Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](=C[C:4](C=[N+]=[N-])=[O:5])=[N-].NC1SC=[C:13]([C@@H:15]([NH:27]C(OC(C)(C)C)=O)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23]C(=O)C)=[CH:19][CH:18]=2)N=1.C1C[O:38]CC1.CO>C(N(CC)CC)C.C([O-])(=O)C1C=CC=CC=1.[Ag+]>[CH3:4][O:5][C:13](=[O:38])[C@H:15]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=1)[NH2:27]
Reactant: [N-]=[N+]=CC(=O)C=[N+]=[N-]
Reactant: CC(=O)Oc1ccc(C[C@H](NC(=O)OC(C)(C)C)c2csc(N)n2)cc1
Reactant: C1CCOC1
Agent: [Ag+]
Agent: O=C([O-])c1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The diazomethylketone derived from Bis-Boc-Tyr (Example 64, 0.750 g, 1.85 mmol) was dissolved in a 1/1 mixture of THF/MeOH (10 mL). A solution of silver benzoate (50 mg) in triethylamine (1 mL) was added. After 15 min of stirring at room temperature the solvent was evaporated and the residue purified by flash chromatography (gradient 10-25% EtOAc/hexane) to yield 749 mg of protected tyrosine methyl ester.
Reaction SMILES: [Br:1]Br.[C:3]([O:9][C:10]1[CH:11]=[C:12]([C:23](=[O:25])[CH3:24])[CH:13]=[CH:14][C:15]=1[O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].C(OC(C)(C)C)(=O)C.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)(Cl)Cl>[Br:1][CH2:24][C:23]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[C:10]([O:9][C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])[CH:11]=1)=[O:25]
Reactant: CC(=O)c1ccc(OC(=O)C(C)(C)C)c(OC(=O)C(C)(C)C)c1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)Oc1ccc(C(=O)CBr)cc1OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of bromine (3.15 ml., 0.061 mole) in chloroform (50 ml.) was added dropwise at room temperature to a stirred solution of 3',4'-bis(pivaloyloxy)acetophenone (19.5 g., 0.061 mole) and t-butyl acetate (8.2 ml., 0.06 mole) in chloroform (150 ml.) containing a catalytic amount of anhydrous aluminium chloride (0.2 g.). The reaction mixture was stirred at room temperature for 1 hour after the addition was complete, chromatographic silica gel (75 g.) was then added and the mixture evaporated in vacuo. The residual solid was added to the top of a column of dry chromatographic silica-gel (1 kg., previously deactivated by addition of 10% w/w water and then equilibrated with 10% v/w of a 5% v/v solution of ethyl acetate in toluene). The column was developed by elution with a 5% v/v solution (1.1 l.) of ethyl acetate in toluene. The column was then eluted with ethyl acetate (2×500 ml.) and the fractions collected were monitored by thin layer chromatography (TLC) (on silica plates developed in a 50% v/v mixture of ethyl acetate and toluene). The later fractions were combined and evaporated to give 2-bromo-3',4'-bis(pivaloyloxy)acetophenone as an oil (14.2 g.) which rapidly crystallised to give a solid of m.p. 64°-66° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][CH2:18][CH2:19][O:20][C:21]1[C:22]([CH2:27][OH:28])=[N:23][CH:24]=[CH:25][CH:26]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][CH2:18][CH2:19][O:20][C:21]1[C:22]([CH:27]=[O:28])=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: OCc1ncccc1OCCOC1CCCCO1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: O=Cc1ncccc1OCCOC1CCCCO1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a three-necked round flask containing dry DCM (500 mL) cooled down to −78° C. under an atmosphere of N2 was added oxalyl chloride (20.0 mL, 157 mmol) followed by a careful dropwise addition of DMSO (24.5 g, 315 mmol). To the cold reaction mixture was {3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridin-2-yl}methanol (from Example 19, Step 1; 21.0 g, 82.9 mmol) in DCM (25 mL) carefully added, the temperature never exceeded −65° C. After the addition, the reaction mixture was stirred at −78° C. for one hour after which time TEA (50.2 g, 497 mmol) was added and the mixture was stirred another 30 minutes at ambient temperature. To the mixture was added ice water (400 mL) and the organic phase was washed H2O, brine, dried (MgSO4), the brown organic phase was filtered through a pad (60 mm×40 mm) of silica and finally the solvent was removed under reduced pressure to give a brown oil. The hydrated aldehyde was dissolved in toluene (150 mL) and heated for 3 h under Dean-Stark conditions to give 19.9 g (95%) of the title compound as a black oil. HRMS m/z calcd for C13H17NO4 (M)+ 251.1158. found 251.1153.
Reaction SMILES: [NH:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(N(C(C)C)CC)(C)C.[Br:29][C@H:30]([CH3:34])[C:31](Cl)=[O:32]>ClCCl>[Br:29][C@H:30]([CH3:34])[C:31]([N:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][C@H:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:32]
Reactant: C[C@@H](Br)C(=O)Cl
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H]2CCCC[C@@H]2N1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Br)C(=O)N1[C@H](C(=O)OCc2ccccc2)C[C@@H]2CCCC[C@@H]21
Reaction time: 1 h

