Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:6][C:7]1[NH:8][C:9](=[O:24])[C:10]2[N:11]=[CH:12][N:13]([C:22]=2[N:23]=1)[C@@H:14]1[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].CC(N(C)C)=O.[C:31](Cl)(=[O:47])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].C(=O)(O)[O-].[K+]>N1C=CC=CC=1>[C:31]([O:20][CH2:19][C@H:18]1[O:21][C@@H:14]([N:13]2[C:22]3[N:23]=[C:7]([NH:6][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[NH:8][C:9](=[O:24])[C:10]=3[N:11]=[CH:12]2)[CH2:15][C@@H:16]1[OH:17])(=[O:47])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(NC(=O)C(C)C)nc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To an oven-dried 100 mL round-bottomed flask containing a stir bar was added N2-isobutyryl-2′-deoxyguanosine (0.75 g, 1 eq.). The flask was fitted with a septum and dry dimethylacetamide (DMA, 32 mL) and dry pyridine (16 mL) were added via cannula, with swirling and stirring. The flask was purged with argon gas, the slurry was allowed to cool 10 min. in an ice bath, and palmitoyl chloride (2.5 eq.) was added dropwise over 5 min. The mixture was allowed to stir while it slowly warmed to 25° C. After 24 h, the mixture was poured into 200 mL of 0.5 M potassium bicarbonate solution giving a white solid which was isolated by suction filtration, washed with 3×30 mL H2O, air dried, and finally dried under high vacuum giving a white powder. This crude product was purified by flash chromatography (silica gel bed, eluted with chloroform-methanol) giving a white powder. 1H-NMR and elemental analysis data were consistent with the assigned structure.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:34][CH2:35][O:36][CH3:37])=[CH:6][C:7]([O:30][CH2:31][O:32][CH3:33])=[C:8]([C:10]2[N:11]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[C:12](=[S:15])[NH:13][N:14]=2)[CH:9]=1)([CH3:3])[CH3:2].[C:38](=O)([O-])[O-].[K+].[K+].C(O)C.CI>C(OCC)C>[CH:1]([C:4]1[C:5]([O:34][CH2:35][O:36][CH3:37])=[CH:6][C:7]([O:30][CH2:31][O:32][CH3:33])=[C:8]([C:10]2[N:11]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]4)=[CH:20][CH:21]=3)[C:12]([S:15][CH3:38])=[N:13][N:14]=2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1-c1n[nH]c(=S)n1-c1ccc(CN2CCN(C)CC2)cc1
Agent: [K+]
Solvent: CCOCC
Solvent: CI
Solvent: CCO
Product: COCOc1cc(OCOC)c(C(C)C)cc1-c1nnc(SC)n1-c1ccc(CN2CCN(C)CC2)cc1
Yield: 63.1 %

Procedure:
5-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-4-[4-(4-methylpiperazin-1-ylmethyl)phenyl]-2,4-dihydro-[1,2,4]triazol-3-thione (F652-06, 3.17 g, 6.01 mmol) and potassium carbonate (829 mg, 6.00 mmol) were weighed and placed in a reaction vessel. After adding ethanol (30 mL), methyl iodide (0.374 mL, 6.01 mmol) was added to the mixture. After heating for 1 hour under reflux, the temperature was returned to room temperature, and the solvent was distilled off under reduced pressure. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and then filtered to remove sodium sulfate, and the solvent was distilled off under reduced pressure to obtain pale yellow foam. Diethyl ether was added to the foam and the insoluble material was removed by filtration. After washing with water, the filtrate was washed with saturated sodium chloride solution. The extract was dried with sodium sulfate, and sodium sulfate was removed by filtration. The solvent was distilled off under reduced pressure to obtain 3-(5-isopropyl-2,4-bis-methoxymethoxyphenyl)-4-[4-(4-methylpiperazin-1-ylmethyl)phenyl]-5-methylsulfanyl-[1,2,4]triazole (F652-07, pale yellow foam, 2.05 g, 63%).
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)(=O)[CH2:12][CH3:13].Cl>C(O)C.O1CCOCC1>[ClH:1].[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:11]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[C:12]2[CH3:13]
Reactant: CCC(=O)c1cccnc1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1c(-c2cccnc2)[nH]c2ccc(Br)cc12

