Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:9]([O:24][CH3:25])[CH:8]=1>C1C=CC=CC=1.C(OCC)(=O)C>[Cl:4][C:12]1[C:7]([OH:6])=[CH:8][C:9]([O:24][CH3:25])=[C:10]([CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:11]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCCCC(CC(=O)OC)c1ccc(O)cc1OC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CCCCCC(CC(=O)OC)c1cc(Cl)c(O)cc1OC
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 88 %

Procedure:
604 mg (4.48 mmol) of sulfuryl chloride were added to a solution of 1.26 g (4.48 mmol) of methyl 3-(4-hydroxy-2-methoxyphenyl)octanoate (prepared as described in Preparation 44) in 10 ml of benzene, and the resulting mixture was stirred at 70° C. for 3.5 hours. At the end of this time, the reaction mixture was diluted with ethyl acetate, and the diluted solution was washed with an aqueous solution of sodium carbonate, with water and with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 100 g of silica gel, using a 1:2 by volume mixture of ethyl acetate and hexane as the eluent, to give the title compound as an oily substance in a 88% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:10][C:11]([CH3:16])([CH3:15])[C:12](O)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[Si:19]([O:18][CH2:17][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][C:11]([CH3:15])([CH3:16])[CH2:12][OH:13])([C:22]([CH3:23])([CH3:24])[CH3:25])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)CC(C)(C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CO)C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 82.6 %

Procedure:
To a solution of (S)-4-(tert-butoxycarbonylamino)-5-(tert-butyldimethylsilyloxy)-2,2-dimethylpentanoic acid (2.5 g, 6.7 mmol) and TEA (1.9 mL, 13.4 mmol) in THF (50 mL) was added isobutyl chloroformate (1.1 mL, 8.04 mmol) at 0-5° C. The reaction mixture was stirred at 0-5° C. for 15 min and filtered. To the filtrate was added a suspension of NaBH4 (0.5 g, 13.4 mmol) in water (5 mL) at 0-5° C. The reaction mixture was stirred at 0-5° C. for 30 min, quenched with saturated NH4Cl solution, and extracted with EtOAc (200 mL). The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel column using a mixture of EtOAc and hexanes to give (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-5-hydroxy-4,4-dimethylpentan-2-ylcarbamate (2.0 g, 83.1%). LRMS (M+H+-Boc) m/z 262.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH2:20][CH2:19]2)=[O:17])[C@H:13]([C:27]([NH:29][C:30]2([C:33]#[N:34])[CH2:32][CH2:31]2)=[O:28])[CH2:12]1)(=[O:10])=[O:9].[CH:35](=O)[CH3:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1.[OH-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:16]([C:18]2([N:21]3[CH2:22][CH2:23][N:24]([CH2:35][CH3:36])[CH2:25][CH2:26]3)[CH2:19][CH2:20]2)=[O:17])[C@H:13]([C:27]([NH:29][C:30]2([C:33]#[N:34])[CH2:31][CH2:32]2)=[O:28])[CH2:12]1)(=[O:10])=[O:9]
Reactant: CC=O
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2(N3CCNCC3)CC2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCN1CCN(C2(C(=O)N3C[C@H](S(=O)(=O)c4ccccc4Cl)C[C@H]3C(=O)NC3(C#N)CC3)CC2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 19.8 %

Procedure:
To a solution of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(piperazin-1-yl)cyclopropanecarbonyl)pyrrolidine-2-carboxamide (35.4 mg, 70 μmol) in THF (1.05 mL) was added at room temperature acetaldehyde (4.35 μL, 77.0 μmol), sodium triacetoxyborohydride (44.5 mg, 210 μmol) and acetic acid (8.01 μL, 140 μmol). The reaction was stirred at room temperature for 2 days. It was diluted with 1N aqueous sodium hydroxid solution and water and extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by preparative HPLC to yield the title compound as a white solid (7.4 mg, 20%). MS ISP (m/e): 534.2/536.3 (100/38) [(M+H)]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=O)[NH:12][CH:11]3[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=3)[C:5]2=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:42]2)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[S:42])[NH:12][CH:11]3[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2ccc(F)c(F)c2)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: O=C1Nc2cc(Cl)ccc2C12C(c1cccc(Cl)c1)CC(=S)NC2c1ccc(F)c(F)c1
Yield: 94.1 %

