:1]
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2c1ccc(N=C=O)c2Br
Agent: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2c1ccc(NC(=O)NCCO)c2Br
Solvent: CC(C)=O
Solvent: CCOCC
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2c1ccc(N)c2Br

Procedure:
From 4.5 g (0.011 mol) of 7-amino-6-bromo-5-(o-chlorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one there is obtained, in analogy to the details in Example 4, via [6-bromo-5-(o-chlorophenyl)-2,3-dihydro-1,3,3-trimethyl-2-oxo-1H-1,4-benzodiazepin-7-yl]isocyanate, 1-[6-bromo-5-(o-chlorophenyl)-2,3-dihydro-1,3,3-trimethyl-2-oxo-1H-1,4-benzodiazepin-7yl]-3-(2-hydroxyethyl)urea of melting point 214°-218° (acetone/ether).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH3:12])=[N+:9]([O-])[CH:10]=1)[CH3:3].CO.[C:15]([O:18]C(=O)C)(=[O:17])[CH3:16]>>[C:15]([O:18][CH2:12][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH:2]([CH3:3])[CH3:1])=[CH:10][N:9]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(OC(C)C)c[n+]1[O-]
Solvent: CO
Product: CC(=O)OCc1ccc(OC(C)C)cn1
Yield: 71 %

Procedure:
5-(1-Methylethoxy)-2-methylpyridine 1-oxide (234 mg, 1.40 mmol) was dissolved in acetic anhydride (3.0 mL) and the resultant mixture was stirred at 140° C. for 1 hour. The reaction solution was added with methanol at room temperature, stirred, then concentrated in vacuo, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate), and [5-(1-methylethoxy)pyridin-2-yl]methyl acetate (209 mg, yield 71%) was obtained as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([N:31]3[CH2:35][CH2:34][O:33][C:32]3=[O:36])=[CH:28][CH:29]=2)[CH:24]=[CH:23]1>>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([O:8][C:5]2[CH:6]=[N:7][C:2]([N:22]3[C:30]4[C:25](=[CH:26][C:27]([N:31]5[CH2:35][CH2:34][O:33][C:32]5=[O:36])=[CH:28][CH:29]=4)[CH:24]=[CH:23]3)=[CH:3][CH:4]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C1OCCN1c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)nc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(-n3ccc4cc(N5CCOC5=O)ccc43)nc2)CC1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using tert-butyl 4-((6-chloropyridin-3-yl)oxy)piperidine-1-carboxylate (intermediate-06) and 3-(1H-indol-5-yl)oxazolidin-2-one (intermediate-59) (0.390 g, 63%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][O:14][C:15](=[O:17])[NH2:16])[O:10][N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26]>C(#N)C>[C:27]1([CH:25]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:12]=[C:11]([CH2:13][O:14][C:15](=[O:17])[NH2:16])[O:10][N:9]=3)=[CH:6][CH:7]=2)[CH3:26])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NC(=O)OCc1cc(-c2ccc(O)cc2)no1
Reactant: CC(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(Oc1ccc(-c2cc(COC(N)=O)on2)cc1)c1ccccc1