Procedure:
To a suspension of 4-bromophenylhydrazine hydrochloride (10.00 g, 42.95 mmol) in anhydrous ethanol (200 mL) is added 3-propionylpyridine (7.51 g, 42.95 mmol) and the mixture is stirred at reflux for 30 min. 4M HCl in 1,4-dioxane (42.9 mL) is added to the yellow solution and stirring is continued at reflux overnight. The reaction mixture is cooled with an ice-water bath and the yellow precipitate is filtered through a sintered funnel to give 5-bromo-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride as a yellow solid. The product is dissolved in methanol (100 mL) and treated with sodium methoxide to give the free base, which is used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[N:8]=[C:9]([N:12]2[CH2:15][CH:14]([OH:16])[CH2:13]2)[S:10][CH:11]=1)=[O:6])[CH:2]=[CH2:3].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:4][C:5]([C:7]1[N:8]=[C:9]([N:12]2[CH2:13][CH:14]([O:16][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:15]2)[S:10][CH:11]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCOC(=O)c1csc(N2CC(O)C2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
To a solution of 1-(4-allyloxycarbonyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (2.91 g, 11.1 mmol) (obtained as described in Reference Example 41(2)) in methylene chloride (146 ml) were added methanesulfonyl chloride (2.58 ml, 33.3 mmol) and triethylamine (4.67 ml, 33.3 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 2 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. To the residue were added ethyl acetate and diisopropyl ether, and then the mixture was filtered and the resulting residue was washed with diisopropyl ether to give 1-(4-allyloxycarbonyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (2.71 g, yield 77%) as pale brown crystals.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.Cl.[OH:12][C:13]1[C:14]([CH:29]([CH3:32])[CH:30]=[CH2:31])=[CH:15][C:16]([CH3:28])=[C:17]2[C:25]=1[CH:24]([NH:26][CH3:27])[CH:23]1[CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]1>O>[OH:12][C:13]1[C:14]([CH:29]([CH3:32])[CH:30]=[CH2:31])=[CH:15][C:16]([CH3:28])=[C:17]2[C:25]=1[CH:24]([N:26]([CH3:27])[CH:8]=[O:10])[CH:23]1[CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: O=CO
Reactant: C=CC(C)c1cc(C)c2c(c1O)C(NC)C1CCCCC21
Agent: Cl
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: C=CC(C)c1cc(C)c2c(c1O)C(N(C)C=O)C1CCCCC21
Reaction time: 15 h

Procedure:
2.0 Milliliters of acetic anhydride and 1.0 ml of 98% formic acid were mixed and the mixture was stirred under heating for 2 hours and left to stand of cooling. To the resulting solution were added 3.0 g of 8-hydroxy-5-methyl-9-methylamino-7-(1-methyl-2-propenyl)-1,2,3,4,4a,9a-hexahydrofluorene hydrochloride and 10 ml of acetic anhydride and reaction was carried out at 60° C. for 2 hours and at room temperature for 15 hours. To the reaction mixture was added water and the separated solid was collected by filtration, washed with water and once dissolved in chloroform and the solution was dried with magnesium sulfate. The solvent was distilled off and the residue was recrystallized from ethanol to obtain 1.42 g of 8-hydroxy-5-methyl-9-(N-methyl-N-formylamino)-7-(1-methyl-2-propenyl)-1,2,3,4,4a,9a-hexahydrofluorene.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:29]=[CH:28][C:9]3[N:10]([C:13]4[CH:14]=[C:15]([NH:24]C(=O)C)[CH:16]=[C:17]([N:19]5[CH:23]=[CH:22][CH:21]=[CH:20]5)[CH:18]=4)[CH:11]=[N:12][C:8]=3[CH:7]=2)=[CH:4][N:3]=[CH:2]1.[OH-].[Na+]>C(O)C>[O:1]1[C:5]([C:6]2[CH:29]=[CH:28][C:9]3[N:10]([C:13]4[CH:14]=[C:15]([CH:16]=[C:17]([N:19]5[CH:23]=[CH:22][CH:21]=[CH:20]5)[CH:18]=4)[NH2:24])[CH:11]=[N:12][C:8]=3[CH:7]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)Nc1cc(-n2cccc2)cc(-n2cnc3cc(-c4cnco4)ccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(-n2cccc2)cc(-n2cnc3cc(-c4cnco4)ccc32)c1
Temperature: 85 °C
Yield: 70 %