Procedure:
Introduce 200 g of benzyl (2S,3aS,7aS)-octahydro-1H-indole-2-carboxylate and 1.5 liters of dichloromethane into a reactor, then bring the temperature of the reaction mixture to 0° C. and add 201 ml of diisopropylethylamine followed by 132 g of (2R)-2-bromo-propionyl chloride. Subsequently, bring the mixture to ambient temperature. After stirring for 1 hour at that temperature, wash the mixture with water and then with a dilute acetic acid solution. The benzyl (2S,3aS,7aS)-1-[(2R)-2-bromopropionyl]octahydro-1H-indole-2-carboxylate solution so obtained is used as it is in the following Step.
Reaction SMILES: C(=O)(O)[O-].[Na+].[Br:6]N1C(=O)CCC1=O.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[C:32]3[N:33]([CH2:38][C:39]#[C:40][CH3:41])[C:34](=[O:37])[N:35]([CH3:36])[C:31]=3[CH:30]=[CH:29][N:28]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(OCC)(=O)C>CN(C)C=O.O>[C:14]([O:18][C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27]2[C:32]3[N:33]([CH2:38][C:39]#[C:40][CH3:41])[C:34](=[O:37])[N:35]([CH3:36])[C:31]=3[C:30]([Br:6])=[CH:29][N:28]=2)[CH2:25][CH2:26]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC#CCn1c(=O)n(C)c2ccnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCn1c(=O)n(C)c2c(Br)cnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 60 h
Yield: 37.3 %

Procedure:
Sodium bicarbonate (0.146 g) and N-bromosuccinimide (0.288 g) were added to a solution of 4-[3-(2-butynyl)-1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4.5-c]pyridin-4-yl]-piperazine-1-carboxylic acid t-butyl ester (0.447 g) in N,N-dimethylformamide (20 mL). This was then stirred at room temperature for 60 hours. Sodium bicarbonate (0.219 g) and N-bromosuccinimide (0.432 g) were added again, and this was stirred at room temperature for 15 hours. Ethyl acetate (100 mL) and water (50 mL) were then added, and the organic layer was washed twice with 50 mL of water and then once with 50 mL of saturated aqueous sodium chloride solution, then was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography, and the hexane:ethyl acetate 1:1 fraction gave the title compound (0.201 g).
Reaction SMILES: FC(F)(F)C(O)=[O:4].[CH3:8][C:9]1[S:13][C:12]([S:14]([N:17]2[CH2:22][CH2:21][NH:20][C:19](=O)[CH2:18]2)(=[O:16])=[O:15])=[N:11][N:10]=1.[N:24]1([CH2:33][C:34](O)=[O:35])[CH:32]=[C:30]([CH3:31])[C:28](=[O:29])[NH:27][C:25]1=[O:26]>>[CH3:8][C:9]1[S:13][C:12]([S:14]([N:17]2[CH2:22][CH2:21][N:20]([C:34](=[O:35])[CH2:33][N:24]3[CH:32]=[C:30]([CH3:31])[C:28](=[O:29])[NH:27][C:25]3=[O:26])[CH2:19][C:18]2=[O:4])(=[O:16])=[O:15])=[N:11][N:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: Cc1nnc(S(=O)(=O)N2CCNC(=O)C2)s1
Product: Cc1nnc(S(=O)(=O)N2CCN(C(=O)Cn3cc(C)c(=O)[nH]c3=O)CC2=O)s1