Procedure:
Carbamic acid 3-(4-hydroxy-phenyl)-isoxazol-5-ylmethyl ester (150 mg, 0.64 mmol) and potassium carbonate (180 mg, 1.28 mmol) were dissolved in 10 ml of acetonitrile, to which was added dropwise (1-bromoethyl)benzene (131 μl, 0.96 mmol), and reacted at room temperature overnight. The completion of the reaction was confirmed by liquid chromatography, and then acetonitrile was distilled under reduced pressure. A crude solid compound was extracted with ethyl acetate and the solvent was distilled under reduced pressure to obtain a white solid compound. This was recrystallized from methylene chloride:MeOH (9:1) to obtain carbamic acid 3-[4-(1-phenyl-ethoxy)-phenyl]-isoxazol-5-ylmethyl ester as a white solid compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=O)=[N:6][CH:7]=1.Cl.[NH2:11][OH:12].[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[N:11][OH:12])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(F)cn1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
To a solution of 5-fluoro-2-formylpyridine (5.0 g, 41 mmol) and hydroxylamine hydrochloride (3.06 g, 44 mmol) in ethanol (3.2 mL) and water (9.6 mL) was added ice (18.6 g). Then a solution of NaOH (4.0 g, 100 mmol) in water (4.6 mL) was added dropwise over 10 min keeping the temperature between −5° C. and 5° C. The reaction mixture was then stirred at room temperature for 30 min. Then HCl (4 N) was added to acidify the mixture and the resulting precipitate was filtered off and washed with water to afford the title compound (4.41 g, 79%) as a light brown solid. MS: m/e=141.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C.O.[Cu]I>[CH3:1][C:2]1[N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[N:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1nc[nH]c1C
Reactant: OB(O)c1ccccc1
Agent: [Cu]I
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1ncn(-c2ccccc2)c1C
Temperature: 25 °C
Yield: 28.4 %

Procedure:
Part A: A magnetically stirred mixture of ethyl 5-methyl-1H-imidazole-4-carboxylate (13.875 g, 0.090 mol), phenylboronic acid (13.16 g, 0.108 mol) and CuI (0.85 g, 0.0045 mol) in ethanol/water (900 ml, 1/1 (v/v)) was divided in 12 equal portions and reacted in parallel at 85° C. for 60 hours. After cooling to room temperature the 12 portions were combined and concentrated in vacuo. The residue was purified by flash chromatography (Ethylacetate/petroleum ether 40-65=1/1 (v/v)) to give ethyl 5-methyl-1-phenyl-1H-imidazole-4-carboxylate (5.88 g, 26% yield). 1H-NMR (400 MHz, CDCl3): 1.42 (t, J=7 Hz, 3H), 2.47 (s, 3H), 4.40 (q, J=7 Hz, 2H), 7.26-7.31 (m 7.56 (m, 3H), 7.59 (s, 1H).
Reaction SMILES: [C:1]([NH:4][N:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([NH:8][CH3:9])=[O:7])(=[O:3])[CH3:2].CI.[C:18](=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]([N:4]([CH3:18])[N:5]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6]([NH:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: CNC(=O)N(NC(C)=O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CI
Product: CNC(=O)N(c1ccccc1)N(C)C(C)=O
Yield: 55.1 %

Procedure:
A mixture of 17 g (0.082 mol) of the semicarbazide prepared above, 14.2 g (0.1 mol) methyl iodide, 14.0 g (0.1 mol) potassium carbonate, and 200 ml ethanol was refluxed for 2 hours, cooled, filtered and evaporated under reduced pressure. The resulting residue was diluted with dichloromethane, filtered to remove suspended solids, washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to give 10 g of crude 1-acetyl-1,4-dimethyl-2-phenyl-semicarbazide.
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]1=[O:11].[CH:12](I)([CH3:14])[CH3:13]>>[CH:12]([O:11][C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[N:1]=1)([CH3:14])[CH3:13]
Reactant: O=c1ccc2c([nH]1)CCCC2
Reactant: CC(C)I
Product: CC(C)Oc1ccc2c(n1)CCCC2

Procedure:
Following the procedure described in Example 1A, step 2, 5,6,7,8-tetrahydroquinolin-2 (1H)-one and i-PrI gave the title compound as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Br:12][C:10]1[CH:11]=[C:2]([NH:1][CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)[C:3]([CH3:13])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: O=C1CCOCC1
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.2 %