Procedure:
In a manner similar to the method described in example 30, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3,4-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.3 g, 0.63 mmol) prepared in example 46b was reacted with 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (0.32 g, 0.77 mmol) in toluene to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3,4-difluorophenyl)-6′-thioxospiro[3H-indole-3,3′-piperidine]-2(1H)-one (Yield 0.29 g, 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][CH:3]=1.[Cl:15][C:16]1[N:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[Cl:15][C:16]1[N:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:17]=1[C:18]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][CH:3]=1)=[O:19]
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Reactant: CN1C(=O)C(C)(C)c2ccc(N)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccc3c(c2)N(C)C(=O)C3(C)C)c(Cl)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of 6-amino-1,3,3-trimethylindolin-2-one (120 mg, 631 μmol), 2-chloro-6-methylnicotinic acid (108 mg, 631 μmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (480 mg, 1.26 mmol) and N,N-diisopropylethylamine (408 mg, 536 μl, 3.15 mmol) in DMF (3 ml) was stirred at room temperature for 16 hours. An aqueous solution of Na2CO3 was added. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as white solid (167 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[OH:8].CO[CH:11](OC)[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14]>C1(C)C=CC=CC=1>[CH2:13]([N:12]([CH:11]=[N:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[OH:8])[CH2:15][CH3:16])[CH3:14]
Reactant: CCN(CC)C(OC)OC
Reactant: Nc1ccncc1O
Solvent: Cc1ccccc1
Product: CCN(C=Nc1ccncc1O)CC
Yield: 61.5 %

Procedure:
A mixture of 4-amino-3-pyridinol (3.90 g), N,N-diethylformamide dimethyl acetal (11.68 g) and toluene (20 mL) was heated under nitrogen for 2 hours. The solution was concentrated under reduced pressure. The resulting liquid was filtered through silica gel with 10% ethanol in tetrahydrofuran to give a solid. Recrystallization of the purified product from ethyl acetate/hexanes afforded 4.21 g of crystalline solid, m.p. 104°-106° C.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)C.[OH-].[K+]>C(O)C.O.CO>[OH2:3].[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:7]2[N:6]([CH2:5][C:4]([OH:22])=[O:3])[C:14]3[C:9]([N:8]=2)=[N:10][CH:11]=[CH:12][CH:13]=3)=[CH:16][CH:17]=1
Reactant: CCOC(=O)Cn1c(-c2ccc(Cl)cc2)nc2ncccc21
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCO
Product: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2ncccc21
Yield: 3.9 %

Procedure:
A mixture of 2-(4-chlorophenyl)-1H-imidazo[4,5-b]pyridine-1-acetic acid ethyl ester (8.4 g, 0.027 mole) and potassium hydroxide (2.25 g, 0.04 mole) in 95% ethanol (75 ml) and water (5 ml) was heated at reflux for 2.5 hours. The mixture was evaporated to dryness. The residue was dissolved in water and acidified with glacial acetic acid. The precipitate was collected by filtration, washed with water, and dried under high vacuum overnight at 60° C. to give 7.4 g (95%) yield). A 1.4-g sample was dissolved in ~450 ml of boiling methanol, and the solution was treated with Florsil® and filtered. The filtrate was concentrated and diluted with water. A crystalline precipitate was collected by filtration, washed with water, and dried under high vacuum at 60° C. for 4 hours, then at room temperature over the weekend to give 0.16 g of solids, mp. 194°-96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1
Reactant: COc1ccc(Cl)cc1C(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(Cl)cc1C(C)O
Reaction time: 3 h
Yield: 86.6 %