Procedure:
To a solution of the compound of Example 106 (800 mg, 2.1 mmol) in ethanol (15 ml) was added aqueous solution of NaOH (0.72 g, 18.06 mmol, 8.6 eq.) and the mixture was heated at 85° C. for 5 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to afford the product in 70% yield (0.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][CH:10]([OH:13])[C:11]#[CH:12].N(C(C)C)C(C)C>ClCCl.[Cu]I.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]#[C:11][CH:10]([OH:13])[CH3:9])=[CH:4][CH:3]=1
Reactant: Clc1ccc(I)cc1
Reactant: C#CC(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CC(O)C#Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
To a solution of 4-chloro iodobenzene (10 g, 42 mmol), 3-butyn-2-ol (6.6 mL, 84 mmol, 2 eq.), and iPr2NH (14.8 mL, 105 mmol, 2.5 eq.) in 200 mL dichloromethane was added CuI (1.6 g, 8.4 mmol, 0.2 eq.) followed by Pd(PPh3)2Cl2 (1.5 g, 2.1 mmol, 5 mol %). The mixture was stirred for 1.5 hr at room temperature, concentrated and diluted with ether. The insoluble components of the mixture were filtered off and the filtrate washed with 1N HCl and brine, dried over MgSO4, filtered, concentrated and chromatographed with 20% ethyl acetate-hexane to provide 7.6 g of 4-(4-chloro-phenyl)-but-3-yn-2-ol.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[C:29]([CH3:33])[NH:30]2)=[CH:26][CH:25]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[C:29]([CH3:33])[NH:30]2)=[CH:26][CH:25]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Reactant: Cc1cc2ccc(O)cc2[nH]1
Product: COc1cc2c(Oc3ccc4cc(C)[nH]c4c3)ncnc2cc1OCCCN1CCCC1
Yield: 83.6 %

Procedure:
Using an analogous procedure to that described for Example 121, 4-chloro-6-methoxy-7-(3-pyrrolidinopropoxy)quinazoline (150 mg, 0.47 mmol), (prepared as described for the starting material in Example 9), was reacted with 6-hydroxy-2-methylindole (83 mg, 0.56 mol), (Eur. J. Med. Chem. 1975, 10, 187), to give 6-methoxy-4-(2-methylindol-6-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (170 mg, 85%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH2:15])([CH3:4])([CH3:3])[CH3:2].C([O:21][C:22](=O)[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:39])[CH:33]=2)[CH:27]=1)=[O:25])(C)(C)C>>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH:15][C:22](=[O:21])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[C:34]([CH3:39])[N:35]=[C:36]([CH3:38])[CH:37]=2)[CH:27]=1)=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)ccc3NC(=O)OC(C)(C)C)c2)cc(C)n1

Procedure:
The title compound was prepared from (2-amino-4-chloro-phenyl)-carbamic acid tert-butyl ester (Example J4) (243 mg, 1.0 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (325 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (240 mg, 49%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][CH2:30][CH2:31][OH:32].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[OH:32][CH2:31][CH2:30][CH2:29][O:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C@H:7]([NH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:27])=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCO)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.6 %