Procedure:
The title compound was synthesized by the reaction of 4-(5-methyl-1,3,4-thiadiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with (thymin-1-yl)-acetic acid as per the procedure of method B described in example 64,
Reaction SMILES: [H-].[Na+].[CH:3]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8][C:7]=2[C:6]([OH:16])=[CH:5][CH:4]=1.[CH3:17]I>CN(C=O)C>[CH3:17][O:16][C:6]1[C:7]2[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[C:11]=2[CH:3]=[CH:4][CH:5]=1
Reactant: CI
Reactant: Oc1cccc2c1oc1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc2c1oc1ccccc12

Procedure:
To a solution of 50% NaH (15.6 g, 0.32 mol) in DMF (100 ml), a solution of dibenzofuran-4-ol (40 g, 0.217 mol) in DMF (200 ml) was added drop wise at 0-5° C. under stirring and under a nitrogen atmosphere. The reaction mass was allowed to stir for 15 min at a temperature of 0-5° C. under N2. A solution of methyl iodide (20.3 ml, 0.32 mol) in DMF (50 ml) was added drop wise at 0-5° C. and the reaction mass was allowed to stir for 1 hr at room temperature. When TLC confirmed absence of starting material, the reaction mass was quenched with water and extracted with ethyl acetate. The organic layer was dried with sodium sulfate and evaporated under vacuum to give product 4-Methoxydibenzofuran. Yield 43 g (98%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:17])[CH2:5][CH:6]=[CH2:7].[CH2:20]([N:27]([C:34]1[CH:39]=[CH:38][C:37](I)=[CH:36][CH:35]=1)[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][C:9](=[O:18])[C:10]1[C:11]([Cl:17])=[CH:12][CH:13]=[CH:14][C:15]=1[Cl:16])[CH2:5]/[CH:6]=[CH:7]/[C:37]1[CH:36]=[CH:35][C:34]([N:27]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:39][CH:38]=1
Reactant: Ic1ccc(N(Cc2ccccc2)c2ncccn2)cc1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Product: COC(=O)C(C/C=C/c1ccc(N(Cc2ccccc2)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Yield: 60.4 %

Procedure:
In the same manner as in Example 1, 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (59.3 mg) was reacted with N-benzyl-N-(4-iodophenyl)pyrimidin-2-amine (67.0 mg) to obtain (E)-5-[4-(benzyl-pyrimidin-2-yl-amino)-phenyl]-2-(2,6-dichlorobenzamido)-pent-4-enoic acid methyl ester (58.7 mg). Column chromatography (silica gel, eluent: chloroform/cyclohexane=2/1→chloroform) and thin layer chromatography (silica gel, developing solvent: cyclohexane/ethyl acetate=2/1) were used for purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([CH3:13])[N:9]=[CH:10]2)=[CH:5][CH:4]=1.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1C(=O)C[Br:23]>C(COC)OC>[Br-:23].[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([CH3:13])[N+:9]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH3:14])=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C=NC(C)C2
Reactant: Cc1ccccc1C(=O)CBr
Solvent: COCCOC
Product: COc1ccc2c(c1)C=[N+](c1ccccc1C)C(C)C2
Product: [Br-]
Temperature: 25 °C
Reaction time: 14 h
Yield: 54.8 %

