Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:37])[CH2:10][CH:11]([S:24](=[O:36])(=[O:35])[NH:25][CH:26]1[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]1)[CH2:12][NH:13]C(OCC1C=CC=CC=1)=O)C1C=CC=CC=1.B(Br)(Br)Br.[OH-].[Na+]>ClCCl.O>[NH2:13][CH2:12][CH:11]([S:24](=[O:36])(=[O:35])[NH:25][CH:26]1[CH2:27][CH2:28][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:30][CH2:31]1)[CH2:10][C:9]([OH:37])=[O:8]
Reactant: CC(C)N1CCC(NS(=O)(=O)C(CNC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)CC1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)N1CCC(NS(=O)(=O)C(CN)CC(=O)O)CC1
Temperature: 25 °C

Procedure:
24 mg (0.04 mmol) 4-Benzyloxycarbonylamino-3-(1-isopropyl-piperidin-4-ylsulfamoyl)-butyric acid benzyl ester were dissolved in 3 ml dichloromethane. At 0° C., 0.1 ml of a 1 M BBr3-solution in dichloromethane were added and the reaction mixture was allowed to warm to room temperature. After 24 h a few drops of water and 0.3 ml of a 1 M aqueous NaOH-solution were added. The mixture was concentrated under reduced pressure. The residue was taken up in DMF and filtered in order to get rid of salts. The filtrate was concentrated under vacuo to give crude 4-amino-3-(1-isopropyl-piperidin-4-ylsulfamoyl)-butyric acid, which was pure enough for further transformations. Yield: 14 mg
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:34])[CH:10]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.[Br:35][CH2:36][CH2:37]Br>C(#N)C>[CH3:7][O:8][C:9](=[O:34])[CH:10]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:37][CH2:36][Br:35])=[CH:16][CH:17]=1
Reactant: BrCCBr
Reactant: COC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(Cc1ccc(OCCBr)cc1)Nc1ccccc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
To a solution of potassium carbonate (2 kg) in acetonitrile (5000 ml) is added 2-((2-benzoylphenyl)amino)-3-(4-hydroxyphenyl)-propionic acid methyl ester (555 g, 1.48 mol) and 1,2-dibromoethane (1000 ml). Then the mixture is stirred at room temperature for 24 hours. After that, the reaction mixture is filtered, and then the filtrate is evaporated under a vacuum. The crude product is purified by silica gel chromatography using hexane/EtOAc (4:1) as eluent to give 2-((2-benzoylphenyl)amino)-3-[4-(2-bromoethoxy)-phenyl]-propionic acid methyl ester (442 g, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Sn](C)(C)C)=[CH:5][N:4]=1.FC(F)(F)S(O[C:19]1[CH:20]=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([O:29][CH3:30])=[C:24]([O:31][CH3:32])[CH:23]=2)(=O)=O.[Cl-].[Li+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:19]2[CH:20]=[N:21][C:22]3[C:27]([CH:28]=2)=[CH:26][C:25]([O:29][CH3:30])=[C:24]([O:31][CH3:32])[CH:23]=3)=[CH:5][N:4]=1
Reactant: COc1cc2cc(OS(=O)(=O)C(F)(F)F)cnc2cc1OC
Reactant: COc1ccc([Sn](C)(C)C)cn1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: COc1ccc(-c2cnc3cc(OC)c(OC)cc3c2)cn1

Procedure:
A mixture of 800 mg (2.94 mmol) of 2-methoxy-5-trimethylstannyl-pyridine, mg (2.94 mmol) of 6,7-dimethoxyquinolin-3-yl trifluoromethane sulfonate, 374 mg (8.82 mmol) of anhydrous lithium chloride and 170 mg (0.147 mmol) of Pd(PPh3)hd in 15 mL of anhydrous dioxane is flushed thoroughly with nitrogen and refluxed for 6 hours. The mixture is diluted with ethyl acetate (100 mL), washed with saturated NaHCO3 (75 mL), dried (Na2SO4) and evaporated. The resulting residue is chromatographed on silica gel (eluting with chloroform) to give a solid material which is recrystallized from ethyl acetate to give 3-(2-methoxypyrid-5-yl)-6,7-dimethoxyquinoline m.p. 170.5°-171.5° C.
Reaction SMILES: C([C:3]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[C:15]=1OC)([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:4]([O:6]CC)=[O:5])#N.I.C(O)(=O)C>O>[CH2:9]([CH:3]1[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])[C:15]=2[O:5][C:4]1=[O:6])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCC(C#N)(C(=O)OCC)c1cccc(Oc2ccccc2C)c1OC
Agent: I
Solvent: O
Solvent: CC(=O)O
Product: CCCCCC1C(=O)Oc2c(Oc3ccccc3C)cccc21
Yield: 54 %