Procedure:
To a stirred solution of methyl 3-amino-5-bromo-2-methylbenzoate (2 g, 8.23 mmol) and tetrahydro pyran-4-one (1.06 g, 10.66 mmol) in methanol (20 mL), acetic acid (0.5 g, 8.23 mmol) was added and reaction stirred at room temperature for 18 h. Then sodium cyanoborohydride (0.62 g, 9.83 mmol) was added and reaction stirred 3 h. On completion, solvent was removed under reduced pressure; water was added and extracted with DCM. Combined organic were dried, concentrated and purified by column chromatography using silica (100-200 mesh size) to afford the desired compound (1.6 g, 62%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:9].[N-:10]=[N+:11]=[N-:12].[Na+]>C(#N)C>[N:10]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:9])=[N+:11]=[N-:12]
Reactant: [N-]=[N+]=[N-]
Reactant: Clc1ccccc1CBr
Agent: [Na+]
Solvent: CC#N
Product: [N-]=[N+]=NCc1ccccc1Cl

Procedure:
A mixture of 1-(bromomethyl)-2-chlorobenzene (5 g, 24.3 mmol) and sodium azide (2.37 g, 36.5 mmol) in acetonitrile (48.7 mL) was refluxed for 3 h under N2 atmosphere. Then, the mixture was filtered and concentrated in vacuo. The residue was diluted in DCM, washed with H2O and brine, dried over Na2SO4 and concentrated in vacuo to afford crude 1-(azidomethyl)-2-chlorobenzene. The residue was used for the next reaction without further purification. A mixture of the above crude residue, 2-cyanoacetamide (1.82 g, 21.7 mmol) and sodium ethanolate (1.47 g, 21.7 mmol) in ethanol (43.3 mL) was refluxed for 3 h under N2 atmosphere. The mixture was concentrated in vacuo, diluted with 4M AcOH aq. and filtered. The residue was washed with H2O and dried in vacuo to afford 5-amino-1-(2-chlorobenzyl)-1H-1,2,3-triazole-4-carboxamide as pale-orange solid (5.10 g, 94% for 2 steps). MS(m/e): 252.1 (MH+).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([N:23]1[CH2:27][CH2:26][CH:25]([CH2:28][OH:29])[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.P(Cl)(Cl)(Cl)(Cl)Cl.C(Cl)Cl>CS(C)=O>[CH2:16]([N:23]1[CH2:27][CH2:26][CH:25]([CH:28]=[O:29])[CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCC1CCN(Cc2ccccc2)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CC1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of 61.8 g (0.3 mole) of dicyclohexylcarbodiimide in 400 ml of dry dimethylsulfoxide is dropwise added a solution of 19.10 g (0.1 mole) of 1-benzyl-3-hydroxymethylpyrrolidine [prepared in the manner described in J. O. C. 26, 1519 (1961) by YAO-HUA WU and R. F Feldkamp] under ice-cooling for 15 minutes, and the mixture is stirred at room temperature overnight. Dicyclohexylcarbodiimide (13.26 g; 60 mmoles) and phosphorus pentachloride (4.40 g; 30 mmoles) are added thereto and the mixture is stirred overnight, poured into ice water, mixed with 300 ml of methylene chloride and stirred for 30 minutes. The insoluble materials, which appear, are filtered off and washed with water. The combined filtrate and washings are washed twice with 200 ml of methylene chloride, adjusted to pH 9 with 20 (w/w) % aqueous sodium carbonate solution, and extracted four times with 200 ml of methylene chloride. The extract is washed with 20 (w/w) % aqueous sodium hydrogensulfite solution. The aqueous layer is separated, washed thrice with 100 ml of methylene chloride, mixed with 20 (w/w) % aqueous sodium carbonate solution, and extracted with methylene chloride. The extract is washed with water, dried over sodium sulfate and evaporated under reduced pressure to yield crude oily 1-benzyl-3-formylpyrrolidine in 66% yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([O:23]C4C(F)=C(F)C(F)=C(F)C=4F)(=[O:22])=O)=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)=[C:4]([O:35][CH3:36])[CH:3]=1.[S:37]1[C:41]([NH2:42])=[N:40][CH:39]=[N:38]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>CCOC(C)=O.Cl>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([NH:42][C:41]4[S:37][N:38]=[CH:39][N:40]=4)(=[O:23])=[O:22])=[CH:17][CH:18]=3)[CH:13]=[CH:12][N:11]=2)=[C:4]([O:35][CH3:36])[CH:3]=1
Reactant: COc1cc(Cl)c(C#N)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Nc1ncns1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(Cl)c(C#N)cc1-c1nccc2cc(S(=O)(=O)Nc3ncns3)ccc12
Reaction time: 1 h
Yield: 58.6 %