Procedure:
To a solution of 12 g of 7-methoxy-3-methyl-3,4-dihydroisoquinoline in 120 ml of dimethoxyethane was added 16 g of 2'-methyl-2-bromoacetophenone, and the mixture was stirred at room temperature for 14 hours. The resulting white powder was collected by filtration to give 13 g of 7-methoxy-3-methyl-2-(2-methylphenyl)-3,4-dihydroisoquinolinium bromide. A mixture of this white powder, 80 ml of acetic acid and 12.8 g of ammonium acetate was then refluxed for 3 hours. After being cooled, the reaction mixture was poured into water, rendered alkaline by the addition of a saturated sodium carbonate solution and extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel to give 5.3 g of the title compound as a yellow oily material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:50]=[CH:49][C:16]([C:17]([N:19]([CH2:45][C:46](O)=[O:47])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[N:31]=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([C:38]6[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=6)=[CH:34][CH:33]=5)[O:29][N:28]=4)=[CH:23][CH:22]=3)=[O:18])=[CH:15][CH:14]=2)=[O:11])=[C:5]([C:51]([F:54])([F:53])[F:52])[CH:4]=1.[CH3:55][S:56]([NH2:59])(=[O:58])=[O:57].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]4[N:31]=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([C:38]6[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][CH:43]=6)=[CH:34][CH:33]=5)[O:29][N:28]=4)=[CH:25][CH:26]=3)[CH2:45][C:46]([NH:59][S:56]([CH3:55])(=[O:58])=[O:57])=[O:47])=[O:18])=[CH:49][CH:50]=2)=[O:11])=[C:5]([C:51]([F:53])([F:54])[F:52])[CH:4]=1
Reactant: CS(N)(=O)=O
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)O)Cc3ccc(-c4noc(-c5ccc(-c6ccc(C)cc6)cc5)n4)cc3)cc2)c(C(F)(F)F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)NS(C)(=O)=O)Cc3ccc(-c4noc(-c5ccc(-c6ccc(C)cc6)cc5)n4)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)benzamido)acetic acid 354 (15 mg, 0.02 mmol), methanesulfonamide (2.9 mg, 0.03 mmol) and N,N-dimethylaminopyridine (5 mg, 0.04 mmol) in anhydrous DCM (1 mL) was added dicylcohexylcarbodiimide (6.3 mg). The reaction mixture was stirred at room temperature for 12 h. The reaction was diluted with DCM (2 mL) and washed with saturated NaHCO3 solution (5 mL), brine (5 mL), dried over (MgSO4) then concentrated. The crude product was isolated by HPLC to afford 4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(5-(4′-methyl-[1,1′-biphenyl]-4-yl)-1,2,4-oxadiazol-3-yl)benzyl)-N-(2-(methylsulfonamido)-2-oxoethyl)benzamide 493. LCMS-ESI (m/z) calculated for C42H36F3N5O7S: 812; no ion observed, tR=11.03 min (Method 2).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13](Cl)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].[C:19]1([CH2:25][C:26]#[N:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([CH:25]([C:26]#[N:27])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:31][CH:30]=3)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1C
Reactant: N#CCc1ccccc1
Reactant: Nc1ccc(O)cc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(C(C#N)c4ccccc4)cc3)c2c1C

Procedure:
4-Chloro-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester (5 mg, 0.019 mmol) and (4-Amino-phenol)-phenyl-acetonitrile (8 mg, 0.016 mmol) in DMF (0.5 ml) were heated at 110° C. for 3 hrs. The reaction mixture was purified by silica gel flash chromatography to isolate 3-cyano-4-[4-cyano-phenyl-methyl)phenylamino]-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester 368 as yellow film (4.3 mg, 52%). [M+H]+=436.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:13][CH2:12]2)[CH:6]=[CH:5][C:4]=1[OH:23].C(=O)([O-])[O-].[Cs+].[Cs+].[N:30]1([C:36]([Cl:38])=[O:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>C(#N)C.ClCCl.C(OCC)(=O)C>[ClH:38].[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:15][CH2:16]2)[CH:6]=[CH:5][C:4]=1[O:23][C:36]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:37]
Reactant: COc1cc(CCN2CCN(c3ccccn3)CC2)ccc1O
Reactant: O=C(Cl)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC#N
Product: COc1cc(CCN2CCN(c3ccccn3)CC2)ccc1OC(=O)N1CCOCC1
Product: Cl
Yield: 40.6 %