Procedure:
A mixture of ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]-n-heptanoate (5.9 g), hydriodic acid (58%, 10 ml) and acetic acid (20 ml) was refluxed under heating for 48 hours. The reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with aqueous sodium hydrogen sulfite and water in turn, dried and evaporated under reduced pressure. To the oily residue was added acetic anhydride (5 ml), and the mixture was refluxed under heating for 10 minutes and then evaporated under reduced pressure. The resultant oily residue was purified by column chromatography (silica gel 80 g, benzene) to give oily 3-(n-pentyl)-7-(o-tolyloxy)-2,3-dihydrobenzofuran-2-one (2.5 g).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])=[CH:24][CH:23]=2)(=[O:21])=[O:20])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OCC(CC)CC)cc2)CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccccc3)CC2)cc1

Procedure:
1-Benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic acid was prepared starting from 1-Benzyl-4-[4-(2-ethyl-butoxy)-benzenesulfonyl]-piperidine-4-carboxylic ethyl ester (4.8 g, 10 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4 g (87%); Semi solid; MS: 460 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]2[O:15][C:16](=[O:25])[C:17]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:18]=3[N:19]=2)[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[N:6]=1.[NH3:26]>O>[C:16]([C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:18]=1[NH:19][C:14]([C:4]1[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[N:6]=[C:2]([Br:1])[CH:3]=1)=[O:15])(=[O:25])[NH2:26]
Reactant: N
Reactant: Cc1cccc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Solvent: O
Product: Cc1cccc(C(N)=O)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Reaction time: 72 h

Procedure:
1.00 g 2-[5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazol-3-yl]-8-methyl-benzo[d][1,3]oxazin-4-one was taken up in 10 ml of a 25% ammonia solution in water and stirred for 72 h. The solids were filtered and washed with cold water to yield 0.80 g of the amide.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:5]=1[CH:6]=[C:7]1[S:11]C(=S)N[C:8]1=[O:13])([OH:3])=O.CC[OH:24]>>[CH3:21][O:20][C:15]1[CH:14]=[C:5]2[C:4](=[CH:17][C:16]=1[O:18][CH3:19])[C:1](=[O:3])[S:11][C:7]([C:8]([OH:24])=[O:13])=[CH:6]2
Reactant: CCO
Reactant: COc1cc(C=C2SC(=S)NC2=O)c(C(=O)O)cc1OC
Product: COc1cc2cc(C(=O)O)sc(=O)c2cc1OC

Procedure:
6,7-Dimethoxy-2-thiaisocoumarin-3-carboxylic acid, mp. (EtOH) 300°-2°, (lit. mp. 306°-7°), (Found: C, 54.03; H, 3.80; S, 11.83, C12H10SO5 requires C, 54.13; H, 3.79; S, 12.04) was prepared from 5-(2'-carboxy-4',5'-dimethoxybenzylidene) rhodanine by an analogous procedure to that described in Example 12.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][C:11]=1[S:12]([OH:15])(=[O:14])=[O:13])[NH2:8])(=O)C.[OH-].[Na+].S(OC)(OC)(=O)=O.Cl.[Cl-].[Na+]>O.C(O)=O>[CH3:1][NH:4][C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][C:11]=1[S:12]([OH:15])(=[O:14])=[O:13])[NH2:8]
Reactant: CC(=O)Nc1cc(N)ccc1S(=O)(=O)O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: O=CO
Product: CNc1cc(N)ccc1S(=O)(=O)O
Temperature: 20 °C