Procedure:
A vial was charged with perfluorophenyl 1-(4-chloro-5-cyano-2-methoxyphenyl)isoquinoline-6-sulfonate (INTERMEDIATE VVVV, 154.38 mg, 0.285 mmol), 1,2,4-thiadiazol-5-amine (34.6 mg, 0.343 mmol), and cesium carbonate (279 mg, 0.856 mmol). Acetonitrile (1427 μl) was added, and the mixture was stirred for 1 h. The mixture was diluted with EtOAc and 0.5 N aq. HCl. The layers were separated, and the organic extract was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-10% MeOH/DCM, product eluted over a long period of time). The resulting white solid was taken up in MeOH and filtered. The collected solid was washed with MeOH (2×), dried under a stream of N2 (g), then dried under vacuum to give 1-(4-chloro-5-cyano-2-methoxyphenyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (76.6 mg, 0.167 mmol, 58.6% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=7.43 (d, J=5.7 Hz, 1H), 7.32 (d, J=1.7 Hz, 1H), 7.21 (s, 1H), 6.90 (d, J=5.6 Hz, 1H), 6.70 (s, 1H), 6.62-6.55 (m, 1H), 6.52-6.46 (m, 1H), 6.37 (s, 1H), 2.50 (s, 3H). m/z (ESI) 458.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH3:16])=[C:6]2[C:17]([O:19][C:20](=O)[C:5]=12)=[O:18])[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][CH:24]=1.O>C(O)(=O)C>[CH2:15]([O:14][C:7]1[C:6]2[C:17](=[O:18])[N:22]([C:23]3[CH:24]=[CH:25][C:26]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:27][CH:28]=3)[C:20](=[O:19])[C:5]=2[C:4]([O:3][CH2:1][CH3:2])=[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12)[CH3:16]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCOc1c2c(c(OCC)c3ccccc13)C(=O)OC2=O
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2=O)cc1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
1,4-Diethoxy-2,3-naphthalenedicarboxylic anhydride (23.3 g, 81.5 mmol) and ethyl (4-aminophenyl)acetate (14.8 g, 82 mmol) were refluxed under nitrogen in acetic acid (160 ml) overnight. The mixture was cooled to room temperature and poured into water (1 L). The white solid was filtered, washed with water and dissolved in dichloromethane (800 ml). The solution was washed with water, brine and dried (MgSO4) and the solvent evaporated under vacuum to give ethyl [4-(4,9-diethoxy-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetate as an off-white solid (33 g, 96%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:19]([O:22][CH2:23][CH3:24])(=[O:21])[CH3:20]>>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[CH2:20][C:19]([O:22][CH2:23][CH3:24])=[O:21])[CH2:12][CH2:13]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCOC(C)=O
Product: CCOC(=O)CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.1 %

Procedure:
To a mixture of ethyl N-Boc-piperidine-4-carboxylate (0.5 mol) and ethyl acetate (3 mol) t-BuOK (1.5 mol) was added in some portions at 0 C. The mixture was stirred at room temperature for 3 h (monitored by TLC), concentrated up to a half of volume, diluted with water (200 mL) and extracted with ether. Organic layer was dried over sodium sulfate and evaporated in vacuo. Purification by column chromatography (silica gel, ethyl acetate/hexane) afforded 4-(2-ethoxycarbonyl-acetyl)-piperidine-1-carboxylic acid tert-butyl ester (78 g, 52%)
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:16][OH:17].N1C=CC=CC=1>C(O)C>[C:1](=[N:16][OH:17])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=C(c1ccccc1)c1ccccc1
Yield: 73 %