Procedure:
A mixture of N-(benzyloxycarbonyl)-L-tyrosine tert-butyl ester (0.37 g, 1.0 mmol), 3-bromo-1-propanol (0.09 mL, 1.0 mmol), and cesium carbonate (0.33 g, 1.0 mmol) in anhydrous N,N-dimethylformamide (5 mL) was stirred at room temperature for 24 h. The reaction mixture was evaporated to dryness under high vacuum and the residue was partitioned between water and ethyl acetate. The aqueous layer was separated and extracted with ethyl acetate. The ethyl acetate extracts were combined and washed once with saturated sodium bicarbonate and brine. The ethyl acetate was dried and evaporated to dryness. The residue was purified on a silica gel column (10 g Waters Sep-Pak) by eluting with a gradient of ethyl acetate and hexane from 20:80 to 30:70. The pure fractions were combined and evaporated to dryness to give the title compound (0.269 g, 63% yield) as a clear oil. 1H NMR (300 MHz, CDCl3) δ7.34 (m, 5H), 7.05 (d, J=8.6 Hz, 2H), 6.80 (m, 2H), 5.22 (d, J=8.1 Hz, 1H), 5.10 (d, J=2.8 Hz, 2H), 4.48 (q, J=8.1 Hz, 1H), 4.09 (t, J=6.0 Hz, 2H), 3.86 (t, J=6.0 Hz, 2H), 3.02 (m, 2H), 2.03 (p, J=6.0 Hz, 2H), 1.41 (s, 9H).
Reaction SMILES: [CH2:1]([CH:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][C:18]([O:20]C)=[N:19][C:4]1=2)[CH3:2].C(=O)(O)[O-].[Na+]>C(O)(=O)C.Br>[CH2:1]([CH:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][C:18]([OH:20])=[N:19][C:4]1=2)[CH3:2]
Reactant: CCC1c2ncccc2C(=O)N(C)c2ccc(OC)nc21
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC1c2ncccc2C(=O)N(C)c2ccc(O)nc21
Yield: 102.3 %

Procedure:
A solution of 5,11-dihydro-11-ethyl-2-methoxy-5-methyl-dipyrido[3,2-b:2',3'-e]azepine-6-one (0.181 g) in acetic acid (1 mL) and 48% HBr in acetic acid (1 mL) was heated at 110° C. for 10 minutes. The mixture was cooled, neutralized with saturated sodium bicarbonate, and extracted with chloroform. The organic phase was dried, filtered and evaporated to give 5,11-dihydro-11-ethyl-2-hydroxy-5-methyl-dipyrido[3,2-b:2',3'-e]azepine-6-one (0.176 g) which was used directly in the next reaction.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]/[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24]C(=O)OC(C)(C)C)=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O-])([O-])=O.[K+].[K+]>CC(O)C>[NH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH:17][C:15](=[O:16])/[CH:14]=[CH:13]/[CH2:12][CH2:11][CH2:10][NH:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/CCCNC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: Nc1ccccc1NC(=O)/C=C/CCCNC(=O)c1ccccc1
Yield: 55.1 %

Procedure:
To a solution of (E)-tert-butyl 2-(6-benzamidohex-2-enamido)phenylcarbamate (14)(170 mg, 0.402 mmol) in propan-2-ol (10 mL). The mixture was stirred at 0° C. with HCl gas for 1 hour, To the reaction mixture was added 10% K2CO3 to adjust the pH value to 7-8, then the mixture was extracted with DCM (3×50 mL), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the desired compound of (E)-N-(6-(2-aminophenylamino)-6-oxohex-4-enyl)benzamide (71.6 mg, yield 62%) as an off-white solid after purification by column chromatography (eluent: DCM:MeOH=50:1). 1H NMR (300 MHz, DMSO): δ 1.724 (t, 2H), 2.258 (t, 2H), 3.465 (m, 2H), 4.875 (s, 1H), 6.165-6.216 (d, J=15.3 1H), 6.511-6.991 (m, 4H), 7.232-7.258 (d, 1H), 7.425-7.512 (m, 3H). 7.802-7.852 (m, 2H), 8.507 (s, 1H), 9.200 (s, 1H); LC-MS found 324 (M+H)+; HPLC (214 nm, 99.6%, 254 nm, 100%).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:7]=[C:6]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:5]=1.C1COCC1.O[Li].O>CO>[CH3:22][O:21][C:20]1[C:15]([C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([N:10]3[CH:14]=[N:13][N:12]=[N:11]3)[CH:7]=2)[C:3]([OH:23])=[O:2])=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)c1cc(-c2ncccc2OC)cc(-n2cnnn2)c1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cccnc1-c1cc(C(=O)O)cc(-n2cnnn2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.6 %