Procedure:
To a solution of 1-(5-chloro-2-methoxyphenyl)ethanone (7.97 g, 43.1 mmol) in anhydrous tetrahydrofuran (40 mL) at 0° C. was added a 1M solution of lithium aluminium hydride In THF (14.2 mL, 14.2 mmol). After 3 hours, ethyl acetate (200 mL) was added and the mixture was washed with a 1M aqueous solution of hydrogen chloride (50 mL). The organic phase was concentrated in vacuo to afford the title compound (6.97 g, 86%)
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][CH2:14][C:13](=[C:17]2[C:25]3[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:27])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>CO.O>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][CH2:14][CH:13]([CH:17]2[C:25]3[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:27])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCCC(=C2C(=O)Nc3cc(Cl)ccc32)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(C2C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
Sodium borohydride (1.42 g, 37.5 mmol) (Aldrich) was added in small portions to a solution of rac-4-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidene)-azepane-1-carboxylic acid tert-butyl ester (1.36 g, 3.75 mmol) (from Example 61a supra) in methanol (25 mL) and water (0.5 mL). After stirring at room temperature for 30 minutes, the reaction mixture was concentrated. The residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate three times. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated to give rac-4-(6-chloro-2-oxo-2,3-dihydro-1H-indol-3-yl)-azepane-1-carboxylic acid tert-butyl ester as a white solid (Yield 1.37 g, 100%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:12][CH:9]([CH:10]=[CH2:11])[CH:4]([CH:5]([OH:8])[CH2:6][OH:7])[O:3]1.N1C=CC=CC=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.Cl>C(Cl)(Cl)Cl>[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([O:7][CH2:6][CH:5]([OH:8])[CH:4]2[O:3][C:2]([CH3:13])([CH3:1])[O:12][CH:9]2[CH:10]=[CH2:11])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: C=CC1OC(C)(C)OC1C(O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: C=CC1OC(C)(C)OC1C(O)COS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 100.6 %

Procedure:
3,4-(Dimethylmethylenedioxy)-5-hexene-1,2-diol (9.77 g) was mixed with 155 ml of pyridine and 52 ml of chloroform, and 11.39 g of p-toluenesulfonyl chloride was added gradually in four portions at 0° C. The mixture was stirred at 0° C. for 6 hours, poured into 6N hydrochloric acid with ice and extracted with diethyl ether. The extract was washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution in sequence, dried with anhydrous ride aqueous solution in sequence, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to afford 17.88 g of 3,4-(dimethylmethylenedioxy)-2-hydroxy-5-hexen-1-yl p-toluenesulfonate having the following properties.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1>[CH2:11]([NH:18][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1cccnc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Grams 47.4 of 2-chloro-3-nitropyridine are refluxed for 2 hours in 600 ml toluene with 33 ml benzylamine and 31.8 g sodium carbonate. The reaction mixture is cooled to room temperature and 200 ml water are added thereto. The phases are separated, the organic phase evaporated to small volume, diluted with 400 ml isopropyl ether and kept under stirring for 30 minutes while cooling with water. It is filtered, washed with isopropyl ether, evaporated to dryness to give 46 g 2-benzylamino-3-nitropyridine melting at 81°-82° C.
Reaction SMILES: [NH2:1][CH:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1.Cl>CC(C)=O.O>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:1][CH:2]([CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[C:13]([OH:15])=[O:14])=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NC(Cc1c[nH]c2ccccc12)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(NC(Cc1c[nH]c2ccccc12)C(=O)O)c1ccc(Cl)cc1
Reaction time: 2 h

Procedure:
10 Grams of DL-tryptophane was dissolved in a mixture of 100 ml of acetone with 20 ml of water, then to this solution was added 6 g of potassium carbonate. Under an ice-cooled condition, 9 g of 4-chlorobenzoyl chloride was added dropwise to the above-mentioned mixture, and the reaction mixture was stirred at the same temperature for 2 hours. Then, acetone was removed by evaporation, to the residue thus obtained was added water, and mixture was acidified by adding concentrated hydrochloric acid, the crystals formed were collected by filtration, and washed with water. Recrystallized from ethanol to obtain 14 g of 2-(4-chlorobenzoylamino)-3-(indol-3-yl)propionic acid. White powdery substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH:8][C:9]([NH2:11])=[O:10].C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[C:19]([N:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[NH:8][C:9]([NH2:11])=[O:10])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC(=O)NNc1ccccn1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NC(=O)NN(C(=O)c1ccccc1)c1ccccn1