Procedure:
115 g of 3-(N-acetylamino)aniline-4-sulfonic acid in 430 ml of water and 70 g of formic acid were boiled under reflux for 7 hours. The mixture was cooled to 20° C. and its pH then adjusted to 12 with caustic soda solution. 75 g of dimethyl sulfate were then added, and after 40 minutes the pH was adjusted to -0.5 with hydrochloric acid. The mixture was heated under reflux for 3 hours and then salted out with 150 g of sodium chloride. The pH was adjusted to 1.0 with caustic soda solution, and the precipitated 3-(N-methylamino)aniline-4-sulfonic acid was isolated by filtration.
Reaction SMILES: Cl[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[K+].[K+].[SH:18][CH2:19][CH2:20][OH:21]>CN(C=O)C.C(OCC)(=O)C>[NH2:4][C:3]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:2]=1[S:18][CH2:19][CH2:20][OH:21]
Reactant: OCCS
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cc([N+](=O)[O-])ccc1SCCO
Temperature: 60 °C
Yield: 95.9 %

Procedure:
To a stirred solution of 2-chloro-5-nitroaniline (1.0 g, 5.79 mmol) in DMF (10 mL) was added potassium carbonate (1.60 g, 11.59 mmol) followed by 2-mercaptoethanol (0.813 mL, 11.59 mmol). The resulting mixture was then heated at 60° C. for 2 hours and then at room temperature overnight. The mixture was then diluted with ethyl acetate and washed with water (3×), 1N NaOH, and brine. The organic phase was dried, filtered, and concentrated, giving a red/orange solid (1.19 g, 96%). 1H NMR (DMSO-d6) δ 7.52 (s, 1H), 7.42-7.33 (m, 2H), 5.79 (s, 2H), 4.99 (t, J=5.4 Hz, 1H), 3.55 (q, J=6.2 Hz, 2H), 3.02 (t, J=6.6 Hz, 2H); ESI-MS (m/z, %): 215 (MH+, 23), 169 (100), 111 (63).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].[N+:12]([O-])([OH:14])=[O:13]>CC(O)=O>[N+:12]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[C:4]=1[OH:9])([O-:14])=[O:13]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc(C(F)(F)F)c1O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 44 %

Procedure:
To a solution of commercially available 2-trifluoromethylphenol (2.5 g, 15.42 mmol) in AcOH (3 mL) cooled to 0° C. was added dropwise concentrated HNO3 (1.5 mL). After the addition, the mixture was stirred at 0° C. for 5 min, at rt for 10 min, then poured into ice/water, and extracted with ether (3×). The combined ether extracts were washed with water, brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was chromatographed (silica gel) eluting with 0% to 10% EtOAc/hexane to yield the title compound (1.4 g, 44% yield).
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:24]=[CH:23][C:8]([CH2:9][CH:10]([C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])=[CH:7][CH:6]=1)#[N:4].Br[CH2:26][CH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1.O>CN(C=O)C>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][C:10]([CH2:26][CH2:27][C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)([C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])=[CH:23][CH:24]=1)#[N:4]
Reactant: C=CCOC(=O)C(Cc1ccc(C#N)cc1)C(=O)OCC=C
Reactant: COC(=O)c1ccc(CCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(CCc1ccc(C(=O)OC)cc1)(Cc1ccc(C#N)cc1)C(=O)OCC=C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
7.13 g (178.36 mmol) of sodium hydride are added in portions to a solution of 48.53 g (162.14 mmol) of diallyl 2-(4-cyanobenzyl)malonate in 180 ml of DMF at 0° C. The reaction solution is then allowed to reach room temperature and is stirred for 30 min. The reaction solution is then cooled to 0° C. again and, after addition of 55 g (194.6 mmol) of methyl 4-(2-bromoethyl)benzoate [CAS No. 136333-97-6] in 195 ml of DMF, stirred at this temperature for 30 min. The mixture is then stirred at room temperature overnight. Water is added dropwise to the reaction mixture, which is then extracted three times with ethyl acetate, and the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness in vacuo. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: petroleum ether/ethyl acetate 10:1). 33.4 g (72.37 mol, 44% of theory) of a colorless solid are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.[H-].[Na+].[CH3:38]I.[Cl-].[NH4+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[N:23]([CH3:38])[C:22]2=[O:35])[CH2:17][CH2:16]1
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cc([N+](=O)[O-])ccc5n(C)c4=O)CC3)c2cc1OC
Reaction time: 0.33 h
Yield: 62.1 %