Procedure:
To a solution of 2-methoxy-4-[2-(4-pyridin-2-yl-piperazin-1-yl)ethyl)phenol (1.5 g) and cesium carbonate (1.6 g) in 25% acetonitrile/dichloromethane was added 4-morpholinecarbonyl chloride (1.4 g), with stirring, under nitrogen. The reaction mixture was stirred for 18 hrs under nitrogen, diluted with ethyl acetate, and the layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was flash chromatographed (silica), eluting with 2% methanoludichloromethane. The appropriate fractions were collected and concentrated. The residue was dissolved in ethyl acetate and ethereal hydrochloride was added. The precipitate was collected and recrystallized from ethyl ethanol/ether to give 0.9 g (75%) of product, mp 185-186° C.
Reaction SMILES: [C:1]1(=[CH:7][CH:8]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]1([S:16]([C:19]#[N:20])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.B(OCCCC)(OCCCC)OCCCC.C(O)CCC>C1(C)C=CC=CC=1>[C:10]1([S:16]([C:19]2[C:2]3[CH2:3][CH2:4][CH2:5][CH2:6][C:1]=3[CH:7]=[CH:8][N:20]=2)(=[O:17])=[O:18])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=CC=C1CCCCC1
Reactant: N#CS(=O)(=O)c1ccccc1
Agent: CCCCOB(OCCCC)OCCCC
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: O=S(=O)(c1ccccc1)c1nccc2c1CCCC2
Temperature: 110 °C
Yield: 15.8 %

Procedure:
First, 106 mg (purity of 84%, 0.72 mmol) of cyclohexylidene acetaldehyde, 120 mg (0.72 mmol) of benzenesulfonyl cyanide, 17 mg (0.072 mmol) of tributyl borate, 11 mg (0.14 mmol) of 1-butanol, and molecular sieves 4A (310 mg) as dehydrator were introduced to a flask (5 ml volume). Toluene (1.5 ml) was added as the solvent, and the mixture was heated for 14 hours at an internal temperature of 110° C. After this solution was cooled to room temperature, the molecular sieves was filtered off and the low-boiling components, such as solvent, etc., were removed under reduced pressure to give the desired, crude product. The crude product was purified by silica gel column chromatography (eluting solvent: ethyl acetate/hexane=1/3) to give 31 mg of 1-benzenesulfonyl-5,6,7,8-tetrahydroisoquinoline with the following properties as yellow crystals (yield of 16% based on benzenesulfonyl cyanide).
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].[O:5]=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][O:9][C:8]2[CH:17]=[C:18](C=O)[CH:19]=[CH:20][C:7]1=2.[OH-:23].[Na+]>C(O)(=O)C>[OH:23][NH:2][CH2:1][C:18]1[CH:19]=[CH:20][C:7]2[C:6](=[O:5])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][O:9][C:8]=2[CH:17]=1
Reactant: [OH-]
Reactant: [BH3-]C#N
Reactant: O=Cc1ccc2c(c1)OCc1ccccc1C2=O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1c2ccccc2COc2cc(CNO)ccc21
Temperature: 65 °C
Reaction time: 2.5 h