Procedure:
A solution of benzophenone (10.0 g), hydroxylamine hydrochloride (10.0 g), pyridine (50 ml), and absolute ethanol (50 ml) was pumped through the CMR (15 ml/min; 155°-60° C., 700 kPa). The effluent was cooled and the solvent removed by rotary evaporation, and the residue stirred with cold water (50 ml). The crued oxime was filtered off and recrystallised from ethanol to afford pure product (8.0 g; 73% yield), m.p. 140.5°-141° C., cf lit.5 for a batchwise preparation by microwave heating.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[N:15]([CH2:16][CH2:17][C:18]([NH:20]O)=[NH:19])[C:14]3[CH:22]=[CH:23][CH:24]=[CH:25][C:13]=3[N:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[C:26]([O:29]C(=O)C)(=[O:28])[CH3:27].C(OCC)C>C(O)(=O)C.[Pd]>[C:26]([OH:29])(=[O:28])[CH3:27].[C:26]([OH:29])(=[O:28])[CH3:27].[N:1]1([CH2:10][C:11]2[N:15]([CH2:16][CH2:17][C:18]([NH2:20])=[NH:19])[C:14]3[CH:22]=[CH:23][CH:24]=[CH:25][C:13]=3[N:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: CC(=O)OC(C)=O
Reactant: N=C(CCn1c(Cn2nnc3ccccc32)nc2ccccc21)NO
Agent: [Pd]
Solvent: CCOCC
Solvent: CC(=O)O
Product: N=C(N)CCn1c(Cn2nnc3ccccc32)nc2ccccc21
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 64 %

Procedure:
N-[3-(2-Benzotriazol-1-ylmethyl-benzimidazol-1-yl)-1-imino-propyl)-hydroxyamine (57 mg, 0.17 mmol) was dissolved in acetic acid (1 mL). Acetic anhydride was added and the solution was stirred at room temperature for 5-10 minutes. The solution was then added to 10% Pd/C (15 mg) in a Parr reaction vessel. The mixture was agitated under H2 (at 55 psi) for 4 hours. The catalyst was removed by filtration. Evaporation of the filtrate gave a yellow gum which was azeotroped with hexane several times. Trituration with diethyl ether gave 64 mg (64% yield) of the title compound as a tan solid.
Reaction SMILES: C(O)(=O)C.[I:5]Cl.[CH3:7][N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:11][CH:10]=[N:9]1.C([O-])(=O)C.[Na+]>O>[I:5][C:11]1[CH:10]=[N:9][N:8]([CH3:7])[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=1
Reactant: Cn1nccc1-c1ccc(C(F)(F)F)cc1
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cn1ncc(I)c1-c1ccc(C(F)(F)F)cc1
Reaction time: 4 h
Yield: 83.8 %

Procedure:
An acetic acid (3.3 mL) solution of iodine monochloride (2.64 g) was added dropwise to an acetic acid (22 mL) solution that contained 1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazole (3.70 g) and sodium acetate (1.38 g) at a room temperature, and the obtained solution was then stirred for 4 hours. Thereafter, water (250 mL) was added to the reaction solution, and the obtained solution was then stirred for 30 minutes. Then, a precipitated solid was collected by filtration, and was then washed with water. The obtained solid was dissolved in ethyl acetate, and the obtained solution was then washed with water and a saturated sodium hydrogencarbonate aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and was then concentrated under a reduced pressure. Thereafter, the residue was purified by column chromatography (silica gel 60N, hexane:ethyl acetate=5:1 to 7:3), so as to obtain the title compound (4.80 g) in the form of a brownish-red oily substance.