Procedure:
In 1 ml of DMF was dissolved 239 mg (0.5 mmol) of 3-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-1,2,3, 4-tetrahydro-6-nitro-2,4-dioxoquinazoline (Compound 24) obtained in Reference Example 6, and the solution was added dropwise to a solution of 22 mg (0.55 mmol) of 60% sodium hydride in 2 ml of DMF under ice cooling. After stirring for 20 minutes, 0.031 ml (0.5 mmol) of methyl iodide was added thereto, followed by stirring at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the precipitated solid was collected by filtration. The solid was washed with water, dried by heating, and recrystallized from ethanol/ether to give 152.9 mg (yield: 62%) of Compound 1 as pale yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=O)[CH3:21])=[CH:15][CH:14]=3)=[N:6][C:5]=2[C:4]([CH2:23][CH2:24][CH3:25])=[N:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[CH2:20]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:7]2[NH:8][C:9](=[O:11])[C:10]3[N:2]([CH3:1])[N:3]=[C:4]([CH2:23][CH2:24][CH3:25])[C:5]=3[N:6]=2)=[CH:14][CH:15]=1)[CH3:21]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(NC(C)=O)cc3)nc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCc1nn(C)c2c(=O)[nH]c(Cc3ccc(NCC)cc3)nc12

Procedure:
N-{4-[(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)methyl]phenyl}acetamide (2.37 g, 0.007 mol) was added to a mixture of lithium aluminium hydride (705 mg, 0.0186 mol) in tetrahydrofuran (250 ml), under a nitrogen atmosphere. After the effervescence had subsided, the reaction was refluxed for 2 hours. On cooling, the mixture was treated dropwise with aqueous sodium hydroxide solution (5M, 1.1 ml), and the resulting solid filtered and washed well with tetrahydrofuran (250 ml). The filtrate was concentrated under reduced pressure and the residue partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous phase was extracted with ethyl acetate (200 ml) and the organic phases combined, dried (MgSO4), filtered and concentrated under reduced pressure.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH2:26][O:27]C2C=CC=C3C(NC(=O)C=23)=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:40]N>ClCCl>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH2:26][O:27][NH2:40])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2c(OCc3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cccc21
Reactant: NN
Solvent: O
Solvent: ClCCl
Product: NOCc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.3 %

Procedure:
To a solution of 12.0 g of the (2-tritylaminothiazol-4-yl)methoxyphthalimide in 400 ml of dichloromethane was added 1.161 g of hydrazine hydrate with cooling, and the mixture was stirred at room temperature for 5 hours. The formed precipitates were removed by filtration, the dichloromethane layer was washed with 300 ml of 10% ammonia water three times and then with 300 ml of saturated saline twice, dried on anhydrous magnesium sulfate, and concentrated to dryness to obtain 8.74 g of (2-tritylaminothiazol-4-yl)methoxyamine.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[BH4-].[Na+].O>CO>[Cl:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5]
Reactant: COc1c([N+](=O)[O-])ccc(C=O)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c([N+](=O)[O-])ccc(CO)c1Cl
Reaction time: 1.5 h
Yield: 67.9 %

Procedure:
To a solution of 2-chloro-3-methoxy-4-nitrobenzaldehyde (Compound 54I, 1.6 g, 7.44 mmol) in methanol (25 mL) at 0° C. was added sodium borohydride (330 mg, 8.91 mmol). After stirring for 1.5 h, water (15 mL) was added. The solid obtained was filtered and dried to obtain the desired intermediate (1.1 g, 69%). 1H NMR (300 MHz, CDCl3) δ 7.78 (d, J=4.8 Hz, 1H), 7.47 (d, J=5.1 Hz, 1H), 4.83 (d, J=3.6 Hz, 2H), 4.02 (s, 3H), 2.25 (t, J=3.6 Hz, 1H).
Reaction SMILES: [ClH:1].N[C:3]1[N:7]([CH3:8])[N:6]=[CH:5][C:4]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(Cl)(Cl)Cl>[Cl:1][C:3]1[N:7]([CH3:8])[N:6]=[CH:5][C:4]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1cnn(C)c1N
Reactant: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cnn(C)c1Cl
Reaction time: 1 h