Procedure:
Sodium cyanoborohydride (13.6 g, 0.22 mol) is added in portions to a solution of 6,11-dihydro-11-oxodibenz[b,e]oxepin-3-carboxaldehyde, oxime (11 g; 0.04 mol) in acetic acid (150 ml) at 15°-20° C. (cooling). After the mixture is stirred for 2.5 hours, an additional portion of sodium cyanoborohydride (2 g) is added and the solution is stirred for an additional 2 and 3/4 hours. The mixture is neutralized to pH -7 with 50% sodium hydroxide solution, the temperature being maintained at 65° C. The product is extracted with ethyl acetate, followed by washings with water, saturated sodium chloride solution, drying and evaporating under reduced pressure to give 13.2 g of a solid residue. The residue is flash chromatographed on silica gel with chloroform then with chloroform:methanol=95:5, as eluant to give 8.66 g (78%); 3[(hydroxyamino)methyl]dibenz[b,el]oxepin-11(6H)-one, as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([NH:18][CH2:19][C@H:20]3[O:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[CH:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:40][CH2:41][CH2:42][OH:43].O>CN(C=O)C>[OH:43][CH2:42][CH2:41][CH2:40][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:17]=[C:16]([NH:18][CH2:19][C@H:20]3[O:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]3)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: OCCCBr
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CNc2nc(-c3ccc(O)cc3)cc3nccnc23)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCO[C@H](CNc2nc(-c3ccc(OCCCO)cc3)cc3nccnc23)C1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-tert-butyl 2-((7-(4-hydroxyphenyl)pyrido[4,3-b]pyrazin-5-ylamino)methyl)morpholine-4-carboxylate (115 mg, 0.26 mmol) in DMF (5 mL) was added Cs2CO3 (128 mg, 0.39 mmol) and 3-bromopropan-1-ol (55 mg, 0.39 mmol). The reaction was stirred at 80° C. for 0.5 hours. TLC and LC-Ms showed the reaction had completed and the reaction was poured into water, extracted with EA, washed with water and brine, dried and concentrated, purified on TLC (CH2Cl2:MeOH=30:1) to give yellow solid. MS (m/z): 496 (M+H)+
Reaction SMILES: [Si]([O:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=1[NH2:11])(C(C)(C)C)(C)C.Cl[C:20](Cl)([O:22]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[Cl:38][C:39]1[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=1[CH2:41][NH2:42]>C1(C)C=CC=CC=1>[OH:8][C:9]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=1[NH:11][C:20]([NH:42][CH2:41][C:40]1[CH:43]=[CH:44][CH:45]=[CH:46][C:39]=1[Cl:38])=[O:22]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCc1ccccc1Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1cc([N+](=O)[O-])ccc1N
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1Cl)Nc1ccc([N+](=O)[O-])cc1O
Temperature: 80 °C
Reaction time: 3 h
Yield: 145.1 %

Procedure:
To a solution of 2-tert-butyldimethylsilyloxy-4-nitroaniline (300 mg, 1.12 mmol) in toluene (10 mL), triphosgene (126 mg, 0.45 mmol) and triethylamine (0.195 mL, 1.34 mmol) were added. The reaction mixture was stirred at 80° C. for 3 hours. Then the reaction mixture was cooled to room temperature and all the solvent was evaporated. The residue was dissolved in DMF (1 mL). 2-chlorobenzylamine (158.6 mg, 1.12 mmol) was added. The reaction mixture was stirred at 80° C. for 16 hours Chromatography of the resulting liquid on silica gel (30% Ethyl acetate/Hexane) gave desired product (210 mg, 57%). EI-MS m/z 322.8 (M+); m.p. 199.2-199.6° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][NH:23][O:24][CH3:25])=[CH:16][CH:15]=1>>[CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([N:23]([CH2:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)[O:24][CH3:25])=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CONCCCc1ccc(F)cc1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CON(CCCc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 97 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-[3-(4-fluorophenyl)-propyl]-O-methyl-hydroxylamine as described in the preparation of compound 1-A gave the title amide as white crystals (97% yield): mp 90-91° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.77 (6H, s, CH3), 1.98 (2H, m, CH2), 2.64 (2H, t, J=7.9 Hz, CH2), 3.71 (2H, t, J=7.6 Hz, NCH2), 3.73 (3H, s, OCH3), 6.41 (1H, broad s, CH), 6.98 (2H, m, aromatics), 7.16 (2H, m, aromatics). Anal. calcd for C17H20FNO5: C, 60.53; H, 5.98; N, 4.15. Found: C, 60.43; H, 5.99; N, 4.09.