Procedure:
3-(3-Methoxy-pyridin-2-yl)-5-tetrazol-1-yl-benzoic acid methyl ester (170 mg, 0.52 mmol) was added to a mixture of THF (20 mL) and MeOH (5 mL) and cooled to ice bath temperature under nitrogen atmosphere. LiOH.H2O (8.8 g, 2.1 mmol) was added, and the reaction mixture was stirred for 18 hours at room temperature. The reaction mixture was concentrated under reduced pressure and 10.0 g of water ice and 10 mL of 10% aqueous HOAc were added to the residue. The resulting mixture was filtered, and the filtrate was washed with 10% aqueous HOAc. The collected solid was dried under vacuum at 60° C. for 3 horus to give 140 mg of 3-(3-methoxy-pyridin-2-yl)-5-tetrazol-1-yl-benzoic acid, MS (M+H)=298.
Reaction SMILES: [C:1]1([CH:7]2[S:20][C:14]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1.C(=O)(O)[O-].[Na+]>ClCCl>[CH:21]1([C:24]([N:17]2[CH2:16][CH2:15][C:14]3([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[S:20]3)[CH2:19][CH2:18]2)=[O:25])[CH2:23][CH2:22]1
Reactant: c1ccc(C2SC3(CCNCC3)c3ccccc32)cc1
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(C1CC1)N1CCC2(CC1)SC(c1ccccc1)c1ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.5 g of 1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine], Example 4, 0.4 g of cyclopropylcarbonyl chloride and 1.0 g of sodium bicarbonate in 20 ml of dichloromethane is stirred at ambient temperature for 16 hours. The well stirred mixture is filtered and the filtrate is concentrated to dryness. The residue is passed through a silica gel/ether column with an ether eluant to provide pure 1'-cyclopropylcarbonyl-1,3-dihydro-3-phenylspiro[benzo(c)thiophene-1,4'-piperidine].
Reaction SMILES: C(N(CC)CC)C.[I-].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]2[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=2SC)=[CH:12][CH:11]=1.[Cl-].[CH3:25][O:26][NH3+:27]>C(O)C>[CH3:25][O:26][N:27]=[C:21]1[CH2:20][CH2:19][CH2:18][CH2:17][N:16]1[C:13]1[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][CH:12]=1
Reactant: CO[NH3+]
Reactant: CSC1=[N+](c2ccc(N)cc2)CCCC1
Agent: [Cl-]
Agent: [I-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CON=C1CCCCN1c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3.5 ml (25 mmol) of triethylamine are added to a solution of 2.68 g (12.1 mmol) of 1-(4-aminophenyl)-6-methylsulfanyl-2,3,4,5-tetrahydro-pyridinium iodide and 1.01 g (12.1 mmol) of O-methylhydroxylammonium chloride in 30 ml of ethanol, and the mixture is stirred at room temperature for 20 hours. The reaction mixture is evaporated and taken up in water, and the resultant precipitate is filtered off, giving 1-(4-aminophenyl)-piperidin-2-one O-methyl oxime as a colourless solid; ESI 220.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:26])[O:5][CH2:6][CH:7]([NH:18]C(OC(C)(C)C)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])[CH3:2].[ClH:27]>O1CCOCC1>[ClH:27].[CH2:1]([NH:3][C:4](=[O:26])[O:5][CH2:6][CH:7]([NH2:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:15])([F:16])[F:17])[CH3:2]
Reactant: CCNC(=O)OCC(NC(=O)OC(C)(C)C)c1ccccc1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: CCNC(=O)OCC(N)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Of the compound from Example 186A, 345 mg (0.92 mmol) were admixed with 10 ml of a 4N solution of hydrogen chloride in dioxane, and the mixture was stirred at RT for 30 min All volatile constituents were then removed on a rotary evaporator. The residue (311 mg, 100% of theory) was the title compound.