Procedure:
A mixture was prepared by admixing 15.22 g (0.1 mole) of 2-(2-pyridinyl)hydrazinecarboxamide with a solution of 16.2 g (0.16 m) of triethylamine in 200 ml of acetonitrile. The mixture was stirred while a solution of 21.08 g (0.15 m) of benzoyl chloride in 50 ml of acetonitrile was added. After an induction period of ~5 minutes, the mixture exothermed reaching a peak temperature of 52° C. after 10 minutes. The reaction mixture was then stirred, without heating, for 51/2 hours and then heated under reflux for 2 hours. The mixture was cooled and the crude solid 2-benzoyl-2-(2-pyridinyl)hydrazinecarboxamide product was collected by filtration. The product was washed with water and air dried and recovered in a yield of 6.1 g (24 percent of theoretical). The product was recrystallized from methanol and melted at 206° C. and upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 60.53, 4.62 and 21.47 percent, respectively, as compared with the theoretical contents of 60.92, 4.72 and 21.87 percent, respectively, calculated for the above named compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[OH:17])[O:9][CH2:8][CH2:7][O:6]1.S(OC)(O[CH3:22])(=O)=O>CN(C=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:22])[O:9][CH2:8][CH2:7][O:6]1
Reactant: COS(=O)(=O)OC
Reactant: Oc1ccc(Cl)cc1C1(CCCCl)OCCO1
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1C1(CCCCl)OCCO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
A mixture of 4-chloro-1-(5-chloro-2-hydroxyphenyl)-1,1-ethylenedioxybutane (0.86 g, 2.5 mmol) sodium hydride (0.18 g, 4.5 mmol in mineral oil) and DMF (3 mL) was stirred 30 minutes. The mixture was cooled to approximately 0° C. and dimethyl sulfate (0.44 g, 3.5 mmol) was added. The mixture was heated 4 hours with stirring at approximately 25° C. and then poured into ice cold water. The mixture was extracted with ether/pentane (7:3) and the extract concentrated to give 4-chloro-1-(5-chloro-2-methoxyphenyl)-1,1-ethylenedioxybutane (0.85 g, 2.4 mmol).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:14][NH:15][C:16]([NH2:18])=[S:17]>CN(C)C=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([NH:14][NH:15][C:16]([NH2:18])=[S:17])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNC(N)=S
Reactant: O=C(Cl)CCCCc1ccccc1
Solvent: CN(C)C=O
Product: NC(=S)NNC(=O)CCCCc1ccccc1

Procedure:
A mixture of 9.9 g. of 5-phenylvaleroylchloride and 4.6 g. of thiosemicarbazide was stirred in 20 ml. of dimethylformamide for 6 hours at 22° C. The solvent was evaporated and 10 ml. of water and 10 ml.of ether were added to the residue. The precipitate was filtered off to give the intermediate 1-(5-phenylvaleroyl)-3-thiosemicarbazide, m.p. 140°-141° C.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]1[O:14][CH:13]1[CH2:15][OH:16]>>[C:1]1([C:7]2[N:11]([CH2:12][CH:13]([OH:14])[CH2:15][OH:16])[CH:10]=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: OCC1CO1
Product: OCC(O)Cn1ccnc1-c1ccccc1
Yield: 72 %

Procedure:
The procedure of Synthesis Example 1 was repeated aside from using an equimolar amount of 2-phenylimidazole instead of imidazole and an equimolar amount of glycidol instead of ethylene oxide. There was synthesized 3-(2-phenyl-1H-imidazol-1-yl)-1,2-propanediol (yield 72%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:18][OH:19])[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC(C)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:18][OH:19])[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: OCC1(c2ccc(Br)cc2)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCC(CO)(c2ccc(Br)cc2)CC1
Temperature: 75 °C