Procedure:
For a period of 60 minutes, hydrogen chloride gas was bubbled into a solution of 5-amino-1-methyl-1H-pyrazole-4-carboxylic acid, ethyl ester (12 grams, 0.07 mole) in 75 ml. of chloroform. The reaction mixture set up and nitrosyl chloride was bubbled into the reaction mixture for a period of five minutes. TLC indicated that starting material was still present, therefore, nitrosyl chloride was bubbled into the reaction mixture for an additional five minutes. The solution was heated on a steam bath for five minutes, then cooled and the solvent removed in vacuo, yielding 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid, ethyl ester. The identity of the product was confirmed by NMR.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:14]2[CH2:18][CH2:17][C@H:16]([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)[O:15]2)[CH:6]=[C:7]([NH2:13])[C:8]=1[O:9][CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].I[CH2:38][CH2:39][OH:40]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:14]2[CH2:18][CH2:17][C@H:16]([C:19]3[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=3)[O:15]2)[CH:6]=[C:7]([NH:13][CH2:38][CH2:39][OH:40])[C:8]=1[O:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCOc1c(N)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1OC
Reactant: OCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1c(NCCO)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1OC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of trans-2-(3-methoxy-4-propoxy-5-aminophenyl)-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran (20 mg. 0.048 mmol), potassium carbonate (0.4 g), and 2-iodoethanol (82.47 mg, 0.48 mmol) was suspended in 2 mL of DMF. The reaction mixture was stirred at room temperature for 20 hours, quenched with water and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to an oil which was purified by column using 3:1 hexane/ethyl acetate as solvent (12.8 mg, 57.9%). 1H NMR (CDCl3): 1.02 (t, 3H), 1.79 (m, 2H), 1.99 (m, 2H), 2.43 (m, 2H), 3.33 (m, 2H), 3.81 (m, 2H), 3.82 (s, 3H), 3.83 (s, 3H), 3.88 (s, 6H), 3.90 (t, 2H), 5.18 (m, 2H), 6.40 (d, 2 H), 6.61 (s, 2H).
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[N:19]1([C:25]2[N:30]=[C:29]([CH:31]=O)[CH:28]=[CH:27][CH:26]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[CH:2]1[N:1]([CH2:31][C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:30]=2)[C:5](=[O:7])[CH2:4][CH2:3]1
Reactant: O=Cc1cccc(N2CCCCC2)n1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1cccc(N2CCCCC2)n1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available 6-(piperidin-1-yl)picolinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.61 min.; [M+H]+: 396.00 g/mol.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[O:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][C:32](O)=[O:33]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:32](=[O:33])[CH2:31][CH:27]5[CH2:28][CH2:29][CH2:30][O:26]5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)CC1CCCO1
Agent: Cl
Product: O=C(CC1CCCO1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (9 mg, 25%), MS (ISP) m/z=443.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (29.4 mg, 0.080 mmol) and 2-(tetrahydrofuran-2-yl)acetic acid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[C:19]1(=O)[NH:23][C:22](=[O:24])[CH:21]=[CH:20]1>FC(F)(F)C(O)=O>[CH:6]1[C:5]2[O:1][C:2]3[C:10]4[NH:11][C:12]5[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=5)[C:18]=4[C:20]4=[CH:21][C:22](=[O:24])[N:23]=[C:19]4[C:3]=3[C:4]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=C1C=CC(=O)N1
Reactant: c1ccc2[nH]c(-c3cc4ccccc4o3)cc2c1
Solvent: O=C(O)C(F)(F)F
Product: O=C1C=c2c(c3c4ccccc4oc3c3[nH]c4ccccc4c23)=N1
Temperature: 125 °C
Yield: 48.3 %

Procedure:
A mixture of 2-(2-benzofuryl)indole 2 (250 mg; 1.0 mmol) and maleimide (110 mg; 1.2 mmol) in trifluoroacetic acid (2 mL) was heated in a sealed reaction vial at 125° C. for 18 h. The solid precipitated was collected, washed with TFA and dried to give 150 mg (48%) of product. Recrystallization (THF) gave a tan solid; mp>300° C., MS (ES+) 312 (M+), 1H NMR (DMSO--d6) δ 4.00 (s, 2H), 4.13 (s, 2H), 7.12 (t, 1H), 7.37 (t, 2H), 7.45 (t, 2H), 7.71 (d, 1H), 7.95 (d, 1H), 8.54 (d, 1H), 10.12 (s, 1H), 11.79 (s, 1H). Anal. calcd for C20 H12N2O2 0.4 H2O; C, 75.18; H, 4.04; N, 8.77. Found: C, 75.29, H, 3.86, N, 8.60.