Reaction SMILES: [Cl-].[NH4+].[CH3:3][C:4]1[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29]([O:31][CH3:32])=[O:30])[C:5]=1[CH2:6][NH:7][C:8]1[C:9]2[N:10]([C:17]([CH2:21][C:22]#[CH:23])=[C:18]([CH3:20])[N:19]=2)[CH:11]=[C:12]([N+:14]([O-])=O)[CH:13]=1.[CH2:33]([OH:35])[CH3:34]>O.[Fe]>[CH3:3][C:4]1[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29]([O:31][CH3:32])=[O:30])[C:5]=1[CH2:6][NH:7][C:8]1[C:9]2[N:10]([C:17]([CH2:21][C:22]#[CH:23])=[C:18]([CH3:20])[N:19]=2)[CH:11]=[C:12]([NH:14][C:33](=[O:35])[CH3:34])[CH:13]=1
Reactant: CCO
Reactant: C#CCc1c(C)nc2c(NCc3c(C)cccc3NC(=O)OC)cc([N+](=O)[O-])cn12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: C#CCc1c(C)nc2c(NCc3c(C)cccc3NC(=O)OC)cc(NC(C)=O)cn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of iron powder (145 mg) and ammonium chloride (15 mg) in ethanol (12 ml) and water (2.2 ml) was added 8-(2-methyl-6-methoxycarbonylaminobenzylamino)-6-nitro-3-(2-propynyl)-2-methylimidazo[1,2-a]pyridine (360 mg) and the mixture was refluxed for 40 minutes. The inorgnic materials were removed by filtration and the solvent was evaporated under reduced pressure. An aqueous solution of sodium bicarbonate (5 ml) was added to the residue and the resultant solid was collected by filtration. The solid was dissolved in methylene chloride (10 ml) and acetic anhydride (94 mg) was added thereto. After stirring for 1 hour at room temperature, the organic layer was washed with an aqueous solution of sodium bicarbonate and then with water. The solvent was evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (10 g), eluting with a mixture of chloroform and methanol (100:3). The fractions containing the desired product were combined, and the solvent was removed under reduced pressure. The residue was triturated with a mixture of ethanol and diethyl ether (1:1) to give 8-(2-methyl-6-methoxycarbonylaminobenzylamino)-6-acetamido-3-(2-propynyl)-2-methylimidazo[1,2-a]pyridine (70 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH2:13][OH:14])[S:11][CH:12]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:22][S:23]([O:14][CH2:13][C:10]1[S:11][CH:12]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[N:9]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1nc(-c2ccccc2Cl)cs1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1nc(-c2ccccc2Cl)cs1
Temperature: 0 °C

Procedure:
(4-(2-chlorophenyl)thiazol-2-yl)methanol 3 (0.41 g, 1.82 mmol) is dissolved in dichloromethane (25 mL). Triethylamine (0.50 mL, 3.56 mmol) is added and the solution is cooled to 0° C. Methanesulfonyl chloride (0.17 mL, 2.19 mmol) is added dropwise to the cooled solution, with stirring. The bath is removed and the mixture is stirred at room temperature for 3 h. Addition of water, extraction with DCM, drying over MgSO4 and concentration yielded (4-(2-chlorophenyl)thiazol-2-yl)methyl methanesulfonate 4 as an oil: 1H-NMR (400 MHz, CDCl3) δ=7.93 (s, 1H) 7.90 (dd, J=1.9, 7.7 Hz, 1H), 7.48 (dd, J=1.4, 7.7 Hz, 1H), 7.36 (ddd, J=1.4, 7.4, 7.6 Hz, 1H), 7.30 (ddd, J=1.9, 7.7, 7.5 Hz, 1H), 5.56 (s, 2H), 3.13 (s, 3H). MS calcd. for C11H11ClNO3S2 (M+H+) 304.0. found 303.9.