Procedure:
To a round bottom flask containing (8-(4-bromophenyl)-1,4-dioxaspiro[4.5]decan-8-yl)methanol (4.88 g, 14.91 mmol) was added acetone (34 ml) and water (17 ml) at room temperature. p-toluenesulfonic acid (57 mg, 0.30 mmol) was then added and the mixture heated to 75° C. for 1 hour. The content was cooled to room temperature and concentrated under reduced pressure to remove the excess acetone. The resulting aqueous mixture was extracted with EtOAc twice. The combined organic portion was dried over sodium sulfate and concentrated to afford the title compound as white solid. (4.22 g) LC/MS, ESI-MS: non-ionizable, RT: 1.05 (Condition E).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[NH2:39][CH2:40][CH2:41][N:42]1[CH2:46][CH2:45][NH:44][C:43]1=[O:47].OS([O-])(=O)=O.[Na+]>CCO>[NH2:3][CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:39][CH2:40][CH2:41][N:42]2[CH2:46][CH2:45][NH:44][C:43]2=[O:47])=[O:34])[C:15]1=[O:38]
Reactant: NCCN1CCNC1=O
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCO
Product: NCCn1c(=O)c(C(=O)NCCN2CCNC2=O)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Temperature: 25 °C

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.025 g, 0.049 mmol) in EtOH (1 mL) under nitrogen was treated with 1-(2-aminoethyl)-2-imidazolidinone (0.0078 g, 0.03 mmol, 50% W/W in IPA) for 30 min. (150° C. The reaction was further microwaved for 30 min.@150° C. after the addition of an additional 0.6 equivalents (0.015 mL) of the amine, cooled to ambient temperature, and treated with 1N NaHSO4. The resulting suspension was filtered and the filtrate was concentrated in vacuo. The filtrate residue was purified by reversed phase HPLC. Pure fractions were combined and concentrated to afford the title compound as an off-white solid: ES+ MS: 469 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:8][CH2:9][NH2:10])[CH2:5][CH2:6][NH2:7].[C:11]([O:15][CH3:16])(=[O:14])[CH:12]=[CH2:13]>CO>[CH3:16][O:15][C:11]([CH2:12][CH2:13][N:1]([CH2:13][CH2:12][C:11]([O:15][CH3:16])=[O:14])[CH2:2][CH2:3][N:4]([CH2:8][CH2:9][N:10]([CH2:13][CH2:12][C:11]([O:15][CH3:16])=[O:14])[CH2:13][CH2:12][C:11]([O:15][CH3:16])=[O:14])[CH2:5][CH2:6][N:7]([CH2:13][CH2:12][C:11]([O:15][CH3:16])=[O:14])[CH2:13][CH2:12][C:11]([O:15][CH3:16])=[O:14])=[O:14]
Reactant: C=CC(=O)OC
Reactant: NCCN(CCN)CCN
Solvent: CO
Product: COC(=O)CCN(CCC(=O)OC)CCN(CCN(CCC(=O)OC)CCC(=O)OC)CCN(CCC(=O)OC)CCC(=O)OC
Temperature: 20 °C

Procedure:
14.69 g (0.100 mol) of tris-(2-aminoethyl)-amine, dissolved in 20 ml of methanol, is instilled in 103.3 g (1.20 mol) of methyl acrylate with stirring at 20° C. The batch is stirred under argon atmosphere for 5 days at room temperature and for 2 days at 50° C. Then, it is concentrated by evaporation in a vacuum and excess methyl acrylate is removed by azeotropic distillation with toluene. The residue is taken up in 150 ml of methanol and 30 ml of diethyl ether, absorptively precipitated with 150 ml of hexane and, after separation of the hexane phase, concentrated by evaporation in a vacuum. The product is obtained as yellowish liquid, which is further reacted without purification.